Replicating Huntington's disease phenotype in experimental animals
Identifieur interne : 000406 ( Istex/Corpus ); précédent : 000405; suivant : 000407Replicating Huntington's disease phenotype in experimental animals
Auteurs : Emmanuel Brouillet ; Françoise Condé ; M. F Beal ; Philippe HantrayeSource :
- Progress in Neurobiology [ 0301-0082 ] ; 1999.
Abstract
Huntington's disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder characterized by involuntary choreiform movements, cognitive decline and a progressive neuronal degeneration primarily affecting the striatum. There is at present no effective therapy against this disorder. The gene responsible for the disease (IT15) has been cloned and the molecular defect identified as an expanded polyglutamine tract in the N-terminal region of a protein of unknown function, named huntingtin (The Huntington's Disease Collaborative Research Group, 1993. Cell 72, 971–983). An intense, search for the cell pathology attached to this molecular defect is currently under way [see Sharp and Ross (1996, Neurobiol. Dis. 3, 3–15) for review]. Huntingtin interacts with a number of proteins, some of which have well identified functions, and it has thus been suggested that alterations in glycolysis, vesicle trafficking or apoptosis play a role in the physiopathology of HD. On the other hand data derived from positron emission tomography (PET), magnetic resonance spectroscopy and post-mortem biochemical evidence for a defect in succinate oxidation have suggested the implication of a primary impairment of mitochondrial energy metabolism. All these hypotheses are not necessarily to be opposed and recent findings indicate that the HD mutation could possibly directly alter mitochondrial functions which would in turn activate apoptotic pathways. To test this mitochondrial hypothesis, we studied the effects in rodents and non-human primates of a chronic blockade of succinate oxidation by systemic administration of the mitochondrial toxin 3-nitropropionic acid (3NP). Extensive behavioural and neuropathological evaluations showed that a partial but prolonged energy impairment induced by 3NP is sufficient to replicate most of the clinical and pathophysiological hallmarks of HD, including spontaneous choreiform and dystonic movements, frontal-type cognitive deficits, and progressive heterogeneous striatal degeneration at least partially by apoptosis. 3NP produces the preferential degeneration of the medium-sized spiny GABAergic neurons with a relative sparing of interneurons and afferents, as was observed in HD striatum. The present manuscript reviews the different aspects of this neurotoxic treatment in rodents and non-human primates, and its interest as a phenotypic model of HD to understand the degenerative process of HD and test new therapeutic strategies.
Url:
DOI: 10.1016/S0301-0082(99)00005-2
Links to Exploration step
ISTEX:586DD76B8EF766EE1511E78D271AAD533DF2D52DLe document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Replicating Huntington's disease phenotype in experimental animals</title><author><name sortKey="Brouillet, Emmanuel" sort="Brouillet, Emmanuel" uniqKey="Brouillet E" first="Emmanuel" last="Brouillet">Emmanuel Brouillet</name><affiliation><mods:affiliation>E-mail: brouille@shfj.cea.fr</mods:affiliation></affiliation><affiliation><mods:affiliation>URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du General Leclerc, 91401 Orsay Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Conde, Francoise" sort="Conde, Francoise" uniqKey="Conde F" first="Françoise" last="Condé">Françoise Condé</name><affiliation><mods:affiliation>URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du General Leclerc, 91401 Orsay Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Beal, M F" sort="Beal, M F" uniqKey="Beal M" first="M. F" last="Beal">M. F Beal</name><affiliation><mods:affiliation>Department of Neurology, Cornell University Medical College, A569, 525 East 68th Street, New York, NY 10021, USA</mods:affiliation></affiliation></author><author><name sortKey="Hantraye, Philippe" sort="Hantraye, Philippe" uniqKey="Hantraye P" first="Philippe" last="Hantraye">Philippe Hantraye</name><affiliation><mods:affiliation>Department of Neurology, Cornell University Medical College, A569, 525 East 68th Street, New York, NY 10021, USA</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:586DD76B8EF766EE1511E78D271AAD533DF2D52D</idno><date when="1999" year="1999">1999</date><idno type="doi">10.1016/S0301-0082(99)00005-2</idno><idno type="url">https://api.istex.fr/document/586DD76B8EF766EE1511E78D271AAD533DF2D52D/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000406</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000406</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Replicating Huntington's disease phenotype in experimental animals</title><author><name sortKey="Brouillet, Emmanuel" sort="Brouillet, Emmanuel" uniqKey="Brouillet E" first="Emmanuel" last="Brouillet">Emmanuel Brouillet</name><affiliation><mods:affiliation>E-mail: brouille@shfj.cea.fr</mods:affiliation></affiliation><affiliation><mods:affiliation>URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du General Leclerc, 91401 Orsay Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Conde, Francoise" sort="Conde, Francoise" uniqKey="Conde F" first="Françoise" last="Condé">Françoise Condé</name><affiliation><mods:affiliation>URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du General Leclerc, 91401 Orsay Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Beal, M F" sort="Beal, M F" uniqKey="Beal M" first="M. F" last="Beal">M. F Beal</name><affiliation><mods:affiliation>Department of Neurology, Cornell University Medical College, A569, 525 East 68th Street, New York, NY 10021, USA</mods:affiliation></affiliation></author><author><name sortKey="Hantraye, Philippe" sort="Hantraye, Philippe" uniqKey="Hantraye P" first="Philippe" last="Hantraye">Philippe Hantraye</name><affiliation><mods:affiliation>Department of Neurology, Cornell University Medical College, A569, 525 East 68th Street, New York, NY 10021, USA</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Progress in Neurobiology</title><title level="j" type="abbrev">PRONEU</title><idno type="ISSN">0301-0082</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999">1999</date><biblScope unit="volume">59</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="427">427</biblScope><biblScope unit="page" to="468">468</biblScope></imprint><idno type="ISSN">0301-0082</idno></series><idno type="istex">586DD76B8EF766EE1511E78D271AAD533DF2D52D</idno><idno type="DOI">10.1016/S0301-0082(99)00005-2</idno><idno type="PII">S0301-0082(99)00005-2</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0301-0082</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Huntington's disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder characterized by involuntary choreiform movements, cognitive decline and a progressive neuronal degeneration primarily affecting the striatum. There is at present no effective therapy against this disorder. The gene responsible for the disease (IT15) has been cloned and the molecular defect identified as an expanded polyglutamine tract in the N-terminal region of a protein of unknown function, named huntingtin (The Huntington's Disease Collaborative Research Group, 1993. Cell 72, 971–983). An intense, search for the cell pathology attached to this molecular defect is currently under way [see Sharp and Ross (1996, Neurobiol. Dis. 3, 3–15) for review]. Huntingtin interacts with a number of proteins, some of which have well identified functions, and it has thus been suggested that alterations in glycolysis, vesicle trafficking or apoptosis play a role in the physiopathology of HD. On the other hand data derived from positron emission tomography (PET), magnetic resonance spectroscopy and post-mortem biochemical evidence for a defect in succinate oxidation have suggested the implication of a primary impairment of mitochondrial energy metabolism. All these hypotheses are not necessarily to be opposed and recent findings indicate that the HD mutation could possibly directly alter mitochondrial functions which would in turn activate apoptotic pathways. To test this mitochondrial hypothesis, we studied the effects in rodents and non-human primates of a chronic blockade of succinate oxidation by systemic administration of the mitochondrial toxin 3-nitropropionic acid (3NP). Extensive behavioural and neuropathological evaluations showed that a partial but prolonged energy impairment induced by 3NP is sufficient to replicate most of the clinical and pathophysiological hallmarks of HD, including spontaneous choreiform and dystonic movements, frontal-type cognitive deficits, and progressive heterogeneous striatal degeneration at least partially by apoptosis. 3NP produces the preferential degeneration of the medium-sized spiny GABAergic neurons with a relative sparing of interneurons and afferents, as was observed in HD striatum. The present manuscript reviews the different aspects of this neurotoxic treatment in rodents and non-human primates, and its interest as a phenotypic model of HD to understand the degenerative process of HD and test new therapeutic strategies.</div></front></TEI><istex><corpusName>elsevier</corpusName><author><json:item><name>Emmanuel Brouillet</name><affiliations><json:string>E-mail: brouille@shfj.cea.fr</json:string><json:string>URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du General Leclerc, 91401 Orsay Cedex, France</json:string></affiliations></json:item><json:item><name>Françoise Condé</name><affiliations><json:string>URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du General Leclerc, 91401 Orsay Cedex, France</json:string></affiliations></json:item><json:item><name>M.F Beal</name><affiliations><json:string>Department of Neurology, Cornell University Medical College, A569, 525 East 68th Street, New York, NY 10021, USA</json:string></affiliations></json:item><json:item><name>Philippe Hantraye</name><affiliations><json:string>Department of Neurology, Cornell University Medical College, A569, 525 East 68th Street, New York, NY 10021, USA</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>3NP,3-Nitropropionic acid</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>18F-FDG,[18F]Fluorodeoxuglucose</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>BHK,Baby hamster kidney cells</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CB-D28k,Calbindin-D28k</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>ChAT,Choline acetyl transferase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CNTF,Ciliary neurotrophic factor</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CT,Computed tomography</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>GABA,γ-Aminobutyric acid</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>GAPDH,Glyceraldehyde-3-phosphate deshydrogenase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>GFAP,Glial fibrillary acidic protein</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>HD,Huntington's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>IC,Internal capsule</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>IR,Immunoreactive</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>KO,Knock out</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>MRI,Magnetic resonance imaging</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>NMDA,N-Methyl-d-aspartate</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>NADPH,β-Nicotinamide adenine dinucleotide phosphate</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>NMR,Nuclear magnetic resonance</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>NOS,Nitric oxide synthase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>ORDT,Object retrieval detour task</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PET,Positon emission tomography</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PARP,Poly-ADP-ribosyl polymerase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PTV,Peak tangential velocity</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>SDH,Succinate deshydrogenase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>SPECT,Single photon emission computed tomography</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>VMA,Video movement analysis</value></json:item></subject><language><json:string>eng</json:string></language><originalGenre><json:string>Review article</json:string></originalGenre><abstract>Huntington's disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder characterized by involuntary choreiform movements, cognitive decline and a progressive neuronal degeneration primarily affecting the striatum. There is at present no effective therapy against this disorder. The gene responsible for the disease (IT15) has been cloned and the molecular defect identified as an expanded polyglutamine tract in the N-terminal region of a protein of unknown function, named huntingtin (The Huntington's Disease Collaborative Research Group, 1993. Cell 72, 971–983). An intense, search for the cell pathology attached to this molecular defect is currently under way [see Sharp and Ross (1996, Neurobiol. Dis. 3, 3–15) for review]. Huntingtin interacts with a number of proteins, some of which have well identified functions, and it has thus been suggested that alterations in glycolysis, vesicle trafficking or apoptosis play a role in the physiopathology of HD. On the other hand data derived from positron emission tomography (PET), magnetic resonance spectroscopy and post-mortem biochemical evidence for a defect in succinate oxidation have suggested the implication of a primary impairment of mitochondrial energy metabolism. All these hypotheses are not necessarily to be opposed and recent findings indicate that the HD mutation could possibly directly alter mitochondrial functions which would in turn activate apoptotic pathways. To test this mitochondrial hypothesis, we studied the effects in rodents and non-human primates of a chronic blockade of succinate oxidation by systemic administration of the mitochondrial toxin 3-nitropropionic acid (3NP). Extensive behavioural and neuropathological evaluations showed that a partial but prolonged energy impairment induced by 3NP is sufficient to replicate most of the clinical and pathophysiological hallmarks of HD, including spontaneous choreiform and dystonic movements, frontal-type cognitive deficits, and progressive heterogeneous striatal degeneration at least partially by apoptosis. 3NP produces the preferential degeneration of the medium-sized spiny GABAergic neurons with a relative sparing of interneurons and afferents, as was observed in HD striatum. The present manuscript reviews the different aspects of this neurotoxic treatment in rodents and non-human primates, and its interest as a phenotypic model of HD to understand the degenerative process of HD and test new therapeutic strategies.</abstract><qualityIndicators><score>8</score><pdfVersion>1.2</pdfVersion><pdfPageSize>595 x 792 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>26</keywordCount><abstractCharCount>2486</abstractCharCount><pdfWordCount>27398</pdfWordCount><pdfCharCount>174593</pdfCharCount><pdfPageCount>42</pdfPageCount><abstractWordCount>348</abstractWordCount></qualityIndicators><title>Replicating Huntington's disease phenotype in experimental animals</title><pii><json:string>S0301-0082(99)00005-2</json:string></pii><genre><json:string>review-article</json:string></genre><serie><volume>117</volume><pages><last>520</last><first>507</first></pages><language><json:string>unknown</json:string></language><title>Progress in Brain Research</title></serie><host><volume>59</volume><pii><json:string>S0301-0082(00)X0101-3</json:string></pii><pages><last>468</last><first>427</first></pages><issn><json:string>0301-0082</json:string></issn><issue>5</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><title>Progress in Neurobiology</title><publicationDate>1999</publicationDate></host><categories><wos><json:string>science</json:string><json:string>neurosciences</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>neurology & neurosurgery</json:string></scienceMetrix></categories><publicationDate>1999</publicationDate><copyrightDate>1999</copyrightDate><doi><json:string>10.1016/S0301-0082(99)00005-2</json:string></doi><id>586DD76B8EF766EE1511E78D271AAD533DF2D52D</id><score>0.056557603</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/586DD76B8EF766EE1511E78D271AAD533DF2D52D/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/586DD76B8EF766EE1511E78D271AAD533DF2D52D/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/586DD76B8EF766EE1511E78D271AAD533DF2D52D/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Replicating Huntington's disease phenotype in experimental animals</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>ELSEVIER</publisher><availability><p>©1999 Elsevier Science Ltd</p></availability><date>1999</date></publicationStmt><notesStmt><note type="content">Fig. 1: Schematic representation of the differential cell losses and deficits observed in the HD striatum (right) compared to the normal striatum (left). Whereas the border between the dorsal aspect of the caudate nucleus (CN) and the lateral ventricle (LV) is normally a convex outline, in HD patients it becomes either a straight or a concave outline, depending on the extent of striatal atrophy. Although the striatal neuronal loss can be almost complete in the late stages of the disease, the various populations of striatal neurons appear differentially affected by the HD neurodegenerative process. Thus, whereas the GABAergic medium-sized spiny projection neurons bear the brunt of the neurodegeneration, there is a relative sparing of the interneurons (large-sized cholinergic neurons, medium-sized calretinin neurons and medium-sized NADPH positive interneurons, which also contain nitric oxide synthase and somatostatin). This neuronal loss is accompanied by an increased number of reactive astrocytes. Striatal afferents are relatively spared. Accordingly, biochemical analyses of the HD striatum usually indicate decreased concentrations (as expressed per mg of protein) of all markers associated with GABAergic neurons (GABA, substance P and methionine-enkephaline), increased levels in somatostatin and unchanged concentrations of dopamine and serotonin. IC, Internal capsule.</note><note type="content">Fig. 2: Schematic representation of the different events implicated in indirect excitotoxicity. (A) Under physiological conditions, the production of ATP (open arrows) through oxidative phosphorylation within the mitochondria (mt) is sufficient to maintain normal membrane potential (mV) through the activity of the membrane Na+/K+ ATPases. Normal (low) cytosolic levels of Ca2+ ([Ca2+]cyt) are regulated by ATPases located in the plasma and endoplasmic reticulum (ER) membranes. Transient elevations of [Ca2+]cyt resulting from the physiological activation of the NMDA gated-Ca2+-channels by endogenous glutamate can be regulated by several intra-cellular mechanisms, including a rapid uptake of Ca2+ by the mitochondria and the ER, followed later on by active extra-cellular Ca2+ transport by the plasma membrane ATPases. Tight control of [Ca2+]cyt ensures that several factors potentially harmful for the cell, such as the generation of oxidative radicals and activation of several proteases, phospholipases, phosphatases and endonucleases, can be kept in a resting state. (B) Under partial impairment of energy metabolism, a decrease in ATP production due to mitochondrial dysfunction will impair the ability of the membrane ATPases to maintain membrane potential at normal values, leading to partial depolarization of the cell. In addition, the blockade of the oxidative phosphorylation will also affect the ability of the mitochondria and the endoplasmic reticulum to buffer the [Ca2+]cyt. Together with the relief of the voltage-dependent Mg2+ block of the calcium channel of NMDA receptors (NMDA-R), these events will progressively induce an increase in the [Ca2+]cyt. (C) Under prolonged mitochondrial impairment, the sustained activation of NMDA receptors by ambient glutamate concentrations will result in a massive increase in [Ca2+]cyt which, in turn, will activate Ca2+-dependent `toxic' pathways (represented by the shift from a `OFF' to a `ON' position of the box containing oxidative radicals and several proteases, phospholipases, phosphatases and endonucleases). (D) Initiation of the classical `excitotoxic cascade' leads to amplification phenomenon involving increased free radical production and activation of several enzymes deleterious to the cell. Although the cell death associated with failure in energy production is morphologically of rather a necrotic nature, biochemical pathways associated with apoptosis such as caspase activation may also be involved.</note><note type="content">Fig. 3: 3NP, an irreversible SDH inhibitor. (A) The chemical structure of 3NP is closely related to that of succinic acid which may explain that 3NP can, like the natural substrate, occupy the catalytic site of the enzyme. (B) Schematic representation of the mechanism of irreversible SDH inactivation [redrawn from Coles et al. (1979)]. In the top part of (B), the dianion form of 3NP binds to SDH, leading to the formation of nitroacrylate [middle of (B)]. The nitroacrylate then reacts with an essential thiol group of SDH, and remains covalently attached to the enzyme [bottom of (B)], blocking the access of succinate to the enzyme. (C) Since SDH participates in both oxidative phosphorylation and tricarboxylic acid cycle (TCA), 3NP-induced SDH inhibition impairs the entry into the electron transport chain of reducing equivalents generated by succinate oxidation and decreases the ability of TCA cycle to make NADH available for complex I.</note><note type="content">Fig. 4: Schematic representation of the excitotoxic cascade involved in 3NP neurotoxicity. The primary effect of 3NP is the blockade of succinate oxidation through the irreversible inactivation of SDH. Partial enzyme inhibition by 3NP (ca 50%) is sufficient to trigger the excitotoxic cascade. The SDH inhibition may decrease the availability of ATP equivalent, which reduces the plasma membrane (Mb) potential, resulting in the relief of the voltage-dependent Mg2+ block of the NMDA receptors (NMDA-R). This, in turn, allows excessive activation of the NMDA receptors by ambient glutamate concentrations, producing a massive entry of Ca2+. As a first step, calcium may be partly uptaken by the mitochondria (mt) and the endoplasmic reticulum (ER), leading to a progressive increase in [Ca2+]mt, an increase in free radical production and a dysfunction of the respiratory chain. In the long term, the entry of Ca2+ cannot be appropriately buffered by the endoplasmic reticulum and the mitochondria, leading to further mitochondrial impairment, and activation of a number of Ca2+ dependent cytoplasmic enzymes including proteases (caspases, calpain), kinases, phospholipases and endonucleases. One early activated protein is NO synthase, whose inhibition blocks 3NP neurotoxicity in vivo. All these events ultimately lead to cell death through possibly different pathways (depending on cell type, severity of energy impairment and possible compensatory mechanisms) which are related either to necrosis or apoptosis. In the case of necrosis, plasma membrane integrity is rapidly lost. In case of apoptosis, cytoplasm condenses and the nucleus (Nc) shows typical fragmentation with apoptotic bodies.</note><note type="content">Fig. 5: Schematic representation of the rostro-caudal distribution of the lesioned areas observed following subacute (15mgkg−1day−1 for 5–10days, i.p.) or chronic (10mgkg−1day−1 for 4weeks, s.c. using osmotic pumps) systemic 3NP injections. The minimal and maximal extents of lesions observed on coronal sections, in five animals per group (each animal corresponding to a different level of grey), are represented for seven different brain levels encompassing the striatum, the globus pallidus and the dorsal part of the hippocampus. Numbers in brackets indicate the distance in millimetres to bregma (Paxinos and Watson, 1986). Note that while `chronic' lesions are small and consistently restricted to the dorsolateral part of the anterior striatum, `subacute' lesions are larger, invading the entire lateral striatum and involving, in several cases, the most caudal part of the striatum. In addition, whereas chronic 3NP-treatment is not associated with extra-striatal lesions, subacute 3NP treatment is frequently associated with pallidal and hippocampal neurodegenerations.</note><note type="content">Fig. 6: Kinetic movement parameters in sham animals and chronic 3NP-treated rats during the elevated board test. In this task, rats were trained to walk along a board (120cm long, 7cm wide, 35cm above the floor) to reach a platform on which their home-cage was placed. After a training period of 5days, their axial and lateral movements were evaluated from top-view images using a video movement analysis system (VMA) allowing the detection of a centroid, corresponding to the geometric centre of the animal, as a function of time and space (X–Y coordinates, 50msec sampling rate). (A) Schematic representation of the elevated board viewed from above and animal's coordinates during the board crossing. Dashed and solid lines correspond to the X–Y coordinates of centroids for one sham and one 3NP-treated rat, respectively. Note the typical irregularities (wobbling) in the 3NP-treated rat compared to the sham. (B) Tangential velocity as a function of the distance traveled on the board for the same two animals. Note the reduced speed (bradykinesia) in the 3NP-treated animal compared to the sham. (C) Lateral velocity (wobbling) in the same two animals, represented as a function of the distance traveled during the board crossing. Note that the highest lateral velocity (6cmsec-1) was found in the 3NP-treated animal which presented gait abnormalities. (D) Kinetic parameters for two groups of sham animals and 3NP-treated animals with (`lesioned') or without (`unlesioned') significant striatal cell loss. The striatal cell loss was considered significant when the mean neuron density was 1SD below the mean cell density of sham animals. Kinetic parameters were determined for each animal (mean of three board tests) using VMA. Sham animals (n=9; open bars), `unlesioned' (n=6, grey bars) and `lesioned' (n=7, black bars) 3NP-treated rats. Note that the significant changes in kinematic parameters are only observed in the 3NP-treated rats belonging to the `lesioned' group (ANOVA and post-hoc Scheffé F-test).</note><note type="content">Fig. 7: Schematic representation of the 3NP intoxication regimen used in non-human primates (Macaca fascicularis monkeys) to induce progressive striatal degeneration. Starting from 10mgkg−1day−1, the daily dose of 3NP is progressively increased to 29mgkg−1day−1. The doses of 3NP is incremented at weekly intervals to induce progressive SDH inhibition. A first dose increment (2mgkg−1day−1) from week 1 to week 6 is followed by a dose increment of 0.5mgkg−1day−1 from week 6 to week 25. Such a dose regimen is associated with a progressive body weight loss and the progressive appearance of motor and cognitive deficits. Note a marked drop in body weight ca 9–11weeks of treatment, corresponding to the beginning of the symptomatic phase.</note><note type="content">Fig. 8: Motor syndrome in chronic 3NP-treated baboons during the presymptomatic and the symptomatic phase of the neurotoxic treatment. To assess striatal function, time-sampled neurological observations are obtained after i.m. administration of apomorphine. Briefly, four different categories of abnormal movements including orofacial dyskinesia, dyskinesia of extremities, dystonia and choreiform movements, are monitored after video-recording from front-view images and rated as being present (=1) or absent (=0) during each 5min time period of a 40-min test session. A dyskinesia index (sum of incidences) is computed by adding together the incidence of each symptom (maximum score=8) during the 40min test-period (maximum score=32, minimum score=0). (A)–(D) Rate of incidence in different categories of abnormal movements observed in 3NP-treated non-human primates. (E and F) Video movement analysis (kinematic analysis, VMA) of the apomorphine-inducible motor syndrome. VMA is used to determine the animal's position as a function of time, during the 40-min duration of the test. Derived data include: (E) the total distance travelled by each animal during the 40-min test (an index of locomotor activity); and (F) the maximal (peak) tangential velocity (an index of hyperkinesia/bradykinesia). Note that the kinematic analysis but not the clinical rating scale discriminates an early (presymptomatic) phase of the 3NP treatment characterized by hyperactive (increase in travelled distance) and hyperkinetic (increase in peak tangential velocity) status of the animals and a late (symptomatic) phase associated with bradykinesia (decrease in peak tangential velocity). ***p<0.01 and *p<0.05 vs controls.</note><note type="content">Fig. 9: The ORDT: experimental set-up and principles. The ORDT assesses the ability of monkeys to retrieve an object from inside a transparent box only open on one side. The cognitive and motor skills required for the subject to complete the task and retrieve the banana slice can be modified by the experimenter by varying the location of the box relative to the subject, the location of the reward inside the box and finally, the orientation of the open side of the box relative to the subject. A total of 15 different configurations are randomly presented to the animals. Subject's responses are video recorded and measures of performance include: number of `success' responses (retrieval of the reward on the first reach of the trial), number of `correct' responses (retrieval of the reward within the 60-sec time period, whatever the strategy used by the monkey to get the reward), `barrier hits' responses (hitting the closed transparent side of the box instead of making a detour), `motor problems' responses [reaching the correct (open) side of the box but failing to retrieve the reward]. (A) A transparent box (8×8×9cm), made in plexiglass, is fixed on a tray adaptable to the monkey's home cage. (B)–(E) Examples of success (B, D) and barrier hit (C, E) responses for easy (direct reach possible, B and C) and difficult (detour required, D and E) configurations.</note><note type="content">Fig. 10: Frontal-type cognitive deficits in 3NP-treated baboons compared to age-matched control animals. The percentage of (A) `success', (B) `barrier hits', (C) ` correct ' and (D) `motor problems' responses are represented as a mean of four consecutive test-sessions performed at weekly intervals. Open bars represent control animals (n=10) and solid black bars, 3NP treated animals (n=3). Values are mean±SEM. Note that performances of the two groups differ in `success' and `barrier hits' responses but not in `correct' responses (which represent the ability of each animal to finally reach the reward) or in `motor problems'. Consequently, neither alterations in motor control nor a disinterest of the animals in the task could explain the differences observed between the two groups.</note><note type="content">Fig. 11: T2-weighted magnetic resonance imaging (MRI, 1.5T General Electric magnet) in a 3NP-treated primate at an advanced stage of the neurotoxic treatment. Two brain levels are represented at the level of the anterior commissure (A) and at the level of the globus pallidus (B). Lesions, detected as an hypersignal (white), are restricted to the dorsal aspect of the caudate nucleus and putamen. In contrast, the ventral striatum and the nucleus accumbens appear spared. No other damage was identified in any other brain area.</note><note type="content">Fig. 12: Caudate-putamen complex of a baboon presenting a 3NP lesion, associated with a putaminal T2-hypersignal at MRI. (A) and (B) Direct `negative' printings through sections immunostained for (A) neuron-specific nuclear protein (NeuN, Chemicon, USA, diluted 1:1000) and (B) the calcium binding protein calbindin-D28k (Swant, Switzerland, diluted 1:3000). (C) Photomicrogaph of the border between the lesion area (right) and the normal tissue (left) from the section shown in (A). (D) Photomicrograph of immunoreactivity for calbindin-D28k in the core of the lesion. Note that the severe decrease in calbindin-D28k immunoreactivity is associated with a strong decrease in immunoreactivity for NeuN. Moreover the border between the core of the lesion and the normal tissue is sharp in the case of the neuronal marker (A, C) whereas it is more diffuse and larger in the case of the marker of projection neurons (B), indicating the presence of a transition area in which the immunoreactivity of projection neurons for calbindin-D28k is weak whereas the immunoreactivity for NeuN does not seem to be affected. Microphotographs of immunoreactivity for (E, G) calretinin (Swant, Switzerland, diluted 1:10,000) and (F–H) calbindin-D28k, in the intermediate zone (E and F) and in the normal putamen (G and H) surrounding the lesion shown in (A) and (B). Note that in the intermediate area the immunoreactivity of projections neurons for calbindin-D28k is largely affected whereas the immunoreactivity for calretinin of short-circuit neurons does not exhibit marked change. Calibration bar: (A and B) 1mm, (C–H) 100μm.</note><note type="content">Fig. 13: Photomicrographs of the striatum of one control animal (A, C, E and G) and one macaque intoxicated with 3NP (B, D, F and H), and presenting motor and cognitive deficits but no T2-hypersignal at MRI examination. Distribution of neurons immunoreactive for (A) and (B) the neuron-specific protein (NeuN, Chemicon, USA, diluted 1:1000) and (C and D) for the calcium binding protein calbindin-D28k (Swant, Switzerland, diluted 1:3000). (E) and (F) Neurons containing NADPH. Note the decrease in NeuN and calbindin-D28k immunoreactivity and the absence of obvious changes in NADPH labeling, suggesting a specific cell loss or dysfunction of the striate projection neurons within the dorsolateral part of the caudate nucleus. Calibration bar: 50μm.</note><note type="content">Fig. 14: Schematic representation of the 3NP-treatment and experimental protocol used in striatal allografting experiments. The six macaques (M. fascicularis) were intoxicated on a chronic basis with 3NP and regularly tested on motor (VMA) and cognitive (ORDT) tasks, before and after surgery. MRI was performed at regular intervals in the post-operative period, up to 5months post-grafting. Animals were killed immediately after the last behavioural testing.</note><note type="content">Fig. 15: Dystonia index in the apomorphine test (A) and ORDT results for success (B) and barrier hit responses (C) before and after chronic 3NP lesion and fetal striatal allografting. In the motor test (A), a significant increase in the incidence of dystonia was observed in the 3NP-treated animals (solid bars, n=6) compared to controls (open bars, n=6). After bilateral allografting, the grafted group (grey bars, n=3) demonstrated a significant decrease in the incidence of the dystonia compared to the sham group (cross-hatched bars, n=3). In the ORDT test (B and C), monkeys treated with 3NP were significantly less successful than controls in reaching the reward at their first attempt (B, success responses) and made significantly more reaching errors than controls (C, barrier hit responses). As early as 2months postgrafting, a significant increase in success responses (B) was observed in the grafted macaques compared to the sham-operated animals. Similarly, starting 2months post-implantation, a significant decrease in the number of reaching errors was observed in the grafted macaques compared to the sham-operated macaques (C). All data are expressed as mean±SEM. *p<0.03 vs sham ANOVA.</note><note type="content">Fig. 16: Fetal strial implants. Microphotographs of the caudate nucleus of one control macaque (A) and of one 3NP-treated macaques in which fetal striatal cells were implanted (B–D). In the mediolateral part of the caudate nucleus of the 3NP-treated animal (B) immunoreactivity for the neuron-specific nuclear protein (NeuN, Chemicon International, diluted 1:5000) was strongly decreased (L), compared to control animal (A), suggesting a neuronal loss or severe neuronal dysfunction. Fetal striatal cells (transplant: T) were implanted in this area: the implanted cells were strongly immunoreactive for calbindin-D28k (C and D) and for DARPP32 (D encart), whereas there were almost no cells immunoreactive for these two antibodies left in the host caudate nucleus. Implanted striatal cells expressed calbindin-D28K and DARPP32 in their cell body as well as in their processes (D). Calibration bar: 500μm (A–C) and 50μm (D).</note><note type="content">Fig. 17: Schematic representation of the experimental protocol used in the CNTF experiments. Six macaques were treated daily (5days a week) with 3NP and regularly tested on motor (VMA) and cognitive tasks (ORDT), that is, before neurotoxic treatment, immediately before capsule implantation and on a monthly basis after capsule implantation. Note that 3NP treatment was continued after surgery. Animals were killed immediately after the last behavioural testing and retrieval of capsules (i.e. 3months post-surgery). MRI: 1.5T.</note><note type="content">Fig. 18: VMA test of motor performances in CNTF-treated animals (A) and animals implanted with native BHK cells (B). The mean peak tangential velocity (or PTV) was measured in cmsec−1 in the two experimental groups before (Ctrl), after 10weeks of 3NP treatment, that is, just before surgical implantation of capsules (3NP) and every month following implantation of the encapsulated cells (1, 2 and 3month). Following 10weeks of 3NP administration, PTV significantly increased in both groups but, after implantation, animals from the CNTF-treated group recovered a normal PTV value whereas animals from the sham-operated group became significantly bradykinetic (decrease in PTV below normal value) due to the occurence of severe dystonia.</note><note type="content">Fig. 19: ORDT test of cognitive performances in CNTF-treated animals (grey bars) and animals implanted with native BHK cells (cross-hatched bars). CNTF-treated and sham-operated animals were tested before (Ctrl), following 10weeks of 3NP treatment (i.e. just before surgical implantation: 3NP) and every month following surgery (1, 2 and 3months). Before capsule implantation, a severe decrease in the success score (A) and a significant increase in the barrier hit score (B) evidenced a frontal-type cognitive deficit in all 3NP-treated animals. For both cognitive indices, the performances of the CNTF-treated animals progressively improved after surgery until they reached control values, whereas those of the sham-operated animals remained severely impaired.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Replicating Huntington's disease phenotype in experimental animals</title><author xml:id="author-1"><persName><forename type="first">Emmanuel</forename><surname>Brouillet</surname></persName><email>brouille@shfj.cea.fr</email><note type="correspondence"><p>Corresponding author. Tel.: 0033 1 69 86 78 15; Fax: 0033 1 69 86 78 75</p></note><affiliation>URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du General Leclerc, 91401 Orsay Cedex, France</affiliation></author><author xml:id="author-2"><persName><forename type="first">Françoise</forename><surname>Condé</surname></persName><affiliation>URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du General Leclerc, 91401 Orsay Cedex, France</affiliation></author><author xml:id="author-3"><persName><forename type="first">M.F</forename><surname>Beal</surname></persName><affiliation>Department of Neurology, Cornell University Medical College, A569, 525 East 68th Street, New York, NY 10021, USA</affiliation></author><author xml:id="author-4"><persName><forename type="first">Philippe</forename><surname>Hantraye</surname></persName><affiliation>Department of Neurology, Cornell University Medical College, A569, 525 East 68th Street, New York, NY 10021, USA</affiliation></author></analytic><monogr><title level="j">Progress in Neurobiology</title><title level="j" type="abbrev">PRONEU</title><idno type="pISSN">0301-0082</idno><idno type="PII">S0301-0082(00)X0101-3</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999"></date><biblScope unit="volume">59</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="427">427</biblScope><biblScope unit="page" to="468">468</biblScope></imprint></monogr><idno type="istex">586DD76B8EF766EE1511E78D271AAD533DF2D52D</idno><idno type="DOI">10.1016/S0301-0082(99)00005-2</idno><idno type="PII">S0301-0082(99)00005-2</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1999</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Huntington's disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder characterized by involuntary choreiform movements, cognitive decline and a progressive neuronal degeneration primarily affecting the striatum. There is at present no effective therapy against this disorder. The gene responsible for the disease (IT15) has been cloned and the molecular defect identified as an expanded polyglutamine tract in the N-terminal region of a protein of unknown function, named huntingtin (The Huntington's Disease Collaborative Research Group, 1993. Cell 72, 971–983). An intense, search for the cell pathology attached to this molecular defect is currently under way [see Sharp and Ross (1996, Neurobiol. Dis. 3, 3–15) for review]. Huntingtin interacts with a number of proteins, some of which have well identified functions, and it has thus been suggested that alterations in glycolysis, vesicle trafficking or apoptosis play a role in the physiopathology of HD. On the other hand data derived from positron emission tomography (PET), magnetic resonance spectroscopy and post-mortem biochemical evidence for a defect in succinate oxidation have suggested the implication of a primary impairment of mitochondrial energy metabolism. All these hypotheses are not necessarily to be opposed and recent findings indicate that the HD mutation could possibly directly alter mitochondrial functions which would in turn activate apoptotic pathways. To test this mitochondrial hypothesis, we studied the effects in rodents and non-human primates of a chronic blockade of succinate oxidation by systemic administration of the mitochondrial toxin 3-nitropropionic acid (3NP). Extensive behavioural and neuropathological evaluations showed that a partial but prolonged energy impairment induced by 3NP is sufficient to replicate most of the clinical and pathophysiological hallmarks of HD, including spontaneous choreiform and dystonic movements, frontal-type cognitive deficits, and progressive heterogeneous striatal degeneration at least partially by apoptosis. 3NP produces the preferential degeneration of the medium-sized spiny GABAergic neurons with a relative sparing of interneurons and afferents, as was observed in HD striatum. The present manuscript reviews the different aspects of this neurotoxic treatment in rodents and non-human primates, and its interest as a phenotypic model of HD to understand the degenerative process of HD and test new therapeutic strategies.</p></abstract><textClass><keywords scheme="keyword"><list><head>Abbreviations</head><item><term>3NP,3-Nitropropionic acid</term></item><item><term>18F-FDG,[18F]Fluorodeoxuglucose</term></item><item><term>BHK,Baby hamster kidney cells</term></item><item><term>CB-D28k,Calbindin-D28k</term></item><item><term>ChAT,Choline acetyl transferase</term></item><item><term>CNTF,Ciliary neurotrophic factor</term></item><item><term>CT,Computed tomography</term></item><item><term>GABA,γ-Aminobutyric acid</term></item><item><term>GAPDH,Glyceraldehyde-3-phosphate deshydrogenase</term></item><item><term>GFAP,Glial fibrillary acidic protein</term></item><item><term>HD,Huntington's disease</term></item><item><term>IC,Internal capsule</term></item><item><term>IR,Immunoreactive</term></item><item><term>KO,Knock out</term></item><item><term>MRI,Magnetic resonance imaging</term></item><item><term>NMDA,N-Methyl-d-aspartate</term></item><item><term>NADPH,β-Nicotinamide adenine dinucleotide phosphate</term></item><item><term>NMR,Nuclear magnetic resonance</term></item><item><term>NOS,Nitric oxide synthase</term></item><item><term>ORDT,Object retrieval detour task</term></item><item><term>PET,Positon emission tomography</term></item><item><term>PARP,Poly-ADP-ribosyl polymerase</term></item><item><term>PTV,Peak tangential velocity</term></item><item><term>SDH,Succinate deshydrogenase</term></item><item><term>SPECT,Single photon emission computed tomography</term></item><item><term>VMA,Video movement analysis</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1999">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/586DD76B8EF766EE1511E78D271AAD533DF2D52D/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: ce:floats; body; tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="gr1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="gr3"></istex:entity><istex:entity SYSTEM="gr4" NDATA="IMAGE" name="gr4"></istex:entity><istex:entity SYSTEM="gr5" NDATA="IMAGE" name="gr5"></istex:entity><istex:entity SYSTEM="gr6" NDATA="IMAGE" name="gr6"></istex:entity><istex:entity SYSTEM="gr7" NDATA="IMAGE" name="gr7"></istex:entity><istex:entity SYSTEM="gr8" NDATA="IMAGE" name="gr8"></istex:entity><istex:entity SYSTEM="gr9" NDATA="IMAGE" name="gr9"></istex:entity><istex:entity SYSTEM="gr10" NDATA="IMAGE" name="gr10"></istex:entity><istex:entity SYSTEM="gr11" NDATA="IMAGE" name="gr11"></istex:entity><istex:entity SYSTEM="gr12" NDATA="IMAGE" name="gr12"></istex:entity><istex:entity SYSTEM="gr13" NDATA="IMAGE" name="gr13"></istex:entity><istex:entity SYSTEM="gr14" NDATA="IMAGE" name="gr14"></istex:entity><istex:entity SYSTEM="gr15" NDATA="IMAGE" name="gr15"></istex:entity><istex:entity SYSTEM="gr16" NDATA="IMAGE" name="gr16"></istex:entity><istex:entity SYSTEM="gr17" NDATA="IMAGE" name="gr17"></istex:entity><istex:entity SYSTEM="gr18" NDATA="IMAGE" name="gr18"></istex:entity><istex:entity SYSTEM="gr19" NDATA="IMAGE" name="gr19"></istex:entity></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="rev"><item-info><jid>PRONEU</jid><aid>400</aid><ce:pii>S0301-0082(99)00005-2</ce:pii><ce:doi>10.1016/S0301-0082(99)00005-2</ce:doi><ce:copyright type="full-transfer" year="1999">Elsevier Science Ltd</ce:copyright></item-info><head><ce:title>Replicating Huntington's disease phenotype in experimental animals</ce:title><ce:author-group><ce:author><ce:given-name>Emmanuel</ce:given-name><ce:surname>Brouillet</ce:surname><ce:cross-ref refid="AFF1"><ce:sup>a</ce:sup></ce:cross-ref><ce:cross-ref refid="CORR1">*</ce:cross-ref><ce:e-address>brouille@shfj.cea.fr</ce:e-address></ce:author><ce:author><ce:given-name>Françoise</ce:given-name><ce:surname>Condé</ce:surname><ce:cross-ref refid="AFF1"><ce:sup>a</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>M.F</ce:given-name><ce:surname>Beal</ce:surname><ce:cross-ref refid="AFF2"><ce:sup>b</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Philippe</ce:given-name><ce:surname>Hantraye</ce:surname><ce:cross-ref refid="AFF2"><ce:sup>a</ce:sup></ce:cross-ref></ce:author><ce:affiliation id="AFF1"><ce:label>a</ce:label><ce:textfn>URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du General Leclerc, 91401 Orsay Cedex, France</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>b</ce:label><ce:textfn>Department of Neurology, Cornell University Medical College, A569, 525 East 68th Street, New York, NY 10021, USA</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text>Corresponding author. Tel.: 0033 1 69 86 78 15; Fax: 0033 1 69 86 78 75</ce:text></ce:correspondence></ce:author-group><ce:date-received day="7" month="1" year="1999"></ce:date-received><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>Huntington's disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder characterized by involuntary choreiform movements, cognitive decline and a progressive neuronal degeneration primarily affecting the striatum.</ce:simple-para><ce:simple-para>There is at present no effective therapy against this disorder. The gene responsible for the disease (IT15) has been cloned and the molecular defect identified as an expanded polyglutamine tract in the N-terminal region of a protein of unknown function, named huntingtin (The Huntington's Disease Collaborative Research Group, 1993. <ce:italic>Cell</ce:italic> <ce:bold>72,</ce:bold> 971–983). An intense, search for the cell pathology attached to this molecular defect is currently under way [see Sharp and Ross (1996, <ce:italic>Neurobiol. Dis.</ce:italic> <ce:bold>3,</ce:bold> 3–15) for review].</ce:simple-para><ce:simple-para>Huntingtin interacts with a number of proteins, some of which have well identified functions, and it has thus been suggested that alterations in glycolysis, vesicle trafficking or apoptosis play a role in the physiopathology of HD.</ce:simple-para><ce:simple-para>On the other hand data derived from positron emission tomography (PET), magnetic resonance spectroscopy and post-mortem biochemical evidence for a defect in succinate oxidation have suggested the implication of a primary impairment of mitochondrial energy metabolism.</ce:simple-para><ce:simple-para>All these hypotheses are not necessarily to be opposed and recent findings indicate that the HD mutation could possibly directly alter mitochondrial functions which would in turn activate apoptotic pathways.</ce:simple-para><ce:simple-para>To test this mitochondrial hypothesis, we studied the effects in rodents and non-human primates of a chronic blockade of succinate oxidation by systemic administration of the mitochondrial toxin 3-nitropropionic acid (3NP).</ce:simple-para><ce:simple-para>Extensive behavioural and neuropathological evaluations showed that a partial but prolonged energy impairment induced by 3NP is sufficient to replicate most of the clinical and pathophysiological hallmarks of HD, including spontaneous choreiform and dystonic movements, frontal-type cognitive deficits, and progressive heterogeneous striatal degeneration at least partially by apoptosis.</ce:simple-para><ce:simple-para>3NP produces the preferential degeneration of the medium-sized spiny GABAergic neurons with a relative sparing of interneurons and afferents, as was observed in HD striatum.</ce:simple-para><ce:simple-para>The present manuscript reviews the different aspects of this neurotoxic treatment in rodents and non-human primates, and its interest as a phenotypic model of HD to understand the degenerative process of HD and test new therapeutic strategies.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="abr"><ce:section-title>Abbreviations</ce:section-title><ce:keyword><ce:text>3NP,3-Nitropropionic acid</ce:text></ce:keyword><ce:keyword><ce:text><ce:sup>18</ce:sup>F-FDG,[<ce:sup>1</ce:sup>8F]Fluorodeoxuglucose</ce:text></ce:keyword><ce:keyword><ce:text>BHK,Baby hamster kidney cells</ce:text></ce:keyword><ce:keyword><ce:text>CB-D28k,Calbindin-D28k</ce:text></ce:keyword><ce:keyword><ce:text>ChAT,Choline acetyl transferase</ce:text></ce:keyword><ce:keyword><ce:text>CNTF,Ciliary neurotrophic factor</ce:text></ce:keyword><ce:keyword><ce:text>CT,Computed tomography</ce:text></ce:keyword><ce:keyword><ce:text>GABA,γ-Aminobutyric acid</ce:text></ce:keyword><ce:keyword><ce:text>GAPDH,Glyceraldehyde-3-phosphate deshydrogenase</ce:text></ce:keyword><ce:keyword><ce:text>GFAP,Glial fibrillary acidic protein</ce:text></ce:keyword><ce:keyword><ce:text>HD,Huntington's disease</ce:text></ce:keyword><ce:keyword><ce:text>IC,Internal capsule</ce:text></ce:keyword><ce:keyword><ce:text>IR,Immunoreactive</ce:text></ce:keyword><ce:keyword><ce:text>KO,Knock out</ce:text></ce:keyword><ce:keyword><ce:text>MRI,Magnetic resonance imaging</ce:text></ce:keyword><ce:keyword><ce:text>NMDA,<ce:italic>N</ce:italic>-Methyl-<ce:small-caps>d</ce:small-caps>-aspartate</ce:text></ce:keyword><ce:keyword><ce:text>NADPH,β-Nicotinamide adenine dinucleotide phosphate</ce:text></ce:keyword><ce:keyword><ce:text>NMR,Nuclear magnetic resonance</ce:text></ce:keyword><ce:keyword><ce:text>NOS,Nitric oxide synthase</ce:text></ce:keyword><ce:keyword><ce:text>ORDT,Object retrieval detour task</ce:text></ce:keyword><ce:keyword><ce:text>PET,Positon emission tomography</ce:text></ce:keyword><ce:keyword><ce:text>PARP,Poly-ADP-ribosyl polymerase</ce:text></ce:keyword><ce:keyword><ce:text>PTV,Peak tangential velocity</ce:text></ce:keyword><ce:keyword><ce:text>SDH,Succinate deshydrogenase</ce:text></ce:keyword><ce:keyword><ce:text>SPECT,Single photon emission computed tomography</ce:text></ce:keyword><ce:keyword><ce:text>VMA,Video movement analysis</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Replicating Huntington's disease phenotype in experimental animals</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Replicating Huntington's disease phenotype in experimental animals</title></titleInfo><name type="personal"><namePart type="given">Emmanuel</namePart><namePart type="family">Brouillet</namePart><affiliation>E-mail: brouille@shfj.cea.fr</affiliation><affiliation>URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du General Leclerc, 91401 Orsay Cedex, France</affiliation><description>Corresponding author. Tel.: 0033 1 69 86 78 15; Fax: 0033 1 69 86 78 75</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Françoise</namePart><namePart type="family">Condé</namePart><affiliation>URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place du General Leclerc, 91401 Orsay Cedex, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M.F</namePart><namePart type="family">Beal</namePart><affiliation>Department of Neurology, Cornell University Medical College, A569, 525 East 68th Street, New York, NY 10021, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Philippe</namePart><namePart type="family">Hantraye</namePart><affiliation>Department of Neurology, Cornell University Medical College, A569, 525 East 68th Street, New York, NY 10021, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="review-article" displayLabel="Review article"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1999</dateIssued><copyrightDate encoding="w3cdtf">1999</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Huntington's disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder characterized by involuntary choreiform movements, cognitive decline and a progressive neuronal degeneration primarily affecting the striatum. There is at present no effective therapy against this disorder. The gene responsible for the disease (IT15) has been cloned and the molecular defect identified as an expanded polyglutamine tract in the N-terminal region of a protein of unknown function, named huntingtin (The Huntington's Disease Collaborative Research Group, 1993. Cell 72, 971–983). An intense, search for the cell pathology attached to this molecular defect is currently under way [see Sharp and Ross (1996, Neurobiol. Dis. 3, 3–15) for review]. Huntingtin interacts with a number of proteins, some of which have well identified functions, and it has thus been suggested that alterations in glycolysis, vesicle trafficking or apoptosis play a role in the physiopathology of HD. On the other hand data derived from positron emission tomography (PET), magnetic resonance spectroscopy and post-mortem biochemical evidence for a defect in succinate oxidation have suggested the implication of a primary impairment of mitochondrial energy metabolism. All these hypotheses are not necessarily to be opposed and recent findings indicate that the HD mutation could possibly directly alter mitochondrial functions which would in turn activate apoptotic pathways. To test this mitochondrial hypothesis, we studied the effects in rodents and non-human primates of a chronic blockade of succinate oxidation by systemic administration of the mitochondrial toxin 3-nitropropionic acid (3NP). Extensive behavioural and neuropathological evaluations showed that a partial but prolonged energy impairment induced by 3NP is sufficient to replicate most of the clinical and pathophysiological hallmarks of HD, including spontaneous choreiform and dystonic movements, frontal-type cognitive deficits, and progressive heterogeneous striatal degeneration at least partially by apoptosis. 3NP produces the preferential degeneration of the medium-sized spiny GABAergic neurons with a relative sparing of interneurons and afferents, as was observed in HD striatum. The present manuscript reviews the different aspects of this neurotoxic treatment in rodents and non-human primates, and its interest as a phenotypic model of HD to understand the degenerative process of HD and test new therapeutic strategies.</abstract><note type="content">Fig. 1: Schematic representation of the differential cell losses and deficits observed in the HD striatum (right) compared to the normal striatum (left). Whereas the border between the dorsal aspect of the caudate nucleus (CN) and the lateral ventricle (LV) is normally a convex outline, in HD patients it becomes either a straight or a concave outline, depending on the extent of striatal atrophy. Although the striatal neuronal loss can be almost complete in the late stages of the disease, the various populations of striatal neurons appear differentially affected by the HD neurodegenerative process. Thus, whereas the GABAergic medium-sized spiny projection neurons bear the brunt of the neurodegeneration, there is a relative sparing of the interneurons (large-sized cholinergic neurons, medium-sized calretinin neurons and medium-sized NADPH positive interneurons, which also contain nitric oxide synthase and somatostatin). This neuronal loss is accompanied by an increased number of reactive astrocytes. Striatal afferents are relatively spared. Accordingly, biochemical analyses of the HD striatum usually indicate decreased concentrations (as expressed per mg of protein) of all markers associated with GABAergic neurons (GABA, substance P and methionine-enkephaline), increased levels in somatostatin and unchanged concentrations of dopamine and serotonin. IC, Internal capsule.</note><note type="content">Fig. 2: Schematic representation of the different events implicated in indirect excitotoxicity. (A) Under physiological conditions, the production of ATP (open arrows) through oxidative phosphorylation within the mitochondria (mt) is sufficient to maintain normal membrane potential (mV) through the activity of the membrane Na+/K+ ATPases. Normal (low) cytosolic levels of Ca2+ ([Ca2+]cyt) are regulated by ATPases located in the plasma and endoplasmic reticulum (ER) membranes. Transient elevations of [Ca2+]cyt resulting from the physiological activation of the NMDA gated-Ca2+-channels by endogenous glutamate can be regulated by several intra-cellular mechanisms, including a rapid uptake of Ca2+ by the mitochondria and the ER, followed later on by active extra-cellular Ca2+ transport by the plasma membrane ATPases. Tight control of [Ca2+]cyt ensures that several factors potentially harmful for the cell, such as the generation of oxidative radicals and activation of several proteases, phospholipases, phosphatases and endonucleases, can be kept in a resting state. (B) Under partial impairment of energy metabolism, a decrease in ATP production due to mitochondrial dysfunction will impair the ability of the membrane ATPases to maintain membrane potential at normal values, leading to partial depolarization of the cell. In addition, the blockade of the oxidative phosphorylation will also affect the ability of the mitochondria and the endoplasmic reticulum to buffer the [Ca2+]cyt. Together with the relief of the voltage-dependent Mg2+ block of the calcium channel of NMDA receptors (NMDA-R), these events will progressively induce an increase in the [Ca2+]cyt. (C) Under prolonged mitochondrial impairment, the sustained activation of NMDA receptors by ambient glutamate concentrations will result in a massive increase in [Ca2+]cyt which, in turn, will activate Ca2+-dependent `toxic' pathways (represented by the shift from a `OFF' to a `ON' position of the box containing oxidative radicals and several proteases, phospholipases, phosphatases and endonucleases). (D) Initiation of the classical `excitotoxic cascade' leads to amplification phenomenon involving increased free radical production and activation of several enzymes deleterious to the cell. Although the cell death associated with failure in energy production is morphologically of rather a necrotic nature, biochemical pathways associated with apoptosis such as caspase activation may also be involved.</note><note type="content">Fig. 3: 3NP, an irreversible SDH inhibitor. (A) The chemical structure of 3NP is closely related to that of succinic acid which may explain that 3NP can, like the natural substrate, occupy the catalytic site of the enzyme. (B) Schematic representation of the mechanism of irreversible SDH inactivation [redrawn from Coles et al. (1979)]. In the top part of (B), the dianion form of 3NP binds to SDH, leading to the formation of nitroacrylate [middle of (B)]. The nitroacrylate then reacts with an essential thiol group of SDH, and remains covalently attached to the enzyme [bottom of (B)], blocking the access of succinate to the enzyme. (C) Since SDH participates in both oxidative phosphorylation and tricarboxylic acid cycle (TCA), 3NP-induced SDH inhibition impairs the entry into the electron transport chain of reducing equivalents generated by succinate oxidation and decreases the ability of TCA cycle to make NADH available for complex I.</note><note type="content">Fig. 4: Schematic representation of the excitotoxic cascade involved in 3NP neurotoxicity. The primary effect of 3NP is the blockade of succinate oxidation through the irreversible inactivation of SDH. Partial enzyme inhibition by 3NP (ca 50%) is sufficient to trigger the excitotoxic cascade. The SDH inhibition may decrease the availability of ATP equivalent, which reduces the plasma membrane (Mb) potential, resulting in the relief of the voltage-dependent Mg2+ block of the NMDA receptors (NMDA-R). This, in turn, allows excessive activation of the NMDA receptors by ambient glutamate concentrations, producing a massive entry of Ca2+. As a first step, calcium may be partly uptaken by the mitochondria (mt) and the endoplasmic reticulum (ER), leading to a progressive increase in [Ca2+]mt, an increase in free radical production and a dysfunction of the respiratory chain. In the long term, the entry of Ca2+ cannot be appropriately buffered by the endoplasmic reticulum and the mitochondria, leading to further mitochondrial impairment, and activation of a number of Ca2+ dependent cytoplasmic enzymes including proteases (caspases, calpain), kinases, phospholipases and endonucleases. One early activated protein is NO synthase, whose inhibition blocks 3NP neurotoxicity in vivo. All these events ultimately lead to cell death through possibly different pathways (depending on cell type, severity of energy impairment and possible compensatory mechanisms) which are related either to necrosis or apoptosis. In the case of necrosis, plasma membrane integrity is rapidly lost. In case of apoptosis, cytoplasm condenses and the nucleus (Nc) shows typical fragmentation with apoptotic bodies.</note><note type="content">Fig. 5: Schematic representation of the rostro-caudal distribution of the lesioned areas observed following subacute (15mgkg−1day−1 for 5–10days, i.p.) or chronic (10mgkg−1day−1 for 4weeks, s.c. using osmotic pumps) systemic 3NP injections. The minimal and maximal extents of lesions observed on coronal sections, in five animals per group (each animal corresponding to a different level of grey), are represented for seven different brain levels encompassing the striatum, the globus pallidus and the dorsal part of the hippocampus. Numbers in brackets indicate the distance in millimetres to bregma (Paxinos and Watson, 1986). Note that while `chronic' lesions are small and consistently restricted to the dorsolateral part of the anterior striatum, `subacute' lesions are larger, invading the entire lateral striatum and involving, in several cases, the most caudal part of the striatum. In addition, whereas chronic 3NP-treatment is not associated with extra-striatal lesions, subacute 3NP treatment is frequently associated with pallidal and hippocampal neurodegenerations.</note><note type="content">Fig. 6: Kinetic movement parameters in sham animals and chronic 3NP-treated rats during the elevated board test. In this task, rats were trained to walk along a board (120cm long, 7cm wide, 35cm above the floor) to reach a platform on which their home-cage was placed. After a training period of 5days, their axial and lateral movements were evaluated from top-view images using a video movement analysis system (VMA) allowing the detection of a centroid, corresponding to the geometric centre of the animal, as a function of time and space (X–Y coordinates, 50msec sampling rate). (A) Schematic representation of the elevated board viewed from above and animal's coordinates during the board crossing. Dashed and solid lines correspond to the X–Y coordinates of centroids for one sham and one 3NP-treated rat, respectively. Note the typical irregularities (wobbling) in the 3NP-treated rat compared to the sham. (B) Tangential velocity as a function of the distance traveled on the board for the same two animals. Note the reduced speed (bradykinesia) in the 3NP-treated animal compared to the sham. (C) Lateral velocity (wobbling) in the same two animals, represented as a function of the distance traveled during the board crossing. Note that the highest lateral velocity (6cmsec-1) was found in the 3NP-treated animal which presented gait abnormalities. (D) Kinetic parameters for two groups of sham animals and 3NP-treated animals with (`lesioned') or without (`unlesioned') significant striatal cell loss. The striatal cell loss was considered significant when the mean neuron density was 1SD below the mean cell density of sham animals. Kinetic parameters were determined for each animal (mean of three board tests) using VMA. Sham animals (n=9; open bars), `unlesioned' (n=6, grey bars) and `lesioned' (n=7, black bars) 3NP-treated rats. Note that the significant changes in kinematic parameters are only observed in the 3NP-treated rats belonging to the `lesioned' group (ANOVA and post-hoc Scheffé F-test).</note><note type="content">Fig. 7: Schematic representation of the 3NP intoxication regimen used in non-human primates (Macaca fascicularis monkeys) to induce progressive striatal degeneration. Starting from 10mgkg−1day−1, the daily dose of 3NP is progressively increased to 29mgkg−1day−1. The doses of 3NP is incremented at weekly intervals to induce progressive SDH inhibition. A first dose increment (2mgkg−1day−1) from week 1 to week 6 is followed by a dose increment of 0.5mgkg−1day−1 from week 6 to week 25. Such a dose regimen is associated with a progressive body weight loss and the progressive appearance of motor and cognitive deficits. Note a marked drop in body weight ca 9–11weeks of treatment, corresponding to the beginning of the symptomatic phase.</note><note type="content">Fig. 8: Motor syndrome in chronic 3NP-treated baboons during the presymptomatic and the symptomatic phase of the neurotoxic treatment. To assess striatal function, time-sampled neurological observations are obtained after i.m. administration of apomorphine. Briefly, four different categories of abnormal movements including orofacial dyskinesia, dyskinesia of extremities, dystonia and choreiform movements, are monitored after video-recording from front-view images and rated as being present (=1) or absent (=0) during each 5min time period of a 40-min test session. A dyskinesia index (sum of incidences) is computed by adding together the incidence of each symptom (maximum score=8) during the 40min test-period (maximum score=32, minimum score=0). (A)–(D) Rate of incidence in different categories of abnormal movements observed in 3NP-treated non-human primates. (E and F) Video movement analysis (kinematic analysis, VMA) of the apomorphine-inducible motor syndrome. VMA is used to determine the animal's position as a function of time, during the 40-min duration of the test. Derived data include: (E) the total distance travelled by each animal during the 40-min test (an index of locomotor activity); and (F) the maximal (peak) tangential velocity (an index of hyperkinesia/bradykinesia). Note that the kinematic analysis but not the clinical rating scale discriminates an early (presymptomatic) phase of the 3NP treatment characterized by hyperactive (increase in travelled distance) and hyperkinetic (increase in peak tangential velocity) status of the animals and a late (symptomatic) phase associated with bradykinesia (decrease in peak tangential velocity). ***p<0.01 and *p<0.05 vs controls.</note><note type="content">Fig. 9: The ORDT: experimental set-up and principles. The ORDT assesses the ability of monkeys to retrieve an object from inside a transparent box only open on one side. The cognitive and motor skills required for the subject to complete the task and retrieve the banana slice can be modified by the experimenter by varying the location of the box relative to the subject, the location of the reward inside the box and finally, the orientation of the open side of the box relative to the subject. A total of 15 different configurations are randomly presented to the animals. Subject's responses are video recorded and measures of performance include: number of `success' responses (retrieval of the reward on the first reach of the trial), number of `correct' responses (retrieval of the reward within the 60-sec time period, whatever the strategy used by the monkey to get the reward), `barrier hits' responses (hitting the closed transparent side of the box instead of making a detour), `motor problems' responses [reaching the correct (open) side of the box but failing to retrieve the reward]. (A) A transparent box (8×8×9cm), made in plexiglass, is fixed on a tray adaptable to the monkey's home cage. (B)–(E) Examples of success (B, D) and barrier hit (C, E) responses for easy (direct reach possible, B and C) and difficult (detour required, D and E) configurations.</note><note type="content">Fig. 10: Frontal-type cognitive deficits in 3NP-treated baboons compared to age-matched control animals. The percentage of (A) `success', (B) `barrier hits', (C) ` correct ' and (D) `motor problems' responses are represented as a mean of four consecutive test-sessions performed at weekly intervals. Open bars represent control animals (n=10) and solid black bars, 3NP treated animals (n=3). Values are mean±SEM. Note that performances of the two groups differ in `success' and `barrier hits' responses but not in `correct' responses (which represent the ability of each animal to finally reach the reward) or in `motor problems'. Consequently, neither alterations in motor control nor a disinterest of the animals in the task could explain the differences observed between the two groups.</note><note type="content">Fig. 11: T2-weighted magnetic resonance imaging (MRI, 1.5T General Electric magnet) in a 3NP-treated primate at an advanced stage of the neurotoxic treatment. Two brain levels are represented at the level of the anterior commissure (A) and at the level of the globus pallidus (B). Lesions, detected as an hypersignal (white), are restricted to the dorsal aspect of the caudate nucleus and putamen. In contrast, the ventral striatum and the nucleus accumbens appear spared. No other damage was identified in any other brain area.</note><note type="content">Fig. 12: Caudate-putamen complex of a baboon presenting a 3NP lesion, associated with a putaminal T2-hypersignal at MRI. (A) and (B) Direct `negative' printings through sections immunostained for (A) neuron-specific nuclear protein (NeuN, Chemicon, USA, diluted 1:1000) and (B) the calcium binding protein calbindin-D28k (Swant, Switzerland, diluted 1:3000). (C) Photomicrogaph of the border between the lesion area (right) and the normal tissue (left) from the section shown in (A). (D) Photomicrograph of immunoreactivity for calbindin-D28k in the core of the lesion. Note that the severe decrease in calbindin-D28k immunoreactivity is associated with a strong decrease in immunoreactivity for NeuN. Moreover the border between the core of the lesion and the normal tissue is sharp in the case of the neuronal marker (A, C) whereas it is more diffuse and larger in the case of the marker of projection neurons (B), indicating the presence of a transition area in which the immunoreactivity of projection neurons for calbindin-D28k is weak whereas the immunoreactivity for NeuN does not seem to be affected. Microphotographs of immunoreactivity for (E, G) calretinin (Swant, Switzerland, diluted 1:10,000) and (F–H) calbindin-D28k, in the intermediate zone (E and F) and in the normal putamen (G and H) surrounding the lesion shown in (A) and (B). Note that in the intermediate area the immunoreactivity of projections neurons for calbindin-D28k is largely affected whereas the immunoreactivity for calretinin of short-circuit neurons does not exhibit marked change. Calibration bar: (A and B) 1mm, (C–H) 100μm.</note><note type="content">Fig. 13: Photomicrographs of the striatum of one control animal (A, C, E and G) and one macaque intoxicated with 3NP (B, D, F and H), and presenting motor and cognitive deficits but no T2-hypersignal at MRI examination. Distribution of neurons immunoreactive for (A) and (B) the neuron-specific protein (NeuN, Chemicon, USA, diluted 1:1000) and (C and D) for the calcium binding protein calbindin-D28k (Swant, Switzerland, diluted 1:3000). (E) and (F) Neurons containing NADPH. Note the decrease in NeuN and calbindin-D28k immunoreactivity and the absence of obvious changes in NADPH labeling, suggesting a specific cell loss or dysfunction of the striate projection neurons within the dorsolateral part of the caudate nucleus. Calibration bar: 50μm.</note><note type="content">Fig. 14: Schematic representation of the 3NP-treatment and experimental protocol used in striatal allografting experiments. The six macaques (M. fascicularis) were intoxicated on a chronic basis with 3NP and regularly tested on motor (VMA) and cognitive (ORDT) tasks, before and after surgery. MRI was performed at regular intervals in the post-operative period, up to 5months post-grafting. Animals were killed immediately after the last behavioural testing.</note><note type="content">Fig. 15: Dystonia index in the apomorphine test (A) and ORDT results for success (B) and barrier hit responses (C) before and after chronic 3NP lesion and fetal striatal allografting. In the motor test (A), a significant increase in the incidence of dystonia was observed in the 3NP-treated animals (solid bars, n=6) compared to controls (open bars, n=6). After bilateral allografting, the grafted group (grey bars, n=3) demonstrated a significant decrease in the incidence of the dystonia compared to the sham group (cross-hatched bars, n=3). In the ORDT test (B and C), monkeys treated with 3NP were significantly less successful than controls in reaching the reward at their first attempt (B, success responses) and made significantly more reaching errors than controls (C, barrier hit responses). As early as 2months postgrafting, a significant increase in success responses (B) was observed in the grafted macaques compared to the sham-operated animals. Similarly, starting 2months post-implantation, a significant decrease in the number of reaching errors was observed in the grafted macaques compared to the sham-operated macaques (C). All data are expressed as mean±SEM. *p<0.03 vs sham ANOVA.</note><note type="content">Fig. 16: Fetal strial implants. Microphotographs of the caudate nucleus of one control macaque (A) and of one 3NP-treated macaques in which fetal striatal cells were implanted (B–D). In the mediolateral part of the caudate nucleus of the 3NP-treated animal (B) immunoreactivity for the neuron-specific nuclear protein (NeuN, Chemicon International, diluted 1:5000) was strongly decreased (L), compared to control animal (A), suggesting a neuronal loss or severe neuronal dysfunction. Fetal striatal cells (transplant: T) were implanted in this area: the implanted cells were strongly immunoreactive for calbindin-D28k (C and D) and for DARPP32 (D encart), whereas there were almost no cells immunoreactive for these two antibodies left in the host caudate nucleus. Implanted striatal cells expressed calbindin-D28K and DARPP32 in their cell body as well as in their processes (D). Calibration bar: 500μm (A–C) and 50μm (D).</note><note type="content">Fig. 17: Schematic representation of the experimental protocol used in the CNTF experiments. Six macaques were treated daily (5days a week) with 3NP and regularly tested on motor (VMA) and cognitive tasks (ORDT), that is, before neurotoxic treatment, immediately before capsule implantation and on a monthly basis after capsule implantation. Note that 3NP treatment was continued after surgery. Animals were killed immediately after the last behavioural testing and retrieval of capsules (i.e. 3months post-surgery). MRI: 1.5T.</note><note type="content">Fig. 18: VMA test of motor performances in CNTF-treated animals (A) and animals implanted with native BHK cells (B). The mean peak tangential velocity (or PTV) was measured in cmsec−1 in the two experimental groups before (Ctrl), after 10weeks of 3NP treatment, that is, just before surgical implantation of capsules (3NP) and every month following implantation of the encapsulated cells (1, 2 and 3month). Following 10weeks of 3NP administration, PTV significantly increased in both groups but, after implantation, animals from the CNTF-treated group recovered a normal PTV value whereas animals from the sham-operated group became significantly bradykinetic (decrease in PTV below normal value) due to the occurence of severe dystonia.</note><note type="content">Fig. 19: ORDT test of cognitive performances in CNTF-treated animals (grey bars) and animals implanted with native BHK cells (cross-hatched bars). CNTF-treated and sham-operated animals were tested before (Ctrl), following 10weeks of 3NP treatment (i.e. just before surgical implantation: 3NP) and every month following surgery (1, 2 and 3months). Before capsule implantation, a severe decrease in the success score (A) and a significant increase in the barrier hit score (B) evidenced a frontal-type cognitive deficit in all 3NP-treated animals. For both cognitive indices, the performances of the CNTF-treated animals progressively improved after surgery until they reached control values, whereas those of the sham-operated animals remained severely impaired.</note><subject><genre>Abbreviations</genre><topic>3NP,3-Nitropropionic acid</topic><topic>18F-FDG,[18F]Fluorodeoxuglucose</topic><topic>BHK,Baby hamster kidney cells</topic><topic>CB-D28k,Calbindin-D28k</topic><topic>ChAT,Choline acetyl transferase</topic><topic>CNTF,Ciliary neurotrophic factor</topic><topic>CT,Computed tomography</topic><topic>GABA,γ-Aminobutyric acid</topic><topic>GAPDH,Glyceraldehyde-3-phosphate deshydrogenase</topic><topic>GFAP,Glial fibrillary acidic protein</topic><topic>HD,Huntington's disease</topic><topic>IC,Internal capsule</topic><topic>IR,Immunoreactive</topic><topic>KO,Knock out</topic><topic>MRI,Magnetic resonance imaging</topic><topic>NMDA,N-Methyl-d-aspartate</topic><topic>NADPH,β-Nicotinamide adenine dinucleotide phosphate</topic><topic>NMR,Nuclear magnetic resonance</topic><topic>NOS,Nitric oxide synthase</topic><topic>ORDT,Object retrieval detour task</topic><topic>PET,Positon emission tomography</topic><topic>PARP,Poly-ADP-ribosyl polymerase</topic><topic>PTV,Peak tangential velocity</topic><topic>SDH,Succinate deshydrogenase</topic><topic>SPECT,Single photon emission computed tomography</topic><topic>VMA,Video movement analysis</topic></subject><relatedItem type="host"><titleInfo><title>Progress in Neurobiology</title></titleInfo><titleInfo type="abbreviated"><title>PRONEU</title></titleInfo><genre type="journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">199912</dateIssued></originInfo><identifier type="ISSN">0301-0082</identifier><identifier type="PII">S0301-0082(00)X0101-3</identifier><part><date>199912</date><detail type="volume"><number>59</number><caption>vol.</caption></detail><detail type="issue"><number>5</number><caption>no.</caption></detail><extent unit="issue pages"><start>427</start><end>582</end></extent><extent unit="pages"><start>427</start><end>468</end></extent></part></relatedItem><identifier type="istex">586DD76B8EF766EE1511E78D271AAD533DF2D52D</identifier><identifier type="DOI">10.1016/S0301-0082(99)00005-2</identifier><identifier type="PII">S0301-0082(99)00005-2</identifier><accessCondition type="use and reproduction" contentType="copyright">©1999 Elsevier Science Ltd</accessCondition><recordInfo><recordContentSource>ELSEVIER</recordContentSource><recordOrigin>Elsevier Science Ltd, ©1999</recordOrigin></recordInfo></mods></metadata></istex></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Psychologie/explor/DanceTherParkinsonV1/Data/Istex/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000406 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Istex/Corpus/biblio.hfd -nk 000406 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Psychologie
|area= DanceTherParkinsonV1
|flux= Istex
|étape= Corpus
|type= RBID
|clé= ISTEX:586DD76B8EF766EE1511E78D271AAD533DF2D52D
|texte= Replicating Huntington's disease phenotype in experimental animals
}}
| This area was generated with Dilib version V0.6.35. |  |