Calpain Inhibition Protected Spinal Cord Motoneurons against 1-methyl-4-phenylpyridinium ion and Rotenone
Identifieur interne : 000D48 ( Ncbi/Curation ); précédent : 000D47; suivant : 000D49Calpain Inhibition Protected Spinal Cord Motoneurons against 1-methyl-4-phenylpyridinium ion and Rotenone
Auteurs : Supriti Samantaray [États-Unis] ; Varduhi H. Knaryan [États-Unis] ; Charlene Le Gal [France] ; Swapan K. Ray [États-Unis] ; Naren L. Banik [États-Unis]Source :
- Neuroscience [ 0306-4522 ] ; 2011.
Abstract
Parkinson's disease (PD), characterized by selective midbrain nigrostriatal dopaminergic degeneration, is consistently associated with moderate systemic mitochondrial dysfunction. Downstream degeneration of spinal cord has also been suggested in PD, although the mechanisms have not been much investigated. In the present study, two mitochondrial toxicants, 1-methyl-4-phenylpyridinium ion (MPP+) and rotenone were tested in ventral spinal cord (VSC 4.1) motoneuronal cells. Cell death was assessed by morphological and biochemical means to discern a lower apoptosis-inducing concentration and LC50, which were subsequently compared in further cytoprotection experiments. Mitochondrial toxicants dose-dependently induced increase in intracellular free Ca2+ level, which was conducive for increased expression and activities of Ca2+-activated neutral protease calpain and downstream caspase-3. Thus, mitochondrial damage triggered apoptotic mechanisms in spinal cord motoneurons. Inhibition of calpain by calpeptin significantly attenuated damaging effects of MPP+ and rotenone on motoneurons, especially at low apoptosis-inducing concentrations of toxicants and partly at their LC50, as demonstrated by absence of DNA ladder formation and decrease in TUNEL-positive cells. Cytoprotection by calpeptin was observed with marked decreases in Bax:Bcl-2 ratio and activities of calpain and caspase-3, which affirmed the role of mitochondrial dysfunction and involvement of intrinsic pathway in mediation of apoptosis. These findings strongly suggested that parkinsonian toxicants MPP+ and rotenone at low doses induced cascade of cell damaging effects in spinal cord motoneurons, thus, highlighting the possibility of induction of apoptotic mechanisms in these cells, when subjected to mitochondrial stress. Cytoprotection rendered by calpeptin further validated the involvement of calpain in apoptosis and suggested calpain inhibition as a potential neuroprotective strategy.
Url:
DOI: 10.1016/j.neuroscience.2011.06.007
PubMed: 21723922
PubMed Central: 3166419
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<front><div type="abstract" xml:lang="en"><p id="P1">Parkinson's disease (PD), characterized by selective midbrain nigrostriatal dopaminergic degeneration, is consistently associated with moderate systemic mitochondrial dysfunction. Downstream degeneration of spinal cord has also been suggested in PD, although the mechanisms have not been much investigated. In the present study, two mitochondrial toxicants, 1-methyl-4-phenylpyridinium ion (MPP<sup>+</sup>
) and rotenone were tested in ventral spinal cord (VSC 4.1) motoneuronal cells. Cell death was assessed by morphological and biochemical means to discern a lower apoptosis-inducing concentration and LC<sub>50</sub>
, which were subsequently compared in further cytoprotection experiments. Mitochondrial toxicants dose-dependently induced increase in intracellular free Ca<sup>2+</sup>
level, which was conducive for increased expression and activities of Ca<sup>2+</sup>
-activated neutral protease calpain and downstream caspase-3. Thus, mitochondrial damage triggered apoptotic mechanisms in spinal cord motoneurons. Inhibition of calpain by calpeptin significantly attenuated damaging effects of MPP<sup>+</sup>
and rotenone on motoneurons, especially at low apoptosis-inducing concentrations of toxicants and partly at their LC<sub>50</sub>
, as demonstrated by absence of DNA ladder formation and decrease in TUNEL-positive cells. Cytoprotection by calpeptin was observed with marked decreases in Bax:Bcl-2 ratio and activities of calpain and caspase-3, which affirmed the role of mitochondrial dysfunction and involvement of intrinsic pathway in mediation of apoptosis. These findings strongly suggested that parkinsonian toxicants MPP<sup>+</sup>
and rotenone at low doses induced cascade of cell damaging effects in spinal cord motoneurons, thus, highlighting the possibility of induction of apoptotic mechanisms in these cells, when subjected to mitochondrial stress. Cytoprotection rendered by calpeptin further validated the involvement of calpain in apoptosis and suggested calpain inhibition as a potential neuroprotective strategy.</p>
</div>
</front>
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