Ceramide is a lipid second‐messenger generated in response to stimuli associated with neurodegeneration that induces apoptosis, a mechanism underlying neuronal death in Parkinson's disease. We tested the hypothesis that insulin‐like growth factor‐1 (IGF‐1) could mediate a metabolic response in CAD cells, a dopaminergic cell line of mesencephalic origin that differentiate into a neuronal‐like phenotype upon serum removal, extend processes resembling neurites, synthesize abundant dopamine and noradrenaline and express the catecholaminergic biosynthetic enzymes tyrosine hydroxylase and dopamine β‐hydroxylase, and that this process was phosphatidylinositol 3‐kinase (PI 3‐K)–Akt‐dependent and could be inhibited by C2‐ceramide. The metabolic response was evaluated as real‐time changes in extracellular acidification rate (ECAR) using microphysiometry. The IGF‐1‐induced ECAR response was associated with increased glycolysis, determined by increased NAD(P)H reduction, elevated hexokinase activity and Akt phosphorylation. C2‐ceramide inhibited all these changes in a dose‐dependent manner, and was specific, as it was not induced by the inactive C2‐ceramide analogue C2‐dihydroceramide. Inhibition of the upstream kinase, PI 3‐K, also inhibited Akt phosphorylation and the metabolic response to IGF‐1, similar to C2‐ceramide. Decreased mitochondrial membrane potential occurred after loss of Akt phosphorylation. These results show that IGF‐1 can rapidly modulate neuronal metabolism through PI 3‐K–Akt and that early metabolic inhibition induced by C2‐ceramide involves blockade of the PI 3‐K–Akt pathway, and may compromise the first step of glycolysis. This may represent a new early event in the C2‐ceramide‐induced cell death pathway that could coordinate subsequent changes in mitochondria and commitment of neurons to apoptosis.

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{{Explor lien
   |wiki=    Wicri/Canada
   |area=    ParkinsonCanadaV1
   |flux=    Main
   |étape=   Exploration
   |type=    RBID
   |clé=     ISTEX:62EC02BE61195C4899FF6E3497EFAFF8BAC6820E
   |texte=   Insulin‐like growth factor‐1‐dependent maintenance of neuronal metabolism through the phosphatidylinositol 3‐kinase–Akt pathway is inhibited by C2‐ceramide in CAD cells
}}