Neuroprotection via pro‐survival protein kinase C isoforms associated with Bcl‐2 family members

This study provides new insights into neuroprotection involving interaction of protein kinase C (PKC) pathway with Bcl‐2 family proteins. Using a model of serum deprivation, we investigated the mechanism by which the anti‐Parkinson/monoamine oxidase (MAO)‐B inhibitor drug, rasagiline, exerts its neuroprotective effect in rat pheochromocytoma PC12 cells. Here, we report that rasagiline (0.1–10 µM) decreased apoptosis via multiple protection mechanisms, including the stimulation of PKC phosphorylation; up‐regulation of PKCα and PKCε mRNAs, induction of Bcl‐xL, Bcl‐w, and brain‐derived neurotrophic factor (BDNF) mRNAs; and down‐regulation of Bad and Bax mRNAs. Moreover, rasagiline inhibited the cleavage and activation of procaspase‐3 and poly (ADP‐ribose) polymerase (PARP), whereas the PKC inhibitor, GF109203X, reversed these actions. Similarly, rasagiline decreased serum‐free‐induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC in rasagiline‐induced cell survival. Furthermore, these studies have established that PKC‐ and Bcl‐2‐dependent neuroprotective activity of rasagiline is dependent on its propargyl moiety, because propargylamine had similar effects with the same potency.