Cerebrolysin reduces excitotoxicity by modulation of cell-death proteins in delayed hours of ischemic reperfusion injury.

Abstract

Recent preclinical and clinical reports suggest that cerebrolysin shows neuroprotective properties similar to endogenous neurotrophic factors in neurodegenerative disorders including ischemic stroke. However, little is known about its underlying antiexcitotoxic action. Adult male Wistar rats were intraperitoneally treated with cerebrolysin (0.15 or 0.30mg/kg) or vehicle at 3, 6 and 12h after ischemic reperfusion and were assessed 24h after reperfusion in ischemic rats. We added cerebrolysin (2.5 or 5mg/ml) or vehicle in primary cortical culture cells at 3, 6 and 12h of post-glutamate exposure and performed cell viability assays at 24h. Our in-vivo and in-vitro findings showed that cerebrolysin substantially reduced neuronal cell death in delayed hours of post ischemic- and glutamate-insult conditions respectively. Further, we have assessed the influence of NR-2A/-2B receptor antagonism on neuroprotective action of cerebrolysin at 6h in in-vivo as well as in-vitro conditions. Neuroprotective effect of cerebrolysin at 6h of reperfusion was enhanced by pretreatment of NR2B antagonist RO25-6981.We found that cerebrolysin restrained upregulation of extrasynaptic NR2B responsible for triggering apoptotic pathways. Cerebrolysin reduced expression of important cell death proteins such as, JNK, PTEN, Calpain and Caspase-3 components. Importantly, we also found that cerebrolysin reduced SREBP1 expression, which gets activated only after 6h of ischemia. These results demonstrate that cerebrolysin reduces excitotoxicity and protect neuronal cells in delayed hours of ischemic reperfusion injuries by decreasing cell death proteins.