Neuroprotective effects of carnosine and homocarnosine on pheochromocytoma PC12 cells exposed to ischemia

The development of neuroprotective drugs against ischemic insults is hampered by the lack of pharmacological in vitro models. We developed an ischemic model using PC12 cell cultures exposed to oxygen-glucose-deprivation (OGD) followed by reoxygenation (18 hr) under regular atmospheric oxygen level. The toxicity induced in this model, that is partially caused by generation of reactive oxygen species (ROS), was measured morphologically as well as by the release of lactate dehydrogenase (LDH) and the prostaglandin PGE₂ from the cells. Carnosine and homocarnosine, histidine dipeptides antioxidants, found in high concentration in the brain, have been suggested to provide neuroprotection. Using the OGD model we found that 5 mM carnosine and 1 mM homocarnosine provided maximal neuroprotection of about 50% against OGD insult. This neuroprotective effect was similar to that of a known antioxidant, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol), and was not observed in a serum-deprivation toxicity model of PC12 cells, indicating that carnosine and homocarnosine may act as antioxidant-neuroprotective agents in the brain. Our ischemic model may provide a useful tool for investigating the mechanisms involved in the neuroprotection afforded by histidine dipeptides.