NEUROPROTECTIVE ACTIONS OF DIPYRIDAMOLE ON CULTURED CNS NEURONS

We report that dipyridamole is neuroprotective for a variety of rat em bryonic CNS neurons cultured in serum-free basal medium lacking trophi c factors or other additives. We also describe the mechanism underlyin g this action. Neurons died rapidly in basal medium but were rescued i n large measure by 10 mu M dipyridamole. The protective action of dipy ridamole seems to be attributable to its antioxidant property. Vitamin E and N-acetylcysteine provided comparable neuroprotection in basal m edium, whereas an array of compounds that mimic other actions of dipyr idamole (inhibition of phosphodiesterases, blockade of nucleoside and chloride transport, interference with the multidrug resistance protein , and enhancement of prostacyclin synthesis) failed to promote surviva l. Thus, a major cause of neuronal death in this system seems to be ox idative stress that is relieved by dipyridamole. Iron plays a signific ant role in generation of such stress, as indicated by the observation s that addition of apotransferrin or iron chelators to basal medium or use of iron-free medium also afforded protection. Although oxidative stress was a major determinant of neuronal death, ii was not the only factor. Dipyridamole or other antioxidant measures did not provide sus tained neuroprotection. However, provision of insulin, which was not p rotective alone in basal medium, along with dipyridamole significantly enhanced long-term neuronal survival. Hence, optimal protection requi res both trophic support and relief from oxidative stress, These findi ngs lend credence to the potential use of dipyridamole or its derivati ves in prevention and/or treatment of CNS injuries and degenerative di sorders in which oxidative stress is a significant component.