ANTICONVULSANTS ATTENUATE AMYLOID BETA-PEPTIDE NEUROTOXICITY, CA2+ DEREGULATION, AND CYTOSKELETAL PATHOLOGY

Increasing evidence supports the involvement of amyloid beta-peptide ( A beta) and an excitotoxic mechanism of neuronal injury in the pathoge nesis of Alzheimer's disease. However, approaches aimed at preventing A beta toxicity and neurofibrillary degeneration are undeveloped. We n ow report that anticonvulsants (carbamazepine, phenytoin, and valproic acid) can protect cultured rat hippocampal neurons against A beta- an d glutamate-induced injury. Each of the anticonvulsants attenuated the elevation of intracellular free calcium levels [(Ca2+)(i)] elicited b y A beta or glutamate suggesting that their neuroprotective mechanism of action involved stabilization of [Ca2+](i). These compounds were ef fective at clinically relevant concentrations (carbamazepine, 100 nM-1 0 mu M; phenytoin, 100 nM-1 mu M; valproic acid, 100 nM-100 mu M). The anticonvulsants suppressed glutamate-induced alterations in tau and u biquitin immunoreactivities. Compounds that stabilize [Ca2+](i) may af ford protection against the kinds of insults believed to underlie neur onal injury in Alzheimer's disease.