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 pathogenesis of Alzheimer's disease. However, approaches aimed at preventing A beta toxicity and neurofibrillary degeneration are undeveloped. We now report that anticonvulsants (carbamazepine, phenytoin, and valproic acid) can protect cultured rat hippocampal neurons against A beta- and glutamate-induced injury. Each of the anticonvulsants attenuated the elevation of intracellular free calcium levels [(Ca2+)(i)] elicited by A beta or glutamate suggesting that their neuroprotective mechanism of action involved stabilization of [Ca2+](i). These compounds were effective at clinically relevant concentrations (carbamazepine, 100 nM-10 mu M; phenytoin, 100 nM-1 mu M; valproic acid, 100 nM-100 mu M). The anticonvulsants suppressed glutamate-induced alterations in tau and ubiquitin immunoreactivities. Compounds that stabilize [Ca2+](i) may afford protection against the kinds of insults believed to underlie neuronal injury in Alzheimer's disease.