Mark R J, Ashford J W, Goodman Y, Mattson M P
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536, USA.
Neurobiol Aging. 1995 Mar-Apr;16(2):187-98. doi: 10.1016/0197-4580(94)00150-2.
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 microM; phenytoin, 100 nM-1 microM; valproic acid, 100 nM-100 microM). The anticonvulsants suppressed glutamate-induced alterations in tau and buiquitin immunoreactivities. Compounds that stabilize [Ca2+]i may afford protection against the kinds of insults believed to underlie neuronal injury in Alzheimer's disease.
越来越多的证据支持β-淀粉样肽（Aβ）的参与以及神经元损伤的兴奋性毒性机制在阿尔茨海默病发病机制中的作用。然而，旨在预防Aβ毒性和神经原纤维变性的方法尚未得到开发。我们现在报告，抗惊厥药（卡马西平、苯妥英和丙戊酸）可以保护培养的大鼠海马神经元免受Aβ和谷氨酸诱导的损伤。每种抗惊厥药都减弱了由Aβ或谷氨酸引起的细胞内游离钙水平[（Ca2+）i]的升高，这表明它们的神经保护作用机制涉及[Ca2+]i的稳定。这些化合物在临床相关浓度下有效（卡马西平，100 nM - 10 μM；苯妥英，100 nM - 1 μM；丙戊酸，100 nM - 100 μM）。抗惊厥药抑制了谷氨酸诱导的tau和泛素免疫反应性的改变。稳定[Ca2+]i的化合物可能为预防被认为是阿尔茨海默病神经元损伤基础的各种损伤提供保护。
