Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain
Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain
复制标题
DOI：
10.1016/j.neurobiolaging.2006.10.020
复制
发表时间：
2008-02-01
影响因子：
4.2
通讯作者：
Olney, John W.
中科院分区：
文献类型：
--
作者：
Creeley, Catherine E.;Wozniak, David F.;Olney, John W.
NMDA拮抗剂美金刚（memantine，NH 4a）和胆碱酯酶抑制剂多奈哌齐（donepezil，Aricept）目前被广泛地单独或联合用于治疗阿尔茨海默病（Alzheimer's disease，AD）。NMDA拮抗剂具有神经保护和神经毒性特性;后者通过增加胆碱能活性的药物如毛果芸香碱增强。是否多奈哌齐，通过增加胆碱能活性，可能会增加美金刚的神经毒性潜力还没有调查。在本研究中，我们确定美金刚（20 mg/kg，i. p.），被认为在大鼠的治疗（神经保护）范围内，在成年大鼠大脑中引起轻度神经毒性反应。美金刚（20或30 mg/kg）与多奈哌齐（2.5-10 mg/kg）的联合给药显著增强了这种神经毒性反应，在较低剂量的美金刚时引起神经元损伤，并导致毒性反应扩散并对许多脑区的神经元致死。这些发现提出了关于在AD中使用这种药物组合的问题，特别是在没有证据表明这种组合是有益的，或者药物可以阻止或逆转疾病过程的情况下。(C)2006年爱思唯尔公司All rights reserved.
The NMDA antagonist, memantine (Namenda), and the cholinesterase, inhibitor, donepezil (Aricept), are currently being used widely, either individually or in combination, for treatment of Alzheimer's disease (AD). NMDA antagonists have both neuroprotective and neurotoxic properties; the latter is augmented by drugs, such as pilocarpine, that increase cholinergic activity. Whether donepezil, by increasing cholinergic activity, might augment memantine's neurotoxic potential has not been investigated. In the present study, we determined that a dose of memantine (20 mg/kg, i.p.), considered to be in the therapeutic (neuroprotective) range for rats, causes a mild neurotoxic reaction in the adult rat brain. Co-administration of memantine (20 or 30 mg/kg) with donepezil (2.5-10 mg/kg) markedly potentiated this neurotoxic reaction, causing neuronal injury at lower doses of memantine, and causing the toxic reaction to become disseminated and lethal to neurons throughout many brain regions. These findings raise questions about using this drug combination in AD, especially in the absence of evidence that the combination is beneficial, or that either drug arrests or reverses the disease process. (C) 2006 Elsevier Inc. All rights reserved.