Glutamate Carboxypeptidase Inhibition Reduces the Severity of Chemotherapy-Induced Peripheral Neurotoxicity in Rat
Glutamate Carboxypeptidase Inhibition Reduces the Severity of Chemotherapy-Induced Peripheral Neurotoxicity in Rat
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DOI：
10.1007/s12640-009-9114-1
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发表时间：
2010-05-01
影响因子：
3.7
通讯作者：
Cavaletti, Guido
中科院分区：
文献类型：
--
作者：
Carozzi, Valentina A.;Chiorazzi, Alessia;Cavaletti, Guido
化疗是治疗癌症最常用的方法。然而，某些抗肿瘤药物的使用与周围神经病变的发展有关，这可能是剂量限制的。兴奋性毒性谷氨酸释放，导致过度的谷氨酸能神经传递和n -甲基- d -天冬氨酸（NMDA）受体的激活，与几种神经系统疾病中的神经元损伤和死亡有关。n -乙酰-天冬氨酸谷氨酸（NAAG）是一种丰富的神经肽，广泛分布于中枢和周围神经系统，经谷氨酸羧肽酶生理水解成n -乙酰-天冬氨酸（NAA）和谷氨酸。谷氨酸羧肽酶的药理抑制导致谷氨酸减少和内源性NAAG增加，并在几个临床前模型中显示出神经保护作用。在这里，我们报告了口服谷氨酸羧肽酶抑制剂对三种成熟的化疗动物模型（顺铂、紫杉醇、硼替佐米）诱导的周围神经病变的神经保护作用。在所有病例中，谷氨酸羧肽酶抑制显著改善化疗诱导的神经传导速度缺陷。此外，顺铂和硼替佐米可通过抑制谷氨酸羧肽酶改善背根神经节（DRG）的形态学和形态计量学改变。我们的数据支持一种治疗化疗引起的周围神经病变的新方法。
Chemotherapy is the most common method to treat cancer. The use of certain antineoplastic drugs, however, is associated with the development of peripheral neuropathy that can be dose-limiting. Excitotoxic glutamate release, leading to excessive glutamatergic neurotransmission and activation of N-methyl-D-aspartate (NMDA) receptors, is associated with neuronal damage and death in several nervous system disorders. N-Acetyl-aspartyl-glutamate (NAAG) is an abundant neuropeptide widely distributed in the central and peripheral nervous system which is physiologically hydrolyzed by the enzyme glutamate carboxypeptidase into N-Acetyl-aspartyl (NAA) and glutamate. Pharmacological inhibition of glutamate carboxypeptidase results in decreased glutamate and increased endogenous NAAG and has been shown to provide neuroprotection in several preclinical models. Here, we report the neuroprotective effect of an orally available glutamate carboxypeptidase inhibitor on three well-established animal models of chemotherapy (cisplatin, paclitaxel, bortezomib)-induced peripheral neuropathy. In all cases, glutamate carboxypeptidase inhibition significantly improved the chemotherapy-induced nerve conduction velocity deficits. In addition, morphological and morphometrical alterations induced by cisplatin and bortezomib in dorsal root ganglia (DRG) were improved by glutamate carboxypeptidase inhibition. Our data support a novel approach for the treatment of chemotherapy-induced peripheral neuropathy.