Takeichi Toshiaki, Wang Elaine Lu, Kitamura Osamu
Department of Legal Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada-Machi, Kahoku-Gun, Ishikawa, Japan.
Leg Med (Tokyo). 2012 Mar;14(2):69-77. doi: 10.1016/j.legalmed.2011.12.004. Epub 2012 Jan 31.
Methamphetamine (METH) neurotoxicity is involved in METH-related deaths. It has been suggested that the midbrain, together with the striatum, is affected by METH neurotoxicity and the endoplasmic reticulum (ER) stress is induced in the processes of METH neurotoxicity. In this study, we examined the effects of low-dose METH administration for 5d on GRP78 and C/EBP homologous protein (CHOP), both of which are induced under ER stress, and METH neurotoxicity in the rat midbrain. We showed that 1mg/kg of METH induced an increase in GRP78 protein and mRNA expression 1d after the last injection, but had no effect on the levels of CHOP, tyrosine hydroxylase (TH), or GFAP. Secondly, we evaluated the induction of ER stress and the extent of METH neurotoxicity in the midbrain of animals pretreated with METH. In animals pretreated with saline, we observed elevated CHOP levels, together with decreased TH levels and increased GFAP levels, indicative of METH neurotoxicity, after neurotoxic METH administration, while there was no significant change in GRP78 levels. In contrast, low-dose METH (1.0mg/kg) pretreatment increased GRP78 levels and inhibited the induction of CHOP in the midbrain without METH neurotoxicity. These findings of ER stress in animals pretreated with METH were associated with an early increase in SOD1 levels and upregulation of Bcl-2. Therefore, our study suggests that pretreatment with low-dose METH may be protective against METH neurotoxicity in the midbrain, leading to the suppression of oxidative stress and apoptotic mechanisms, in part via ER stress-related pathways. Because chronic human METH abusers administrate low-dose METH repeatedly over an extended period before lethal injection, investigation of the pathophysiology of METH neurotoxicity in animals pretreated with low-dose METH might provide useful information on the pathophysiology of chronic and/or lethal METH use in cases of METH-related deaths.
甲基苯丙胺（METH）神经毒性与METH相关死亡有关。有人提出，中脑与纹状体一起受到METH神经毒性的影响，并且在内质网（ER）应激过程中会诱导METH神经毒性。在本研究中，我们研究了连续5天给予低剂量METH对GRP78和C/EBP同源蛋白（CHOP）的影响，这两种蛋白均在ER应激下被诱导，同时研究了其对大鼠中脑METH神经毒性的影响。我们发现，1mg/kg的METH在最后一次注射后1天诱导GRP78蛋白和mRNA表达增加，但对CHOP、酪氨酸羟化酶（TH）或胶质纤维酸性蛋白（GFAP）水平没有影响。其次，我们评估了用METH预处理的动物中脑ER应激的诱导情况以及METH神经毒性的程度。在用生理盐水预处理的动物中，在给予神经毒性METH后，我们观察到CHOP水平升高，同时TH水平降低和GFAP水平升高，这表明存在METH神经毒性，而GRP78水平没有显著变化。相比之下，低剂量METH（1.0mg/kg）预处理可增加中脑GRP78水平并抑制CHOP的诱导，且不存在METH神经毒性。在用METH预处理的动物中，这些ER应激的发现与SOD1水平的早期升高和Bcl-2的上调有关。因此，我们的研究表明，低剂量METH预处理可能对中脑的METH神经毒性具有保护作用，部分通过与ER应激相关的途径导致氧化应激和凋亡机制的抑制。由于慢性人类METH滥用者在致命注射前很长一段时间内反复给予低剂量METH，研究用低剂量METH预处理的动物中METH神经毒性的病理生理学可能为METH相关死亡病例中慢性和/或致命性METH使用的病理生理学提供有用信息。
