Brain levels of the neurotoxic pyridinium metabolite HPP+ and extrapyramidal symptoms in haloperidol-treated mice.
Brain levels of the neurotoxic pyridinium metabolite HPP+ and extrapyramidal symptoms in haloperidol-treated mice.
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DOI：
10.1016/j.neuro.2013.09.005
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发表时间：
2013-12
期刊：
影响因子：
3.4
通讯作者：
Sullivan, Patrick F.
中科院分区：
文献类型：
--
作者：
Crowley, James J.;Ashraf-Khorassani, Mehdi;Castagnoli, Neal, Jr.;Sullivan, Patrick F.
典型的抗精神病药氟哌啶醇是一种非常有效的治疗精神分裂症的药物，但它的使用受到一些严重的、通常是不可逆的运动副作用的限制。这些药物不良反应被称为锥体外系综合征（EPS），是由一种未知的病理生理机制引起的。一种理论与氟哌啶醇代谢物HPP+（4-（4-氯苯基）-1-[4-（4-氟苯基）-4-氧丁基]-吡啶）在结构上与MPP+（1-甲基-4-苯基吡啶）相似，MPP+（1-甲基-4-苯基吡啶）是一种神经毒素，可导致类似帕金森病的不可逆神经退行性疾病。为了确定HPP+是否有助于氟哌啶醇诱导的EPS，我们测量了慢性治疗后对氟哌啶醇诱导EPS的高（C57BL/6J和NZO/HILtJ）和低（BALB/cByJ和PWK/PhJ）小鼠品系（每个品系7-10只成年雄性小鼠）脑HPP+和氟哌啶醇水平。氟哌啶醇敏感组和氟哌啶醇耐药组脑HPP+水平及HPP+与氟哌啶醇之比无显著差异（P = 0.50）。各组间差异显著（P < 0.01），表明存在调控HPP+稳态水平的遗传变异。由于我们在小鼠大脑中观察到的HPP+水平与慢性氟哌啶醇治疗后死后人类大脑中检测到的HPP+水平重叠，因此本研究的结果与人类具有生理学相关性。结果表明，稳态HPP+水平的品系差异并不能解释我们研究的小鼠对氟哌啶醇诱导的EPS的敏感性。
The typical antipsychotic haloperidol is a highly effective treatment for schizophrenia but its use is limited by a number of serious, and often irreversible, motor side effects. These adverse drug reactions, termed extrapyramidal syndromes (EPS), result from an unknown pathophysiological mechanism. One theory relates to the observation that the haloperidol metabolite HPP+ (4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium) is structurally similar to MPP+ (1-methyl-4-phenylpyridinium), a neurotoxin responsible for an irreversible neurodegenerative condition similar to Parkinson's disease. To determine whether HPP+ contributes to haloperidol-induced EPS, we measured brain HPP+ and haloperidol levels in strains of mice at high (C57BL/6J and NZO/HILtJ) and low (BALB/cByJ and PWK/PhJ) liability to haloperidol-induced EPS following chronic treatment (7–10 adult male mice per strain). Brain levels of HPP+ and the ratio of HPP+ to haloperidol were not significantly different between the haloperidol-sensitive and haloperidol-resistant strain groups (P = 0.50). Within each group, however, strain differences were seen (P < 0.01), indicating that genetic variation regulating steady-state HPP+ levels exists. Since the HPP+ levels that we observed in mouse brain overlap the range of those detected in post-mortem human brains following chronic haloperidol treatment, the findings from this study are physiologically relevant to humans. The results suggest that strain differences in steady-state HPP+ levels do not explain sensitivity to haloperidol-induced EPS in the mice we studied.
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影响因子：
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作者：
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通讯作者：
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