Lee Chan, Jang Jung-Hee, Park Gyu Hwan
Department of Pharmacology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
Biomol Ther (Seoul). 2023 Jul 1;31(4):411-416. doi: 10.4062/biomolther.2022.132. Epub 2023 Feb 3.
Methamphetamine (METH) is a powerful neurotoxic psychostimulant affecting dopamine transporter (DAT) activity and leading to continuous excess extracellular dopamine levels. Despite recent advances in the knowledge on neurobiological mechanisms underlying METH abuse, there are few effective pharmacotherapies to prevent METH abuse leading to brain damage and neuropsychiatric deficits. α-Pinene (APN) is one of the major monoterpenes derived from pine essential oils and has diverse biological properties including anti-nociceptive, anti-anxiolytic, antioxidant, and anti-inflammatory actions. In the present study, we investigated the therapeutic potential of APN in a METH abuse mice model. METH (1 mg/kg/day, i.p.) was injected into C57BL/6 mice for four alternative days, and a conditioned place preference (CPP) test was performed. The METH-administered group exhibited increased sensitivity to place preference and significantly decreased levels of dopamine-related markers such as dopamine 2 receptor (D2R) and tyrosine hydroxylase in the striatum of the mice. Moreover, METH caused apoptotic cell death by induction of inflammation and oxidative stress. Conversely, APN treatment (3 and 10 mg/kg, i.p.) significantly reduced METH-mediated place preference and restored the levels of D2R and tyrosine hydroxylase in the striatum. APN increased the anti-apoptotic Bcl-2 to pro-apoptotic Bax ratio and decreased the expression of inflammatory protein Iba-1. METH-induced lipid peroxidation was effectively mitigated by APN by up-regulation of antioxidant enzymes such as manganese-superoxide dismutase and glutamylcysteine synthase via activation of nuclear factor-erythroid 2-related factor 2. These results suggest that APN may have protective potential and be considered as a promising therapeutic agent for METH-induced drug addiction and neuronal damage.
甲基苯丙胺（METH）是一种强效神经毒性精神兴奋剂，会影响多巴胺转运体（DAT）的活性，导致细胞外多巴胺水平持续过高。尽管最近在METH滥用背后的神经生物学机制方面的知识有所进展，但很少有有效的药物疗法来预防METH滥用导致的脑损伤和神经精神缺陷。α-蒎烯（APN）是从松树精油中提取的主要单萜之一，具有多种生物学特性，包括抗伤害感受、抗焦虑、抗氧化和抗炎作用。在本研究中，我们研究了APN在METH滥用小鼠模型中的治疗潜力。将METH（1毫克/千克/天，腹腔注射）注射到C57BL/6小鼠体内，每隔一天注射一次，共注射四天，然后进行条件性位置偏爱（CPP）测试。给予METH的组对位置偏爱的敏感性增加，并且小鼠纹状体中多巴胺相关标志物如多巴胺2受体（D2R）和酪氨酸羟化酶的水平显著降低。此外，METH通过诱导炎症和氧化应激导致凋亡性细胞死亡。相反，APN治疗（3和10毫克/千克，腹腔注射）显著降低了METH介导的位置偏爱，并恢复了纹状体中D2R和酪氨酸羟化酶的水平。APN增加了抗凋亡蛋白Bcl-2与促凋亡蛋白Bax的比例，并降低了炎症蛋白Iba-1的表达。APN通过激活核因子-红系2相关因子2上调抗氧化酶如锰超氧化物歧化酶和谷氨酰半胱氨酸合成酶，有效减轻了METH诱导的脂质过氧化。这些结果表明，APN可能具有保护潜力，可被视为治疗METH诱导的药物成瘾和神经元损伤的有前景的治疗剂。
