Possible role of propofol's cyclooxygenase-inhibiting property in alleviating dopaminergic neuronal loss in the substantia nigra in an MPTP-induced murine model of Parkinson's disease
Possible role of propofol's cyclooxygenase-inhibiting property in alleviating dopaminergic neuronal loss in the substantia nigra in an MPTP-induced murine model of Parkinson's disease
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DOI：
10.1016/j.brainres.2011.02.079
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发表时间：
2011-04
期刊：
影响因子：
2.9
通讯作者：
Kozue Kubo;T. Inada;K. Shingu
中科院分区：
文献类型：
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作者：
Kozue Kubo;T. Inada;K. Shingu
异丙酚是一种静脉麻醉药，广泛用于镇静和全身麻醉。我们研究了异丙酚对激活的小胶质细胞产生前列腺素的影响。从新生C57 BL/6小鼠的脑获得原代小胶质细胞培养物。在丙泊酚存在下用脂多糖（LPS）刺激小胶质细胞。异丙酚抑制LPS诱导的前列腺素E2和血栓素B2的产生。异丙酚对环氧化酶（考克斯）蛋白表达和花生四烯酸释放无影响，但对考克斯酶活性有明显抑制作用。用纯化的酶也观察到COX抑制活性，其中考克斯-2抑制显著大于考克斯-1抑制。接下来，我们研究了丙泊酚的COX抑制活性是否在帕金森病的1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）小鼠模型中导致多巴胺能神经保护，其中考克斯抑制剂，如非甾体抗炎药，被报道为具有神经保护作用。C57 BL/6小鼠腹腔注射MPTP后，观察其黑质多巴胺能神经元酪氨酸羟化酶阳性细胞的变化。MPTP处理显著减少了SNPC中多巴胺能神经元的数量，而用丙泊酚或选择性考克斯-2抑制剂NS-398处理后，MPTP诱导的神经元损失最小。这些结果表明，异丙酚可能是有益的，在减轻MPTP诱导的多巴胺能神经元，可能通过其COX抑制活性。
Propofol is an intravenous anesthetic widely used for sedation and general anesthesia. We investigated the effect of propofol on prostanoid production by activated microglia. Primary microglial culture was obtained from the brains of neonatal C57BL/6 mice. The microglia were stimulated with lipopolysaccharide (LPS) in the presence of propofol. Propofol suppressed the LPS-induced production of prostaglandin E2and thromboxane B2. Cyclooxygenase (COX) protein expression and arachidonic acid release were not affected by propofol, while COX enzyme activity was significantly inhibited by propofol. The COX-inhibiting activity was also observed with purified enzymes, with COX-2 inhibition being significantly greater than COX-1 inhibition. Next, we studied whether the COX-inhibiting activity of propofol resulted in dopaminergic neuroprotection in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease, in which COX inhibitors, such as non-steroidal anti-inflammatory drugs, are reported to be neuroprotective. C57BL/6 mice received intraperitoneal injections of MPTP with or without propofol treatment, and the dopaminergic neurons in the substantia nigra pars compacta (SNpc) were examined immunohistochemically by observing the tyrosine hydroxylase-positive cells. The number of dopaminergic neurons in the SNpc was significantly reduced by MPTP treatment, while the MPTP-induced neuronal loss was minimal upon treatment with propofol or the selective COX-2 inhibitor, NS-398. These results indicate that propofol might be beneficial in mitigating MPTP-induced dopaminergic neurons, possibly via its COX-inhibiting activity.