Effect of sex and gonadectomy on brain MPTP toxicity and response to dutasteride treatment in mice
Effect of sex and gonadectomy on brain MPTP toxicity and response to dutasteride treatment in mice
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DOI：
10.1016/j.neuropharm.2021.108784
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发表时间：
2021-11-01
影响因子：
4.7
通讯作者：
Di Paolo, Therese
中科院分区：
文献类型：
--
作者：
Isenbrandt, Amandine;Morissette, Marc;Di Paolo, Therese
帕金森病（PD）的主要神经病理特征是黑质（SN）多巴胺（DA）神经元的变性；男性PD患病率较高，提示性激素在神经保护中的作用。本研究在小鼠PD模型中寻求性激素对大脑的影响，并通过5 α -还原酶抑制剂度他雄胺调节类固醇代谢/合成，显示出对1-甲基-4-苯基-1,2,3,6四氢吡啶（MPTP）雄性小鼠的保护作用。分别对雄性和雌性小鼠进行性腺切除术（GDX）或SHAM手术。给药10天，分别给药5 mg/kg或杜他雄胺（5mg /kg），第5天给药低剂量MPTP （5.5 mg/kg）或生理盐水；之后采集了大脑。纹状体活性代谢物1-甲基-4-苯基吡啶（MPP+）含量无差异，支持实验条件的影响。在SHAM MPTP雄性小鼠中，杜他雄胺治疗可阻止纹状体DA及其代谢物、DA转运体（DAT）和囊泡单胺转运体2 （VMAT2）在纹状体和SN中的特异性结合的丧失；这些变化与胶质纤维酸性蛋白（GFAP，一种星形胶质细胞形成标志物）水平呈负相关。在SHAM雌性小鼠中，MPTP处理对纹状体和SN DA标记物以及GFAP水平的影响很小或没有影响，而GDX雄性和雌性小鼠纹状体DA标记物的损失和GFAP的增加相似。在GDX雄性和雌性小鼠中均未观察到杜他雄胺治疗的效果。总之，观察到小鼠MPTP毒性和对杜他雄胺反应的性别差异，在性腺切除术后神经炎症消失。
The main neuropathological feature of Parkinson's disease (PD) is degeneration of dopamine (DA) neurons in the substantia nigra (SN); PD prevalence is higher in men, suggesting a role of sex hormones in neuroprotection. This study sought the effects of sex hormones in the brain in a mouse model of PD and modulation of steroid metabolism/synthesis with the 5 alpha-reductase inhibitor dutasteride shown to protect 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) male mice. Male and female mice were gonadectomized (GDX) or SHAM operated. They were treated with vehicle or dutasteride (5 mg/kg) for 10 days and administered a low dose of MPTP (5.5 mg/kg) or saline on the 5th day to model early PD; brains were collected thereafter. Striatal measures of the active metabolite 1-methyl-4-phenylpyridinium (MPP+) contents showed no difference supporting an effect of the experimental conditions investigated. In SHAM MPTP male mice loss of striatal DA and metabolites, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding in the striatum and SN was prevented by dutasteride treatment; these changes were inversely correlated with glial fibrillary acidic protein (GFAP, an astrogliosis marker) levels. In SHAM female mice MPTP treatment had little or no effect on striatal and SN DA markers and GFAP levels whereas GDX male and female mice showed a similar loss of striatal DA markers and increase of GFAP. No effect of dutasteride treatment was observed in GDX male and female mice. In conclusion, sex differences in mice MPTP toxicity and response to dutasteride were observed that were lost upon gonadectomy implicating neuroinflammation.