Parkinson’s disease (PD) is a neurodegenerative disorder characterised by nigrostriatal dopaminergic (DA) neurodegeneration. There is a critical need for neuroprotective therapies, particularly those that do not require direct intracranial administration. Small molecule inhibitors of histone deacetylases (HDIs) are neuroprotective in in vitro and in vivo models of PD, however it is unknown whether Class IIa-specific HDIs are neuroprotective when administered peripherally. Here we show that 6-hydroxydopamine (6-OHDA) treatment induces protein kinase C (PKC)-dependent nuclear accumulation of the Class IIa histone deacetylase (HDAC)5 in SH-SY5Y cells and cultured DA neurons in vitro. Treatment of these cultures with the Class IIa-specific HDI, MC1568, partially protected against 6-OHDA-induced cell death. In the intrastriatal 6-OHDA lesion in vivo rat model of PD, MC1568 treatment (0.5 mg/kg i.p.) for 7 days reduced forelimb akinesia and partially protected DA neurons in the substantia nigra and their striatal terminals from 6-OHDA-induced neurodegeneration. MC1568 treatment prevented 6-OHDA-induced increases in microglial activation in the striatum and substantia nigra. Furthermore, MC1568 treatment decreased 6-OHDA-induced increases in nuclear HDAC5 in nigral DA neurons. These data suggest that peripheral administration of Class IIa-specific HDIs may be a potential therapy for neuroprotective in PD.

帕金森病 (PD) 是一种以黑质纹状体多巴胺能 (DA) 神经变性为特征的神经退行性疾病。迫切需要神经保护疗法，尤其是那些不需要直接颅内给药的疗法。组蛋白去乙酰化酶 (HDI) 的小分子抑制剂在PD的体外和体内模型中具有神经保护作用，但是当外周给药时，IIa 类特异性 HDIs 是否具有神经保护作用尚不清楚。在这里，我们显示 6-羟基多巴胺 (6-OHDA) 处理诱导 SH-SY5Y 细胞和体外培养的 DA 神经元中 IIa 类组蛋白脱乙酰酶 (HDAC)5 的蛋白激酶 C (PKC) 依赖性核积累. 用 IIa 类特异性 HDI MC1568 处理这些培养物，部分保护免受 6-OHDA 诱导的细胞死亡。在 PD 大鼠体内纹状体 6-OHDA 损伤模型中，MC1568 治疗（0.5 mg/kg ip）7 天减少了前肢运动障碍，并部分保护了黑质及其纹状体末端的 6-OHDA 诱导的神经变性中的 DA 神经元。MC1568 治疗可防止 6-OHDA 诱导的纹状体和黑质小胶质细胞活化增加。此外，MC1568 处理降低了 6-OHDA 诱导的黑质 DA 神经元中核 HDAC5 的增加。这些数据表明，IIa 类特异性 HDIs 的外周给药可能是 PD 神经保护的潜在疗法。