Ximenes José Christian Machado, Neves Kelly Rose Tavares, Leal Luzia Kalyne A M, do Carmo Marta Regina Santos, Brito Gerly Anne de Castro, Naffah-Mazzacoratti Maria da Graça, Cavalheiro Ésper Abrão, Viana Glauce Socorro de Barros
Faculty of Medicine Estácio of Juazeiro do Norte, Avenida Tenente Raimundo Rocha 515, 63048-080 Juazeiro do Norte, CE, Brazil.
Faculty of Medicine of the Federal University of Ceará, Rua Coronel Nunes de Melo 1127, 60430-270 Fortaleza, CE, Brazil.
J Neurodegener Dis. 2015;2015:313702. doi: 10.1155/2015/313702. Epub 2015 Feb 19.
Parkinson's disease is a neurodegenerative disorder where the main hallmark is the dopaminergic neuronal loss. Besides motor symptoms, PD also causes cognitive decline. Although current therapies focus on the restoration of dopamine levels in the striatum, prevention or disease-modifying therapies are urgently needed. Valproic acid (VA) is a wide spectrum antiepileptic drug, exerting many biochemical and physiological effects. It has been shown to inhibit histone deacetylase which seems to be associated with the drug neuroprotective action. The objectives were to study the neuroprotective properties of VA in a model of Parkinson's disease, consisting in the unilateral striatal injection of the neurotoxin 6-OHDA. For that, male Wistar rats (250 g) were divided into the groups: sham-operated (SO), untreated 6-OHDA-lesioned, and 6-OHDA-lesioned treated with VA (25 or 50 mg/kg). Oral treatments started 24 h after the stereotaxic surgery and continued daily for 2 weeks, when the animals were subjected to behavioral evaluations (apomorphine-induced rotations and open-field tests). Then, they were sacrificed and had their mesencephalon, striatum, and hippocampus dissected for neurochemical (DA and DOPAC determinations), histological (Fluoro-Jade staining), and immunohistochemistry evaluations (TH, OX-42, GFAP, TNF-alpha, and HDAC). The results showed that VA partly reversed behavioral and neurochemical alterations observed in the untreated 6-OHDA-lesioned rats. Besides, VA also decreased neuron degeneration in the striatum and reversed the TH depletion observed in the mesencephalon of the untreated 6-OHDA groups. This neurotoxin increased the OX-42 and GFAP immunoreactivities in the mesencephalon, indicating increased microglia and astrocyte reactivities, respectively, which were reversed by VA. In addition, the immunostainings for TNF-alpha and HDAC demonstrated in the untreated 6-OHDA-lesioned rats were also decreased after VA treatments. These results were observed not only in the CA1 and CA3 subfields of the hippocampus, but also in the temporal cortex. In conclusion, we showed that VA partly reversed the behavioral, neurochemical, histological, and immunohistochemical alterations observed in the untreated 6-OHDA-lesioned animals. These effects are probably related to the drug anti-inflammatory activity and strongly suggest that VA is a potential candidate to be included in translational studies for the treatment of neurodegenerative diseases as PD.
帕金森病是一种神经退行性疾病，其主要特征是多巴胺能神经元丧失。除运动症状外，帕金森病还会导致认知能力下降。尽管目前的治疗方法主要集中在恢复纹状体中的多巴胺水平，但迫切需要预防或改善疾病的治疗方法。丙戊酸（VA）是一种广谱抗癫痫药物，具有多种生化和生理作用。研究表明，它能抑制组蛋白脱乙酰酶，这似乎与该药物的神经保护作用有关。本研究的目的是在帕金森病模型中研究丙戊酸的神经保护特性，该模型通过单侧纹状体内注射神经毒素6-羟基多巴胺（6-OHDA）构建。为此，将雄性Wistar大鼠（250 g）分为以下几组：假手术组（SO）、未治疗的6-OHDA损伤组以及用丙戊酸（25或50 mg/kg）治疗的6-OHDA损伤组。立体定向手术后24小时开始口服给药，持续2周，之后对动物进行行为学评估（阿扑吗啡诱导的旋转试验和旷场试验）。然后，处死动物，解剖中脑、纹状体和海马进行神经化学分析（测定多巴胺和3,4-二羟基苯乙酸）、组织学分析（荧光金染色）和免疫组织化学评估（酪氨酸羟化酶、OX-42、胶质纤维酸性蛋白、肿瘤坏死因子-α和组蛋白脱乙酰酶）。结果表明，丙戊酸部分逆转了未治疗的6-OHDA损伤大鼠所观察到的行为和神经化学改变。此外，丙戊酸还减少了纹状体中的神经元变性，并逆转了未治疗的6-OHDA组中脑内观察到的酪氨酸羟化酶耗竭。这种神经毒素增加了中脑内OX-42和胶质纤维酸性蛋白的免疫反应性，分别表明小胶质细胞和星形胶质细胞反应性增加，而丙戊酸可使其逆转。此外，丙戊酸治疗后，未治疗的6-OHDA损伤大鼠中观察到的肿瘤坏死因子-α和组蛋白脱乙酰酶免疫染色也减少。这些结果不仅在海马的CA1和CA3亚区观察到，在颞叶皮质也观察到。总之，我们表明丙戊酸部分逆转了未治疗的6-OHDA损伤动物所观察到的行为、神经化学、组织学和免疫组织化学改变。这些作用可能与该药物的抗炎活性有关，并强烈表明丙戊酸是治疗帕金森病等神经退行性疾病转化研究中的一个潜在候选药物。
