title: Valproic Acid Neuroprotection in the 6-OHDA Model of Parkinson's Disease Is Possibly Related to Its Anti-Inflammatory and HDAC Inhibitory Properties.
abstract: 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.
authors: Faculty of Medicine Estácio of Juazeiro do Norte, Avenida Tenente Raimundo Rocha 515, 63048-080 Juazeiro do Norte, CE, Brazil.
authors: José Christian Machado
authors: JC
authors: Ximenes
authors: Faculty of Medicine of the Federal University of Ceará, Rua Coronel Nunes de Melo 1127, 60430-270 Fortaleza, CE, Brazil.
authors: Kelly Rose Tavares
authors: KR
authors: Neves
authors: Faculty of Medicine of the Federal University of Ceará, Rua Coronel Nunes de Melo 1127, 60430-270 Fortaleza, CE, Brazil.
authors: Luzia Kalyne A M
authors: LK
authors: Leal
authors: Faculty of Medicine of the Federal University of Ceará, Rua Coronel Nunes de Melo 1127, 60430-270 Fortaleza, CE, Brazil.
authors: Marta Regina Santos
authors: MR
authors: do Carmo
authors: Faculty of Medicine of the Federal University of Ceará, Rua Coronel Nunes de Melo 1127, 60430-270 Fortaleza, CE, Brazil.
authors: Gerly Anne de Castro
authors: GA
authors: Brito
authors: School of Medicine of the Federal University of São Paulo, Rua Botucatu 862, 04023-900 São Paulo, SP, Brazil.
authors: Maria da Graça
authors: Mda G
authors: Naffah-Mazzacoratti
authors: School of Medicine of the Federal University of São Paulo, Rua Botucatu 862, 04023-900 São Paulo, SP, Brazil.
authors: Ésper Abrão
authors: ÉA
authors: Cavalheiro
authors: 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.
authors: Glauce Socorro de Barros
authors: GS
authors: Viana