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.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, primarily characterized by bradykinesia, rigidity, resting tremor, and postural instability.These motor signs are mainly due to progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc)
The results showed that the untreated 6-OHDA-lesioned group presented an average of 207.2 contralateral rotations per hour, as related to the SO group which presented almost no behavioral alteration after the apomorphine administration
The number of crossings per 5 min was reduced by 25% and unexpectedly by 60% in the untreated 6-OHDA-lesioned group and in the 6-OHDA-lesioned group treated with Valproic acid (VA) at the lower dose (25 mg/kg), respectively, as related to the SO group (Figure 2(a))
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, primarily characterized by bradykinesia, rigidity, resting tremor, and postural instability. These motor signs are mainly due to progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). PD is associated with nonmotor features such as cognitive deficits, emotional. Long-term treatment with L-DOPA commonly leads to progressive loss of efficacy, the development of dyskinesias, and nonmotor manifestations [4,5,6]. Effective management of PD can minimize disability and potentially improve long-term outcomes which would decrease health care costs [8]
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