Valproic acid attenuates manganese-induced reduction in expression of GLT-1 and GLAST with concomitant changes in murine dopaminergic neurotoxicity

Neurotoxicology
James JohnsonEunsook Lee

Abstract

Exposure to elevated levels of manganese (Mn) causes manganism, a neurological disorder with similar characteristics to those of Parkinson's disease (PD). Valproic acid (VPA), an antiepileptic, is known to inhibit histone deacetylases and exert neuroprotective effects in many experimental models of neurological disorders. In the present study, we investigated if VPA attenuated Mn-induced dopaminergic neurotoxicity and the possible mechanisms involved in VPA's neuroprotection, focusing on modulation of astrocytic glutamate transporters (glutamate aspartate transporter, GLAST and glutamate transporter 1, GLT-1) and histone acetylation in H4 astrocyte culture and mouse models. The results showed that VPA increased promoter activity, mRNA/protein levels of GLAST/GLT-1 and glutamate uptake, and reversed Mn-reduced GLAST/GLT-1 in in vitro astrocyte cultures. VPA also attenuated Mn-induced reduction of GLAST and GLT-1 mRNA/protein levels in midbrain and striatal regions of the mouse brain when VPA (200 mg/kg, i.p., daily, 21 d) was administered 30 min prior to Mn exposure (30 mg/kg, intranasal instillation, daily, 21 d). Importantly, VPA attenuated Mn-induced dopaminergic neuronal damage by reversing Mn-induced decrease of tyrosine hy...Continue Reading

Citations

Jan 11, 2020·Frontiers in Pharmacology·Mohammad Afaque Alam, Prasun K Datta
Dec 16, 2019·Biological Trace Element Research·Zhao-Cong LiYue-Ming Jiang
Oct 3, 2020·International Journal of Molecular Sciences·Rui WangHaigang Ren
Dec 17, 2020·Frontiers in Neuroscience·Ji WangShaogang Qu
Dec 17, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ivan Nyarko-DanquahEunsook Lee
Jul 28, 2020·Journal of Trace Elements in Medicine and Biology : Organ of the Society for Minerals and Trace Elements (GMS)·Susana Rivera-MancíaSergio Montes
May 1, 2021·International Journal of Molecular Sciences·Alexey A TinkovMichael Aschner
May 16, 2021·Neuropharmacology·Ada G Rodríguez-Campuzano, Arturo Ortega

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