Histone deacetylase inhibitors as novel neuroprotective agents in in vitro and in vivo models of Parkinson’s disease
Histone deacetylases (HDAC) shift the balance towards chromatin condensation and silence gene expression. Aberrant recruitment of HDACs to alter transcription suggests the use of HDAC inhibitors (HDAC-Is) as potential therapeutic candidates for neurodegenerative disorders such as Parkinson’s disease (PD). Post mortem studies of PD, characterised by progressive loss of dopaminergic neurones in the substantia nigra, have linked α-synuclein toxicity and oxidative stress to the pathogenesis of the disorder. Interestingly HDAC-Is have been shown to prevent α-synuclein and 1-methyl-4-phenylpyridinium (MPP+)-induced cellular toxicity in vitro, but there is limited reports on the inhibition HDACs in in vitro and in vivo models of PD. For this reason, the effects of the HDAC-Is, suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA) were investigated in in vitro and in vivo models of PD. Neither inhibitors protected dopaminergic cell lines, SH-SY5Y and N1E-115, against hydrogen-peroxide (H2O2) and MPP+-induced toxicity. Except, at the highest concentrations (10-3M), where SAHA tended to decrease cell death. However, in the more complex rat ventral mesencephalic cultures, although HDAC-Is did not protect dopaminergic neurones against MPP+- or Lipopolysaccharide (LPS)-induced toxicity, interestingly, they reduced the number of astrocytes and activated microglia suggesting a positive anti-inflammatory effect. The effects of the HDAC-Is were then assessed in the 6-hydroxydopamine- and LPS-lesioned mouse models of PD. Both SAHA and VPA protected dopaminergic neurones and decreased the number of astrocytes in substantia nigra pars compacta (SNpc), although the number of active microglial cells were not reduced except at the highest dose of VPA. The results suggest that although the HDAC-Is, SAHA and VPA, are toxic to the immortalised dopaminergic cells in vitro, they protect nigral dopamine cells from toxin-induced cell loss in vivo. The reduction in astrocyte and microglia activation induced by the HDAC-Is suggest they may exert their protective effects by reducing inflammation associated with PD.
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