Novel HDAC inhibitors provide neuroprotection in MPTP-induced Parkinson's disease model of rats

Parkinson's Disease (PD) is the most rapidly growing neurological disorder globally in terms of disability and mortality. While symptomatic treatment is available for PD, there is a critical unmet need for effective disease-modifying therapies. Recently, histone deacetylase inhibitors (HDACi), an important class of epigenetic modulators grabbed significant attention as drug targets for neurodegenerative diseases including PD. In this regard, novel pan-HDACi, cinnamyl sulphonamide hydroxamate derivatives (NMJ-2 and NMJ-3), synthesized and characterized in our laboratory, were screened for neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rat model of PD. Twenty-four hours after the bilateral intranigral injection of MPTP, rats were administered orally with NMJ-2 or NMJ-3 (150 mg/kg) daily for 30 days. MPTP administration resulted in a marked rise in lipid peroxidation, and interleukin-1β concentration accompanied by reduced tyrosine hydroxylase and dopamine levels in the striatum compared to the sham group. These biochemical changes were associated with functional motor and non-motor deficits as revealed by loss of motor coordination (rota rod test), impaired grip strength (beam walk test), enhanced rigidity (catalepsy scores), loss of memory (novel object recognition test) and depressive-like behaviour (forced swim test). However, oral treatment with NMJ-2 or NMJ-3, or valproic acid for 30 days significantly attenuated the PD-induced adverse changes in motor and non-motor functions by ameliorating the oxidative stress as well as inflammation, and restoring the dopamine levels in the striatum comparable to the valproic acid group. These results suggest that targeting HDACi could be a rational therapeutic strategy for the development of disease-modifying therapies for PD.