Valsartan promotes neuroprotection in Parkinson's disease via epigenetic modulation and activation of the ASCL1/Nurr1 pathway.

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by degeneration of dopaminergic neurons and associated motor impairments. Current pharmacotherapies only offer symptomatic relief hampered by multiple adverse effects. Herein, pharmacologic, molecular and histopathologic studies were employed to determine whether valsartan (VAL) has functional neurorestorative potential in PD male rat model induced by intraperitoneal (IP) injection of haloperidol (HALO) (1.5 mg/kg/day, for 42 days). Administration of VAL (40 mg/kg PO) for 21 days markedly improved motor functions as revealed by i) reduced muscle rigidity in catalepsy bar test, ii) increase in performance in rotarod and beam walking tests, iii) increased total distance travelled, grooming duration, rearing duration, and maximum speed in open field test. Western blot analysis revealed that VAL restored the markers of dopaminergic neuronal degeneration as indicated by increased protein expression of dopaminergic-specific transcription factors (Nurr1, ASCL1) and mRNA expression of Nurr1 regulatory proteins (PIN1, CoREST), the dopamine (DA) neurons detoxifier ALDH1A1, and markers for dopaminergic transmission (D2 receptor, tyrosine hydroxylase (TH), DA transporter (DAT). Histopathological analyses confirmed neuronal integrity in the substantia nigra (SN). Furthermore, VAL exerted epigenetic modulation by downregulating histone deacetylases HDAC1/5 and upregulating sirtuin 1 (SIRT1), decreased α-synuclein (α-syn) and restored ApoA1. Co-administration of Nurr1 inhibitor meloxicam (MLX; 3 mg/Kg/day PO) significantly attenuated VAL's neuroprotective effects, confirming Nurr1's central role, but did not fully reverse its epigenetic actions. In conclusion, VAL demonstrated potent neuroprotective, restorative of neuronal function, and epigenetic modulatory effects in PD, highlighting its promising role as a novel disease-modifying therapeutic candidate and warranting further investigation.