Novel trajectories of the NK1R antagonist aprepitant in rotenone-induced Parkinsonism-like symptoms in rats: Involvement of ERK5/KLF4/p62/Nrf2 signaling axis

Regulation of the interplay between autophagy and oxidative stress is vital in maintaining neuronal homeostasis during neurotoxicity. The interesting involvement of NK1 receptor (NK1R) in neurodegeneration has highlighted the value of investigating the neuroprotective effect of aprepitant (Aprep), an NK1R antagonist in Parkinson's disease (PD). This study was conducted to disclose Aprep's ability to modulate extracellular signal-regulated kinase 5/Krüppel-like factor 4 (ERK5/KLF4) cue as molecular signaling implicated in regulating autophagy and redox signaling in response to rotenone neurotoxicity. Rotenone (1.5 mg/kg) was administered on alternate days, and rats were given Aprep simultaneously with or without PD98059, an ERK inhibitor, for 21 days. Aprep ameliorated motor deficits as verified by restored histological features, and intact neurons count in SN and striata along with tyrosine hydroxylase immunoreactivity in SN. The molecular signaling of Aprep was illustrated by the expression of KLF4 following the phosphorylation of its upstream target, ERK5. Nuclear factor erythroid 2-related factor 2 (Nrf2) was up-regulated, shifting the oxidant/antioxidant balance towards the antioxidant side, as evidenced by elevated GSH and suppressed MDA levels. In parallel, Aprep noticeably reduced phosphorylated α-synuclein aggregates due to autophagy induction as emphasized by marked LC3II/LC3I elevation and p62 level reduction. These effects were diminished upon PD98059 pre-administration. In conclusion, Aprep showed neuroprotective effects against rotenone-induced PD, which may be partially attributed to the activation of the ERK5/KLF4 signaling pathway. It modulated p62-mediated autophagy and Nrf2 axis which act cooperatively to counter rotenone-associated neurotoxicity pointing to Aprep's prospect as a curious candidate in PD research.