Nerolidol Mitigates 3-Nitropropionic Acid-Induced Neurotoxicity: In Silico , In Vitro , and In Vivo Approach

Huntington’s disease (HD) is an inherited hyperkinetic movement disorder allied with chorea, cognitive impairment, and psychological disorders. Nerolidol (NRD) is a natural sesquiterpene alcohol obtained from many plants that has been shown to display neuroprotective properties. The current study focused on investigating the mechanism behind the neuroprotective role of NRD against 3-nitropropionic acid (3-NP)-induced neurotoxicity in experimental animals. Initial prediction was carried out through computational modeling ( in silico ), followed by a series of in vitro and in vivo experiments utilizing batteries of behavioral and molecular tests. Molecular docking was performed using Schrödinger (Maestro 2.0) to further explore NRD’s neuroprotective capacity against 3-NP-induced neurotoxicity in SH-SY5Y cell lines and rats. For the in vivo study, 24 adult Wistar rats were randomly divided into four different groups, while NRD (50 and 100 mg/kg) was chosen to study their neuroprotective impact against HD-like symptoms utilizing different behavioral, biochemical, and histopathological parameters. In silico studies demonstrated that NRD has a high binding affinity for active sites of targeted enzymes, while in vitro data showed that NRD can counteract the neurotoxic effects of 3-NP in SH-SY5Y cells. NRD therapy (50 and 100 mg/kg) significantly improved motor activity, levels of malondialdehyde and glutathione, and histopathological changes. The findings revealed that NRD offers antioxidant and neuroprotective effects against 3-NP-induced neurotoxicity. The observed results indicated that NRD may exert its effects by activating the Nrf2 and heme oxygenase-1 pathways. Thus, it is suggested that it may be employed as an alternative treatment to fight against neurotoxicity.