Artemisinin Ameliorates the Neurotoxic Effect of 3-Nitropropionic Acid: A Possible Involvement of the...

Neurodegenerative disorders like Huntington's disease (HD) are a major threat to human health, with severe gait abnormalities and pathological changes (oxidative stress, neuroinflammation, and apoptosis) playing important roles in their development. The effects of artemisinin (ART) alone and in combination with the ERK antagonist PD98059 against 3-nitropropionic acid (3-NPA)-induced cell death and oxidative stress in SH-SY5Y cells were determined using the MTT and DCFH-DA assays, as well as RT-qPCR assays. In vivo, possible neuroprotective effects of ART (10, 20, and 40 mg/kg i.p.) against the neurotoxicity generated by 21-day 3-NPA (10 mg/kg i.p.) treatment was evaluated in rats by assessing behavioral parameters on days 1, 14, and 21. Further, various biochemical, inflammatory, apoptotic markers, histopathological changes, and protein expression were assessed using brain striatal samples. ART significantly mitigated the neurotoxic effect of 3-NPA in SH-SY5Y cells by regulating the mRNA expression of ERK, Bax, Bcl2, and cytochrome C. However, ART's neuroprotective activity was reduced in the presence of PD98059. Also, ART treatment for 21 days substantially alleviated the behavioral impairments associated with 3-NPA toxicity. It reduced the oxidative stress induced by 3-NPA, as evidenced by the lower levels of MDA, nitrite, and improved catalase, SOD activity, and GSH levels. ART treatment restored 3-NPA-induced histopathological alterations in the striatal area. ART effectively suppressed neuroinflammatory (IL-6) and apoptotic markers (caspase 3 and 9), increasing BDNF levels and restoring the p-ERK1/2, Nrf2, and HO-1 expression. ART could exert its neuroprotective effect via antioxidant, anti-inflammatory, and antiapoptotic properties with a possible involvement of the ERK/BDNF/Nrf2/HO-1 pathway.