Reinwardtia indica Dumort. protects against ponatinib-induced cerebral ischemia in adult zebrafish via attenuation of oxidative stress, neuroinflammation, mitochondrial dysfunction, and neurotransmitter dysregulation: A multi-target therapeutic strategy

Ethnopharmacological relevance: Reinwardtia indica Dumort. holds substantial importance in traditional medicine systems across Asian countries, particularly in India, Nepal, and China. The plant has been utilized in folk medicine for treating a wide range of ailments, treating neurological disorders, particularly paralysis; managing wound care and various skin conditions; providing pain relief for headaches and backaches; and aiding in gastrointestinal issues such as indigestion.

Aim of the study: This study investigated the potential neuroprotective effects of R. indica, a medicinal plant well recognized for its numerous ethnopharmacological uses, against cerebral ischemia-induced brain damage in adult zebrafish.

Material and methods: Zebrafish were subjected to a ponatinib-induced ischemic insult for 24 h and afterwards treated with the hydroalcoholic leaf extract of R. indica for 7 consecutive days. After treatment, zebrafish were evaluated for diverse biochemical parameters, including oxidative stress, neuroinflammatory markers, mitochondrial complexes, and neurotransmitter profiles, along with survival rate and brain damage analysis. Furthermore, several behavioural parameters, such as novel tank test, light and dark maze, and open field test, were also analysed to assess locomotive and cognitive impairments.

Results: The results demonstrated that R. indica post-treatment significantly attenuated oxidative stress, as evidenced by reduced levels of lipid peroxidation and increased antioxidant enzyme activity of SOD and catalase. Additionally, the extract restored mitochondrial function, as indicated by increased levels of mitochondrial complexes. Furthermore, R. indica treatment reduced neuroinflammation, characterized by decreased levels of inflammatory cytokines, i.e. TNF-α and IL-1β. Furthermore, R. indica effectively restored and normalized the level of key neurotransmitters such as glutamate, GABA, acetylcholine, serotonin, dopamine and noradrenaline, along with improvement in locomotion ability and reduced depressive-like behaviours as evident by various behavioural outcomes.

Conclusion: These findings suggest that R. indica may be a promising therapeutic candidate for mitigating the detrimental effects of cerebral ischemia by targeting behavioural alterations, oxidative stress, mitochondrial dysfunction, and neuroinflammation. However, further research is warranted to explore the potential clinical applications of R. indica in the treatment of stroke and Other ischemic brain injuries.

Cerebral ischemia; Mitochondrial dysfunction; Oxidative stress; Ponatinib-induced brain damage; Reinwardtia indica; Zebrafish; neuroinflammation.