Amelioration of cisplatin-induced neurodegenerative changes in rats and restoration of mitochondrial biogenesis by 6-bromoindirubin-3'-oxime: The implication of the GSK-3β/PGC1-α axis.

Background: The cognitive deficits observed after treatment with chemotherapeutic drugs are obvious clinical problems. For treating chemotherapy-induced cognitive deficits (CICD), the treatment modalities must target its underlying mechanisms. Specifically, cisplatin may activate glycogen synthase kinase-3β (GSK-3β), thereby enhancing neuronal apoptosis. 6-bromoindirubin-3'-oxime (6BIO) was not investigated previously in a model of CICD. Therefore, this investigation aimed to address the impacts of GSK3 inhibition on regulating cell signaling, which contributes to neurodegeneration and cognitive impairment.
Methods: Thirty adult male Wistar rats were randomly allocated into control groups, while two experimental groups were exposed to repeated cisplatin injections (2 mg/kg intraperitoneally (ip), twice weekly, nine injections), termed chemobrain groups. The rats in the two experimental groups were equally divided into the chemobrain group (untreated) and the chemobrain-6BIO group (treated with 6BIO at a dose of 8.5 μg/kg ip every two days, started after the last dose of cisplatin and continued for two weeks).
Results: Repeated exposure to cisplatin led to a marked decline in cognitive functions. GSK3 inhibition exerted neuroprotection by decreasing the expression of p-tau and amyloid β, thereby improving cognition. 6BIO, the GSK-3β inhibitor, restored mitochondrial biogenesis by augmenting the protein levels of PGC1-α and increasing the number of mitochondria in the cerebral cortex and hippocampus.
Conclusion: 6BIO provided neuroprotection and exhibited anti-apoptotic and anti-oxidative effects in a rat model of chemobrain.
Competing Interests: Declaration of Competing Interest All authors declare the absence of any conflict.
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