Neuroprotective effects of granulocyte colony-stimulating factor against tramadol-induced cerebellar neurotoxicity

Tramadol (TRM) is a centrally acting synthetic opioid and serotonin/norepinephrine reuptake inhibitor. Despite being a potent painkiller, long-term use can induce permanent neurotoxicity. Granulocyte colony-stimulating factor (G-CSF) is a cytokine that helps to mobilize stem cells and facilitate their integration over injured neurons.

This work aims to study the histopathological, biochemical, and molecular alterations in the cerebellar cortex induced by TRM in comparison to the postulated protective effect of G-CSF versus TRM withdrawal.

32 adult male albino rats were equally divided into four groups: control, TRM, TRM+G-CSF-treated, and TRM withdrawal groups. The TRM group received a daily dose of 80 mg/kg body weight orally via gastric tube for 12 weeks. The TRM+G-CSF-treated group received subcutaneous injections of 100 μg/kg body weight of G-CSF for seven consecutive days, then TRM from the 8th day. The TRM withdrawal group received TRM for 12 weeks; then, the rats were left without TRM administration for a further 12 weeks. The structural, biochemical, and molecular changes of the cerebellum were measured.

The study revealed that TRM not only induced cerebellar atrophy but also triggered microgliosis, neuroinflammation, and apoptotic indicators, all while suppressing autophagy. However, G-CSF and TRM withdrawal reversed these alterations with superiority to G-CSF.

The current investigation shows that G-CSF may improve behavioral, neurochemical, immunohistochemical, and molecular metrics in the rat cerebellum after tramadol-induced injury. G-CSF exhibits a superior protective effect compared to tramadol withdrawal. This is achieved through its antioxidant, anti-apoptotic, and autophagic enhancement properties, as well as its ability to reduce cerebellar gliosis.