Beneficial Effects of Tofacitinib in Long-Standing Diabetes-Induced Cognitive Impairment in Rats through BDNF-TNF-α-Nrf2 Signalling Pathway

Suobing Fan and Rui Song

Background and Objective: Tofacitinib is a Janus kinase inhibitor and it improves memory in an experimental model of Alzheimer disease. It is hypothesized that tofacitinib may also prevent diabetes-induced cognitive decline. The study was aimed to investigate the beneficial effects of tofacitinib in diabetes-induced cognitive impairment and explore the signalling pathway involved in its beneficial effects. Materials and Methods: Diabetes was induced by a single injection of streptozotocin (60 mg kg^–1) and rats were kept for 10 weeks for the development of cognitive dysfunction. The comparison of escape latency time (ELT) of day 1 with ELT of day 4 on the Morris Water Maze test was made to measure learning, while the time spent in the target quadrant (TSTQ) on the 5th day assessed memory. Tofacitinib (15 and 30 mg kg^–1) was administered for the last fourteen days of the experimental protocol. The levels of Brain-Derived Neurotrophic Factor (BDNF), Nrf2, reduced glutathione and TNF-α were measured in the brain. The role of BDNF in tofacitinib-mediated effects was explored by co-administering ANA-12, a TrkB antagonist, along with tofacitinib. Results: Tofacitinib significantly attenuated the diabetes-induced increase in day 4 ELT and decrease in day 5 TSTQ suggesting the improvement in learning and memory. It also increased BDNF, reduced glutathione, Nrf2 and decreased TNF-α. Co-administration of ANA-12 abolished the effects of tofacitinib on memory and biochemical parameters suggesting that the effects of tofacitinib are mediated through BDNF. Conclusion: Tofacitinib may be effective in diabetes-induced cognitive dysfunction, which may involve the BDNF-TNF-α-Nrf2 signalling pathway.

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