Teriflunomide mitigates pain-depression dyad in mice: Modulation of PI3K-mediated defensive signaling

The pain-depression dyad refers to a complex and often bidirectional relationship between physical pain and depression. It suggests that these two experiences can interact and exacerbate each other, leading to a cycle of worsening symptoms. Both pain and depression involve changes in brain chemistry and neural pathways. The phosphoinositide 3-kinase (PI3K) signaling pathway often contributes to mood stabilization and in alleviating pain. Teriflunomide is an active metabolite of leflunomide that positively impacts brain functioning. Thus, the current study was designed to investigate the potential of teriflunomide against reserpine-induced paindepression dyad and also examined the role of PI3K in the observed effect of teriflunomide. Reserpine (0.5 mg/ Kg; i.p) treatment for 3 consecutive days signiflcantly induced the pain-depression dyad along with memory impairment in mice. Administration of reserpine signiflcantly reduced the brain glutathione (GSH) level, uplifting the brain thiobarbituric acid reactive substance (TBARS) and serum tumor necrosis factor-alpha (TNF-alpha) level. Teriflunomide (10 and 20 mg/Kg) treatment signiflcantly reverted the depressive, pain-inducing and memory-impairing effect of reserpine. Both doses of teriflunomide signiflcantly uplifted the brain GSH level and downregulated the serum TNF-alpha level. Whereas, only a 20 mg/Kg dose of teriflunomide signiflcantly reduced the brain TBARS level. Furthermore, the PI3K inhibitor (LY294002) treatment signiflcantly alleviated the antidepressant, anti-nociceptive and memory-improving effect of teriflunomide (20 mg/Kg). LY294002 treatment also reverted the teriflunomide-induced biochemical modulations (20 mg/Kg). LY294002 signiflcantly reduced the brain GSH and uplifted the level of TBARS and serum TNF-alpha level. Conclusively, the results of the current study delineate that teriflunomide might exert its anti-depressant, anti-nociceptive and memory-improving effect by stimulating the PI3K-mediated protection against oxidative and inflammatory stress.