Exercise and oral melatonin attenuate anxiety and depression like behavior in type 2 diabetic rats

This study was performed to evaluate the therapeutic efficacy of exercise and oral melatonin on metabolic syndrome (MS), anxiety and depression-like behavior (ADB) in type 2 diabetes mellitus (T2DM) model in rat. Rats were allocated into five groups: non diabetes group, diabetes group, three treated group; diabetes rats disciplined with swimming exercise (40 min, 5 days per week) or oral melatonin (10 mg/kg bwt per day at 19.00 PM) alone or with combination. Exercise and oral melatonin significantly attenuated MS evidenced by improvement of hyperglycemia, insulin resistance, dyslipidemia, hyperleptinemia, and hypoadiponectinemia level in comparison with diabetes group. The ADB also markedly improved in exercise and oral melatonin treated rats as represented by decreased anxiety index, increased open arm entries and time spent in elevated plus maze, and reduced freezing behavior, increased entries and time spent in center in open field test. To know underlying molecular mechanisms, hippocampus tissue was analyzed. Interestingly, exercise combined with oral melatonin synergistically reduced serum corticosterone and hippocampus tissue level inflammatory cytokines and improved ATP level. Furthermore, this combination up-regulated the expression of brain-derived neurotrophic factor (BDNF), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and mitochondrial biogenesis related proteins, glucose transporter type 4 (GLUT4) in hippocampus tissue. Exercise and oral melatonin synergistically attenuated ADB in T2DM rats by attenuation of MS, neuroinflammation and normalizing corticosterone level via up-regulation of PGC-1α, mitochondrial biogenesis, BDNF, GLUT4, expression and ATP level. Thus, this treatment combination can be a promising tool in the management of MS, anxiety and depression in T2DM patients.