Glibenclamide treatment prevents depressive-like behavior and memory impairment induced by chronic unpredictable stress in female mice.

Glibenclamide is a second-generation sulfonylurea used in the treatment of Type 2 Diabetes Mellitus. The primary target of glibenclamide is ATP-sensitive potassium channels inhibition; however, other possible targets include the control of inflammation and blood-brain barrier permeability, which makes this compound potentially interesting for the management of brain-related disorders. Here, we showed that systemic treatment with glibenclamide (5 mg/kg, p.o., for 21 days) could prevent the behavioral despair and the cognitive dysfunction induced by chronic unpredictable stress (CUS) in mice. In nonhypoglycemic doses, glibenclamide attenuated the stress-induced weight loss, decreased adrenal weight, and prevented the increase in glucocorticoid receptors in the prefrontal cortex, suggesting an impact in hypothalamic-pituitary-adrenal (HPA) axis function. Additionally, we did not observe changes in Iba-1, NLRP3 and caspase-1 levels in the prefrontal cortex or hippocampus after CUS or glibenclamide treatment. Thus, this study suggests that chronic treatment with glibenclamide prevents the emotional and cognitive effects of chronic stress in female mice. On the other hand, the control of neuroinflammation and NLRP3 inflammasome pathway is not the major mechanism mediating these effects. The behavioral effects might be mediated, in part, by the normalization of glucocorticoid receptors and HPA axis.

Involvement of PI3K/Akt/GSK-3ß signaling pathway in the antidepressant-like and neuroprotective effects of Morus nigra and its major phenolic, syringic acid.

Depression is a common neuropsychiatric disorder whose pathophysiology has been associated with glutamatergic excitotoxicity. Thus, the research for new antidepressant strategies with the ability to mitigate glutamate toxicity has received growing attention. Given this background, the present study sought to investigate the antidepressant-like and neuroprotective effects of Morus nigra (MN) and its major phenolic, syringic acid (SA), against glutamate-induced damage, as well as, the role of the PI3K/Akt/GSK-3ß signaling pathway in these effects. Treatment with MN (3 mg/kg) and SA (1 mg/kg) for 7 days, similar to fluoxetine (10 mg/kg), triggered an antidepressant-like effect. Moreover, the treatments evoked neuroprotection against glutamatergic excitotoxicity in hippocampal slices, and MN treatment also afforded protection in cerebrocortical slices. Notably, ex vivo neuroprotective effect of MN and SA was mediated, at least in part, by PI3K/Akt/GSK-3ß signaling pathway. Furthermore, the ability of MN and SA to counteract the glutamate-induced damage were evaluated in three different in vitro experiments. The hippocampal slices pretreated with MN (0.05 and 0.1 µg/mL) or SA (0.01-0.1 µg/mL) as well as the concomitant treatment with MN (0.01 and 0.05 µg/mL) or SA (0.05 and 0.1 µg/mL) exhibited protection against glutamate toxicity. Interestingly, post-treatment with MN in all doses (0.01-0.1 µg/mL) and SA at dose of 0.1 µg/mL were capable of preventing glutamate-induced cell death. In vitro neuroprotective effect of SA, but not MN, involves the activation of Akt, since the pretreatment with LY294002 completely abolished the protective effect. Overall, MN and SA presented antidepressant-like and neuroprotective effects against glutamatergic excitotoxicity via PI3K/Akt/GSK-3ß.

Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress.

Reactive oxygen species (ROS) have been shown to play a role in the pathophysiology of depression. Taking into account that experimental chronic unpredictable stress (CUS) induces depressive-like behavior and that ascorbic acid has antidepressant-like effect in animals, the objective of this study was to investigate the influence of ascorbic acid on depressive-like behavior induced by CUS paradigm, serum corticosterone levels and markers of oxidative stress in cerebral cortex and hippocampus of mice. Animals were submitted to CUS procedure during 14 days. From the 8th to the 14th day mice received ascorbic acid (10 mg/kg) or fluoxetine (10 mg/kg, conventional antidepressant, positive control) once a day by oral route. On 15th day behavioral and biochemical parameters were analyzed. CUS exposure caused a depressive-like behavior evidenced by the increased immobility time in the tail suspension test and decreased time in which mice spent grooming in the splash test. Depressive-like behavior induced by CUS was accompanied by a significant increased lipid peroxidation (cerebral cortex and hippocampus), decreased catalase (CAT) (cerebral cortex and hippocampus) and glutathione reductase (GR) (hippocampus) activities and reduced levels of glutathione (cerebral cortex). Repeated ascorbic acid or fluoxetine administration significantly reversed CUS-induced depressive-like behavior and oxidative damage. No alteration was observed in locomotor activity, corticosterone levels and glutathione peroxidase (GPx) activity. These findings indicate a rapid and robust effect of ascorbic acid in reversing behavioral and biochemical alterations induced by CUS in mice, suggesting that this vitamin may be an alternative approach for the management of depressive symptoms.