Evaluation of the antidepressant effects of pioglitazone in ovariectomized mice through nitric oxide pathway

Background: Pioglitazone is the selective PPAR-γ receptor agonist, which is prescribed for the treatment of type 2 diabetes and may also have antidepressant effects. Nitric oxide (NO) has been involved in some crucial roles, including learning, cognition and neurogenesis as well as some neurodegenerative diseases, including Parkinson, Alzheimer's disease (AD) and depression. Reduced estrogen levels throughout ovariectomy, postpartum and menopause make women more likely to suffer from depression. The existing study was designed to examine the antidepressant-like effects of pioglitazone, a PPAR-γ agonist, and the probable involvement of NO with the use of non-specific NO synthase inhibitor (L-NAME) or an NO precursor (L-arginine) in female ovariectomized (OVX) mice. Methods: The present study was conducted experimentally on female NMRI mice from April to December 2019 at the Pharmacology Department of Pharmacy Faculty, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. Female mice were subjected to bilaterally ovariectomy, and various doses of pioglitazone (10, 20, 40 mg/kg) were administered either alone or in combination with non-specific NO synthase (NOS) inhibitor (L-NAME) or a NO precursor (L-arginine). Antidepressant-like activity of pioglitazone was evaluated in the forced swimming test (FST) and the tail suspension test (TST). Moreover, the open field test was done to evaluate the locomotor activity of mice following different treatments. Results: OVX mice demonstrated a major increase in immobility time versus sham therapy following procedure (P≤0.05). Mice were injected with 40 mg/kg pioglitazone Intraperitoneally, 4 h before the behavioral test, exhibited marked antidepressant-like effects in OVX mice (P≤0.01, P≤0.05 in FST and TST, respectively). Co-administration of sub-effective dose of L-NAME (2 mg/kg) with a sub-effective dose of pioglitazone (20 mg/kg) resulted in a strong antidepressant-like effect in OVX mice (P≤0.01), whereas L-arginine inhibited this effect. The various treatments did not change the total locomotion of mice in OFT. Conclusion: Antidepressant-like effects of pioglitazone may be associated with inhibition of the NO synthase/NO in OVX mice and provided a new strategy for depression.