Rapamycin Attenuates Depression and Anxiety-like Behaviors Through Modulation of the NLRP3 Pathway in Pentylenetetrazole-kindled Male Wistar Rats

Background: There is cumulative evidence that shows the effect of epilepsy on behavioral conditions like anxiety and depression.

Objectives: The effects of rapamycin on anxiety and depression caused by pentylenetetrazole (PTZ) in the rat and possible underlying mechanisms were evaluated.

Methods: Male Wistar rats were divided into experimental and control groups. The experimental groups were treated with intraperitoneal (i.p.) injection of 0.5, 1, and 2 mg/kg of rapamycin, while the control group received normal saline only. Kindling was induced by sub-threshold dose (35 mg/kg, i.p.) of PTZ for one month. When the kindling procedure was done, the seizure behaviors and the behavioral function were evaluated. For anxiety parameters, the elevated plus maze (EPM) was used. The forced swim test was employed to assess the antidepressant potential. At the end of the experiment, rats were euthanized and the blood serum and brain samples were isolated for respective measurement of oxidative stress and gene expression parameters.

Results: Rapamycin delayed the development of kindling and the onset time of seizures. Rapamycin administration reduced immobility time in the FST, exerting antidepressant-like activity. In the EPM test, rapamycin produced an anxiolytic-like effect. In addition, rapamycin increased the catalase and superoxide dismutase levels in the serum and significantly decreased the gene expression of I11b and Nlrp3 compared to the PTZ group.

Conclusion: Our results showed that the inhibitory effect of mTOR inhibitor (rapamycin) on reactive oxygen species production during NLRP3 inflammasome activation could bring about behavioral alterations in anxiety and depression.