Participation of P2X7-NLRP3 pathway in the modulation of behavioral, neurochemical and neuroplastic changes induced by stress

Abstract

Depression is a complex affective disorder whose most accepted pharmacological cause is monoamine deficiency. In addition, current neurobiological theories have investigated the involvement of glutamate and GABA in order to find new drugs and better understand the neural bases and the cellular and molecular mechanisms involved, since a considerable number of patients do not respond to current therapies. In this sense, the discovery of ATP and ADP as signaling molecules of the purinergic system and its involvement with the NLRP3 inflammatory pathway has gained prominence and enabled the investigation of new therapeutic targets. Corroborating this hypothesis, knockout animals for P2X7 purinergic receptors or treated with an antagonist of that receptor exhibited an antidepressant profile. P2X7 activation can modulate the release of monoamines and glutamate, and neuroplasticity, which are altered in animals submitted to stress models related to depression. In this perspective, we intend to investigate the effects of treatments with a P2X7 antagonist or an inhibitor of the NLRP3 pathway on: 1. Behavior of animals’ submitted to Learned Helplessness (LH) model; 2. Levels of monoamines, GABA and glutamate in limbic structures associated with the neurobiology of depression in animals submitted to LH; 3. Expression of genes and proteins related to neuroplasticity in the same structures. The results will contribute to understanding the mechanisms underlying the anti-depressant effect induced by P2X7 antagonists or inhibitors of the NLRP3 pathway, as well as to the understanding of the involvement of the P2X7-NLRP3 pathway in the neurobiology of depression. (AU)