Anti-inflammatory effects of allopregnanolone are mediated by GABAA receptors
GABA-active agents possess pleitropic actions and are prescribed to treat anxiety, epilepsy, alcohol use disorder and induce sedation and anesthesia (11). Immune cells express receptors for several neurotransmitters, neuropeptides, and hormones. Of note, the GABAergic system can be modulated endogenously within the immune system (12). GABA possesses important anti-inflammatory actions and GABAAreceptors are widely expressed in immune competent cells (13). Indeed, treatment with GABA downregulates autoimmunity mediated by T-cells, inflammation and ameliorates cytotoxic immune responses (14). Activation of GABAA receptors by GABA or their agonists decreased pro-inflammatory cytokines in peripheral macrophages. GABAergic agents also protect in models of experimental autoimmune encephalomyelitis, which underscores the role of GABAA receptors within the immune system. In support, GABA secretion by both antigen presenting cells (APCs) and T cells, functional GABAA receptors on macrophages, and a direct effect of GABA-active molecules on APCs were reported (14). GABAA receptor subtypes were identified in human, mouse and rat CD4+ and CD8+ T cells. Abundant GABAA receptors were observed in T cells from human and rodents with functional GABAA channels expressing a variety of subunit subtypes (15, 16).
In macrophages, the toll-like receptor 4 (TLR4)-specific ligand, lipopolysaccharide (LPS), induces proinflammatory cytokines and chemokines (17). Peripheral inflammation also signals to the brain with production of pro-inflammatory responses. TLR4-mediated pathway is also expressed in neurons. The TLR4 signal cascade involves activation of the GABAA receptor-containing α2 subunit (17, 18).
Allopregnanolone shows protective functions in preclinical studies, including depression, schizophrenia, traumatic brain injury, alcohol use disorder, multiple sclerosis, Parkinson’s and Alzheimer’s disease (17). These pathophysiological conditions enhance proinflammatory signaling mediated by TLR activation in peripheral organs and brain (Figure 1B). Monocytes/macrophages were studied as a model of peripheral immune signaling activation (18) showing LPS activated the TLR4 pathway with downstream activation of NFkB and increased pro-inflammatory mediators (MCP-1 and TNF-α). Allopregnanolone, by inhibiting TLR4 signaling, consistently blocked pro-inflammatory marks with a mechanism that involved blockade of TLR4/MD-2 protein interactions in macrophages (18). This effect was also demonstrated in brain (18). Hence, inhibition of pro-inflammatory processes both in the peripheral and neuroimmune signaling, which can be initiated by allopregnanolone binding at GABAA receptor in monocytes/macrophages and brain cells, underscores the profound protective effects of allopregnanolone. This anti-inflammatory response by allopregnanolone inhibition of TLR4 signal underlies a novel function of allopregnanolone to regulate periphery and the brain immune responses (18).