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).