Neurosteroids

Progesterone has a broad spectrum of actions in the brain. Among these, the neuroprotective effects are well documented. Progesterone neural effects are mediated by multiple signaling pathways involving binding to specific receptors (intracellular progesterone receptors (PR); membrane-associated progesterone receptor membrane component 1 (PGRMC1); and membrane progesterone receptors (mPRs)) and local bioconversion to 3α,5α-tetrahydroprogesterone (3α,5α-THPROG), which modulates GABAA receptors. This brief review aims to give an overview of the synthesis, metabolism, neuroprotective effects, and mechanism of action of progesterone in the rodent and human brain. First, we succinctly describe the biosynthetic pathways and the expression of enzymes and receptors of progesterone; as well as the changes observed after brain injuries and in neurological diseases. Then, we summarize current data on the differential fluctuations in brain levels of progesterone and its neuroactive metabolites according to sex, age, and neuropathological conditions. The third part is devoted to the neuroprotective effects of progesterone and 3α,5α-THPROG in different experimental models, with a focus on traumatic brain injury and stroke. Finally, we highlight the key role of the classical progesterone receptors (PR) in mediating the neuroprotective effects of progesterone after stroke.

The pathophysiology of major depressive disorder (MDD) is thought to result from impaired connectivity between key brain networks. Gamma-aminobutyric acid (GABA) is the key inhibitory neurotransmitter in the brain, working primarily via GABAA receptors, with an important role in virtually all physiologic functions in the brain. Some neuroactive steroids (NASs) are positive allosteric modulators (PAMs) of GABAA receptors and potentiate phasic and tonic inhibitory responses via activation of synaptic and extrasynaptic GABAA receptors, respectively. This review first discusses preclinical and clinical data that support the association of depression with diverse defects in the GABAergic system of neurotransmission. Decreased levels of GABA and NASs have been observed in adults with depression compared with healthy controls, while treatment with antidepressants normalized the altered levels of GABA and NASs. Second, as there has been intense interest in treatment approaches for depression that target dysregulated GABAergic neurotransmission, we discuss NASs approved or currently in clinical development for the treatment of depression. Brexanolone, an intravenous NAS and a GABAA receptor PAM, is approved by the U.S. Food and Drug Administration for the treatment of postpartum depression (PPD) in patients 15 years and older. Other NASs include zuranolone, an investigational oral GABAA receptor PAM, and PH10, which acts on nasal chemosensory receptors; clinical data to date have shown improvement in depressive symptoms with these investigational NASs in adults with MDD or PPD. Finally, the review discusses how NAS GABAA receptor PAMs may potentially address the unmet need for novel and effective treatments with rapid and sustained antidepressant effects in patients with MDD.

The endogenous neurosteroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone) has protective activity in animal models of alcoholism, depression, traumatic brain injury, schizophrenia, multiple sclerosis, and Alzheimer's disease that is poorly understood. Because these conditions involve proinflammatory signaling through toll-like receptors (TLRs), we examined the effects of 3α,5α-THP, and pregnenolone on TLR4 activation in both the periphery and the central nervous system (CNS). We used monocytes/macrophages (RAW264.7) as a model of peripheral immune signaling and studied innately activated TLR4 in the ventral tegmental area (VTA) of selectively bred alcohol-preferring (P) rats. LPS activated the TLR4 pathway in RAW264.7 cells as evidenced by increased levels of p-TAK1, TRAF6, NF-κB p50, phospho-NF-κB- p65, pCREB, HMGB1, and inflammatory mediators, including MCP-1 and TNFα. Both 3α,5α-THP and pregnenolone (0.5-1.0μM) substantially (~80%) inhibited these effects, indicating pronounced inhibition of TLR4 signaling. The mechanism of inhibition appears to involve blockade of TLR4/MD-2 protein interactions in RAW246.7 cells. In VTA, 3α,5α-THP (15 mg/kg, IP) administration reduced TRAF6 (~20%), CRF (~30%), and MCP-1 (~20%) levels, as well as TLR4 binding to GABAA receptor α2 subunits (~60%) and MyD88 (~40%). The data suggest that inhibition of proinflammatory neuroimmune signaling underlies protective effects of 3α,5α-THP in immune cells and brain, apparently involving blocking of protein-protein interactions that initiate TLR4-dependent signaling. Inhibition of pro-inflammatory TLR4 activation represents a new mechanism of 3α,5α-THP action in the periphery and the brain.

Background: This study aimed to investigate the relationship between serum neuroactive steroids (NAS) and oxytocin and craving and psychosocial functioning in men diagnosed with methamphetamine use disorder (MUD). Methods: In this observational cross-sectional study, 40 men with MUD (PG) and 41 non-substance-use-disorder controls (CG) completed measures of emotion dysregulation (DERS-16), attachment (ECR-R), aggression (BPAQ), and suicidal ideation (BSS). PG additionally completed the Substance Craving Scale (SCS) and Addiction Profile Index (API). Serum allopregnanolone (ALLO), DHEAS, testosterone, 17β-estradiol (E2), and oxytocin were assayed. Results: The results indicated that the PG exhibited significantly higher scores than the CG across all psychological measures. Robust adjusted group effects were observed for DERS-16 (Model 1: F = 35.507, p p p p p p = 0.014), testosterone (r = 0.415, p = 0.008), E2 (r = 0.360, p = 0.023), and oxytocin (r = 0.350, p = 0.027). A multivariable model analyzing craving was statistically significant (R2 = 0.350; F(3,36) = 6.474, p = 0.001), with composite hormonal factor (B = 2.390, p = 0.016) serving as an independent predictor, while API Excluding Craving(API-EC) (p = 0.094) and DERS-16 did not emerge as a significant factor (p = 0.056). In hormone-specific models controlling for API-EC and DERS-16, DHEAS (p = 0.012), testosterone (p = 0.007), oxytocin (p = 0.023), and E2 (p = 0.023) retained significance after false discovery rate (FDR) correction; ALLO did not (p = 0.055). Conclusions: Despite the absence of significant differences in peripheral NAS and oxytocin levels between groups, men with MUD exhibited pronounced psychosocial impairments. The craving experienced during inpatient treatment was primarily elucidated by an integrated endocrine profile. These findings underscore the necessity for larger longitudinal studies incorporating repeated hormonal assessments to further explore these relationships.