Editorial: Neuroprotective and Therapeutic Effects of Progesterone, Allopregnanolone, and Their Derivatives

Rachida GUENNOUN^1*Iqbal Sayeed²Donald Stein³

• ¹Inserm and University Paris Saclay, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
• ²Department of Emergency Medicine, Emory university, Atlanta, USA, Emory University, Atlanta, United States
• ³Emeriyus College, Emory university, Atlanta, USA, Emory University, Atlanta, United States

Parkinson's disease ; Alzheimer's disease; Membrane progesterone receptor; Mitochondrial respiration ; BDNF Beyond their classical reproductive roles, steroids exert profound effects on the nervous system (1) (2) (3). In particular, progesterone, allopregnanolone, and synthetic progestins have emerged as key players in modulating neuroprotection, synaptic plasticity, mood, stress, cognition and CNS repair (4) (5) (6) (7). Extensive preclinical research demonstrated their therapeutic potential, but translating preclinical findings into clinical practice has been elusive. Allopregnanolone can promote inhibitory neurotransmission and exert rapid antidepressant effects. It is now approved for clinical treatment of postpartum depression (8). Clinical trials of progesterone and allopregnanolone for treating neurodegenerative disease and traumatic brain injury (TBI) had mixed outcomes. Allopregnanolone was evaluated in Phase 1b/2a clinical trials for Alzheimer's disease (AD), examining its safety and pharmacokinetics. Neuroimaging techniques provided evidence that Allopregnanolone may be helpful in promoting regenerative and therapeutic effects for mild AD (9). Progesterone was evaluated in multiple Phase 2 studies of moderate-to-severe TBI, with early signals of benefit (10) (11); however, two large Phase 3 randomized controlled trials failed to demonstrate its efficacy (12) (13). Subsequent analyses have identified several factors that may have contributed to the failure of these trials, including the high doses of progesterone used; the lack of patient stratification; insufficient consideration of sex-and age-related differences in hormonal status and outcomes; the presence of pre-existing comorbidities; and the use of subjective outcome measures that do not accurately capture deficits or long-term quantitative recovery (5) (14) (15) (16). Importantly, while these reviews highlight major translational challenges, they emphasize the pleiotropic potential of progesterone -including anti-inflammatory, anti-apoptotic, neurogenic, and remyelinating effects-in treating complex pathologies such as TBI.Overall, progesterone and allopregnanolone continue to attract interest as potential therapeutic steroids for neuroprotection and regeneration. Carefully designed future clinical studies, with optimized designs, nuanced patient stratification, and appropriate outcome measures, may help further elucidate their potential role in this evolving field.The current Research Topic assembles original research articles and a review that highlight mechanistic insights, receptor-specific signaling pathways, and translational opportunities for progesterone and allopregnanolone as neuroprotective agents. Wang et al. provide compelling evidence that calcium signaling represents a unifying mechanism for the pleiotropic effects of allopregnanolone in neurons and astrocytes. Using transcriptomic, mitochondrial, and pharmacological analyses, the authors demonstrate that allopregnanolone enhances synaptogenesis, mitochondrial respiration, and oxidative stress resilience through GABAA and L-type Ca²⁺ channel-dependent pathways. The activation of Ca²⁺/CREB and NRF1-TFAM signaling cascades supports mitochondrial biogenesis and cellular recovery. This comprehensive analysis provides an integrated view of how allopregnanolone coordinates cellular and metabolic processes that may support brain repair and functional recovery; highlighting its promise as a multifaceted neuroprotective agent. Extending this perspective to a disease-specific context, Castelnovo and Thomas explore the neuroprotective role of progesterone in a Parkinson's disease (PD) cell model. While progesterone has long been studied for its classical genomic effects via nuclear receptors, the authors uncover a critical role of the membrane progesterone receptor α (mPRα/PAQR7) in neuroprotection. Using a human cellline (SH-SY5Y) as a PD model, they report that progesterone exerts its neuroprotective effects through mPRα/PAQR7 by activating PI3K-AKT and MAPK signaling cascades, which are key pathways for promoting neuronal survival. Nuclear PR and GABAA receptor agonists failed to reproduce this effect, highlighting the specificity of mPRα-mediated signaling. This study underscores the relevance of nonclassical progesterone signaling mechanisms in neuroprotection and identifies mPRα as a promising molecular target for developing new therapeutic strategies for PD and related neurodegenerative conditions. Complementing the other papers, Singh et al. provide an integrative review linking progesterone to brain-derived neurotrophic factor (BDNF) and related signaling networks that contribute to neuroprotection. Their synthesis highlights the importance of glial cells and microRNAs in modulating progesterone's neuroprotective actions. Importantly, they highlight that the type of progestinwhether natural or synthetic-can profoundly influence neuroprotective outcomes, with significant implications for clinical translation and hormone therapy design. The translational aspect of this collection is provided by Jiao Yang et al., who propose a biomarker-based approach to predict stroke risk using hair-derived hypothalamic-pituitary-gonadal axis hormone levels.Their findings suggest that decreased, pre-stroke testosterone and progesterone concentrations in hair can serve as predictive indicators of stroke vulnerability. These preliminary findings introduce a potential non-invasive biomarker approach offering new possibilities for early cerebrovascular risk assessment; thus, expanding the clinical relevance of neuroendocrine markers in preventive neurology. Jie Yang et al. explore shared neuroendocrine mechanisms linking premenstrual dysphoric disorder (PMDD) and Alzheimer's disease (AD). They identify overlapping pathways involving allopregnanolone fluctuations, GABAergic and serotonergic dysregulation and the APOE-ε4 allele. This conceptual framework can be taken to suggest that PMDD may be a biological precursor state for AD, emphasizing the role of sex hormones in late-life neurodegenerative risk. Their analysis supports the view that hormonal instability may contribute to long-term neurodegenerative risk in women while emphasizing the need to incorporate sex-specific endocrine dynamics into models of AD pathogenesis and early intervention strategies. 2.Receptor specificity matters: the differential effects of nuclear versus membrane progesterone receptors underscore the need for precise pharmacological targeting.3.Sex and age are critical biological variables that shape neurosteroid efficacy, influencing outcomes in preclinical studies as well as for designing clinical trials.4.Translational biomarkers, such as plasma or hair-based sex steroid hormone measures, may serve as valuable tools for risk stratification and therapeutic monitoring. Progesterone and allopregnanolone and their derivative continue to emerge as promising therapeutic steroids for neuroprotection and regeneration. Additional clinical investigations, designed with refined methodologies, thoughtful patient stratification, and clinically meaningful outcome measures, would be valuable to further clarify and confirm their clinical potential.