Allopregnanolone: Regenerative therapeutic to restore neurological health.

Chronic stress has been proposed as a driver of altered brain structure and function, including the pathogenesis of neurodegenerative diseases and a driver of disease progression. A key outcome of stress in the brain is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicate failed resilience. Neuroendocrine homeostasis and stress response are mainly dependent upon the functioning of the hypothalamic-pituitary-adrenal axis. Neurosteroids will fluctuate depending on whether the stress is acute or chronic. Advancements in neurosteroid research have led to the identification of multiple targets for drug development, but the most promising innovative target may be neurogenesis, given its potential impact in neurodegenerative disorders like Alzheimer's disease. Allopregnanolone is an endogenous pregnane neurosteroid and a reduced metabolite of progesterone, which acts as a potent allosteric modulator and direct activator of the GABA-chloride channel complex. Perhaps the most intriguing finding related to the potential therapeutic effects of allopregnanolone is its potential to promote neuroregeneration.

Effects of docosahexaenoic acid and eicosapentaoic acid supplementation on white matter integrity after repetitive sub-concussive head impacts during American football: Exploratory neuroimaging findings from a pilot RCT.

Context: Repetitive sub-concussive head impacts (RSHIs) are common in American football and result in changes to the microstructural integrity of white matter. Both docosahexaenoic acid (DHA) and eicosapentaoic acid (EPA) supplementation exerted neuroprotective effects against RSHIs in animal models and in a prior study in football players supplemented with DHA alone. Objective: Here, we present exploratory neuroimaging outcomes from a randomized controlled trial of DHA + EPA supplementation in American football players. We hypothesized that supplementation would result in less white matter integrity loss on diffusion weighted imaging over the season. Design setting participants: We conducted a double-blind placebo-controlled trial in 38 American football players between June 2019 and January 2020. Intervention: Participants were randomized to the treatment (2.442 g/day DHA and 1.020 g/day EPA) or placebo group for five times-per-week supplementation for 7 months. Of these, 27 participants were included in the neuroimaging data analysis (n = 16 placebo; n = 11 DHA + EPA). Exploratory outcome measures: Changes in white matter integrity were quantified using both voxelwise diffusion kurtosis scalars and deterministic tractography at baseline and end of season. Additional neuroimaging outcomes included changes in regional gray matter volume as well as intra-regional, edge-wise, and network level functional connectivity. Serum neurofilament light (NfL) provided a peripheral biomarker of axonal damage. Results: No voxel-wise between-group differences were identified on diffusion tensor metrics. Deterministic tractography using quantitative anisotropy (QA) revealed increased structural connectivity in ascending corticostriatal fibers and decreased connectivity in long association and commissural fibers in the DHA+EPA group compared to the placebo group. Serum NfL increases were correlated with increased mean (ρ = 0.47), axial (ρ = 0.44), and radial (ρ = 0.51) diffusivity and decreased QA (ρ = -0.52) in the corpus callosum and bilateral corona radiata irrespective of treatment group. DHA + EPA supplementation did preserve default mode/frontoparietal control network connectivity (g = 0.96, p = 0.024). Conclusions: These exploratory findings did not provide strong evidence that DHA + EPA prevented or protected against axonal damage as quantified via neuroimaging. Neuroprotective effects on functional connectivity were observed despite white matter damage. Further studies with larger samples are needed to fully establish the relationship between omega-3 supplementation, RSHIs, and neuroimaging biomarkers. Trial registration: ClinicalTrials.gov-NCT04796207.

Effects of Fish Oil on Biomarkers of Axonal Injury and Inflammation in American Football Players: A Placebo-Controlled Randomized Controlled Trial.

There are limited studies on neuroprotection from repeated subconcussive head impacts (RSHI) following docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) supplementation in contact sports athletes. We performed a randomized, placebo-controlled, double-blinded, parallel-group design trial to determine the impact of 26 weeks of DHA+EPA supplementation (n = 12) vs. placebo (high-oleic safflower oil) (n = 17) on serum concentrations of neurofilament light (NfL), a biomarker of axonal injury, and inflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a)) in National Collegiate Athletic Association Division I American football athletes. DHA+EPA supplementation increased (p < 0.01) plasma DHA and EPA concentrations throughout the treatment period. NfL concentrations increased from baseline to week 26 in both groups (treatment (<0.001); placebo (p < 0.05)), with starting players (vs. non-starters) showing significant higher circulating concentrations at week 26 (p < 0.01). Fish oil (DHA+EPA) supplementation did not mitigate the adverse effects of RSHI, as measured by NfL levels; however, participants with the highest plasma DHA+EPA concentrations tended to have lower NfL levels. DHA+EPA supplementation had no effects on inflammatory cytokine levels at any of the timepoints tested. These findings emphasize the need for effective strategies to protect American football participants from the effects of RSHI.

Exploratory imaging outcomes of a phase 1b/2a clinical trial of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: Structural effects and functional connectivity outcomes.

Introduction: Allopregnanolone (ALLO), an endogenous neurosteroid, promoted neurogenesis and oligogenesis and restored cognitive function in animal models of Alzheimer's disease (AD). Based on these discovery research findings, we conducted a randomized-controlled phase 1b/2a multiple ascending dose trial of ALLO in persons with early AD (NCT02221622) to assess safety, tolerability, and pharmacokinetics. Exploratory imaging outcomes to determine whether ALLO impacted hippocampal structure, white matter integrity, and functional connectivity are reported. Methods: Twenty-four individuals participated in the trial (n = 6 placebo; n = 18 ALLO) and underwent brain magnetic resonance imaging (MRI) before and after 12 weeks of treatment. Hippocampal atrophy rate was determined from volumetric MRI, computed as rate of change, and qualitatively assessed between ALLO and placebo sex, apolipoprotein E (APOE) ε4 allele, and ALLO dose subgroups. White matter microstructural integrity was compared between placebo and ALLO using fractional and quantitative anisotropy (QA). Changes in local, inter-regional, and network-level functional connectivity were also compared between groups using resting-state functional MRI. Results: Rate of decline in hippocampal volume was slowed, and in some cases reversed, in the ALLO group compared to placebo. Gain of hippocampal volume was evident in APOE ε4 carriers (range: 0.6% to 7.8% increased hippocampal volume). Multiple measures of white matter integrity indicated evidence of preserved or improved integrity. ALLO significantly increased fractional anisotropy (FA) in 690 of 690 and QA in 1416 of 1888 fiber tracts, located primarily in the corpus callosum, bilateral thalamic radiations, and bilateral corticospinal tracts. Consistent with structural changes, ALLO strengthened local, inter-regional, and network level functional connectivity in AD-vulnerable regions, including the precuneus and posterior cingulate, and network connections between the default mode network and limbic system. Discussion: Indicators of regeneration from previous preclinical studies and these exploratory MRI-based outcomes from this phase 1b/2a clinical cohort support advancement to a phase 2 proof-of-concept efficacy clinical trial of ALLO as a regenerative therapeutic for mild AD (REGEN-BRAIN study; NCT04838301).

Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial.

INTRODUCTION: Allopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and well-established preclinical safety efficacy make it a viable candidate. METHODS: A randomized, double-blinded, placebo-controlled, single and multiple ascending dose trial was conducted. Intravenous allopregnanolone or placebo was administered once-per-week for 12 weeks with a 1-month follow-up. Participants with early AD (mild cognitive impairment due to AD or mild AD), a Mini-Mental State Examination score of 20-26 inclusive, and age ≥55 years were randomized (6:2 to three allopregnanolone dosing cohorts or one placebo cohort). Primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetic (PK) parameters and maximally tolerated dose (MTD). Exploratory endpoints included cognitive and imaging biomarkers. RESULTS: A total of 24 participants completed the trial. Allopregnanolone was safe and well tolerated in all study participants. No differences were observed between treatment arms in the occurrence and severity of adverse events (AE). Most common AE were mild to moderate in severity and included rash (n = 4 [22%]) and fatigue (n = 3 [17%]). A single non-serious AE, dizziness, was attributable to treatment. There was one serious AE not related to treatment. Pharmacokinetics indicated a predictable linear dose-response in plasma concentration of allopregnanolone after intravenous administration over 30 minutes. The maximum plasma concentrations for the 2 mg, 4 mg, 6 mg, and 10 mg dosages were 14.53 ng/mL (+/-7.31), 42.05 ng/mL (+/-14.55), 60.07 ng/mL (+/-12.8), and 137.48 ng/mL (+/-38.69), respectively. The MTD was established based on evidence of allopregnanolone-induced mild sedation at the highest doses; a sex difference in the threshold for sedation was observed (males 10 mg; females 14 mg). No adverse outcomes on cognition or magnetic resonance imaging-based imaging outcomes were evident. CONCLUSIONS: Allopregnanolone was well tolerated and safe across all doses in persons with early AD. Safety, MTD, and PK profiles support advancement of allopregnanolone as a regenerative therapeutic for AD to a phase 2 efficacy trial. TRIAL REGISTRATION: ClinicalTrials.gov-NCT02221622.

Late pregnancy complications can affect risk estimates of elective induction of labor.

OBJECTIVE: Multiple observational studies have emphasized the increased risk of elective induction versus spontaneous labor. We estimated the risks of elective induction before 39 weeks compared to expectant management. METHODS: Using a single institution's delivery data (1996-2004), we identified women with uncomplicated term gestations who underwent elective induction before 39 weeks (Early Induction Group). A comparison group of women eligible for elective induction before 39 weeks but who were managed expectantly was created by identifying the remaining deliveries ≥ 39 weeks and excluding women with "established" pregnancy complications such as diabetes or heart disease (Expectant Management Group), but retaining women with complications that may have developed while waiting, e.g. gestational hypertension or abruption. RESULTS: Pregnancies in the Early Induction Group were generally not at increased risk for morbidity when compared to the entire Expectant Management Group, in whom 49% developed pregnancy complications or went postdates. These pregnancies had poorer maternal and neonatal outcomes when compared to patients who remained uncomplicated with spontaneous labor onset, thus reducing the overall benefit of expectant management. CONCLUSIONS: Failure to account for the large proportion of women who develop late pregnancy complications can falsely elevate the estimated risk of elective induction prior to 39 weeks.