Feasibility of progesterone treatment for ischaemic stroke

Gibson, Claire L.; Bath, Philip M

doi:10.1177/0271678x15616782

Cited by 17 publications

(8 citation statements)

References 31 publications

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“…The current study demonstrating an excitatory action of progesterone is also significant for the treatment of other neurological disorders, such as traumatic brain injury, spinal cord injury, and ischemic injury; progesterone was neuroprotective against these injuries in an extensive array of studies in experimental animals (Deutsch et al, 2013; Gibson & Bath, 2015). However, clinical trials of progesterone therapy for traumatic brain injury and spinal cord injury have also failed to find a beneficial effect over placebo treatment (Skolnick et al, 2014; Wright et al, 2014; Aminmansour et al, 2016).…”

Section: Discussionmentioning

confidence: 82%

A novel therapeutic approach for treatment of catamenial epilepsy

Joshi

Sun

Rajasekaran

et al. 2018

Neurobiology of Disease

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Many women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. There is no effective treatment for this condition, proposed to result from withdrawal of neurosteroid-mediated effects of progesterone. A double-blind, multicenter, phase III, clinical trial of catamenial epilepsy has failed to find a beneficial effect of progesterone. The neurosteroid-mediated effects of progesterone have been extensively studied in relation to catamenial epilepsy; however, the effects mediated by progesterone receptor activation have been overlooked. We determined whether progesterone increased excitatory transmission in the hippocampus via activation of progesterone receptors, which may play a role in regulating catamenial seizure exacerbation. In a double-blind study using a rat model of catamenial epilepsy, we found that treatment with RU-486, which blocks progesterone and glucocorticoid receptors, significantly attenuated neurosteroid withdrawal-induced seizures. Furthermore, progesterone treatment as well as endogenous rise in progesterone during estrous cycle increased the expression of GluA1 and GluA2 subunits of AMPA receptors in the hippocampi, and enhanced the AMPA receptor-mediated synaptic transmission of CA1 pyramidal neurons. The progesterone-induced plasticity of AMPA receptors was blocked by RU-486 treatment and progesterone also failed to increase AMPA receptor expression in progesterone receptor knockout mice. These studies demonstrate that progesterone receptor activation regulates AMPA receptor expression and may play a role in catamenial seizure exacerbation.

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Section: Discussionmentioning

confidence: 82%

A novel therapeutic approach for treatment of catamenial epilepsy

Joshi

Sun

Rajasekaran

et al. 2018

Neurobiology of Disease

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“…There are now over 400 publications in the literature showing that the pleiotropic, neurosteroid PROG and its metabolites are neuroprotective and functionally effective in various, pre-clinical models of brain injury [78][79][80]. Among its pleiotropic effects, PROG reduces pro-inflammatory cytokine production and regulates microglial activation and M1/M2 polarization in rodent models of ischemic brain injury [9,36,42,44,46,81].…”

Section: Prog Treatment Of Stress-induced Microglial Primingmentioning

confidence: 99%

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

Espinosa‐García

Atif

Yousuf

et al. 2020

IJMS

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NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1β production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1β production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone’s (PROG’s) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions.

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“…51 In light of these disappointing outcomes, further clinical developments for IS appear on hold, subject to an indepth investigations with a back-to-basics consideration of questions on issues such as possible interaction of progesterone with tissue plasminogen activator (tPA), sex-specific effects, and development of progesterone receptor-specific targets. 51 Meanwhile, new promising studies on mice suggest a sex difference in stroke effects affecting brain respiratory chain reactions and actions of progesterone on mitochondrial functions, which might participate in its neuroprotective properties. 52 In other areas of research, small cross-sectional clinical studies propose that pre-screenings for certain serum biomarkers (e.g.…”

Section: Mechanisms Translational Studiesmentioning

confidence: 99%

“…Translational applications of this knowledge were discouraging when two multi-center phase III clinical trials failed to demonstrate benefits for patients with traumatic brain injury (TBI). 51 In light of these disappointing outcomes, further clinical developments for IS appear on hold, subject to an in-depth investigations with a back-to-basics consideration of questions on issues such as possible interaction of progesterone with tissue plasminogen activator (tPA), sex-specific effects, and development of progesterone receptor-specific targets. 51 Meanwhile, new promising studies on mice suggest a sex difference in stroke effects affecting brain respiratory chain reactions and actions of progesterone on mitochondrial functions, which might participate in its neuroprotective properties.…”

Section: Mechanisms Translational Studiesmentioning

confidence: 99%

What does the research say about androgen use and cerebrovascular events?

Sadaie¹,

Farhoudi

Zamanlu

et al. 2018

Therapeutic Advances in Drug Safety

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Many studies have investigated the benefits of androgen therapy and neurosteroids in aging men, while concerns remain about the potential associations of exogenous steroids and incidents of cerebrovascular events and ischemic stroke (IS). Testosterone is neuroprotective, neurotrophic and a potent stimulator of neuroplasticity. These benefits are mediated primarily through conversion of a small amount of testosterone to estradiol by the catalytic activity of estrogen synthetase (aromatase cytochrome P450 enzyme). New studies suggest that abnormal serum levels of the nonaromatized potent metabolite of testosterone, either high or low dihydrotestosterone (DHT), is a risk factor for stroke. Associations between pharmacologic androgen use and the incidence of IS are questionable, because a significant portion of testosterone is converted to DHT. There is also insufficient evidence to reject a causal relationship between the pro-testosterone adrenal androgens and incidence of IS. Moreover, vascular intima-media thickness, which is a predictor of stroke and myocardial symptoms, has correlations with sex hormones. Current diagnostic and treatment criteria for androgen therapy for cerebrovascular complications are unclear. Confounding variables, including genetic and metabolic alterations of the key enzymes of steroidogenesis, ought to be considered. Information extracted from pharmacogenetic testing may aid in expounding the protective-destructive properties of neurosteroids, as well as the prognosis of androgen therapy, in particular their cerebrovascular outcomes. This investigative review article addresses relevant findings of the clinical and experimental investigations of androgen therapy, emphasizes the significance of genetic testing of androgen responsiveness towards individualized therapy in post-IS injuries as well as identifying pertinent questions.

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Feasibility of progesterone treatment for ischaemic stroke

Cited by 17 publications

References 31 publications

A novel therapeutic approach for treatment of catamenial epilepsy

A novel therapeutic approach for treatment of catamenial epilepsy

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

What does the research say about androgen use and cerebrovascular events?

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