The Role of Progesterone in Traumatic Brain Injury

Espinoza, Tamara R.; Wright, David W.

doi:10.1097/htr.0b013e31823088fa

Cited by 19 publications

(15 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…P4 ameliorates the increases in inflammatory cytokines such as TGF-β, TNF-α, IL-6, and IL-1β that occur after TBI (He et al, 2004a,b), decreases gliosis and apoptosis (Djebaili et al, 2004, 2005; He et al, 2004b), and increases expression of anti-oxidant enzymes such as superoxide dismutase (Pajović et al, 1996). Most critically, the beneficial effects occurring in the first few days following TBI are also accompanied by significant improvements in long-term deficits in cognition and functionality normally experienced by animals after TBI (Djebaili et al, 2004, 2005; Espinoza and Wright, 2011; Stein, 2012). For example, P4 administration to rats following TBI led to improved locomotor activity and performance on the Morris water maze test used to assess learning and spatial memory (Djebaili et al, 2004, 2005; He et al, 2004a,b).…”

Section: Progesterone Effects In Animal Models Of Tbimentioning

confidence: 99%

Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms

Cooke¹,

Nanjappa²,

Yang³

et al. 2013

Front. Neurosci.

View full text Add to dashboard Cite

Traumatic brain injury (TBI) is an important and costly medical problem for which no clinically proven treatment currently exists. Studies in rodents and humans have shown beneficial effects of progesterone (P4) on both mortality and functional outcomes following TBI. Neuroprotective effects of P4 in TBI likely involve the classical nuclear progesterone receptors (Pgr) that are widely distributed in both glial cells and neurons of the brain. However, P4 may have critical effects not mediated through Pgr. In the brain, P4 is converted to a metabolite, allopregnanolone (ALLO), whose beneficial effects equal or exceed those of P4 in TBI. ALLO does not bind Pgr, suggesting it acts through non-classical pathways. ALLO has effects on GABAA and pregnane X receptors, as well as on the mitochondrial permeability transition pore. In addition, ALLO is metabolized to another compound, 5alpha-dihydroprogesterone, which binds Pgr, suggesting ALLO actions may involve signaling through Pgr as well as the aforementioned mechanisms of action. P4 and ALLO also signal through a number of membrane receptors (progesterone receptor membrane component 1, and membrane progesterone receptors (mPRs) alpha, beta, gamma, delta, and epsilon) in the brain that are distinct from Pgr, although the role of these receptors in the normal brain and in the therapeutic response to P4 and ALLO following TBI is unclear. In summary, P4 has the potential to become the first clinically effective treatment for TBI, and the effects of P4 and its metabolite ALLO in TBI may involve Pgr, mPRs, and other signaling pathways. Elucidating these mechanisms will more clearly reveal the potential of classical and non-classical pathways to mediate important effects of P4 and its metabolites, and potentially offer new therapeutic approaches to TBI.

show abstract

Section: Progesterone Effects In Animal Models Of Tbimentioning

confidence: 99%

Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms

Cooke¹,

Nanjappa²,

Yang³

et al. 2013

Front. Neurosci.

View full text Add to dashboard Cite

show abstract

“…A recent case report in an astrocytoma patient with drug-resistant seizures is also consistent with the possibility of minocycline having clinically significant anti-seizure effects [88], and a phase I/II trial (NCT01058395) aimed at assessing its safety in patients with moderate to severe TBI is currently in progress. Like minocycline, progesterone displays a wide range of anti-inflammatory and neuroprotective effects [89-94] and, in particular, has been found to suppress the synthesis of TNF-α, IL-1β and IL-6 and to increase BDNF expression [95,96]. Likewise, progesterone has been reported to have beneficial effects in a variety of brain injury models, and to decrease lesion volume and reduce apoptosis and blood-brain barrier leakage after brain injury [96,97].…”

Section: Prevention Of Post-traumatic Epilepsy By Mild Cooling: Furthmentioning

confidence: 99%

Novel frontiers in epilepsy treatments: preventing epileptogenesis by targeting inflammation

D’Ambrosio

Eastman

Fattore

et al. 2013

Expert Review of Neurotherapeutics

View full text Add to dashboard Cite

Currently available epilepsy drugs only affect the symptoms (seizures), and there is a need for innovative treatments that target the underlying disease. Increasing evidence points to inflammation as a potentially important mechanism in epileptogenesis. In the last decade, a new generation of etiologically realistic syndrome-specific experimental models have been developed which are expected to capture the epileptogenic mechanisms operating in the corresponding patient populations, and to exhibit similar treatment-responsiveness. Recently, an intervention known have broad-ranging anti-inflammatory effects (selective brain cooling) has been found to prevent the development of spontaneously occurring seizures in an etiologically realistic rat model of post-traumatic epilepsy. Several drugs used clinically for other indications also have the potential for inhibiting inflammation, and should be investigated for anti-epileptogenic activity in these models. If results of such studies are positive, these compounds could enter rapidly Phase III trials in patients at high risk of developing epilepsy.

show abstract

“…Many studies have now concluded that progesterone is a promising neuroprotective drug in experimental models of stroke and TBI [28, 29], but initial analyses of Phase III clinical trials with progesterone have not been successful on their quality-of-life measures of functional outcome [30, 31]. This failure may be due in part to the exclusive use of monotherapies to treat complex, heterogeneous disorders like brain injury.…”

Section: Introductionmentioning

confidence: 99%

Progesterone and vitamin D combination therapy modulates inflammatory response after traumatic brain injury

et al. 2015

View full text Add to dashboard Cite

Objective Inflammation is an important component of the response to traumatic brain injury (TBI). Progesterone has been shown to inhibit neuroinflammation following (TBI), and may do so through Toll-like receptor (TLR) -mediated pathways. In vitro studies indicate that 1,25-dihydroxyvitamin D(3) (VDH) may also modulate the inflammatory response through the TLR4 pathway. We tested the hypothesis PROG and VDH would exert additive and synergistic neuroprotective effects compared with individual treatment by modulating TLR4/NF-κB-mediated inflammation pathways after TBI in rats. Research Design and Methods Bilateral medial frontal cortical impact injury was induced in young adult Sprague-Dawley rats. Progesterone (i.p., 16 mg/kg body weight) and VDH (1 ug/kg body weight) were injected separately or combined at 1 and 6 h after surgery. Rats were killed 24 h post-surgery and peri-contusional brain tissue harvested for immunostaining and protein measurement. Results TLR4, phosphorylation of NF-κB,. neuronal loss, and astrocyte activation were significantly reduced with combination treatment after TBI compared to each agent iven individually. Conclusions At 24h after TBI, combination therapy shows greater efficacy in reducing neuroinflammation compared to progesterone and VDH given separately, and does so by modulating the TLR4/NF-κB signaling pathway.

show abstract

The Role of Progesterone in Traumatic Brain Injury

Cited by 19 publications

References 14 publications

Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms

Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms

Novel frontiers in epilepsy treatments: preventing epileptogenesis by targeting inflammation

Progesterone and vitamin D combination therapy modulates inflammatory response after traumatic brain injury

Contact Info

Product

Resources

About