Abstract
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.
Highlights
Traumatic brain injury (TBI) is defined as a neurotrauma resulting from a mechanical force, such as that caused by rapid acceleration or deceleration, blast waves, crush, an impact, or penetration by a projectile
Centers for Disease Control and Prevention (CDC) estimates of TBI do not include injuries seen at U.S Veterans Health Administration Hospitals
Ciriza et al (Ciriza et al, 2006) demonstrated that inhibiting normal metabolism of P4 to 5α-DHP and ALLO abolished the neuroprotective effects of P4. These results suggest that metabolites of P4 may play key roles in neuroprotective effects of P4, and that the mechanism of action of these compounds may not be exclusively through nuclear progesterone receptors (Pgr)
Summary
Traumatic brain injury (TBI) is defined as a neurotrauma resulting from a mechanical force, such as that caused by rapid acceleration or deceleration, blast waves, crush, an impact, or penetration by a projectile. Over the past two decades, an increasing body of literature (reviewed in Sayeed and Stein, 2009; Stein and Wright, 2010; Stein, 2012) has documented the remarkable beneficial effects of P4 on mortality and morbidity following TBI These treatments were originally developed using animal models that replicate the various aspects of human TBI pathophysiology, such as the controlled cortical impact injury model utilized extensively in rats and mice. Subsequent hormone replacement experiments indicated that P4 was neuroprotective in males and females following TBI (Roof et al, 1994) These initial findings were confirmed and expanded by many different groups using a variety of TBI models (Sayeed and Stein, 2009; Stein and Wright, 2010; Stein, 2012; Table 1). Among 77 patients receiving progesterone and 23 receiving placebos, P4 reduced the overall death rate by 50% compared with placebo, with significant improvements in functional outcomes and level of disability among patients with brain injury (Wright et al, 2007; Table 1)
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