Progesterone Changes VEGF and BDNF Expression and Promotes Neurogenesis After Ischemic Stroke

Abstract

Studies have shown that progesterone enhances functional recovery after ischemic stroke, but the underlying mechanisms are not completely understood. Therefore, we investigated the effect of progesterone on vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and neurogenesis in a rodent stroke model. Rats underwent permanent middle cerebral artery occlusion (pMCAO) and then received intraperitoneal injections of progesterone (15 mg/kg) or vehicle at 1 h followed by subcutaneous injections at 6, 24, and 48 h. We examined VEGF and BDNF expression by Western blotting and/or immunostaining and microvessel density by lectin immunostaining. Neurogenesis in the subventricular zone was determined by immunostaining of Ki67 and doublecortin, and double BrdU/Nestin immunostaining. We calculated brain water content with the wet-dry weight method on day 3 and assessed neurologic deficits with the modified neurological severity score on days 1, 3, 7, and 14. Progesterone-treated rats showed a significant decrease in VEGF expression, but an increase in BDNF expression, compared with that of vehicle-treated pMCAO rats on day 3 post-occlusion. Progesterone did not alter the microvessel density, but it reduced brain water content compared with that in vehicle-treated rats on day 3 post-occlusion. Progesterone treatment increased the numbers of newly generated neurons in the subventricular zone and doublecortin-positive cells in the peri-infarct region on day 7 post-occlusion. In addition, progesterone improved neurologic function on days 7 and 14 post-occlusion. Our data suggest that the enhancement of endogenous BDNF and subsequent neurogenesis could partially underlie the neuroprotective effects of progesterone.

Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice

“…Based on these previous reports and the limited therapeutic options for ICH, we tested the therapeutic effect of progesterone for ICH in a rodent model. As in the animal models of ischemic stroke and TBI (Barha, et al, 2011, Jiang, et al, 2016), we found that progesterone is neuroprotective in the mouse collagenase-induced ICH model. However, recently completed clinical trials with progesterone failed to demonstrate any neuroprotective effect in patients with TBI (Jickling and Sharp, 2015, Schwamm, 2014).…”

“…Progesterone has been shown to have multiple neuroprotective effects. Previous studies also have shown that it has neurotrophic effects and anti-excitotoxic effects (Jiang, et al, 2016, Singh and Su, 2013a). Moreover, progesterone-regulated neural responses may be mediated by membrane progesterone receptors (α-, β-, and γ-isoforms), putative γ-aminobutyric acid type A receptors, or progesterone membrane receptor component 1 (PGRMC1) (Liu, et al, 2012).…”

“…We and others have shown that progesterone is neuroprotective and might be a useful therapeutic agent for traumatic brain injury (TBI) (Howard, et al, 2015), ischemic stroke injury (Jiang, et al, 2016, Won, et al, 2015), and spinal cord injury (Garcia-Ovejero, et al, 2014). To our knowledge, this is the first study to test the efficacy of progesterone in a clinically relevant ICH model, in which the hematoma develops over several hours.…”

“…Progesterone, primarily a sex hormone, has been shown to exert neuroprotective effects by alleviating inflammatory response and improving neurologic function after ischemic stroke (Jiang, et al, 2011, Jiang, et al, 2009, Jiang, et al, 2016, Won, et al, 2015). To our knowledge, no study has reported a therapeutic effect of progesterone after ICH in middle-aged mice.…”

Non-reproductive system effects of progesterone and its non-selective antagonists mifepristone

“…Для эстрадиола подобный эффект показан не был [53]. Большое количество современных работ посвящено изучению влияния прогестерона на нервную ткань и функцию центральной нервной системы (ЦНС) [25,27,33]. Доказана способность прогестерона связываться с рецепторами к нему в ЦНС и модулировать поведение и настроение млекопитающих через геномный и неге-номный пути влияния [50].…”