Progesterone Increases Circulating Endothelial Progenitor Cells and Induces Neural Regeneration after Traumatic Brain Injury in Aged Rats

Abstract

Vascular remodeling plays a key role in neural regeneration in the injured brain. Circulating endothelial progenitor cells (EPCs) are a mediator of the vascular remodeling process. Previous studies have found that progesterone treatment of traumatic brain injury (TBI) decreases cerebral edema and cellular apoptosis and inhibits inflammation, which in concert promote neuroprotective effects in young adult rats. However, whether progesterone treatment regulates circulating EPC level and fosters vascular remodeling after TBI have not been investigated. In this study, we hypothesize that progesterone treatment following TBI increases circulating EPC levels and promotes vascular remodeling in the injured brain in aged rats. Male Wistar 20-month-old rats were subjected to a moderate unilateral parietal cortical contusion injury and were treated with or without progesterone (n = 54/group). Progesterone was administered intraperitoneally at a dose of 16mg/kg at 1 h post-TBI and was subsequently injected subcutaneously daily for 14 days. Neurological functional tests and immnunostaining were performed. Circulating EPCs were measured by flow cytometry. Progesterone treatment significantly improved neurological outcome after TBI measured by the modified neurological severity score, Morris Water Maze and the long term potentiation in the hippocampus as well as increased the circulating EPC levels compared to TBI controls ( p < 0.05). Progesterone treatment also significantly increased CD34 and CD31 positive cell number and vessel density in the injured brain compared to TBI controls ( p < 0.05). These data indicate that progesterone treatment of TBI improves multiple neurological functional outcomes, increases the circulating EPC level, and facilitates vascular remodeling in the injured brain after TBI in aged rats.

Electrical stimulation improved cognitive deficits associated with traumatic brain injury in rats

“…Consistent with these findings, studies have also indicated a positive correlation between the number of EPCs and the clinical outcomes of patients with TBI (Liu et al., 2011). Moreover, our previous study showed that the administration of progesterone increased the number of circulating EPCs and induced neural regeneration after TBI in aged rats (Li et al., 2012). Furthermore, TBI rats treated with atorvastatin exhibited better neurological outcomes with an increasing number of EPCs (Li et al., 2012; Wang et al., 2012).…”

“…Moreover, our previous study showed that the administration of progesterone increased the number of circulating EPCs and induced neural regeneration after TBI in aged rats (Li et al., 2012). Furthermore, TBI rats treated with atorvastatin exhibited better neurological outcomes with an increasing number of EPCs (Li et al., 2012; Wang et al., 2012). In this study, we determined that the level of EPCs was significantly increased in the peripheral blood with ES, and better cognitive function was identified in the same group.…”

Progesterone sharpens temporal response profiles of sensory cortical neurons in animals exposed to traumatic brain injury.

“…It is possible that the response profile sharpening in P4-treated TBI animals is a long-term consequence of short-term P4 actions that subsequently affect only the response profile but not response strength. Following TBI, P4 removes free radicals and decreases edema, limits lipid peroxidation and consequently curbs the size of BBB lesions, 57 regulates the expression of proinflammatory cytokines, 68 promotes vascular repair via upregulation of endothelial progenitor cells, 69 and limits mitochondrial dysfunction, stemming apoptosis and reducing excitatory amino acid induced excitotoxicity. 18,33,47,48,[70][71][72] Amelioration of some of these short-term TBI-induced pathologies by P4 may help to normalize some of the later pathological mechanisms responsible for the broad response profile seen across the entire cortical column in P4-untreated TBI animals.…”

Rehabilitation Considerations for Traumatic Brain Injury in the Geriatric Population: Epidemiology, Neurobiology, Prognosis, and Management

“…The experimental literature suggests that the provision of female sex hormones can attenuate oxidative damage [40] and lessen the evolution of other secondary injury cascades that occur early after TBI [41]. Also, increasing evidence shows that progesterone can improve mortality and outcomes following a TBI, via effects on vascular remodeling, restoration of the bloodbrain barrier, and attenuating edema, inflammation, and cell death [42][43][44]. Estrogen therapy can provide these neurologic protective effects in both men and women [43,44], but specific effects in the aging patient with TBI are unclear.…”