The role of Raloxifene on neurological score, BDNF level and brain edema after traumatic brain injury in Female mice: the role of Negative and positive MMP

Background and Aim: raloxifene (a selective estrogen receptor modulator), a selective estrogen receptor modulator, has successfully been used to treat several animal models of brain injury, but the underlying mechanisms remain unclear. This study was undertaken to evaluate the effect of raloxifene on the toll-like receptor ۴ (TLR۴)- and nuclear factor-KB (NF-kB)-related inflammatory signaling pathway and secondary brain injury in rats after subarachnoid hemorrhage (SAH). The effect of continuous immobilization stress on anxiety-like behaviour, spatial learning and memory, and a forced swim test in NMRI male mice was examined in the present study. The plasma cortisol changes and the brain-derived neurotrophic factor (BDNF) were also evaluated. Adult male Sprague-Dawley rats were divided into four groups: (۱) control group (n=۲۸); (۲) SAH group (n=۲۸); (۳) SAH+ vehicle group (n=۲۸); and (۴) SAH+ raloxifene group (n=۲۸). All SAH animals were subjected to injection of autologous blood into the prechiasmatic cistern once on day ۰. In SAH + raloxifene group, raloxifene was administered intraperitoneally at a dose of ۵ mg/kg at ۲ h, ۱۲ h, and ۳۶ h after SAH. In the first set of experiments, brain samples were extracted and evaluated at ۴۸ h after SAH. In the second set of experiments, the Morris water maze was used to investigate cognitive and memory changes. Methods: Following intraperitoneal anesthesia of an animal with urethane (۱,۰۰۰ mg/kg), the animal's head was fixed in the stereotactic frame. The body temperature was maintained at ۳۷.۵±۰.۵°C with an automatic heating pad (LSI Letica Scientific Instruments, Barcelona, Spain). The tail artery was cannulated to measure mean arterial blood pressure (MABP) and to obtain blood samples. The animals were placed in a stereotaxic frame (David Kopf Instruments). The levels of inflammatory mediators were quantified using specific ELISA kits for rats according to the manufacturers' instructions (TNF-α from Diaclone Research, Besançon, France; IL-۱ẞ, IL-۶ from Biosource Europe SA, Nivelles, Belgium) and our previous study [۱۶]. Values were expressed as ng/g protein. Results: Post-SAH raloxifene administration may attenuate TLR۴/NF-kappaB-mediated inflammatory response in the rat brain and result in abatement of the development of EBI and cognitive dysfunction after SAH. Conclusion: We found that treatment with raloxifene markedly inhibited the protein expressions of TLR۴, NF-κB and the downstream inflammatory agents, such as interleukin-۱ẞ (IL-۱ẞ), tumor necrosis factor-α (TNF-α), interleukin-۶ (IL-۶), and intercellular adhesion molecule-۱ (ICAM-۱). Administration of raloxifene following SAH significantly ameliorated the early brain injury (EBI), such as brain edema, blood-brain barrier (BBB) impairment, and clinical behavior scale. Learning deficits induced by SAH were markedly alleviated after raloxifene treatment.

کلیدواژه ها:

raloxifene ، Early brain injury ، Learning deficits ، Subarachnoid hemorrhage ، Inflammation