Sex differences in minocycline-induced neuroprotection after experimental stroke.
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ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC2855881 | biostudies-literature | 2009 Apr
REPOSITORIES: biostudies-literature
Publications
Sex differences in minocycline-induced neuroprotection after experimental stroke.
Li Jun J McCullough Louise D LD
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20090204 4
Minocycline is neuroprotective in clinical and experimental stroke studies, due in part to its ability to inhibit poly (ADP-ribose) polymerase. Previous preclinical data have shown that interference with poly (ADP-ribose) polymerase signaling leads to sex-specific neuroprotection, reducing stroke injury only in males. In this study, we show that minocycline is ineffective at reducing ischemic damage in females after middle cerebral artery occlusion, likely due to effects on poly (ADP-ribose) pol ...[more]
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Project description:Ischemic stroke triggers a series of complex pathophysiological processes including autophagy. Differential activation of autophagy occurs in neurons derived from males versus females after stressors such as nutrient deprivation. Whether autophagy displays sexual dimorphism after ischemic stroke is unknown. We used a cerebral ischemia mouse model (middle cerebral artery occlusion, MCAO) to evaluate the effects of inhibiting autophagy in ischemic brain pathology. We observed that inhibiting autophagy reduced infarct volume in males and ovariectomized females. However, autophagy inhibition enhanced infarct size in females and in ovariectomized females supplemented with estrogen compared to control mice. We also observed that males had increased levels of Beclin1 and LC3 and decreased levels of pULK1 and p62 at 24 h, while females had decreased levels of Beclin1 and increased levels of ATG7. Furthermore, the levels of autophagy markers were increased under basal conditions and after oxygen and glucose deprivation in male neurons compared with female neurons in vitro. E2 supplementation significantly inhibited autophagy only in male neurons, and was beneficial for cell survival only in female neurons. This study shows that autophagy in the ischemic brain differs between the sexes, and that autophagy regulators have different effects in a sex-dependent manner in neurons.
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Project description:Physical hypothermia has long been considered a promising neuroprotective treatment of ischemic stroke, but the treatment's various complications along with the impractical duration and depth of therapy significantly narrow its clinical scope. In the present study, the model of reversible right middle cerebral artery occlusion (MCAO) for 2?h was used. We combined hypothermia (33-35?°C for 1?h) with phenothiazine neuroleptics (chlorpromazine & promethazine) as additive neuroprotectants, with the aim of augmenting its efficacy while only using mild temperatures. We also investigated its therapeutic effects on the Phosphatidylinositol 3 kinase/Protein kinase B (PI3K/Akt) apoptotic pathway. The combination treatment achieved reduction in ischemic rat temperatures in the rectum, cortex and striatum significantly (P?<?0.01) faster than hypothermia alone, accompanied by more obvious (P?<?0.01) reduction of brain infarct volume and neurological deficits. The combination treatment remarkably (P?<?0.05) increased expression of p-Akt and anti-apoptotic proteins (Bcl-2 and Bcl-xL), while reduced expression of pro-apoptotic proteins (AIF and Bax). Finally, the treatment's neuroprotective effects were blocked by a p-Akt inhibitor. By combining hypothermia with phenothiazines, we significantly enhanced the neuroprotective effects of mild hypothermia. This study also sheds light on the possible molecular mechanism for these effects which involves the PI3K/Akt signaling and apoptotic pathway.
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Project description:Increasing evidence suggests that sex differences exist in the etiology, presentation, treatment, and outcome from stroke. The reasons for these sex disparities are becoming increasingly explored, but large gaps still exist in our knowledge. Experimental studies over the past several years have demonstrated intrinsic sex differences both in vivo and in animal models which may have relevance to our understanding of stroke in clinical populations. A greater understanding of the differences and similarities between males and females with respect to the risk factors, pathophysiology, and response to stroke will facilitate the design of future clinical trials and enhance the development of treatment strategies to improve stroke care in both sexes. This article reviews the current literature on sex differences in stroke with an emphasis on the clinical data, incorporating an analysis of bench research as it pertains to the bedside.
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Project description:AimsSildenafil, a phosphodiesterase type 5 inhibitor, has been found to produce functional recovery in ischemic rats by increasing the cGMP level and triggering neurogenesis. The aim of this study was to investigate further sildenafil mechanisms.MethodsMale Sprague-Dawley rats underwent middle cerebral artery occlusion and reperfusion, followed by intraperitoneal or intravenous treatment of sildenafil starting 2 h later. Behavioral tests were performed on day 1 or day 7 after reperfusion, while cerebral infarction, edema, Nissl staining, Fluoro-Jade B staining, and electron microscopy studies were carried out 24 h poststroke. The cGMP-dependent Nogo-66 receptor (Nogo-R) pathway, synaptophysin, PSD-95/neuronal nitric oxide synthases (nNOS), brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB), and nerve growth factor (NGF)/tropomyosin-related kinase A (TrkA) were measured.ResultsSildenafil enhanced neurological recovery and inhibited infarction, even following delayed administration 4 h after stroke onset. Furthermore, sildenafil reduced the loss of neurons and modulated the expressions of the cGMP-dependent Nogo-R pathway. Moreover, sildenafil protected the structure of synapses and mediated the expressions of synaptophysin, PSD-95/nNOS, BDNF/TrkB, and NGF/TrkA.ConclusionsSildenafil produces significant neuroprotective effects on injured neurons in acute stroke, and these are mediated by the cGMP-dependent Nogo-R pathway, NGF/TrkA, and BDNF/TrkB.
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