No abstract

No abstract

Stroke risk and poor stroke outcomes in postmenopausal women have usually beeen attributed to decreased levels of estrogen. However, two lines of evidence suggest that this hormone may not be solely responsible for elevated stroke risk in this population. First, the increased risk for CVD and stroke occurs much earlier than menopause at a time when estrogen levels are not yet reduced. Second, estrogen therapy has not successfully reduced stroke risk in all studies. Other sex hormones may therefore also contribute to stroke risk. Prior to menopause, levels of the gonadotrophin Follicle Stimulating Hormone (FSH) are elevated while levels of the gonadal peptide inhibin are lowered, indicating an overall decrease in ovarian reserve. Similarly, reduced estrogen levels at menopause significantly increase the ratio of androgens to estrogens. In view of the evidence that androgens may be unfavorable for CVD and stroke, this elevated ratio of testosterone to estrogen may also contribute to the postmenopause-associated stroke risk. This review synthesizes evidence from different clinical populations including natural menopause, surgical menopause, women on chemotherapy, and preclinical stroke models to dissect the role of ovarian hormones and stroke risk and outcomes.

Cognitive impairment and memory loss are commonly seen after stroke and a third of patients will develop signs of dementia a year after stroke. Despite a large number of studies on the beneficial effects of neuroprotectants, few studies have examined the effects of these compounds/interventions on long-term cognitive impairment. Our previous work showed that the microRNA mir363-3p reduced infarct volume and sensory-motor impairment in the acute stage of stroke in middle-aged females but not males. Thus, the present study determined the impact of mir363-3p treatment on stroke-induced cognitive impairment in middle-aged females. Sprague–Dawley female rats (12 months of age) were subjected to middle cerebral artery occlusion (MCAo; or sham surgery) and injected (iv) with mir363-3p mimic (MCAo + mir363-3p) or scrambled oligos (MCAo + scrambled) 4 h later. Sensory-motor performance was assessed in the acute phase (2–5 days after stroke), while all other behaviors were tested 6 months after MCAo (18 months of age). Cognitive function was assessed by the novel object recognition test (declarative memory) and the Barnes maze (spatial memory). The MCAo + scrambled group showed reduced preference for a novel object after the stroke and poor learning in the spatial memory task. In contrast, mir363-3p treated animals were similar to either their baseline performance or to the sham group. Histological analysis showed significant deterioration of specific white matter tracts due to stroke, which was attenuated in mir363-3p treated animals. The present data builds on our previous finding to show that a neuroprotectant can abrogate the long-term effects of stroke.

Introduction: Stroke survivors suffer from long-term physical, cognitive and affective disabilities. These disabilities lower the quality of life, contribute to social isolation and anhedonia, and clinical disorders such as post-stroke depression (PSD), which disproportionately affects women. Preclinical studies show that lesions of the substantia nigra (pars compacta) impair both motor performance and reward seeking behavior. Neurons from the SNc project to the striatum, a region that is significantly infarcted by middle cerebral artery occlusion (MCAo). Hypothesis: Ischemia induced by MCAo leads to retrograde degeneration of the SNc pathway projecting to the striatum. Methods: Middle-aged Sprague-Dawley female rats (12 months old) were subjected to ischemic stroke using a silicon-coated nylon filament suture to occlude the middle cerebral artery (MCA) which was removed 75min after to allow for reperfusion. After 14 weeks of survival, rats were again anesthetized and Fluorogold (Flg) was injected into the left and right striatum. Four days later, animals were overdosed with anesthetic, perfused with saline and formaldehyde and the brain removed for cryosectioning. In three sections per animal, Flg-labeled cells in the SNc were counted on both hemispheres, using fluorescent illumination. Results: Flg-injections into the striatum retrogradely labeled neurons in the midbrain. There was a 35% decrease (p<0.009) in the number of Flg labeled SNc cells in the ischemic hemisphere (85.5+18.2) as compared to the non-ischemic hemisphere (132.4+22.7). The reduced number of projection neurons in the ischemic hemisphere is consistent with the loss of trophic support from the striatum. Conclusions: SNc neurons are a critical component of reward pathway and motor function, hence degeneration of these neurons could lead to long term motor deficits and depressive symptoms including anhedonia that are common after stroke.

There is an error in Figure 2a image. Figure 2a is changed in the corrected version and all other sub parts are correct.

Introduction: Stroke survivors suffer from long-term physical, cognitive and affective disabilities. Post-stroke depression (PSD), which develops in over one-third of the survivors, disproportionately affects women. Conventional anti-depressant therapies are not as effective in this population of PSD patients. Hypothesis: Mir363-3p treatment after stroke will preserve the meso-striatal ‘reward’ pathway in the ischemic hemisphere, and consequently improve chronic development of PSD. Methods: Middle-aged SD female rats (12 months) were subjected to ischemic stroke using a vasoconstrictor, Endothelin-1, and randomly assigned to one of two treatment groups: scrambled oligos or mir363-3p mimic. T Maze cost/benefit task (TMCBT), Social Interaction (SI) and Forced Swim Test (FST) were performed up to 100 days after stroke to assess depressive-like behavior. Thereafter, rats were injected with Fluorogold (Flg) into the left and right striatum. Four days later, rats were overdosed with anesthetic, perfused with saline and formaldehyde and the brain removed for cryosectioning. Flg-labeled cells in the VTA and SNc were counted in both hemispheres, using fluorescent illumination. Results: After stroke, there was a reduction of high-reward choice (anhedonia) at 98d in the TMCBT in the scrambled group as compared to the mir363-3p group (p=0.0343). SI at 100d decreased 3 fold from the baseline for scrambled group (p=0.0002), but not the mir363-3p group. Similarly, FST at 100d showed significant increase in immobility (helplessness) from baseline for the scrambled group (p=0.0030), but not the mir363-3p group. Neurotrophin levels measured at 3+ months after stroke indicated that circulating BDNF were lower in the scrambled group as compared to Mir363-3p group (p=0.0170). This decrease in BNDF was also accompanied by a reduction in the number of retrogradely-labeled cells in the SNc and VTA in scrambled group. (p=0.022; ischemic Vs non ischemic hemisphere). Conclusions: Our previous work shows that mir363-3p treatment given 4h after stroke reduces infarct volume in the acute phase (5days). The current studies show that post-stroke mir363-3p treatment improves long-term stroke disability (3+ months) by improving depressive-like behavior.

No abstract