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Mir363-3p Treatment Attenuates Long-Term Cognitive Deficits Precipitated by an Ischemic Stroke in Middle-Aged Female Rats.

ABSTRACT: 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.

SUBMITTER: Panta A

PROVIDER: S-EPMC7550720 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Mir363-3p Treatment Attenuates Long-Term Cognitive Deficits Precipitated by an Ischemic Stroke in Middle-Aged Female Rats.

Panta Aditya A Montgomery Karienn K Nicolas Marissa M Mani Kathiresh K KK Sampath Dayalan D Sohrabji Farida F

Frontiers in aging neuroscience 20200929

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 male ...[more]

PMID: 33132904

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Project description:Background. Women account for 60% of all stroke deaths and are more often permanently disabled than men, despite their higher observed stroke incidence. Considering the clinical population affected by stroke, an obvious drawback is that many pre-clinical and clinical studies only investigate young males. To improve therapeutic translation from bench to bedside, we believe that it is advantageous to include both sexes in experimental models of stroke. The aims of this study were to identify early cerebral vascular responses to ischemic stroke in females, compare the differential gene expression patterns with those seen in males, and identify potential new therapeutic targets. Results. Transient middle cerebral artery occlusion (tMCAO) was used to induce stroke in both female and male rats, the middle cerebral arteries (MCAs) were isolated 3 hours post reperfusion and RNA was extracted. Affymetrix whole transcriptome expression profiling was performed on female (n = 12) MCAs to reveal differentially expressed genes. In total, 1076 genes had an increased expression and 879 genes a decreased expression in the occluded MCAs as compared with the control MCAs from female rats. An enrichment of genes related to apoptosis, regulation of transcription, protein autophosphorylation, inflammation, oxidative stress, and tissue repair and recovery were seen in the occluded MCA. The high expression genes chosen for qPCR verification (Adamts4, Olr1, JunB, Fosl1, Serpine1, S1pr3, Ccl2 and Socs3) were all shown to be upregulated in the same manner in both females and males after tMCAO (p < 0.05; n = 23). When comparing the differentially expressed genes in female MCAs (occluded and non-occluded) with our previous findings in males after tMCAO, a total of 297 genes overlapped (all groups had 32 genes in common). Conclusions. The cascades of processes initiated in the vasculature following reperfusion are complex. Dynamic gene expression alterations were observed in the occluded MCAs, and to a less pronounced degree in the non-occluded MCAs. Dysregulation of inflammation and blood-brain barrier breakdown are possible pharmacological targets. The sample of genes (<1% of differentially expressed genes) validated for this microarray did not reveal any sex differences.

Project description:Perforin-mediated cytotoxicity plays a crucial role in microbial defense, tumor surveillance, and primary autoimmune disorders. However, the contribution of the cytolytic protein perforin to ischemia-induced secondary tissue damage in the brain has not been fully investigated. Here, we examined the kinetics and subpopulations of perforin-positive cells and then evaluated the direct effects of perforin-mediated cytotoxicity on outcomes after ischemic stroke. Using flow cytometry, we showed that perforin+CD45+ immune cells could be detected at 12 h and that the percentage of these cells increased largely until on day 3 and then significantly declined on day 7. Surprisingly, the percentage of Perforin+CD45+ cells also unexpectedly increased from day 7 to day 14 after ischemic stroke in Perforin1-EGFP transgenic mice. Our results suggested that Perforin+CD45+ cells play vital roles in the ischemic brain at early and late stages and further suggested that Perforin+CD45+ cells are a heterogeneous population. Surprisingly, in addition to CD8+ T cells, NK cells, and NKT cells, central nervous system (CNS)-resident immune microglia, which are first triggered and activated within minutes after ischemic stroke in mice, also secreted perforin during ischemic brain injury. In our study, the percentage of perforin+ microglia increased from 12 h after ischemic stroke, increased largely until on day 3 after ischemic stroke, and then moderately declined from days 3 to 7. Intriguingly, the percentage of perforin+ microglia also dramatically increased from days 7 to 14 after ischemic stroke. Furthermore, compared with wild-type littermates, Perforin 1-/- mice exhibited significant increases in the cerebral infarct volume, neurological deficits, and neurogenesis and inhibition of neurotoxic astrogliosis. Interestingly, the number of CD45+CD3+ T cells was significantly decreased in Perforin 1-/- mice compared with their wild-type littermates, especially the number of γδ T cells. In addition, Perforin 1-/- mice had lower levels of IL-17 than their wild-type littermates. Our results identified a critical function of perforin-mediated neurotoxicity in the ischemic brain, suggesting that targeting perforin-mediated neurotoxicity in brain-resident microglia and invading perforin+CD45+ immune cells may be a potential strategy for the treatment of ischemic stroke.

Dataset Information

Mir363-3p Treatment Attenuates Long-Term Cognitive Deficits Precipitated by an Ischemic Stroke in Middle-Aged Female Rats.

Publications

Mir363-3p Treatment Attenuates Long-Term Cognitive Deficits Precipitated by an Ischemic Stroke in Middle-Aged Female Rats.

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