Chronic kidney disease in the pathogenesis of acute ischemic stroke

Chronic kidney disease has a graded and independent inverse impact on cerebrovascular health. Both thrombotic and hemorrhagic complications are highly prevalent in chronic kidney disease patients. Growing evidence suggests that in chronic kidney disease patients, ischemic strokes are more common than hemorrhagic strokes. Chronic kidney disease is asymptomatic until an advanced stage, but mild to moderate chronic kidney disease incites various pathogenic mechanisms such as inflammation, oxidative stress, neurohormonal imbalance, formation of uremic toxins and vascular calcification which damage the endothelium and blood vessels. Cognitive dysfunction, dementia, transient infarcts, and white matter lesions are widespread in mild to moderate chronic kidney disease patients. Uremic toxins produced after chronic kidney disease can pass through the blood–brain barrier and mediate cognitive dysfunction and neurodegeneration. Furthermore, chronic kidney disease precipitates vascular risk factors that can lead to atherosclerosis, hypertension, atrial fibrillation, and diabetes. Chronic kidney disease also exacerbates stroke pathogenesis, worsens recovery outcomes, and limits the eligibility of stroke patients to receive available stroke therapeutics. This review highlights the mechanisms involved in the advancement of chronic kidney disease and its possible association with stroke.</jats:p

Gut virome dysbiosis following focal cerebral ischemia in mice

Stroke leads to gut bacterial dysbiosis that impacts the post-stroke outcome. The gut microbiome also contains a high abundance of viruses which might play a crucial role in disease progression and recovery by modulating the metabolism of both host and host’s gut bacteria. We presently analyzed the virome composition (viruses and phages) by shotgun metagenomics in the fecal samples obtained at 1 day of reperfusion following transient focal ischemia in adult mice. Viral genomes, viral auxiliary metabolic genes, and viral protein networks were compared between stroke and sham conditions (stroke vs sham, exclusive to sham and exclusive to stroke). Following focal ischemia, abundances of 2 viral taxa decreased, and 5 viral taxa increased compared with the sham. Furthermore, the abundance of Clostridia-like phages and Erysipelatoclostridiaceae-like phages were altered in the stroke compared with the sham cohorts. This is the first report to show that the gut virome responds acutely to stroke. </jats:p

Abstract WP138: Intermittent Fasting Prevents Ischemic Progression and Promotes Long-Term Recovery

Intermittent fasting (IF) showed a substantial benefit in preventing vascular complications in both humans and animal models. We currently evaluated the effect of IF on post-stroke ischemic progression and motor dysfunction. Cohorts of adult male C57BL/6 mice were subjected to IF (16 h fasting and 8 h feeding) or ad libitum (AL) feeding for 45 days. Mice were subjected to one hour transient middle cerebral artery occlusion (MCAO) on day 45. Infarct size was measured on day 1 and 7 with T2-weighted 4.5T magnetic resonance imaging and Image J software with multi FDF opener plugin. Post-stroke motor deficits were evaluated with rotarod and beam walk tests between days 1 to 14 of reperfusion. Long-term post-stroke survival (till 90 days of reperfusion) was noted in both groups. IF group showed a significant decrease in body weight (by ~5.3g), soft weight (by ~5.6g), and lean weight (~8.1g) compared to AL group as identified by DEXA scanning on day 45 (n=6/group, *p&lt;0.05 by ANOVA with Bonferroni’s multiple comparisons test). The IF group showed significantly decreased brain infarction at both day 1 and day 7 of reperfusion (AL group showed 43% and 39% infarct size on days 1 and 7 while IF group showed 24% and 7.5% infarction on days 1 and 7; n=6-8/group, *p&lt;0.05 by ANOVA with Bonferroni’s multiple comparisons test.) IF cohort also showed significant improvement in post-stroke motor dysfunction identified by fewer foot faults (beam walk test) and more time on rotarod between days 1 to 14 of reperfusion compared with AL cohort. At day 90 of reperfusion, IF mice showed a high survival rate than AL mice (08 of 10 IF mice survived while 04 of 10 AL mice survived). Thus, our studies show that IF significantly preconditions the brain against post-stroke damage and improves the long term functional outcome.</jats:p

Transient Focal Ischemia Significantly Alters the m ⁶ A Epitranscriptomic Tagging of RNAs in the Brain

Background and Purpose— Adenosine in many types of RNAs can be converted to m 6 A (N 6 -methyladenosine) which is a highly dynamic epitranscriptomic modification that regulates RNA metabolism and function. Of all organs, the brain shows the highest abundance of m 6 A methylation of RNAs. As recent studies showed that m 6 A modification promotes cell survival after adverse conditions, we currently evaluated the effect of stroke on cerebral m 6 A methylation in mRNAs and lncRNAs. Methods— Adult C57BL/6J mice were subjected to transient middle cerebral artery occlusion. In the peri-infarct cortex, m 6 A levels were measured by dot blot analysis, and transcriptome-wide m 6 A changes were profiled using immunoprecipitated methylated RNAs with microarrays (44 122 mRNAs and 12 496 lncRNAs). Gene ontology analysis was conducted to understand the functional implications of m 6 A changes after stroke. Expression of m 6 A writers, readers, and erasers was also estimated in the ischemic brain. Results— Global m 6 A levels increased significantly at 12 hours and 24 hours of reperfusion compared with sham. While 139 transcripts (122 mRNAs and 17 lncRNAs) were hypermethylated, 8 transcripts (5 mRNAs and 3 lncRNAs) were hypomethylated (&gt;5-fold compared with sham) in the ischemic brain at 12 hours reperfusion. Inflammation, apoptosis, and transcriptional regulation are the major biological processes modulated by the poststroke differentially m 6 A methylated mRNAs. The m 6 A writers were unaltered, but the m 6 A eraser (fat mass and obesity-associated protein) decreased significantly after stroke compared with sham. Conclusions— This is the first study to show that stroke alters the cerebral m 6 A epitranscriptome, which might have functional implications in poststroke pathophysiology. Visual Overview— An online visual overview is available for this article. </jats:sec

Stem cell treatment after cerebral ischemia regulates the gene expression of apoptotic molecules

Evidence suggests that apoptosis contributes significantly to cell death after cerebral ischemia. Our recent studies that utilized human umbilical cord blood-derived mesenchymal stem cells (hUCBSCs) demonstrated the potential of hUCBSCs to inhibit neuronal apoptosis in a rat model of CNS injury. Therefore, we hypothesize that intravenous administration of hUCBSCs after focal cerebral ischemia would reduce brain damage by inhibiting apoptosis and downregulating the upregulated apoptotic pathway molecules. Male Sprague-Dawley rats were obtained and randomly assigned to various groups. After the animals reached a desired weight, they were subjected to a 2 h middle cerebral artery occlusion (MCAO) procedure followed by 7 days of reperfusion. The hUCBSCs were obtained, cultured, and intravenously injected (0.25 × 10(6) cells or 1 × 10(6) cells) via the tail vein to separate groups of animals 24 h post-MCAO procedure. We performed various techniques including PCR microarray, hematoxylin and eosin, and TUNEL staining in addition to immunoblot and immunofluorescence analysis in order to investigate the effect of our treatment on regulation of apoptosis after focal cerebral ischemia. Most of the apoptotic pathway molecules which were upregulated after focal cerebral ischemia were downregulated after hUCBSCs treatment. Further, the staining techniques revealed a prominent reduction in brain damage and the extent of apoptosis at even the lowest dose of hUCBSCs tested in the present study. In conclusion, our treatment with hUCBSCs after cerebral ischemia in the rodent reduces brain damage by inhibiting apoptosis and downregulating the apoptotic pathway molecules

Impact of Age and Sex on α-Syn (α-Synuclein) Knockdown-Mediated Poststroke Recovery

Background and Purpose: Increased expression of α-Syn (α-Synuclein) is known to mediate secondary brain damage after stroke. We presently studied if α-Syn knockdown can protect ischemic brain irrespective of sex and age. Methods: Adult and aged male and female mice were subjected to transient middle cerebral artery occlusion. α-Syn small interfering RNA (siRNA) was administered intravenous at 30 minutes or 3 hour reperfusion. Poststroke motor deficits were evaluated between day 1 and 7 and infarct volume was measured at day 7 of reperfusion. Results: α-Syn knockdown significantly decreased poststroke brain damage and improved poststroke motor function recovery in adult and aged mice of both sexes. However, the window of therapeutic opportunity for α-Syn siRNA is very limited. Conclusions: α-Syn plays a critical role in ischemic brain damage and preventing α-Syn protein expression early after stroke minimizes poststroke brain damage leading to better functional outcomes irrespective of age and sex. </jats:sec