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In a trial in China, patients with a minor stroke or transient ischemic attack with CYP2C19 loss-of-function alleles as determined by point-of-care testing had modestly fewer second strokes with ticagrelor than with clopidogrel but also had more total bleeding events.

Transient ischemic attack (TIA) refers to a momentary neurologic deficit caused by focal cerebral, spinal or retinal ischemic insult. TIA is associated with a high risk of impending acute ischemic stroke (AIS), a neurologic dysfunction characterized by focal cerebral, spinal or retinal infarction. Understanding the differences in molecular pathways in AIS and TIA has merit for deciphering the underlying cause for neuronal deficits with long-term effects and high risks of morbidity and mortality. In this study, we performed comprehensive investigations into the circulating microRNA (miRNA) profiles of AIS (n = 191) and TIA (n = 61) patients. We performed RNA-Seq on serum samples collected within 24 hrs of clinical diagnosis and randomly divided the study populations into discovery and validation cohorts. We identified a panel of 11 differentially regulated miRNAs at FDR < 0.05. Hsa-miR-548c-5p, -20a-5p, -18a-5p, -484, -652-3p, -486-3p, -24-3p, -181a-5p and -222-3p were upregulated, while hsa-miR-500a-3p and -206 were downregulated in AIS patients compared to TIA patients. We also probed the previously validated gene targets of our identified miRNA panel to highlight the molecular pathways affected in AIS. Moreover, we developed a multivariate classifier with potential utilization as a discriminative biomarker for AIS and TIA patients. The underlying molecular pathways in AIS compared to TIA may be explored further in functional studies for therapeutic targeting in clinical translation.

Mitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK1/Parkin-mediated mitophagy in ischemic tolerance induced by hypoxic postconditioning (HPC) with 8% O 2 against transient global cerebral ischemia (tGCI). Hence, we aimed to test the hypothesis that HPC-mediated PINK1/Parkin-induced mitochondrial ubiquitination and promotes mitophagy, thus exerting neuroprotection in the hippocampal CA1 subregion against tGCI. We found that mitochondrial clearance was disturbed at the late phase of reperfusion after tGCI, which was reversed by HPC, as evidenced by the reduction of the translocase of outer mitochondrial membrane 20 homologs (TOMM20), translocase of inner mitochondrial membrane 23 (TIMM23) and heat shock protein 60 (HSP60) in CA1 after HPC. In addition, HPC further increased the ratio of LC3II/I in mitochondrial fraction and promoted the formation of mitophagosomes in CA1 neurons after tGCI. The administration of lysosome inhibitor chloroquine (CQ) intraperitoneally or mitophagy inhibitor (Mdivi-1) intracerebroventricularly abrogated HPC-induced mitochondrial turnover and neuroprotection in CA1 after tGCI. We also found that HPC activated PINK1/Parkin pathway after tGCI, as shown by the augment of mitochondrial PINK1 and Parkin and the promotion of mitochondrial ubiquitination in CA1. In addition, PINK1 or Parkin knockdown with small-interfering RNA (siRNA) suppressed the activation of PINK1/Parkin pathway and hampered mitochondrial clearance and attenuated neuroprotection induced by HPC, whereas PINK1 overexpression promoted PINK1/Parkin-mediated mitophagy and ameliorated neuronal damage in CA1 after tGCI. Taken together, the new finding in this study is that HPC-induced neuroprotection against tGCI through promoting mitophagy mediated by PINK1/Parkin-dependent pathway.

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL.MethodsPatients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities.Results128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity.ConclusionsA careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.

PurposeInconclusive and limited results have been reported on the clinical utility of CYP2C19 genotyping in stroke/TIA patients of non-East Asian ancestries. We herein performed an updated systematic review and meta-analysis to quantitatively estimate the association of CYP2C19 loss-of function (LOF) status with efficacy and safety of clopidogrel-based antiplatelet therapy in non-East Asian patients affected by stroke or TIA.MethodsA comprehensive search was performed up to July 2023 using PubMed, Web of Knowledge, and Cochrane Library databases. The clinical outcomes investigated were stroke, composite vascular events and bleeding. Pooled estimates were calculated as risk ratios (RR) with 95% CI using the Mantel– Haenszel random-effects model. The quality of evidence was assessed using the GRADEpro tool.ResultsA total number of 1673 stroke/TIA patients from 8 non-East Asian studies, published between 2014 and 2022, were included in the systematic review. Clopidogrel-treated carriers of CYP2C19 LOF alleles were found at increased risk of stroke compared to non-carriers (RR: 1.68, 95%CI: 1.04–2.71, P = 0.03). However, no significant association was observed with the risk of composite vascular events (RR: 1.15, 95%CI: 0.58–2.28, P = 0.69) or bleeding (RR: 0.84, 95%CI: 0.38–1.86, P = 0.67). Similarly, European ancestry patients carrying CYP2C19 LOF alleles displayed a higher risk of stroke (RR: 2.69 (1.11–6.51, P = 0.03), but not of composite vascular events or bleeding.ConclusionThe present updated meta-analysis provides moderate quality evidence of association between CYP2C19 LOF alleles and an increased risk of stroke in non-East Asian patients with stroke/TIA after receiving clopidogrel therapy. Further large pharmacogenetic studies are still warranted to corroborate these findings.

The aggregated risk of recurrent stroke in stroke/transient ischemic attack (TIA) patients carrying CYP2C19 LoF alleles who take clopidogrel has not been investigated recently, and the available research is limited. This study aimed to perform an updated meta‐analysis to assess the association between CYP2C19 LoF alleles and the risk of recurrent stroke in patients taking clopidogrel. Databases were searched for the literature on eligible studies. The end points were recurrent stroke, composite vascular events, and bleeding events. Odds ratios (ORs) were calculated using RevMan software, where p < 0.05 was considered statistically significant. Patients carrying CYP2C19 LoF alleles who were treated with clopidogrel had a significantly increased risk of recurrent ischemic stroke compared with non‐carriers (OR 2.18, 96% CI 1.80–2.63; p < 0.00001). The risk of recurrent stroke was only significantly different in Asian patients (OR 2.29, 96% CI 1.88–2.80; p < 0.00001) but not in patients of other ethnicities; however, there were a limited number of studies in other ethnic groups. Both observational studies (OR 2.83, 96% CI 2.20–3.65; p < 0.00001) and RCTs (OR 1.48, 96% CI 1.10–1.98; p = 0.009) found associations with a significantly increased risk of recurrent ischemic stroke. Asian stroke patients or TIA patients carrying CYP2C19 LoF alleles and taking clopidogrel were at a significantly higher risk of recurrent ischemic stroke than non‐carriers. Significantly increased risk of recurrent ischemic stroke was found in both observational studies and RCTs.

Medically relevant roles of receptor-mediated sphingosine 1-phosphate (S1P) signaling have become a successful or promising target for multiple sclerosis or cerebral ischemia. Animal-based proof-of-concept validation for the latter is particularly through the neuroprotective efficacy of FTY720, a non-selective S1P receptor modulator, presumably via activation of S1P1. In spite of a clear link between S1P signaling and cerebral ischemia, it remains unknown whether the role of S1P1 is pathogenic or neuroprotective. Here, we investigated the involvement of S1P1 along with its role in cerebral ischemia using a transient middle cerebral artery occlusion (“tMCAO”) model. Brain damage following tMCAO, as assessed by brain infarction, neurological deficit score, and neural cell death, was reduced by oral administration of AUY954, a selective S1P1 modulator as a functional antagonist, in a therapeutic paradigm, indicating that S1P1 is a pathogenic mediator rather than a neuroprotective mediator. This pathogenic role of S1P1 in cerebral ischemia was reaffirmed because tMCAO-induced brain damage was reduced by genetic knockdown with an intracerebroventricular microinjection of S1P1 shRNA lentivirus into the brain. Genetic knockdown of S1P1 or AUY954 exposure reduced microglial activation, as assessed by reduction in the number of activated microglia and reversed morphology from amoeboid to ramified, and microglial proliferation in ischemic brain. Its role in microglial activation was recapitulated in lipopolysaccharide-stimulated primary mouse microglia, in which the mRNA expression level of TNF-α and IL-1β, well-known markers for microglial activation, was reduced in microglia transfected with S1P1 siRNA. These data suggest that the pathogenic role of S1P1 is associated with microglial activation in ischemic brain. Additionally, the pathogenic role of S1P1 in cerebral ischemia appears to be associated with the blood-brain barrier disruption and brain-derived neurotrophic factor (BDNF) downregulation. Overall, findings from the current study clearly identify S1P1 signaling as a pathogenic factor in transient focal cerebral ischemia, further implicating S1P1 antagonists including functional antagonists as plausible therapeutic agents for human stroke.

Aims Transient ischemic attack (TIA) serves as a crucial precursor to a potential stroke. Angiogenesis is essential for the renovation of the damaged brain after TIA. This study aimed to elucidate the role of miRNA‐21a‐5p in angiogenesis following TIA and unravel the underlying mechanisms. Methods In vivo and in vitro TIA models were established using the modified suture middle cerebral artery occlusion and oxygen–glucose deprivation/reoxygenation methods. Differentially expressed miRNAs in the TIA group versus the control group were identified using small RNA sequencing. The putative target genes of miRNA‐21a‐5p were predicted via bioinformatics analysis and validated using a dual luciferase reporter gene assay. TIA models were then treated with miRNA‐21a‐5p antagomir/agomir or/and an adeno‐associated virus interfering with the target gene to assess the effects of miRNA‐21a‐5p and the identified target gene on angiogenesis after TIA. Results MiRNA‐21a‐5p was the miRNA with the most significant changes after TIA. RBMS3 was identified as a target gene for miRNA‐21a‐5p. Downregulation of miRNA‐21a‐5p expression reduced angiogenesis in animal and cellular models of TIA, and miRNA‐21a‐5p upregulation had a completely opposite effect. RBMS3 suppression reversed miRNA‐21a‐5p knockdown‐mediated inhibition of angiogenesis in TIA models. Moreover, the TGFBR1/SMAD2/3 pathway was found to be downstream for miRNA‐21a‐5p/RBMS3. Conclusion MiRNA‐21a‐5p conferred neuroprotective effects against TIA by enhancing angiogenesis through the RBMS3/TGFBR1/SMAD2/3 pathway. A schematic diagram showing the modulatory effect of miRNA‐21a‐5p on angiogenesis after TIA. The miRNA‐21a‐5p levels were elevated after TIA. MiRNA‐21a‐5p inhibited the expression of the target gene RBMS3 by binding to its 3′UTR site, and then activated the TGFBR1/SMAD2/3 signaling pathway, thereby enhancing angiogenesis.

Understanding the root causes of neuronal vulnerability to ischemia is paramount to the development of new therapies for stroke. Transient global cerebral ischemia (tGCI) leads to selective neuronal cell death in the CA1 sub-region of the hippocampus, while the neighboring CA3 sub-region is left largely intact. By studying factors pertaining to such selective vulnerability, we can develop therapies to enhance outcome after stroke. Using untargeted liquid chromatography-mass spectrometry, we analyzed temporal metabolomic changes in CA1 and CA3 hippocampal areas following tGCI in rats till the setting of neuronal apoptosis. 64 compounds in CA1 and 74 in CA3 were found to be enriched and statistically significant following tGCI. Pathway analysis showed that pyrimidine and purine metabolism pathways amongst several others to be enriched after tGCI in CA1 and CA3. Metabolomics analysis was able to capture very early changes following ischemia. We detected 6 metabolites to be upregulated and 6 to be downregulated 1 hour after tGCI in CA1 versus CA3. Several metabolites related to apoptosis and inflammation were differentially expressed in both regions after tGCI. We offer a new insight into the process of neuronal apoptosis, guided by metabolomic profiling that was not performed to such an extent previously.

Background and purposeThe ring finger protein 213 gene (RNF213) p.R4810K variant increased the risk of acute ischaemic stroke (AIS) attributable to intracranial arterial stenosis (ICAS) in the Japanese and Korean populations. In this study, we aimed to examine the prevalence of the RNF213 p.R4810K variant in Chinese patients with AIS or transient ischaemic attack and identify the phenotype of the carriers.MethodsWe analysed data from the Third China National Stroke Registry. All included participants were divided into two groups by carrier status of the p.R4810K variant. The aetiological classification was conducted according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. The presence of ICAS and extracranial arterial stenosis (ECAS) was defined as 50%–99% stenosis or occlusion of any intracranial and extracranial artery. Logistic regression models and Cox regression models were used to evaluate the association of the p.R4810K variant with TOAST classification, stenosis phenotypes and clinical outcomes.ResultsA total of 10 381 patients were enrolled, among which 56 (0.5%) had the heterozygote GA genotype for p.R4810K. The variant carriers were younger (p=0.01), and more likely to suffer from peripheral vascular disease (p=0.04). The p.R4810K variant was associated with large-artery atherosclerosis (LAA) (adjusted OR=1.94, 95% CI 1.13 to 3.33), anterior circulation stenosis (adjusted OR=2.12, 95% CI 1.23 to 3.65) and ECAS (adjusted OR=2.29, 95% CI 1.16 to 4.51). Nevertheless, the p.R4810K variant was not associated with recurrence, poor functional outcome and mortality at 3 months and 1 year.ConclusionsThe RNF213 p.R4810K variant was associated with LAA, anterior circulation stenosis and ECAS in Chinese patients. Given the low carrying rate and only 1-year follow-up information, caution should be taken to interpret our findings in no statistically significant association between the p.R4810K variant and stroke prognosis in Chinese patients.