The role of family support in the self-rated health of older adults in eastern Nepal: findings from a cross-sectional study.

BACKGROUND: Nepal's low fertility rate and increasing life expectancy have resulted in a burgeoning older population. For millennia, filial piety shaped family cohesion and helped Nepali older adults achieve positive outcomes, but recently, it has been eroding. Furthermore, there are not enough institutional support options or alternatives to family-based care to deal with the biosocial needs of older adults. This study explored the association between family support and self-rated health among Nepali older adults. METHODS: A community-based cross-sectional survey in eastern Nepal's two districts, Sunsari and Morang, interviewed 847 older adults (≥ 60 years). The final analytical sample was 844. Participants were asked whether they received assistance with various aspects of daily life and activities of daily living from their families. Multivariable logistic regression examined the association between family support and self-rated health. RESULTS: Participants who received support with various aspects of daily life had 43% higher odds of good health, but after adjusting for control variables, the result only approached statistical significance (p = 0.087). Those who received family assistance with activities of daily living had nearly four times higher odds (OR: 3.93; 95% CI: 2.58 - 5.98) of reporting good health than participants who lacked this support. CONCLUSIONS: Given the important role of family support in Nepali older adults' health, government programs and policies should create a conducive environment to foster family-based care until more comprehensive policies for older adults' care can be put into effect. The results of this study can also help shape the global aging environment by highlighting the need for family support in older care, particularly in low-income nations with declining traditional care systems and weak social security policies.

Role of transcription factors, noncoding RNAs, epitranscriptomics, and epigenetics in post-ischemic neuroinflammation.

Post-stroke neuroinflammation is pivotal in brain repair, yet persistent inflammation can aggravate ischemic brain damage and hamper recovery. Following stroke, specific molecules released from brain cells attract and activate central and peripheral immune cells. These immune cells subsequently release diverse inflammatory molecules within the ischemic brain, initiating a sequence of events, including activation of transcription factors in different brain cell types that modulate gene expression and influence outcomes; the interactive action of various noncoding RNAs (ncRNAs) to regulate multiple biological processes including inflammation, epitranscriptomic RNA modification that controls RNA processing, stability, and translation; and epigenetic changes including DNA methylation, hydroxymethylation, and histone modifications crucial in managing the genic response to stroke. Interactions among these events further affect post-stroke inflammation and shape the depth of ischemic brain damage and functional outcomes. We highlighted these aspects of neuroinflammation in this review and postulate that deciphering these mechanisms is pivotal for identifying therapeutic targets to alleviate post-stroke dysfunction and enhance recovery.

Post-stroke brain can be protected by modulating the lncRNA FosDT.

We previously showed that knockdown or deletion of Fos downstream transcript (FosDT; a stroke-induced brain-specific long noncoding RNA) is neuroprotective. We presently tested the therapeutic potential of FosDT siRNA in rodents subjected to transient middle cerebral artery occlusion (MCAO) using the Stroke Treatment Academic Industry Roundtable criteria, including sex, age, species, and comorbidity. FosDT siRNA (IV) given at 30 min of reperfusion significantly improved motor function recovery (rotarod test, beam walk test, and adhesive removal test) and reduced infarct size in adult and aged spontaneously hypertensive rats of both sexes. FosDT siRNA administered in a delayed fashion (3.5 h of reperfusion following 1 h transient MCAO) also significantly improved motor function recovery and decreased infarct volume. Furthermore, FosDT siRNA enhanced post-stroke functional recovery in normal and diabetic mice. Mechanistically, FosDT triggered post-ischemic neuronal damage via the transcription factor REST as REST siRNA mitigated the enhanced functional outcome in FosDT-/- rats. Additionally, NF-κB regulated FosDT expression as NF-κB inhibitor BAY 11-7082 significantly decreased post-ischemic FosDT induction. Thus, FosDT is a promising target with a favorable therapeutic window to mitigate secondary brain damage and facilitate recovery after stroke regardless of sex, age, species, and comorbidity.

Therapeutic Potential of Intravenous miR-21 Mimic after Stroke Following STAIR Criteria.

The microRNA-21 (miR-21) levels in the brain are crucial in determining post-stroke brain damage and recovery. The miR-21 exerts neuroprotection by targeting mRNAs that translate proteins that mediate brain damage. We currently determined the efficacy and efficiency of intravenously administered miR-21 mimic after focal cerebral ischemia in mice. Adult male mice were intravenously administered with either control mimic or miR-21 mimic at 5 min/2 h after reperfusion following 1 h transient middle cerebral artery occlusion to determine the therapeutic window of miR-21 mimic. Adult female, type-2 diabetic male, aged male, and aged female mice were administered with control/miR-21 mimic at 5 min after reperfusion following 35 min/1 h transient middle cerebral artery occlusion. Early administration of miR-21 mimic significantly reduced brain damage and promoted long-term recovery after stroke. Further, miR-21 mimic is more effective in males than in females subjected to stroke. However, delayed treatment with miR-21 mimic is not efficacious, and type-2 diabetic subjects show no improvement with miR-21 mimic treatment.

CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability.

Transient focal ischemia decreased microRNA-7 (miR-7) levels, leading to derepression of its major target α-synuclein (α-Syn) that promotes secondary brain damage. Circular RNA CDR1as is known to regulate miR-7 abundance and function. Hence, we currently evaluated its functional significance after focal ischemia. Transient middle cerebral artery occlusion (MCAO) in adult mice significantly downregulated both CDR1as and miR-7 levels in the peri-infarct cortex between 3 and 72 h of reperfusion. Interestingly, neither pri-miR-7a nor 7b was altered in the ischemic brain. Intracerebral injection of an AAV9 vector containing a CDR1as gene significantly increased CDR1as levels by 21 days that persisted up to 4 months without inducing any observable toxicity in both sham and MCAO groups. Following transient MCAO, there was a significant increase in miR-7 levels and CDR1as binding to Ago2/miR-7 in the peri-infarct cortex of AAV9-CDR1as cohort compared with AAV9-Control cohort at 1 day of reperfusion. CDR1as overexpression significantly suppressed post-stroke α-Syn protein induction, promoted motor function recovery, decreased infarct size, and curtailed the markers of apoptosis, autophagy mitochondrial fragmentation, and inflammation in the post-stroke brain compared with AAV9-Control-treated cohort. Overall, our findings imply that CDR1as reconstitution is neuroprotective after stroke, probably by protecting miR-7 and preventing α-Syn-mediated neuronal death.

Tau and GSK-3ß are Critical Contributors to α-Synuclein-Mediated Post-Stroke Brain Damage.

Post-stroke secondary brain damage is significantly influenced by the induction and accumulation of α-Synuclein (α-Syn). α-Syn-positive inclusions are often present in tauopathies and elevated tau levels and phosphorylation promotes neurodegeneration. Glycogen synthase kinase 3ß (GSK-3ß) is a known promoter of tau phosphorylation. We currently evaluated the interaction of α-Syn with GSK-3ß and tau in post-ischemic mouse brain. Transient focal ischemia led to increased cerebral protein-protein interaction of α-Syn with both GSK-3ß and tau and elevated tau phosphorylation. Treatment with a GSK-3ß inhibitor prevented post-ischemic tau phosphorylation. Furthermore, α-Syn interaction was observed to be crucial for post-ischemic GSK-3ß-dependent tau hyperphosphorylation as it was not seen in α-Syn knockout mice. Moreover, tau knockout mice show significantly smaller brain damage after transient focal ischemia. Overall, the present study indicates that GSK-3ß catalyzes the α-Syn-dependent tau phosphorylation and preventing this interaction is crucial to limit post-ischemic secondary brain damage.

Cerebroprotective Role of N6-Methyladenosine Demethylase FTO (Fat Mass and Obesity-Associated Protein) After Experimental Stroke.

BACKGROUND: FTO (fat mass and obesity-associated protein) demethylates N6-methyladenosine (m6A), which is a critical epitranscriptomic regulator of neuronal function. We previously reported that ischemic stroke induces m6A hypermethylation with a simultaneous decrease in FTO expression in neurons. Currently, we evaluated the functional significance of restoring FTO with an adeno-associated virus 9, and thus reducing m6A methylation in poststroke brain damage. METHODS: Adult male and female C57BL/6J mice were injected with FTO adeno-associated virus 9 (intracerebral) at 21 days prior to inducing transient middle cerebral artery occlusion. Poststroke brain damage (infarction, atrophy, and white matter integrity) and neurobehavioral deficits (motor function, cognition, depression, and anxiety-like behaviors) were evaluated between days 1 and 28 of reperfusion. RESULTS: FTO overexpression significantly decreased the poststroke m6A hypermethylation. More importantly, exogenous FTO substantially decreased poststroke gray and white matter damage and improved motor function recovery, cognition, and depression-like behavior in both sexes. CONCLUSIONS: These results demonstrate that FTO-dependent m6A demethylation minimizes long-term sequelae of stroke independent of sex.

Dysregulation of the Epitranscriptomic Mark m1A in Ischemic Stroke.

Methylation of adenosine at N1 position yields N1-methyladenosine (m1A), which is an epitranscriptomic modification that regulates mRNA metabolism. Recent studies showed that altered m1A methylation promotes acute and chronic neurological diseases. We currently evaluated the effect of focal ischemia on cerebral m1A methylome and its machinery. Adult male C57BL/6J mice were subjected to transient middle cerebral artery occlusion, and the peri-infarct cortex was analyzed at 12 h and 24 h of reperfusion. The bulk abundance of m1A was measured by mass spectrometry and dot blot, and transcriptome-wide m1A alterations were profiled using antibody-independent m1A-quant-seq. Expression of the m1A writers and erasers was estimated by real-time PCR. Ischemia significantly decreased m1A levels and concomitantly upregulated m1A demethylase alkB homolog 3 at 24 h of reperfusion compared to sham. Transcriptome-wide profiling showed differential m1A methylation at 14 sites (8 were hypo- and 6 were hypermethylated). Many of those are located in the 3'-UTRs of unannotated transcripts proximal to the genes involved in regulating protein complex assembly, circadian rhythms, chromatin remodeling, and chromosome organization. Using several different approaches, we show for the first time that m1A epitranscriptomic modification in RNA is highly sensitive to cerebral ischemia.

MicroRNA miR-7 Is Essential for Post-stroke Functional Recovery.

Transient focal ischemia induces a sustained downregulation of miR-7 leading to derepression of its target α-synuclein (α-Syn), which promotes neuronal death. We previously showed that treatment with miR-7 mimic prevents α-Syn induction and protects brain after stroke in rodents irrespective of age and sex. To further decipher the role of miR-7, we currently studied infarction and motor function in miR-7 double knockout mice (lack both miR-7a and miR-7b) subjected to focal ischemia. Adult miR-7-/- mice showed similar motor and cognitive functions to miR-7+/+ mice. However, when subjected to even a mild focal ischemia, the miR-7-/- mice showed exacerbated brain damage and worsened motor function compared with the miR-7+/+ mice. Replenishing miR-7 in miR-7-/- mice (IV injection of miR-7 mimic) restored miR-7 mediated neuroprotection and motor recovery, potentially by preventing α-Syn protein induction. Thus, we show that miR-7 is an essential miRNA in the brain that prevents α-Syn translation and the ensuing brain damage after stroke.

MMP-12 knockdown prevents secondary brain damage after ischemic stroke in mice.

We previously reported that increased expression of matrix metalloproteinase-12 (MMP-12) mediates blood-brain barrier disruption via tight junction protein degradation after focal cerebral ischemia in rats. Currently, we evaluated whether MMP-12 knockdown protects the post-stroke mouse brain and promotes better functional recovery. Adult male mice were injected with negative siRNA or MMP-12 siRNA (intravenous) at 5 min of reperfusion following 1 h transient middle cerebral artery occlusion. MMP-12 knockdown significantly reduced the post-ischemic infarct volume and improved motor and cognitive functional recovery. Mechanistically, MMP-12 knockdown ameliorated degradation of tight junction proteins zonula occludens-1, claudin-5, and occludin after focal ischemia. MMP-12 knockdown also decreased the expression of inflammatory mediators, including monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6, and the expression of apoptosis marker cleaved caspase-3 after ischemia. Overall, the present study indicates that MMP-12 promotes secondary brain damage after stroke and hence is a promising stroke therapeutic target.

Epitranscriptomic Modifications Modulate Normal and Pathological Functions in CNS.

RNA is more than just a combination of four genetically encoded nucleobases as it carries extra information in the form of epitranscriptomic modifications. Diverse chemical groups attach covalently to RNA to enhance the plasticity of cellular transcriptome. The reversible and dynamic nature of epitranscriptomic modifications allows RNAs to achieve rapid and context-specific gene regulation. Dedicated cellular machinery comprising of writers, erasers, and readers drives the epitranscriptomic signaling. Epitranscriptomic modifications control crucial steps of mRNA metabolism such as splicing, export, localization, stability, degradation, and translation. The majority of the epitranscriptomic modifications are highly abundant in the brain and contribute to activity-dependent gene expression. Thus, they regulate the vital physiological processes of the brain, such as synaptic plasticity, neurogenesis, and stress response. Furthermore, epitranscriptomic alterations influence the progression of several neurologic disorders. This review discussed the molecular mechanisms of epitranscriptomic regulation in neurodevelopmental and neuropathological conditions with the goal to identify novel therapeutic targets.

Tenascin-C induction exacerbates post-stroke brain damage.

The role of tenascin-C (TNC) in ischemic stroke pathology is not known despite its prognostic association with cerebrovascular diseases. Here, we investigated the effect of TNC knockdown on post-stroke brain damage and its putative mechanism of action in adult mice of both sexes. Male and female C57BL/6 mice were subjected to transient middle cerebral artery occlusion and injected (i.v.) with either TNC siRNA or a negative (non-targeting) siRNA at 5 min after reperfusion. Motor function (beam walk and rotarod tests) was assessed between days 1 and 14 of reperfusion. Infarct volume (T2-MRI), BBB damage (T1-MRI with contrast), and inflammatory markers were measured at 3 days of reperfusion. The TNC siRNA treated cohort showed significantly curtailed post-stroke TNC protein expression, motor dysfunction, infarction, BBB damage, and inflammation compared to the sex-matched negative siRNA treated cohort. These results demonstrate that the induction of TNC during the acute period after stroke might be a mediator of post-ischemic inflammation and secondary brain damage independent of sex.

Ubisol Coenzyme Q10 promotes mitochondrial biogenesis in HT22 cells challenged by glutamate.

Glutamate-induced excitotoxicity is a well-recognized cause of neuronal cell death. Nutritional supplementation with Coenzyme Q10 (CoQ10) has been previously demonstrated to serve neuro-protective effects against glutamate-induced excitotoxicity. The aim of the present study was to determine whether the protective effect of CoQ10 against glutamate toxicity could be attributed to stimulating mitochondrial biogenesis. Mouse hippocampal neuronal HT22 cells were incubated with glutamate with or without ubisol Q10. The results revealed that glutamate significantly decreased levels of mitochondrial biogenesis related proteins, including peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and nuclear respiratory factor (NRF)2. Additionally, glutamate reduced mitochondrial biogenesis, as determined using a mitochondrial biogenesis kit. Pretreatment with CoQ10 prevented decreases in phosphorylated (p)-Akt, p-cAMP response element-binding protein, PGC-1α, NRF2 and mitochondrial transcription factor A, increasing mitochondrial biogenesis. Taken together, the results described a novel mechanism of CoQ10-induced neuroprotection and indicated a central role for mitochondrial biogenesis in protecting against glutamate-induced excitotoxicity.

Noncoding RNA crosstalk in brain health and diseases.

The mammalian brain expresses several classes of noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs). These ncRNAs play vital roles in regulating cellular processes by RNA/protein scaffolding, sponging and epigenetic modifications during the pathophysiological conditions, thereby controlling transcription and translation. Some of these functions are the result of crosstalk between ncRNAs to form a competitive endogenous RNA network. These intricately organized networks comprise lncRNA/miRNA, circRNA/miRNA, or lncRNA/miRNA/circRNA, leading to crosstalk between coding and ncRNAs through miRNAs. The miRNA response elements predominantly mediate the ncRNA crosstalk to buffer the miRNAs and thereby fine-tune and counterbalance the genomic changes and regulate neuronal plasticity, synaptogenesis and neuronal differentiation. The perturbed levels and interactions of the ncRNAs could lead to pathologic events like apoptosis and inflammation. Although the regulatory landscape of the ncRNA crosstalk is still evolving, some well-known examples such as lncRNA Malat1 sponging miR-145, circRNA CDR1as sponging miR-7, and lncRNA Cyrano and the circRNA CDR1as regulating miR-7, has been shown to affect brain function. The ability to manipulate these networks is crucial in determining the functional outcome of central nervous system (CNS) pathologies. The focus of this review is to highlights the interactions and crosstalk of these networks in regulating pathophysiologic CNS function.

Perceived fear of COVID-19 and its associated factors among Nepalese older adults in eastern Nepal: A cross-sectional study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has affected all age groups worldwide, but older adults have been affected greatly with an increased risk of severe illness and mortality. Nepal is struggling with the COVID-19 pandemic. The normal life of older adults, one of the vulnerable populations to COVID-19 infection, has been primarily impacted. The current evidence shows that the COVID-19 virus strains are deadly, and non-compliance to standard protocols can have serious consequences, increasing fear among older adults. This study assessed the perceived fear of COVID-19 and associated factors among older adults in eastern Nepal. METHODS: A cross-sectional study was conducted between July and September 2020 among 847 older adults (≥60 years) residing in three districts of eastern Nepal. Perceived fear of COVID-19 was measured using the seven-item Fear of COVID-19 Scale (FCV-19S). Multivariate logistic regression identified the factors associated with COVID-19 fear. RESULTS: The mean score of the FCV-19S was 18.1 (SD = 5.2), and a sizeable proportion of older adults, ranging between 12%-34%, agreed with the seven items of the fear scale. Increasing age, Dalit ethnicity, remoteness to the health facility, and being concerned or overwhelmed with the COVID-19 were associated with greater fear of COVID-19. In contrast, preexisting health conditions were inversely associated with fear. CONCLUSION: Greater fear of the COVID-19 among the older adults in eastern Nepal suggests that during unprecedented times such as the current pandemic, the psychological needs of older adults should be prioritized. Establishing and integrating community-level mental health support as a part of the COVID-19 preparedness and response plan might help to combat COVID-19 fear among them.

Long Noncoding RNA Fos Downstream Transcript Is Developmentally Dispensable but Vital for Shaping the Poststroke Functional Outcome.

Background and Purpose: Stroke induces the expression of several long noncoding RNAs in the brain. However, their functional significance in poststroke outcome is poorly understood. We recently observed that a brain-specific long noncoding RNA called Fos downstream transcript (FosDT) is induced rapidly in the rodent brain following focal ischemia. Using FosDT knockout rats, we presently evaluated the role of FosDT in poststroke brain damage. Methods: FosDT knockout rats were generated using CRISPR-Cas9 genome editing on a Sprague-Dawley background. Male and female FosDT−/− and FosDT+/+ cohorts were subjected to transient middle cerebral artery occlusion. Postischemic sensorimotor deficits were evaluated between days 1 and 7 and lesion volume on day 7 of reperfusion. The developmental expression profile of FosDT was determined with real-time polymerase chain reaction and mechanistic implications of FosDT in the ischemic brain were conducted with RNA-sequencing analysis and immunostaining of pathological markers. Results: FosDT expression is developmentally regulated, with the adult cerebral cortex showing significantly higher FosDT expression than neonates. FosDT−/− rats did not show any anomalies in growth and development, fertility, brain cytoarchitecture, and cerebral vasculature. However, when subjected to transient focal ischemia, FosDT−/− rats of both sexes showed enhanced sensorimotor recovery and reduced brain damage. RNA-sequencing analysis showed that improved poststroke functional outcome in FosDT−/− rats is partially associated with curtailed induction of inflammatory genes, reduced apoptosis, mitochondrial dysfunction, and oxidative stress. Conclusions: Our study shows that FosDT is developmentally dispensable, mechanistically important, and a functionally promising target to reduce ischemic brain damage and facilitate neurological recovery.

Using a co-design process to develop an integrated model of care for delivering self-management intervention to multi-morbid COPD people in rural Nepal.

BACKGROUND: People with chronic obstructive pulmonary disease (COPD) in Nepal are not receiving adequate support to self-manage their chronic conditions, and primary health care can play a key role in the effective management of these. In this study, we aimed to develop a model of care, using a co-design approach, for delivering evidence-based biomedical and psycho-social care to support self-management for people with multi-morbid COPD in rural Nepal. METHODS: A co-design approach, guided by the five stages of the design thinking model, was used for this study. Layering on "empathize" and "define" phases, we ideated a model of care that was further refined in a "prototype" stage, which included a series of consultative meetings and a 1-day co-design workshop with stakeholders. This co-design process involved a wide range of stakeholders from Nepal, including people with COPD and their families, community representatives, local government representatives, primary care practitioners, community health workers, policymakers, state-level government representatives and academics. RESULTS: Through our co-design approach, a model of integrated care for delivering evidence-based biomedical and psycho-social care to support self-management for people with multi-morbid COPD was designed. The integrated model of care included: screening of the community members aged > 40 years or exhibiting symptoms for COPD and management of symptomatic patients within primary health care, establishing referral pathways for severe cases to and from secondary/tertiary-level health care and establishing a community-based support system. It involved specific roles for community health workers, patients and their caregivers and community representatives. It was built on existing services and programmes linking primary health care centres and tertiary-level health facilities. CONCLUSION: The co-design approach is different from the currently dominant approach of rolling out models of care, which were designed elsewhere with minimal community engagement. In our study, the co-design approach was found to be effective in engaging various stakeholders and in developing a model of care for rural Nepal. This grassroots approach is more likely to be acceptable, effective and sustainable in rural Nepal. Further research is required to test the effectiveness of an integrated model of care in delivering self-management support for people with multi-morbid COPD in rural Nepal.

Antioxidant Combo Therapy Protects White Matter After Traumatic Brain Injury.

Following traumatic brain injury (TBI), increased production of reactive oxygen species (ROS) and the ensuing oxidative stress promotes the secondary brain damage that encompasses both grey matter and white matter. As this contributes to the long-term neurological deficits, decreasing oxidative stress during the acute period of TBI is beneficial. While NADPH oxidase (NOX2) is the major producer of ROS, transcription factor Nrf2 that induces antioxidant enzymes promotes efficient ROS disposal. We recently showed that treatment with an antioxidant drug combo of apocynin (NOX2 inhibitor) and TBHQ (Nrf2 activator) protects the grey matter in adult mice subjected to TBI. We currently show that this antioxidant combo therapy given at 2 h and 24 h after TBI also protects white matter in mouse brain. Thus, the better functional outcomes after TBI in the combo therapy treated mice might be due to a combination of sparing both grey matter and white matter. Hence, the antioxidant combo we tested is a potent therapeutic option for translation in future.

Epitranscriptomic regulation by m6A RNA methylation in brain development and diseases.

Cellular RNAs are pervasively tagged with diverse chemical moieties, collectively called epitranscriptomic modifications. The methylation of adenosine at N6 position generates N6-methyladenosine (m6A), which is the most abundant and reversible epitranscriptomic modification in mammals. The m6A signaling is mediated by a dedicated set of proteins comprised of writers, erasers, and readers. Contrary to the activation-repression binary view of gene regulation, emerging evidence suggests that the m6A methylation controls multiple aspects of mRNA metabolism, such as splicing, export, stability, translation, and degradation, culminating in the fine-tuning of gene expression. Brain shows the highest abundance of m6A methylation in the body, which is developmentally altered. Within the brain, m6A methylation is biased toward neuronal transcripts and sensitive to neuronal activity. In a healthy brain, m6A maintains several developmental and physiological processes such as neurogenesis, axonal growth, synaptic plasticity, circadian rhythm, cognitive function, and stress response. The m6A imbalance contributes to the pathogenesis of acute and chronic CNS insults, brain cancer, and neuropsychiatric disorders. This review discussed the molecular mechanisms of m6A regulation and its implication in the developmental, physiological, and pathological processes of the brain.

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.