Browsing by Subject "Ischemic Stroke"
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Item Blood Inflammatory Exosomes with Age Prime Microglia through Complement Signaling for Negative Stroke Outcomes(2020-05) Zhang, Hongxia; Jin, Kunlin; Forster, Michael J.; Yang, Shaohua; Shi, Xiangrong; Cunningham, J. ThomasThe systemic inflammatory milieu plays an important role in the age-related decline of functional integrity, but its contribution to age-related disease (e.g., stroke) remains largely unknown. Here, we found that activated complement molecules (C1q, C3a, C3b) in serum exosomes increased with age, whereas CD46, a C3b/C4b-inactivating factor, was higher in serum exosomes from young rats. These serum inflammatory exosomes passed the blood-brain barrier and primed the microglial response that led to exacerbation of synaptic loss and motor deficits after ischemic stroke via microglial C3a receptor (C3aR). When aged rats were exposed to serum exosomes from young rats, microglia-mediated synaptic loss was reduced and motor deficits after stroke were improved. Administration of C3aR inhibitor or microglial depletion attenuated synaptic loss associated with the treatment of serum exosome from aged rats, in parallel with improved post-stroke outcome. Our data suggest that peripheral circulating old exosomes act as inflammatory mediators and influence ischemic stroke outcome through a complement-microglia axis.Item INVOLVEMENT OF P38 MAPK IN REACTIVE ASTROGLIOSIS INDUCED BY ISCHEMIC STROKE(2013-04-12) Roy Choudhury, GouravPurpose: Reactive astrogliosis is an important response during early phase of cerebral ischemia but as time progresses; these activated astrocytes develop into a glial scar. During acute phase of ischemia, astrocyte activation is beneficial as it limits the spread of infarct however in long term the glial scar developed becomes a barrier to migrating axons and hinder the recovery process. The hallmark of astrogliosis is an increase in the expression of GFAP (Glial fibrillary acidic protein). However the signaling events underlying these phenomenons have not been yet clearly elucidated. p38MAPK, a stress signaling Mitogen activate protein kinase plays an essential role in inflammation and has been widely reported to be activated during ischemic injury. Since inflammation is major determinant of events after ischemic injury in brain, we hypothesize that p38 MAPK plays a critical role in reactive astrogliosis after ischemic injury and its inhibition attenuates glial scar formation Methods: For in vitro studies rodent primary astrocytes were used and were subjected to Oxygen-glucose deprivation (OGD) for 3h. p38MAPK's role in astrocyte activation was determined pharmacologically with a p38 inhibitor (SB 239063) and genetically by an astrocyte specific p38 knockout. 24 hours following insult and the expression of GFAP was determined using Western blots. Wound healing and Transwell assay were used to determine role of P38 in astrocyte migration. For in vivo studies astrocyte specific conditional p38 knockout mice (p38KO) were used. Transient or Permanent middle cerebral artery occlusion (tMCAO or pMCAO) was performed to model ischemic stroke. Walk initiation, Negative geotaxis and Ladder rung walking test were used to determine motor dysfunction after MCAO. Astrogliosis morphometric analysis was to quantify glial scar in GFAP stained brain sections Results: In primary astrocyte cultures, hypoxia and scratch injury-induced astrogliosis was attenuated by both p38 inhibition and knockout of p38 MAPK. In vivo studies showed that p38KO mice after permanent MCAO had a significantly smaller glial scar compared to their wild type (WT) littermates. Results also indicated that p38KO mice performed significantly better in behavioral studies compared to their WT only in tMCAO Conclusions: p38MAPK plays an essential role in evolution of glial scar after ischemia and its inhibition attenuates glial scar formation. P38 inhibition significantly improves motor dysfunction in tMCAO but the protection is lost in pMCAOItem Modulation of Astrocyte Phenotype in Response to T-cell Interaction(2021-05) Hersh, Jessica M.; Yang, Shaohua; Smith, Michael L.; Jin, Kunlin; Hodge, Lisa M.We determined that T-cell astrocyte interaction modulates interleukin-10 (IL-10) production from both cell types. The impact of IL-10 on astrocytes was compared to IL-10 generated from T-cell-astrocyte interactions in vitro. We demonstrated that T-cells directly interact with astrocytes to upregulate gene expression and secretion of IL-10, confirmed by elevated STAT3p/STAT3 expression in astrocytes. IL-10 increased astrocytes proliferation. In addition, IL-10 treatment and CD4+ co-culture shifts primary astrocytes toward a more energetic phenotype. These findings indicate that direct interaction of CD4+ T-cells with astrocytes, activated the IL-10 anti-inflammatory pathway, altering astrocyte phenotype, metabolism, and proliferation.Item P38MAPK PROMOTES ASTROGLIOSIS AFTER FOCAL ISCHEMIC STROKE IN MICE(2013-04-12) Roy Choudhury, GouravPurpose: Patients surviving ischemic stroke are often left with long term functional disabilities suggesting that the ischemia associated pathology continues to persist in long term and limits recovery. One such reason for limited functional recovery is formation of glial scar. Glial scar is formed in response to ischemic injury and may protect the cerebral tissue from further injury during early phase of injury. But in long term, this glial scar establishes a physical and chemical barrier to the axonal migration and growth and hinders recovery. The events of a post ischemic brain are prominently influenced by inflammation and p38MAPK is an important signal transducer of cell's response to inflammatory mediators. So in our current study we hypothesize that astrocyte activation and glial scar formation after stroke is regulated by astrocytic p38MAPK and its inhibition will attenuate the glial scar formation Methods: Primary astrocyte cultures isolated from GFAP/p38 knockout mice and wild type littermates were used for in vitro studies. In vitro hypoxic condition (0.5% O2 and 5%CO2) was simulated by depriving Oxygen and glucose (OGD) for 3 hours. Wound healing and Transwell assay were used to determine role of p38MPAK in astrocyte migration. For in vivo studies, permanent middle cerebral artery occlusion (pMCAO) was conducted to induce ischemic stroke. Astrogliosis morphometric analysis was performed using nucleator method to quantify glial scar in GFAP stained brain sections Results: Results from in vitro studies indicated that p38MAPK knockout significantly attenuated OGD induced increase in glial fibrillary acidic protein (GFAP) expression and reduced astrocyte migration. In vivo studies showed that conditional GFAP/p38 knockout mice after MCAO had a significantly smaller glial scar compared to their wild type litter mates Conclusions: Astrocyte reactivation and glial scar formation in brain after ischemic injury is mediated p38MAPK and its inhibition attenuates glial scarItem The role of aging and length of hypogonadism on the neuroprotective effects of dietary genistein following focal cerebral ischemia(2021-05) Oppong-Gyebi, Anthony; Schreihofer, Derek A.; Singh, Meharvan; Sumien, Nathalie; Yang, Shaohua; Shi, XiangrongThe risk of ischemic stroke increases with increasing age. Women beyond menopause have an exponential increase in stroke risk with worse post-stroke prognosis and mortalities compared to men of similar ages. One of the key reasons for this discrepancy is the sudden and drastic drop in the levels of the circulating principal female sex hormones estrogen and progesterone after menopause. Both sex hormones have been shown in several studies to provide neuroprotection against ischemic insults in stroke models and other disease models including Alzheimer's Disease and Parkinson's Disease. However, from clinical studies, neither estrogen nor progesterone alone or in combination has met clinical needs for the prevention of chronic cardiovascular diseases. These clinical failures were mainly evidenced by the absence of benefits in the human population or an increased predisposition to adverse side effects. Reports from studies including the Women's Health Initiative and Nurse's Health Study showed that the timing of initiation and age of recipients significantly influence the outcome of estrogen therapy. In this dissertation project, we investigated the plant-based estrogenic compound genistein as a possible alternative to estrogen therapy. It was hypothesized that the neuroprotective benefits of genistein will be less sensitive to the length of hypogonadism and age under experimental ischemic conditions. We used a rodent model of transient middle cerebral artery occlusion under varied lengths of estrogen deprivation and age to test the neuroprotection of dietary genistein. Findings from this dissertation show that early initiation of dietary genistein after hypogonadism improves aspects of cognition, an effect that is diminished following the long absence of circulating estrogen. Furthermore, pre-treatment with dietary genistein improves age-associated locomotor deficits after long-term hypogonadism after stroke. This dissertation, therefore, provides new considerations on the time-dependent sensitivity of the brain to genistein's effect as a potential therapeutic option to improve aspects of cognition and reduce the severity of stroke in the target population with low circulating estrogens.