Browsing by Subject "ischemic stroke"
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Item A Reliable Nonhuman Primate Model of Ischemic Stroke with Reproducible Infarct Size and Long-term Sensorimotor Deficits(Aging and Disease, 2023-02-24) Lin, Xiao; Wang, Hua; Huang, Shengwei; Chen, Lefu; Yang, Su; Zhao, Peiqi; Lin, Zhongxiao; Yang, Jianjing; Ruan, Linhui; Ni, Haoqi; Wang, Kankai; Wen, Min; Jin, Kunlin; Zhuge, QichuanA nonhuman primate model of ischemic stroke is considered as an ideal preclinical model to replicate various aspects of human stroke because of their similarity to humans in genetics, neuroanatomy, physiology, and immunology. However, it remains challenging to produce a reliable and reproducible stroke model in nonhuman primates due to high mortality and variable outcomes. Here, we developed a focal cerebral ischemic model induced by topical application of 50% ferric chloride (FeCl(3)) onto the MCA-M1 segment through a cranial window in the cynomolgus monkeys. We found that FeCl(3) rapidly produced a stable intraarterial thrombus that caused complete occlusion of the MCA, leading to the quick decrease of the regional cerebral blood flow in 10 min. A typical cortical infarct was detected 24 hours by magnetic resonance imaging (MRI) and was stable at least for 1 month after surgery. The sensorimotor deficit assessed by nonhuman primate stroke scale was observed at 1 day and up to 3 months after ischemic stroke. No spontaneous revascularization or autolysis of thrombus was observed, and vital signs were not affected. All operated cynomolgus monkeys survived. Our data suggested that FeCl(3)-induced stroke in nonhuman primates was a replicable and reliable model that is necessary for the correct prediction of the relevance of experimental therapeutic approaches in human beings.Item Aging Systemic Milieu Impairs Outcome after Ischemic Stroke in Rats(JKL International, 2017-10-01) Pan, Mengxiong; Wang, Peng; Zheng, Chengcai; Zhang, Hongxia; Lin, Siyang; Shao, Bei; Zhuge, Qichuan; Jin, KunlinCompelling evidence indicates that factors in the blood can profoundly reverse aging-related impairments, as exposure of aged mice to young blood rejuvenates adult stem cell function, improves cognition, and ameliorates cardiac hypertrophy. Systemic factors from mice can also extend the life span of a partner exposed to a lethal treatment or disease. These findings suggest that the systemic milieu of a healthy young partner may be beneficial for an aged organism. However, it is unknown whether a healthy young systemic milieu can improve functional recovery after ischemic stroke. Intraperitoneal administration of young plasma into aged rats after ischemic stroke induced by distal middle cerebral artery occlusion (dMCAO) reduced infarct volume and motor impairment, compared with vehicle group. On the contrary, intraperitoneal administration of plasma from aged rats into young ischemic rats worsened brain injury and motor deficits. Using a proteomic approach, we found that haptoglobin levels were significantly increased in serum of aged rats and that intraperitoneal administration of haptoglobin impaired outcome after ischemic stroke in young rats. Our data suggest that the aging systemic milieu plays a critical role in functional outcome after ischemic stroke.Item Astrocytes & Ischemic stroke(2014-08-01) Roy Choudhury, Gourav; Yang, Shaohua; Singh, Meharvan; Schreihofer, DerekAlthough less appreciated, recent findings introduced critical contributions of astrocytes to numerous CNS functions, like neurogenesis, synaptogenesis, ion homeostasis, neurotransmission, and blood brain barrier formation. Their active participation in the progression of specific CNS pathologies has garnered major attention and culminated in thorough investigation of astrocyte function in brain. Reactive astrogliosis, characterized by increases in glial fibrillary acidic protein (GFAP) and cellular hypertrophy, describes the extensive structural and functional changes that astrocytes undergo in response to tissue injury. Despite of extensive investigation, the molecular mechanism of reactive astrogliosis in ischemic stroke still remains elusive. p38 MAPK is a well studied signal transducing pathway known to be involved in modulating cell type specific responses to ischemic injury. The first study presented in the dissertation delineates the involvement p38 MAPK signaling pathway in reactive astrogliosis after ischemic stroke. Results showed that astrocyte specific deletion of p38 MAPK attenuated oxygen-glucose deprivation (OGD)-induced increase in GFAP expression in primary astrocytes in vitro. Additionally, inhibition of p38 MAPK (SB239063/genetic deletion) slowed astrocyte migration without affecting astrocyte proliferation. In vivo deletion of p38 MAPK from astrocytes attenuated reactive astrogliosis after permanent middle cerebral artery occlusion in mice. These findings strongly indicated that p38 MAPK plays a critical role in reactive astrogliosis after ischemic stroke. During ischemic stroke, astrocyte dysfunction causes extensive cell death through excitotoxicity, disruption of ion and water homeostasis. Restoration of astrocyte function thus may be beneficial to ischemic tissue in the long term. Methylene blue (MB), a metabolic enhancer, has been well studied and known to improve cellular respiration, glucose metabolism and attenuate superoxide production by efficient electron transport in mitochondria. In the second part of this dissertation we determined the effect of MB in astrocytes under oxygen glucose deprivation (OGD) and reoxygenation stress and the underlying protective mechanisms. Our studies demonstrated that MB improved astrocyte bioenergetics and promoted astrocyte survival following OGD and reoxygenation. In conclusion both the studies presented, provide a unique perspective of the importance of astroglial response in ischemic injury and how its modulation can benefit the healing and recovery of the brain following ischemic injury.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 Intermittent Hypoxia Training to Foster Brain Recovery after Ischemic Stroke in rats(2018-05) Ruelas, Steven S.; Mallet, Robert T.; Jung, Marianna E.; Schreihofer, Ann M.; Das, Hriday K.Purpose: Ischemic stroke is the leading cause of disability and #5 cause of death in the US. Annually, nearly 800,000 Americans suffer an ischemic stroke, and 130,000 die. The only FDA approved treatment for stroke is recombinant tissue plasminogen activator, but this thrombolytic agent neither protects the affected tissue, nor mitigates the motor or cognitive impairments resulting from stroke. Intermittent hypoxia training (IHT) has been shown to increase cerebral blood flow, reduce oxidative stress, mobilize cerebroprotective signaling cascades and minimize behavioral deficits in a rat model of Alzheimer's Disease. Moreover, a 20 d IHT program attenuated behavioral deficits and protected neurons in ethanol-withdrawn (EW) rats, even when EW began 35 d after IHT. Therefore, we hypothesize that IHT, initiated in rats after stroke, preserves motor and cognitive function, relative to non-IHT rats. Methods: Ischemic stroke will be produced in rats by 90 min occlusion and abrupt reperfusion of the middle cerebral artery (MCA). Motor function and coordination will be evaluated by the rotarod test before and at 1 week intervals after MCA occlusion (MCAO). Rats must balance on a rotating cylinder that accelerates at a constant speed. High fall latency represents intact motor function. The Morris Water Maze (MWM) assesses spatial learning and memory. Rats are placed in an open, circular pool and must find a sunken platform within 90 s. 24 h after stroke, rats undergoing IHT will breathe moderately hypoxic gas (10% O2) for 5-8 cycles, each lasting 5-10 min, with intervening 4 min room air breathing, for 20 consecutive days. These rats will be compared to an MCAO group continuously exposed to 21% O2. At 21 d post-stroke, the brain will be harvested for analyses of infarct and neuroprotective proteins. Results: In pre-stroke testing, the time taken to solve the MWM fell progressively over 10 days, indicating spatial learning and memory, and fall latency on the rotarod lengthened over 5 days, reflecting improved coordination and possibly a training effect. These studies have established the pre-stroke baselines for assessment of IHT's impact on post-stroke recovery. Conclusions: We expect that IHT given after stroke will minimize motor and cognitive impairment by activating neuroprotective signaling cascades culminating in expression of anti-oxidant and anti-inflammatory proteins.Item 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.Item USE OF RECOMBINANT TISSUE PLASMA ACTIVATOR (RT-PA) IN SILENT AORTIC DISSECTION PRESENTING AS AN ISCHEMIC STROKE(2014-03) Cheung, Ryan J.; Mantilla, Emmanuel C. Jr.; Smith-Barbaro, PeggyThe use of thrombolytic therapy in the management of acute ischemic stroke has increased since the National Institute of Neurological Disorders and Stroke (NINDS) established its efficacy in improving clinical outcome at three months in patients when treated within a three-hour window. However, a controversy exists in its use in patients with aortic dissection presenting with neurologic symptoms, mimicking an acute ischemic type of stroke, due to risk for further hemorrhage and interference with hemostasis. This is a case of a 60-year-old female who presented with an acute left sided hemiplegia, and was treated with recombinant tissue plasma activator (rt-PA) after inclusion criteria was met. MRI showed moderate embolic left middle cerebral artery infarct and a computed tomography angiography (CTA) performed post thrombolytic therapy showed a Stanford type A aortic dissection. Following rt-PA administration, the patient improved neurologically the next day, and underwent surgery for repair of the dissection. Despite the neurologic and clinical improvement after thrombolysis, the patient was not able to tolerate the surgery and expired a day after the operation. Nonetheless, this case still provides evidence that rt-PA is an appropriate an effective treatment in the case of an ischemic stroke secondary to an aortic dissection. Purpose (a): This is a case study demonstrating the use of recombinant tissue plasma activator (rt-PA) in the treatment of an ischemic stroke secondary to a silent aortic dissection. In light of recent studies on clinical outcomes, there is debate about the use of rt-PA to treat a questionable stroke with a high suspicion for aortic dissection. This purpose of this case is to show that such time-sensitive, potentially life-saving treatment can be delivered without any negative side effects towards an aortic dissection such as intracranial bleeding or an aortic rupture. This case provides further evidence that rt-PA should not be delayed as the clinical benefits of reducing stroke morbidity and mortality outweighs the potential risks. Methods (b): This case describes a 60 year old patient presenting to the emergency department with an ischemic stroke and treated with rt-PA. The patient initially presented with right sided gaze preference and left-sided hemiplegia. In further reassessing the patient, a Stanford Type A aortic dissection with right carotid artery involvement was discovered upon CTA. The decision was made to attempt a surgical repair of the dissection. During the surgery, the vessel defect was corrected, but the patient sustained right heart failure refractory to vasopressors. Following surgery, the patient was transferred to the ICU, intubated, and in critical condition. Despite being maintained on heparin, a repeat head CT showed no transformation from an ischemic to a hemorrhagic stroke. The patient died two days later due to complications from the surgery. Results (c): During the initial assessment of the ischemic stroke, no signs of hemorrhage were present so the decision to give rt-PA was made. Following administration of rt-PA, the patient subsequently improved; there were no gaze asymmetry and left sided movements were noted. The patient did not show any signs of intracranial bleeding with rt-PA and heparin therapy. It is also important to note that administration of rt-PA did not appear to worsen the aortic dissection. Conclusions (d): The results of this case study suggest that rt-PA, when indicated, is an appropriate and effective treatment in the case of ischemic stroke secondary to an aortic dissection. However, surgical corrections of aortic dissection in these cases do carry a high mortality rate, so clinical judgment must be carefully exercised for each individual case.