Publications by authors named "Tauheed Ishrat"

74 Publications

Verapamil as an Adjunct Therapy to Reduce tPA Toxicity in Hyperglycemic Stroke: Implication of TXNIP/NLRP3 Inflammasome.

Mol Neurobiol 2021 Apr 13. Epub 2021 Apr 13.

Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.

Thrombolytic therapy has remained quite challenging in hyperglycemic patients for its association with poor prognosis and increased hemorrhagic conversions. We recently showed that tissue plasminogen activator (tPA)-induced cerebrovascular damage is associated with thioredoxin-interacting protein (TXNIP) upregulation, which has an established role in the detrimental effects of hyperglycemia. In the present work, we investigated whether verapamil, an established TXNIP inhibitor, may provide protection against hyperglycemic stroke and tPA-induced blood-brain barrier (BBB) disruption. Acute hyperglycemia was induced by intraperitoneal administration of 20% glucose, 15 min prior to transient middle cerebral artery occlusion (tMCAO). Verapamil (0.15 mg/kg) or saline was intravenously infused with tPA at hyperglycemic reperfusion, 1 h post tMCAO. After 24 h of ischemia/reperfusion (I/R), mice were assessed for neurobehavioral deficits followed by sacrifice and evaluation of brain infarct volume, edema, and microbleeding. Alterations in TXNIP, inflammatory mediators, and BBB markers were further analyzed using immunoblotting or immunostaining techniques. As adjunctive therapy, verapamil significantly reduced tPA-induced BBB leakage, matrix metalloproteinase 9 (MMP-9) upregulation, and tight junction protein deregulation, which resulted in lesser hemorrhagic conversions. Importantly, verapamil strongly reversed tPA-induced TXNIP/NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation and reduced infarct volume. This concurred with a remarkable decrease in high-mobility group box protein 1 (HMGB-1) and nuclear factor kappa B (NF-κB) stimulation, leading to less priming of NLRP3 inflammasome. This preclinical study supports verapamil as a safe adjuvant that may complement thrombolytic therapy by inhibiting TXNIP's detrimental role in hyperglycemic stroke.
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http://dx.doi.org/10.1007/s12035-021-02384-zDOI Listing
April 2021

Manifestation of renin angiotensin system modulation in traumatic brain injury.

Metab Brain Dis 2021 Apr 9. Epub 2021 Apr 9.

Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, College of Medicine, 855 Monroe Avenue, Wittenborg Building, Room-231, Memphis, TN, 38163, USA.

Traumatic brain injury (TBI) alters brain function and is a crucial public health concern worldwide. TBI triggers the release of inflammatory mediators (cytokines) that aggravate cerebral damage, thereby affecting clinical prognosis. The renin angiotensin system (RAS) plays a critical role in TBI pathophysiology. RAS is widely expressed in many organs including the brain. Modulation of the RAS in the brain via angiotensin type 1 (AT) and type 2 (AT) receptor signaling affects many pathophysiological processes, including TBI. ATR is highly expressed in neurons and astrocytes. The upregulation of ATR mediates the effects of angiotensin II (ANG II) including release of proinflammatory cytokines, cell death, oxidative stress, and vasoconstriction. The ATR, mainly expressed in the fetal brain during development, is also related to cognitive function. Activation of this receptor pathway decreases neuroinflammation and oxidative stress and improves overall cell survival. Numerous studies have illustrated the therapeutic potential of inhibiting ATR and activating ATR for treatment of TBI with variable outcomes. In this review, we summarize studies that describe the role of brain RAS signaling, through ATR and ATR in TBI, and its modulation with pharmacological approaches.
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http://dx.doi.org/10.1007/s11011-021-00728-1DOI Listing
April 2021

Verapamil Prevents Development of Cognitive Impairment in an Aged Mouse Model of Sporadic Alzheimer's Disease.

Mol Neurobiol 2021 Mar 11. Epub 2021 Mar 11.

Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.

Currently, dementia is the only leading cause of death that is still on the rise, with total costs already exceeding those of cancer and heart disease and projected to increase even further in the coming years. Unfortunately, there are no satisfactory treatments and attempts to develop novel, more effective treatments have been extremely costly, albeit unsuccessful thus far. This has led us to investigate the use of established drugs, licensed for other therapeutic indications, for their potential application in cognitive disorders. This strategy, referred to as "drug repositioning," has been successful in many other areas including cancer and cardiovascular diseases. To our knowledge, this is the first study to investigate the effects of long-term treatment with verapamil, a calcium channel blocker commonly prescribed for various cardiovascular conditions and recently applied for prevention of cluster headaches, on the development of cognitive impairment in aged animals. Verapamil was studied at a low dose (1mg/kg/d) in a mouse model of sporadic Alzheimer's disease (sAD). Oral treatment with verapamil or vehicle was started, 24 h post-intracerebroventricular (ICV) streptozotocin/(STZ), in 12-month-old animals and continued for 3 months. Cognitive function was assessed using established tests for spatial learning, short-term/working memory, and long-term/reference memory. Our findings demonstrate that long-term low-dose verapamil effectively prevents development of ICV/STZ-induced cognitive impairment. It mitigates the astrogliosis and synaptic toxicity otherwise induced by ICV/STZ in the hippocampus of aged animals. These findings indicate that long-term, low-dose verapamil may delay progression of sAD in susceptible subjects of advanced age.
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http://dx.doi.org/10.1007/s12035-021-02350-9DOI Listing
March 2021

The NLRP3 inflammasome: a potential therapeutic target for traumatic brain injury.

Neural Regen Res 2021 Jan;16(1):49-57

Department of Anatomy and Neurobiology; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, USA.

Although the precise mechanisms contributing to secondary brain injury following traumatic brain injury are complex and obscure, a number of studies have demonstrated that inflammatory responses are an obvious and early feature in the pathogenesis of traumatic brain injury. Inflammasomes are multiprotein complexes that prompt the stimulation of caspase-1 and subsequently induce the maturation and secretion of proinflammatory cytokines, such as interleukin-1β and interleukin-18. These cytokines play a pivotal role in facilitating innate immune responses and inflammation. Among various inflammasome complexes, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is the best characterized, a crucial role for NLRP3 has been demonstrated in various brain diseases, including traumatic brain injury. Several recent studies have revealed the contribution of NLRP3 inflammasome in identifying cellular damage and stimulating inflammatory responses to aseptic tissue injury after traumatic brain injury. Even more important, blocking or inhibiting the activation of the NLRP3 inflammasome may have substantial potential to salvage tissue damage during traumatic brain injury. In this review, we summarize recently described mechanisms that are involved in the activation and regulation of the NLRP3 inflammasome. Moreover, we review the recent investigations on the contribution of the NLRP3 inflammasome in the pathophysiology of TBI, and current advances and challenges in potential NLRP3-targeted therapies. A significant contribution of NLRP3 inflammasome activation to traumatic brain injury implies that therapeutic approaches focused on targeting specific inflammasome components could significantly improve the traumatic brain injury outcomes.
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http://dx.doi.org/10.4103/1673-5374.286951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818859PMC
January 2021

HIV Associated Risk Factors for Ischemic Stroke and Future Perspectives.

Int J Mol Sci 2020 Jul 26;21(15). Epub 2020 Jul 26.

Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

Although retroviral therapy (ART) has changed the HIV infection from a fatal event to a chronic disease, treated HIV patients demonstrate high prevalence of HIV associated comorbidities including cardio/cerebrovascular diseases. The incidence of stroke in HIV infected subjects is three times higher than that of uninfected controls. Several clinical and postmortem studies have documented the higher incidence of ischemic stroke in HIV infected patients. The etiology of stroke in HIV infected patients remains unknown; however, several factors such as coagulopathies, opportunistic infections, vascular abnormalities, atherosclerosis and diabetes can contribute to the pathogenesis of stroke. In addition, chronic administration of ART contributes to the increased risk of stroke in HIV infected patients. Concurrently, experimental studies in murine model of ischemic stroke demonstrated that HIV infection worsens stroke outcome, increases blood brain barrier permeability and increases neuroinflammation. Additionally, residual HIV viral proteins, such as Trans-Activator of Transcription, glycoprotein 120 and Negative regulatory factor, contribute to the pathogenesis. This review presents comprehensive information detailing the risk factors contributing to ischemic stroke in HIV infected patients. It also outlines experimental evidence demonstrating the impact of HIV infection on stroke outcomes, in addition to possible novel therapeutic approaches to improve these outcomes.
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http://dx.doi.org/10.3390/ijms21155306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432359PMC
July 2020

The Brain AT2R-a Potential Target for Therapy in Alzheimer's Disease and Vascular Cognitive Impairment: a Comprehensive Review of Clinical and Experimental Therapeutics.

Mol Neurobiol 2020 Aug 12;57(8):3458-3484. Epub 2020 Jun 12.

Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, 855 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.

Dementia is a potentially avertable tragedy, currently considered among the top 10 greatest global health challenges of the twenty-first century. Dementia not only robs individuals of their dignity and independence, it also has a ripple effect that starts with the inflicted individual's family and projects to the society as a whole. The constantly growing number of cases, along with the lack of effective treatments and socioeconomic impact, poses a serious threat to the sustainability of our health care system. Hence, there is a worldwide effort to identify new targets for the treatment of Alzheimer's disease (AD), the leading cause of dementia. Due to its multifactorial etiology and the recent clinical failure of several novel amyloid-β (Aβ) targeting therapies, a comprehensive "multitarget" approach may be most appropriate for managing this condition. Interestingly, renin angiotensin system (RAS) modulators were shown to positively impact all the factors involved in the pathophysiology of dementia including vascular dysfunction, Aβ accumulation, and associated cholinergic deficiency, in addition to tau hyperphosphorylation and insulin derangements. Furthermore, for many of these drugs, the preclinical evidence is also supported by epidemiological data and/or preliminary clinical trials. The purpose of this review is to provide a comprehensive update on the major causes of dementia including the risk factors, current diagnostic criteria, pathophysiology, and contemporary treatment strategies. Moreover, we highlight the angiotensin II receptor type 2 (AT2R) as an effective drug target and present ample evidence supporting its potential role and clinical applications in cognitive impairment to encourage further investigation in the clinical setting.
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http://dx.doi.org/10.1007/s12035-020-01964-9DOI Listing
August 2020

Tissue Plasminogen Activator Promotes TXNIP-NLRP3 Inflammasome Activation after Hyperglycemic Stroke in Mice.

Mol Neurobiol 2020 Jun 14;57(6):2495-2508. Epub 2020 Mar 14.

Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.

Hyperglycemia has been shown to counterbalance the beneficial effects of tissue plasminogen activator (tPA) and increase the risk of intracerebral hemorrhage in ischemic stroke. Thioredoxin interacting protein (TXNIP) mediates hyperglycemia-induced oxidative damage and inflammation in the brain and reduces cerebral glucose uptake/utilization. We have recently reported that TXNIP-induced NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation contributes to neuronal damage after ischemic stroke. Here, we tested the hypothesis that tPA induces TXNIP-NLRP3 inflammasome activation after ischemic stroke, in hyperglycemic mice. Acute hyperglycemia was induced in mice by intraperitoneal (IP) administration of a 20% glucose solution. This was followed by transient middle cerebral artery occlusion (t-MCAO), with or without intravenous (IV) tPA administered at reperfusion. The IV-tPA exacerbated hyperglycemia-induced neurological deficits, ipsilateral edema and hemorrhagic transformation, and accentuated peroxisome proliferator activated receptor-γ (PPAR-γ) upregulation and TXNIP/NLRP3 inflammasome activation after ischemic stroke. Higher expression of TXNIP in hyperglycemic t-MCAO animals augmented glucose transporter 1 (GLUT-1) downregulation and increased vascular endothelial growth factor-A (VEGF-A) expression/matrix metallopeptidase 9 (MMP-9) signaling, all of which result in blood brain barrier (BBB) disruption and increased permeability to endogenous immunoglobulin G (IgG). It was also associated with a discernible buildup of nitrotyrosine and accumulation of dysfunctional tight junction proteins: zonula occludens-1 (ZO-1), occludin and claudin-5. Moreover, tPA administration triggered activation of high mobility group box protein 1 (HMGB-1), nuclear factor kappa B (NF-κB), and tumor necrosis factor-α (TNF-α) expression in the ischemic penumbra of hyperglycemic animals. All of these observations suggest a powerful role for TXNIP-NLRP3 inflammasome activation in the tPA-induced toxicity seen with hyperglycemic stroke.
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http://dx.doi.org/10.1007/s12035-020-01893-7DOI Listing
June 2020

Extracellular Vesicles: A Possible Link between HIV and Alzheimer's Disease-Like Pathology in HIV Subjects?

Cells 2019 08 24;8(9). Epub 2019 Aug 24.

Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Ave, Memphis, TN 38163, USA.

The longevity of people with HIV/AIDS has been prolonged with the use of antiretroviral therapy (ART). The age-related complications, especially cognitive deficits, rise as HIV patients live longer. Deposition of beta-amyloid (Aβ), a hallmark of Alzheimer's disease (AD), has been observed in subjects with HIV-associated neurocognitive disorders (HAND). Various mechanisms such as neuroinflammation induced by HIV proteins (e.g., Tat, gp120, Nef), excitotoxicity, oxidative stress, and the use of ART contribute to the deposition of Aβ, leading to dementia. However, progressive dementia in older subjects with HIV might be due to HAND, AD, or both. Recently, extracellular vesicles (EVs)/exosomes, have gained recognition for their importance in understanding the pathology of both HAND and AD. EVs can serve as a possible link between HIV and AD, due to their ability to package and transport the toxic proteins implicated in both AD and HIV (Aβ/tau and gp120/tat, respectively). Given that Aß is also elevated in neuron-derived exosomes isolated from the plasma of HIV patients, it is reasonable to suggest that neuron-to-neuron exosomal transport of Aβ and tau also contributes to AD-like pathology in HIV-infected subjects. Therefore, exploring exosomal contents is likely to help distinguish HAND from AD. However, future prospective clinical studies need to be conducted to compare the exosomal contents in the plasma of HIV subjects with and without HAND as well as those with and without AD. This would help to find new markers and develop new treatment strategies to treat AD in HIV-positive subjects. This review presents comprehensive literatures on the mechanisms contributing to Aβ deposition in HIV-infected cells, the role of EVs in the propagation of Aβ in AD, the possible role of EVs in HIV-induced AD-like pathology, and finally, possible therapeutic targets or molecules to treat HIV subjects with AD.
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http://dx.doi.org/10.3390/cells8090968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769601PMC
August 2019

Angiotensin II type 2 receptor stimulation with compound 21 improves neurological function after stroke in female rats: a pilot study.

Am J Physiol Heart Circ Physiol 2019 05 1;316(5):H1192-H1201. Epub 2019 Mar 1.

Program in Clinical and Experimental Therapeutics, Charlie Norwood Veterans Affairs Medical Center and University of Georgia, College of Pharmacy , Augusta, Georgia.

The angiotensin II type 2 receptor (ATR) agonist, compound 21 (C21), has been shown to be neurovascularly protective after ischemic stroke in male rats. In the current study, we aim to study the impact of C21 treatment on female rats. Young female Wistar rats were subjected to different durations of middle cerebral artery occlusion (MCAO) (3 h, 2 h, and 1 h) using a silicone-coated monofilament, treated at reperfusion with 0.03 mg/kg ip of C21 and followed up for different times (1, 3, and 14 days) after stroke. Behavioral tests were performed (Bederson, paw grasp, beam walk, and rotarod), and animals were euthanized for infarct size analysis and Western blot analysis. In vitro, primary male and female brain microvascular endothelial cells (ECs) were grown in culture, and the expression of the ATR was compared between males and females. At 1 day, C21 treatment resulted in an improvement in Bederson scores. However, at 3 days and 14 days, the impact of C21 on stroke outcomes was less robust. In vitro, the expression of the ATR was significantly higher in female ECs compared with male ECs. In conclusion, C21 improves Bederson scores after stroke in female rats when administered early at reperfusion. The ability of C21 to exert its neuroprotective effects might be affected by fluctuating levels of female hormones. The present study shows the neuroprotective impact of C21 on ischemic stroke in female rats and how the protective effects of C21 can be influenced by the hormonal status of female rodents.
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http://dx.doi.org/10.1152/ajpheart.00446.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580399PMC
May 2019

Thioredoxin-Interacting Protein (TXNIP) Associated NLRP3 Inflammasome Activation in Human Alzheimer's Disease Brain.

J Alzheimers Dis 2019 ;68(1):255-265

Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA.

Alzheimer's disease (AD) is the most common form of age-associated dementia characterized by amyloid-β plaques and neurofibrillary tangles. Recent studies have demonstrated that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox/glucose induced stress and inflammation, is now known to be upregulated in stroke, traumatic brain injury, diabetes and AD. We hypothesized that TXNIP overexpression sustains neurodegeneration through activation of the nucleotide binding and oligomerization domain-like receptor protein 3 in human AD brains. We analyzed TXNIP and the components of the NLRP3 inflammasome in the cortex of postmortem human brain samples by western blotting, real-time PCR, and immunohistochemical techniques in comparison with age-matched non-demented controls. Our results demonstrate that TXNIP protein as well as its mRNA levels in the cortex was significantly upregulated in AD compared to control brains. Moreover, using double immunofluorescence staining, TXNIP and interlukin-1β (IL-1β) were co-localized near Aβ plaques and p-tau. These results suggest an association between TXNIP overexpression levels and AD pathogenesis. Further, a significant increased expression of cleaved caspase-1 and IL-1β, the products of inflammasome activation, was detected in the cortex of AD brains. Together, these findings suggest that TXNIP, an upstream promising new therapeutic target, is a molecular link between inflammation and AD. The significant contribution of TXNIP to AD pathology suggests that strategies focusing on specific targeting of the TXNIP-NLRP3 inflammasome may lead to novel therapies for the management of AD and other age-related dementias.
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http://dx.doi.org/10.3233/JAD-180814DOI Listing
June 2020

Metabolic Syndrome, Brain Insulin Resistance, and Alzheimer's Disease: Thioredoxin Interacting Protein (TXNIP) and Inflammasome as Core Amplifiers.

J Alzheimers Dis 2018 ;66(3):857-885

Empirical evidence indicates a strong association between insulin resistance and pathological alterations related to Alzheimer's disease (AD) in different cerebral regions. While cerebral insulin resistance is not essentially parallel with systemic metabolic derangements, type 2 diabetes mellitus (T2DM) has been established as a risk factor for AD. The circulating "toxic metabolites" emerging in metabolic syndrome may engage several biochemical pathways to promote oxidative stress and neuroinflammation leading to impair insulin function in the brain or "type 3 diabetes". Thioredoxin-interacting protein (TXNIP) as an intracellular amplifier of oxidative stress and inflammasome activation may presumably mediate central insulin resistance. Emerging data including those from our recent studies has demonstrated a sharp TXNIP upregulation in stroke, aging and AD and well underlining the significance of this hypothesis. With the main interest to illustrate TXNIP place in type 3 diabetes, the present review primarily briefs the potential mechanisms contributing to cerebral insulin resistance in a metabolically deranged environment. Then with a particular focus on plausible TXNIP functions to drive and associate with AD pathology, we present the most recent evidence supporting TXNIP as a promising therapeutic target in AD as an age-associated dementia.
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http://dx.doi.org/10.3233/JAD-180735DOI Listing
November 2019

Angiotensin receptor (AT2R) agonist C21 prevents cognitive decline after permanent stroke in aged animals-A randomized double- blind pre-clinical study.

Behav Brain Res 2019 02 5;359:560-569. Epub 2018 Oct 5.

Program in Clinical and Experimental Therapeutics, Charlie Norwood VA Medical Center and University of Georgia College of Pharmacy, Augusta, GA, United States; Departments of Neurology, Augusta University, Augusta, GA, United States. Electronic address:

Post stroke cognitive impairment (PSCI) is an understudied, long-term complication of stroke, impacting nearly 30-40% of all stroke survivors. No cure is available once the cognitive deterioration manifests. To our knowledge, this is the first study to investigate the long-term effects of C21 treatment on the development of PSCI in aged animals. Treatments with C21 or vehicle were administered orally, 24 h post-stroke, and continued for 30 days. Outcome measures for sensorimotor and cognitive function were performed using a sequence of tests, all blindly conducted and assessed at baseline as well as at different time points post-stroke. Our findings demonstrate that the angiotensin receptor (AT2R) agonist C21 effectively prevents the development of PSCI in aged animals.
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http://dx.doi.org/10.1016/j.bbr.2018.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371811PMC
February 2019

RAS modulation prevents progressive cognitive impairment after experimental stroke: a randomized, blinded preclinical trial.

J Neuroinflammation 2018 Aug 13;15(1):229. Epub 2018 Aug 13.

Program in Clinical and Experimental Therapeutics, Charlie Norwood VA Medical Center and University of Georgia College of Pharmacy, HM Bldg., 1120 15th St, Augusta, GA, 30912, USA.

Background: With the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as well as the number of individuals with vascular cognitive impairment/dementia (VCID). No specific FDA-approved treatments for VCID exist. Although clinical evidence supports that angiotensin receptor blockers (ARBs) prevent cognitive decline in older adults, whether ARBs have a similar effect on VCID after stroke is unknown. Moreover, these agents reduce BP, which is undesirable in the acute stroke period, so we believe that giving C21 in this acute phase or delaying ARB administration would enable us to achieve the neurovascular benefits without the risk of unintended and potentially dangerous, acute BP lowering.

Methods: The aim of our study was to determine the impact of candesartan (ARB) or compound-21 (an angiotensin type 2 receptor--AT2R--agonist) on long-term cognitive function post-stroke, in spontaneously hypertensive rats (SHRs). We hypothesized that AT2R stimulation, either directly with C21, or indirectly by blocking the angiotensin type 1 receptor (AT1R) with candesartan, initiated after stroke, would reduce cognitive impairment. Animals were subjected to a 60-min transient middle cerebral artery occlusion and randomly assigned to either saline/C21 monotherapy, for the full study duration (30 days), or given sequential therapy starting with saline/C21 (7 days) followed by candesartan for the remainder of the study (21 days). Outcome measures included sensorimotor/cognitive-function, amyloid-β determination, and histopathologic analyses.

Results: Treatment with RAS modulators effectively preserved cognitive function, reduced cytotoxicity, and prevented chronic-reactive microgliosis in SHRs, post-stroke. These protective effects were apparent even when treatment was delayed up to 7 days post-stroke and were independent of blood pressure and β-amyloid accumulation.

Conclusion: Collectively, our findings demonstrate that RAS modulators effectively prevent cognitive impairment after stroke, even when treatment is delayed.
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http://dx.doi.org/10.1186/s12974-018-1262-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090822PMC
August 2018

Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia.

Neurochem Res 2018 Oct 7;43(10):1869-1878. Epub 2018 Aug 7.

Charlie Norwood VA Medical Center, and Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA.

The pro-survival effect of VEGF-B has been documented in different in vivo and in vitro models. We have previously shown an enhanced VEGF-B expression in response to candesartan treatment after focal cerebral ischemia. In this study, we aimed to silence VEGF-B expression to assess its contribution to candesartan's benefit on stroke outcome. Silencing VEGF-B expression was achieved by bilateral intracerebroventricular injections of lentiviral particles containing short hairpin RNA (shRNA) against VEGF-B. Two weeks after lentiviral injections, rats were subjected to either 90 min or 3 h of middle cerebral artery occlusion (MCAO) and randomized to intravenous candesartan (1 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 or 72 h and brains were collected and analyzed for hemoglobin (Hb) excess and infarct size, respectively. Functional outcome at 24, 48 and 72 h was assessed blindly. Candesartan treatment improved neurobehavioral and motor function, and decreased infarct size and Hb. While silencing VEGF-B expression diminished candesartan's neuroprotective effect, candesartan-mediated vascular protection was maintained even in the absence of VEGF-B suggesting that this growth factor is not the mediator of candesartan's vascular protective effects. However, VEGF-B is a mediator of neuroprotection achieved by candesartan and represents a potential drug target to improve stroke outcome. Further studies are needed to elucidate the underlying molecular mechanisms of VEGF-B in neuroprotection and recovery after ischemic stroke.
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http://dx.doi.org/10.1007/s11064-018-2604-xDOI Listing
October 2018

Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke.

Sci Rep 2018 04 13;8(1):5971. Epub 2018 Apr 13.

Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN, USA.

Activation of the NOD-like receptor protein (NLRP3)-inflammasome has been postulated to mediate inflammatory responses to brain damage during ischemic/reperfusion (I/R) injury. We therefore hypothesized that MCC950, a selective NLRP3-inflammasome inhibitor provides protection in mouse model of transient middle cerebral artery occlusion (tMCAO). Focal cerebral ischemia was induced by 60 min tMCAO followed by intraperitoneal administration of MCC950 (50 mg/kg) or saline at 1 h and 3 h post-occlusion. After 24 h of I/R, mice were tested for neurological outcome and were sacrificed for the analysis of infarct size and estimating NLRP3-inflammasome and apoptotic markers as well. Spectrophotometric method was used to determine hemoglobin (Hb) content as a marker of intracerebral hemorrhage. MCC950-treated mice showed a substantial reduction in infarction, edema and Hb content compared to saline controls in parallel with improved neurological deficits. MCC950 reduced expression of NLRP3-inflammasome cleavage products Caspase-1 and interlukin-1β (IL-1β) in penumbral region. These protective effects of MCC950 were associated with decreased TNF-α levels as well as poly (ADP-ribose) polymerase (PARP) and Caspase-3 cleavage and paralleled less phosphrylated NFκBp65 and IκBα levels. Taken together, these data indicate that inhibition of NLRP3-inflammasome with MCC950 has therapeutic potential in ischemic stroke models. Further investigations into the therapeutic efficacy and protocols are needed to confirm whether MCC950 treatment could be a promising candidate for clinical trials.
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http://dx.doi.org/10.1038/s41598-018-24350-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899150PMC
April 2018

Dose-response, therapeutic time-window and tPA-combinatorial efficacy of compound 21: A randomized, blinded preclinical trial in a rat model of thromboembolic stroke.

J Cereb Blood Flow Metab 2019 08 14;39(8):1635-1647. Epub 2018 Mar 14.

2 Charlie Norwood VA Medical Center, and Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Athens, GA, USA.

The aim of this translational, randomized, controlled, blinded preclinical trial was to determine the effect of compound 21 (C21) in embolic stroke. Rats were subjected to embolic-middle cerebral artery occlusion (eMCAO). They received C21 (0.01, 0.03 and 0.06 mg/kg/d) or saline (orally) for five days, with the first-dose given IV at 3 h post-eMCAO. For the time-window study, the optimal-dose of C21 was initiated at 3, 6 or 24 h post-eMCAO and continued for five days. For the combinatorial study, animals received IV-tissue plasminogen activator (tPA) at either 2 or 4 h, with IV-C21 (0.01 mg/kg) or saline at 3 h post-eMCAO and daily thereafter for five days. After performing the behavior tests, brains were collected for analyses. The dose-response study showed significant motor improvements with the lowest-dose (0.01 mg/kg) of C21. In the time-window study, this same dose resulted in improvements when given 6 h and 24 h post-eMCAO. Moreover, C21-treated animals performed better on the novel object recognition test. Neither the single treatment with C21 or tPA (4 h) nor the combination therapy was effective in reducing the hemorrhage or infarct size, although C21 alone lowered sensorimotor deficit scores post-eMCAO. Future studies should focus on the long-term cognitive benefits of C21, rather than acute neuroprotection.
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http://dx.doi.org/10.1177/0271678X18764773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681526PMC
August 2019

Thioredoxin-Interacting Protein (TXNIP) in Cerebrovascular and Neurodegenerative Diseases: Regulation and Implication.

Mol Neurobiol 2018 Oct 27;55(10):7900-7920. Epub 2018 Feb 27.

Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, 855 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.

Neurological diseases, including acute attacks (e.g., ischemic stroke) and chronic neurodegenerative diseases (e.g., Alzheimer's disease), have always been one of the leading cause of morbidity and mortality worldwide. These debilitating diseases represent an enormous disease burden, not only in terms of health suffering but also in economic costs. Although the clinical presentations differ for these diseases, a growing body of evidence suggests that oxidative stress and inflammatory responses in brain tissue significantly contribute to their pathology. However, therapies attempting to prevent oxidative damage or inhibiting inflammation have shown little success. Identification and targeting endogenous "upstream" mediators that normalize such processes will lead to improve therapeutic strategy of these diseases. Thioredoxin-interacting protein (TXNIP) is an endogenous inhibitor of the thioredoxin (TRX) system, a major cellular thiol-reducing and antioxidant system. TXNIP regulating redox/glucose-induced stress and inflammation, now is known to get upregulated in stroke and other brain diseases, and represents a promising therapeutic target. In particular, there is growing evidence that glucose strongly induces TXNIP in multiple cell types, suggesting possible physiological roles of TXNIP in glucose metabolism. Recently, a significant body of literature has supported an essential role of TXNIP in the activation of the NOD-like receptor protein (NLRP3)-inflammasome, a well-established multi-molecular protein complex and a pivotal mediator of sterile inflammation. Accordingly, TXNIP has been postulated to reside centrally in detecting cellular damage and mediating inflammatory responses to tissue injury. The majority of recent studies have shown that pharmacological inhibition or genetic deletion of TXNIP is neuroprotective and able to reduce detrimental aspects of pathology following cerebrovascular and neurodegenerative diseases. Conspicuously, the mainstream of the emerging evidences is highlighting TXNIP link to damaging signals in endothelial cells. Thereby, here, we keep the trend to present the accumulative data on CNS diseases dealing with vascular integrity. This review aims to summarize evidence supporting the significant contribution of regulatory mechanisms of TXNIP with the development of brain diseases, explore pharmacological strategies of targeting TXNIP, and outline obstacles to be considered for efficient clinical translation.
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http://dx.doi.org/10.1007/s12035-018-0917-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388721PMC
October 2018

MCC950, the Selective Inhibitor of Nucleotide Oligomerization Domain-Like Receptor Protein-3 Inflammasome, Protects Mice against Traumatic Brain Injury.

J Neurotrauma 2018 06 2;35(11):1294-1303. Epub 2018 Apr 2.

1 Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center , Memphis, Tennessee.

Nucleotide oligomerization domain (NOD)-like receptor protein-3 (NLRP3) inflammasome may intimately contribute to sustaining damage after traumatic brain injury (TBI). This study aims to examine whether specific modulation of NLPR3 inflammasome by MCC950, a novel selective NLRP3 inhibitor, confers protection after experimental TBI. Unilateral cortical impact injury was induced in young adult C57BL/6 mice. MCC950 (50 mg/kg, intraperitoneally) or saline was administration at 1 and 3 h post-TBI. Animals were tested for neurological function and then sacrificed at 24 or 72 h post-TBI. Immunoblotting and histological analysis were performed to identify markers of NLRP3 inflammasome and proapoptotic activity in pericontusional areas of the brains at 24 or 72 h post-TBI. MCC950 treatment provided a significant improvement in neurological function and reduced cerebral edema in TBI animals. TBI upregulated NLRP3, apoptosis-associated speck-like adapter protein (ASC), cleaved caspase-1, and interlukein-1β (IL-1β) in the perilesional area. MCC950 efficiently repressed caspase-1 and IL-1β with a transient effect on ASC and NLRP3 post-TBI. MCC950 treatment also provided protection against proapoptotic activation of poly (ADP-ribose) polymerase and caspase-3 associated with TBI. A concurrent inhibition of inflammasome priming was also detectable at the nuclear factor kappa B/p65 and caspase-1 level. Our findings support the implication of NLRP3 inflammasome in the pathogenesis of TBI and further suggests the therapeutic potential of MCC950.
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http://dx.doi.org/10.1089/neu.2017.5344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962912PMC
June 2018

Role of angiotensin system modulation on progression of cognitive impairment and brain MRI changes in aged hypertensive animals - A randomized double- blind pre-clinical study.

Behav Brain Res 2018 07 8;346:29-40. Epub 2017 Dec 8.

Program in Clinical and Experimental Therapeutics, Charlie Norwood VA Medical Center and University of Georgia College of Pharmacy, Augusta, GA, United States; Department of Neurology, Augusta University, Augusta, GA, United States. Electronic address:

Growing evidence suggests that renin angiotensin system (RAS) modulators support cognitive function in various animal models. However, little is known about their long-term effects on the brain structure in aged hypertensive animals with chronic cerebral hypoperfusion as well as which specific domains of cognition are most affected. Therefore, in the current study we examined the effects of Candesartan and Compound 21 (C21) (RAS modulators) on aspects of cognition known to diminish with advanced age and accelerate with hypertension and vascular disease. Outcome measures for sensorimotor and cognitive function were performed using a sequence of tests, all blindly conducted and assessed at baseline and after 4 and 8 weeks of chronic hypoxic hypoperfusion and treatment. Magnetic resonance imaging (MRI) was performed at the end of the 8 week study period followed by animal sacrifice and tissue collection. Both Candesartan and C21 effectively preserved cognitive function and prevented progression of vascular cognitive impairment (VCI) but only candesartan prevented loss of brain volume in aged hypertensive animals. Collectively, our findings demonstrate that delayed administration of RAS modulators effectively preserve cognitive function and prevent the development / progression of VCI in aged hypertensive animals with chronic cerebral hypoperfusion.
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http://dx.doi.org/10.1016/j.bbr.2017.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866136PMC
July 2018

Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension.

PLoS One 2017 22;12(6):e0178867. Epub 2017 Jun 22.

Departments of Biostatistics, Medical College of Georgia, Augusta University, Augusta, Georgia, Unites States of America.

Stroke is a leading cause of adult disability worldwide. Improving stroke outcome requires an orchestrated interplay that involves up regulation of pro-survival pathways and a concomitant suppression of pro-apoptotic mediators. In this investigation, we assessed the involvement of eNOS in the AT1 blocker-mediated protective and pro-recovery effects in animals with hypertension. We also evaluated the effect of acute eNOS inhibition in hypertensive animals. To achieve these goals, spontaneously hypertensive rats (SHR) were implanted with blood pressure transmitters, and randomized to receive either an eNOS inhibitor (L-NIO) or saline one hour before cerebral ischemia induction. After 3 hours of ischemia, animals were further randomized to receive either candesartan or saline at the time of reperfusion and sacrificed either 24 hours or 7 days later. Candesartan induced an early protective effect that was independent of eNOS inhibition (50% improvement in motor function). However, the protective effect of candesartan was associated with about five fold up regulation of BDNF expression and about three fold reduction in ER stress markers, in an eNOS dependent manner. The early benefit of a single dose of candesartan, present at 24 hours after stroke, was diminished at 7 days, perhaps due to a failure to induce an angiogenic response in these hypertensive animals. In conclusion, our findings demonstrate an early prorecovery effect of candesartan at both functional and molecular levels. Candesartan induced prorecovery signaling was mediated through eNOS. This effect was not maintained at 7 days after experimental ischemia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178867PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480858PMC
September 2017

MyD88 contributes to neuroinflammatory responses induced by cerebral ischemia/reperfusion in mice.

Biochem Biophys Res Commun 2016 Nov 4;480(1):69-74. Epub 2016 Oct 4.

Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China; Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA; Key Laboratory of Anesthesiology of Jiangsu Province, Xuzhou 221002, China. Electronic address:

Myeloid differentiation primary-response protein-88 (MyD88) is one of adaptor proteins mediating Toll-like receptors (TLRs) signaling. Activation of MyD88 results in the activation of nuclear factor kappa B (NFκB) and the increase of inflammatory responses. Evidences have demonstrated that TLRs signaling contributes to cerebral ischemia/reperfusion (I/R) injury. However, the role of MyD88 in this mechanism of action is disputed and needs to be clarified. In the present study, in a mouse model of cerebral I/R, we examined the activities of NFκB and interferon factor-3 (IRF3), and the inflammatory responses in ischemic brain tissue using ELISA, Western blots, and real-time PCR. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. Our results showed that NFκB activity increased in ischemic brains, but IRF3 was not activated after cerebral I/R, in wild-type (WT) mice. MyD88 deficit inhibited the activation of NFκB, and the expression of interleukin-1β (IL-1β), IL-6, Beclin-1 (BECN1), pellino-1, and cyclooxygenase-2 (COX-2) increased by cerebral I/R compared with WT mice. Interestingly, the expression of interferon Beta 1 (INFB1) and vascular endothelial growth factor (VEGF) increased in MyD88 KO mice. Unexpectedly, although the neurological function improved in the MyD88 knockout (KO) mice, the deficit of MyD88 failed to reduce cerebral infarct size compared to WT mice. We concluded that MyD88-dependent signaling contributes to the inflammatory responses induced by cerebral I/R. MyD88 deficit may inhibit the increased inflammatory response and increase neuroprotective signaling.
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http://dx.doi.org/10.1016/j.bbrc.2016.10.007DOI Listing
November 2016

Progesterone improves long-term functional and histological outcomes after permanent stroke in older rats.

Behav Brain Res 2016 May 26;305:46-56. Epub 2016 Feb 26.

Department of Emergency Medicine, Brain Research Laboratory, Emory University, Atlanta, GA, USA. Electronic address:

Previous studies have shown progesterone to be beneficial in animal models of central nervous system injury, but less is known about its longer-term sustained effects on recovery of function following stroke. We evaluated progesterone's effects on a panel of behavioral tests up to 8 weeks after permanent middle cerebral artery occlusion (pMCAO). Male Sprague-Dawley rats 12m.o. were subjected to pMCAO and, beginning 3h post-pMCAO, given intraperitoneal injections of progesterone (8mg/kg) or vehicle, followed by subcutaneous injections at 8h and then every 24h for 7 days, with tapering of the last 2 treatments. The rats were then tested on functional recovery at 3, 6 and 8 weeks post-stroke. We observed that progesterone-treated animals showed attenuation of infarct volume and improved functional outcomes at 8 weeks after stroke on grip strength, sensory neglect, motor coordination and spatial navigation tests. Progesterone treatments significantly improved motor deficits in the affected limb on a number of gait parameters. Glial fibrillary acidic protein expression was increased in the vehicle group and considerably lowered in the progesterone group at 8 weeks post-stroke. With repeated post-stroke testing, sensory neglect and some aspects of spatial learning performance showed spontaneous recovery, but on gait and grip-strength measres progesterone given only in the acute stage of stroke (first 7 days) showed sustained beneficial effects on all other measures of functional recovery up to 8 weeks post-stroke.
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http://dx.doi.org/10.1016/j.bbr.2016.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131565PMC
May 2016

Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke.

Mol Neurobiol 2017 01 12;54(1):661-670. Epub 2016 Jan 12.

Charlie Norwood VA Medical Center and Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA.

Angiotensin type 1 receptor blockers (ARBs) have been shown to be neuroprotective and neurorestorative in experimental stroke. The mechanisms proposed include anti-inflammatory, antiapoptotic effects, as well as stimulation of endogenous trophic factors leading to angiogenesis and neuroplasticity. We aimed to investigate the involvement of the neurotrophin, brain-derived neurotrophic factor (BDNF), in ARB-mediated functional recovery after stroke. To achieve this aim, Wistar rats received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles or nontargeting control (NTC) vector, to knock down BDNF in both hemispheres. After 14 days, rats were subjected to 90-min middle cerebral artery occlusion (MCAO) and received the ARB, candesartan, 1 mg/kg, or saline IV at reperfusion (one dose), then followed for another 14 days using a battery of behavioral tests. BDNF protein expression was successfully reduced by about 70 % in both hemispheres at 14 days after bilateral shRNA lentiviral particle injection. The NTC group that received candesartan showed better functional outcome as well as increased vascular density and synaptogenesis as compared to saline treatment. BDNF knockdown abrogated the beneficial effects of candesartan on neurobehavioral outcome, vascular density, and synaptogenesis. In conclusion, BDNF is directly involved in candesartan-mediated functional recovery, angiogenesis, and synaptogenesis.
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http://dx.doi.org/10.1007/s12035-015-9675-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940333PMC
January 2017

Sequential Therapy with Minocycline and Candesartan Improves Long-Term Recovery After Experimental Stroke.

Transl Stroke Res 2015 Aug 26;6(4):309-22. Epub 2015 May 26.

Charlie Norwood VA Medical Center, Augusta, GA, USA.

Minocycline and candesartan have both shown promise as candidate therapeutics in ischemic stroke, with multiple, and somewhat contrasting, molecular mechanisms. Minocycline is an anti-inflammatory, antioxidant, and anti-apoptotic agent and a known inhibitor of matrix metalloproteinases (MMPs). Yet, minocycline exerts antiangiogenic effects both in vivo and in vitro. Candesartan promotes angiogenesis and activates MMPs. Aligning these therapies with the dynamic processes of injury and repair after ischemia is likely to improve success of treatment. In this study, we hypothesize that opposing actions of minocycline and candesartan on angiogenesis, when administered simultaneously, will reduce the benefit of candesartan treatment. Therefore, we propose a sequential combination treatment regimen to yield a better outcome and preserve the proangiogenic potential of candesartan. In vitro angiogenesis was assessed using human brain endothelial cells. In vivo, Wistar rats subjected to 90-min middle cerebral artery occlusion (MCAO) were randomized into four groups: saline, candesartan, minocycline, and sequential combination of minocycline and candesartan. Neurobehavioral tests were performed 1, 3, 7, and 14 days after stroke. Brain tissue was collected on day 14 for assessment of infarct size and vascular density. Minocycline, when added simultaneously, decreased the proangiogenic effect of candesartan treatment in vitro. Sequential treatment, however, preserved the proangiogenic potential of candesartan both in vivo and in vitro, improved neurobehavioral outcome, and reduced infarct size. Sequential combination therapy with minocycline and candesartan improves long-term recovery and maintains candesartan's proangiogenic potential.
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http://dx.doi.org/10.1007/s12975-015-0408-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559761PMC
August 2015

Sesamin attenuates neurotoxicity in mouse model of ischemic brain stroke.

Neurotoxicology 2014 Dec 12;45:100-10. Epub 2014 Oct 12.

Department of Biological Sciences, Rabigh College of Science and Arts, King Abdulaziz University (Jeddah), P.O. Box 344, Rabigh 21911, Kingdom of Saudi Arabia. Electronic address:

Stroke is a severe neurological disorder characterized by the abrupt loss of blood circulation into the brain resulting into wide ranging brain and behavior abnormalities. The present study was designed to evaluate molecular mechanism by which sesamin (SES) induces neuroprotection in mouse model of ischemic stroke. The results of this study demonstrate that SES treatment (30 mg/kg bwt) significantly reduced infarction volume, lipid per-oxidation, cleaved-caspase-3 activation, and increased GSH activity following MCAO in adult male mouse. SES treatment also diminished iNOS and COX-2 protein expression, and significantly restored SOD activity and protein expression level in the ischemic cortex of the MCAO animals. Furthermore, SES treatment also significantly reduced inflammatory and oxidative stress markers including Iba1, Nox-2, Cox-2, peroxynitrite compared to placebo MCAO animals. Superoxide radical production, as studied by DHE staining method, was also significantly reduced in the ischemic cortex of SES treated compared to placebo MCAO animals. Likewise, downstream effects of superoxide free radicals i.e. MAPK/ERK and P38 activation was also significantly attenuated in SES treated compared to placebo MCAO animals. In conclusion, these results suggest that SES induces significant neuroprotection, by ameliorating many signaling pathways activated/deactivated following cerebral ischemia in adult mouse.
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http://dx.doi.org/10.1016/j.neuro.2014.10.002DOI Listing
December 2014

Compound 21 is pro-angiogenic in the brain and results in sustained recovery after ischemic stroke.

J Hypertens 2015 Jan;33(1):170-80

aCharlie Norwood VA Medical Center, and Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, and Georgia Regents University, Augusta, Georgia, USA bJordan University of Science and Technology, College of Pharmacy, Irbid, Jordan *Both authors contributed equally to this work.

Introduction: Angiotensin II type 2 receptor (AT2R) stimulation is neuroprotective after experimental stroke. However, the therapeutic utility of AT2R stimulation has been hampered by the lack of a specific agonist with favourable bioavailability. Compound 21 (C21) - the first non-peptide AT2R agonist - offers a potential option to enhance stroke recovery. This study aimed to investigate the effect of C21 administration on early and late stroke outcomes, and the molecular mediators involved.

Methods: Rats were subjected to 3 h or 90 min of middle cerebral artery occlusion (MCAO) and randomized to intraperitoneal C21 (0.03 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 h or 7 days and brains were collected for molecular analysis and immunostaining, respectively. Functional outcome at days 1, 4 and 7 was assessed blindly. C21 angiogenic potential was assessed in vitro.

Results: After 3 h of MCAO, C21 treatment reduced infarct size and improved behavioural outcome at 24 h without affecting blood pressure. Co-administration of the AT2R antagonist (PD123319) blocked these effects. On the molecular level, C21 decreased brain haemoglobin content, down-regulated apoptotic and oxidative markers, and increased pro-survival molecules in the brain. After 90 min of MCAO, C21 treatment resulted in sustained functional improvement at 7 days, together with increased vascular density in the ischemic penumbra. In vitro, C21 showed a pro-angiogenic effect that was blocked with brain-derived neurotrophic factor neutralization.

Conclusion: These findings demonstrate that a single dose of C21 is neurovascular-protective and improves stroke outcome possibly through increasing neurotrophin activity, mitigating brain inflammation, and promoting antioxidant and pro-angiogenic effects.
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http://dx.doi.org/10.1097/HJH.0000000000000364DOI Listing
January 2015

Role of inflammasome activation in the pathophysiology of vascular diseases of the neurovascular unit.

Antioxid Redox Signal 2015 May 11;22(13):1188-206. Epub 2014 Nov 11.

1 Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia , Augusta, Georgia .

Significance: Inflammation is the standard double-edged defense mechanism that aims at protecting the human physiological homeostasis from devastating threats. Both acute and chronic inflammation have been implicated in the occurrence and progression of vascular diseases. Interference with components of the immune system to improve patient outcome after ischemic injury has been uniformly unsuccessful. There is a need for a deeper understanding of the innate immune response to injury in order to modulate, rather than to block inflammation and improve the outcome for vascular diseases.

Recent Advances: Nucleotide-binding oligomerization domain-like receptors or NOD-like receptor proteins (NLRPs) can be activated by sterile and microbial inflammation. NLR family plays a major role in activating the inflammasome.

Critical Issues: The aim of this work is to review recent findings that provided insights into key inflammatory mechanisms and define the place of the inflammasome, a multi-protein complex involved in instigating inflammation in neurovascular diseases, including retinopathy, neurodegenerative diseases, and stroke.

Future Directions: The significant contribution of NLRP-inflammasome activation to vascular disease of the neurovascular unit in the brain and retina suggests that therapeutic strategies focused on specific targeting of inflammasome components could significantly improve the outcomes of these diseases.
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http://dx.doi.org/10.1089/ars.2014.6126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403234PMC
May 2015

Role of matrix metalloproteinase activity in the neurovascular protective effects of Angiotensin antagonism.

Stroke Res Treat 2014 24;2014:560491. Epub 2014 Jul 24.

Charlie Norwood VA Medical Center, Augusta, GA 30912, USA ; Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, HM 1212, 1120 15th Street, Augusta, GA 30912, USA ; Department of Neurology, Georgia Regents University, Augusta, GA 30912, USA.

Background and Purpose. Oxidative stress and matrix metalloproteinase (MMP) activity have been identified as key mediators of early vascular damage after ischemic stroke. Somewhat surprisingly, the angiotensin II type 1 receptor (AT1) blocker, candesartan, has been shown to acutely increase MMP activity while providing neurovascular protection. We aimed to determine the contribution of MMP and nitrative stress to the effects of angiotensin blockade in experimental stroke. Methods. Wistar rats (n = 9-14/group; a total of 99) were treated in a factorial design with candesartan 1 mg/kg IV, alone or in combination with either a peroxynitrite decomposition catalyst, FeTPPs, 30 mg/kg IP or GM6001 50 mg/kg IP (MMP inhibitor). Neurological deficit, infarct, size and hemorrhagic transformation (HT) were measured after 3 h of middle cerebral artery occlusion (MCAO) and 21 h of reperfusion. MMP activity and nitrotyrosine expression were also measured. Results. Candesartan reduced infarct size and HT when administered alone (P = 0.0011) and in combination with FeTPPs (P = 0.0016). GM6001 did not significantly affect HT when administered alone, but the combination with candesartan caused increased HT (P < 0.0001) and worsened neurologic score (P = 0.028). Conclusions. Acute administration of candesartan reduces injury after stroke despite increasing MMP activity, likely by an antioxidant mechanism.
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http://dx.doi.org/10.1155/2014/560491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134816PMC
August 2014

Low-dose candesartan enhances molecular mediators of neuroplasticity and subsequent functional recovery after ischemic stroke in rats.

Mol Neurobiol 2015 2;51(3):1542-53. Epub 2014 Aug 2.

Charlie Norwood VA Medical Center, Augusta, GA, USA,

We have previously reported that angiotensin type 1 receptor (AT1R) blockade with candesartan exerts neurovascular protection after experimental cerebral ischemia. Here, we tested the hypothesis that a low, subhypotensive dose of candesartan enhances neuroplasticity and subsequent functional recovery through enhanced neurotrophic factor expression in rats subjected to ischemia reperfusion injury. Male Wistar rats (290-300 g) underwent 90 min of middle cerebral artery occlusion (MCAO) and received candesartan (0.3 mg/kg) or saline at reperfusion and then once every 24 h for 7 days. Functional deficits were assessed in a blinded manner at 1, 3, 7, and 14 days after MCAO. Animals were sacrificed 14-day post-stroke and the brains perfused for infarct size by cresyl violet. Western blot and immunohistochemistry were used to assess the expression of growth factors and synaptic proteins. Candesartan-treated animals showed a significant reduction in the infarct size [t (13) = -5.5, P = 0.0001] accompanied by functional recovery in Bederson [F (1, 13) = 7.9, P = 0.015], beam walk [F (1, 13) = 6.7, P = 0.023], grip strength [F (1, 13) = 15.2, P = 0.0031], and rotarod performance [F (1, 14) = 29.8, P < 0.0001]. In addition, candesartan-treated animals showed significantly higher expression of active metalloproteinase-3 (MMP-3), laminin, and angiopoietin-1 (Ang-1). The expression of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) and its receptor was significantly increased in the animals treated with candesartan. Also, we observed significant increases in neuroplasticity markers, synaptophysin, and PSD-95. These results indicate that low-dose candesartan had a large and enduring effect on measures of plasticity, and this accompanied the functional recovery after ischemic stroke.
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http://dx.doi.org/10.1007/s12035-014-8830-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677667PMC
March 2016