Publications by authors named "Golnoush Mirzahosseini"

5 Publications

  • Page 1 of 1

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

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

Bio-guided isolation of subsp. cytotoxic components.

Nat Prod Res 2019 Jun 19;33(11):1687-1690. Epub 2018 Feb 19.

d Department of Biotechnology , Iranian Research Organization for Science and Technology , Tehran , Iran.

subsp was extracted by 80% ethanol. The total extract was then partitioned into four fractions including chloroform, ethyl acetate and methanol. Cytotoxic effect of fractions was examined by MTT assay in K562 (chronic myelogenous leukemia), AGS (gastric adenocarcinoma), MCF-7 (breast adenocarcinoma) and SW742 (colon adenocarcinoma) cell lines. The Chloroform fraction, with the lowest LC against K-562 cell lines, was partitioned into 14 subfractions and subjected to further purification by reversed-phase (C18) silica gel and sephadex LH-20 column chromatography. Three flavonoids including cirsimaritin, cirsilinelol and eupatilin were isolated for the first time from the species and the structures were confirmed by spectroscopic data. The high selectivity index of the purified flavonoids indicates valuable components with potential few side effects for normal cell lines. However, solubility tests for isolated components indicates the need for novel pharmaceutical dosage forms, in the case for using natural flavonoids as chemotherapeutic agents.
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http://dx.doi.org/10.1080/14786419.2018.1428590DOI Listing
June 2019