Publications by authors named "Sanaz Nasoohi"

23 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

The conditioned medium of human embryonic stem cell-derived mesenchymal stem cells alleviates neurological deficits and improves synaptic recovery in experimental stroke.

J Cell Physiol 2021 Mar 30;236(3):1967-1979. Epub 2020 Jul 30.

Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

The transplantation of mesenchymal stem cells (MSCs) is of main approaches in regenerative therapy for stroke. Due to the potential tumorigenicity and low survival rate of transplanted cells, focuses have been shifted from cell replacement to their paracrine effects. Therefore, stem cell-conditioned medium (CM) therapy has emerged as an alternative candidate. Here, we investigated the effect of CM derived from human embryonic MSCs on experimental ischemic stroke. Wistar rats underwent ischemic stroke by the right middle cerebral artery occlusion (MCAO). CM was infused either one time (1 hr post-MCAO) or three times (1, 24, and 48 hr post-MCAO) through guide cannula into the left lateral ventricle. Neurological functions were evaluated using Bederson's test and modified Neurological Severity Score on Days 1, 3, and 7 following MCAO. Infarction volumes and cerebral edema were measured on Days 3 and 7. growth-associated protein-43, synaptophysin, cAMP response element-binding protein, and phosphorylated-cAMP response element-binding protein levels were also assessed in peri-ischemic cortical tissue on Day 7 postsurgery. Our results indicated that three times injections of CM could significantly reduce body weight loss, mortality rate, infarct volumes, cerebral edema, and improve neurological deficits in MCAO rats. Moreover, three injections of CM could restore decreased levels of synaptic markers in MCAO rats up to its normal levels observed in the sham group. Our data suggest that using the CM obtained from embryonic stem cells-MSCs could be a potent therapeutic approach to attenuate cerebral ischemia insults which may be partly mediated through modulation of synaptic plasticity.
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http://dx.doi.org/10.1002/jcp.29981DOI Listing
March 2021

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

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

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

High intensity exercise preconditioning provides differential protection against brain injury following experimental stroke.

Life Sci 2018 Aug 6;207:30-35. Epub 2018 Mar 6.

Department of Exercise Physiology, School of Physical Education and Sport Sciences, Shahid Beheshti University of Sciences, Tehran, Iran. Electronic address:

Aims: Different modes of physical activity provide cerebrovascular protection against thromboembolic events. Based on recent reports high intensity exercise protocols appear to raise cerebral VEGF levels leading to efficient cerebral angiogenesis. The present study aims to address if moderate continuous training (MCT) and high intensity interval training (HIT) differ in preconditioning against ischemic stroke.

Methods: Wistar rats were subjected to HIT or MCT for 8 weeks before transient middle cerebral artery occlusion (tMCAO) surgery. As indexes for improved angiogenic signals, VEGF-A and its pivotal receptor VEGF-R2 were immunoblotted just before occlusive stroke.

Key Findings: Both training protocols induced a remarkable protection against neurological deficit and tissue injury following stroke. Cerebral infarctions were better improved in HIT animals which explained the slightly but not significantly higher neurological function. HIT brains developed higher levels of cortical VEGF-A and striatal VEGF-R2.

Significance: These data conclude preconditioning with high intensity protocols might excel continued moderate exercise to induce VEGF signaling and alleviate stroke outcomes. Further investigations may provide complementary mechanistic views.
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http://dx.doi.org/10.1016/j.lfs.2018.03.007DOI Listing
August 2018

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

Coenzyme Q10 supplementation improves acute outcomes of stroke in rats pretreated with atorvastatin.

Nutr Neurosci 2019 Apr 26;22(4):264-272. Epub 2017 Sep 26.

c Department of Pharmacology and Toxicology, School of Pharmacy , Shahid Beheshti University of Medical Sciences , Tehran , Iran.

Objectives: Coenzyme Q10 (CoQ10, ubiquinone) stands among the safest supplements in the elderly to protect against cardiovascular disorders. Noteworthy, CoQ10 deficiency is common in many surviving stroke patients as they are mostly prescribed statins for the secondary prevention of stroke incidence lifelong. Accordingly, the current study aims to experimentally examine whether CoQ10 supplementation in animals receiving atorvastatin may affect acute stroke-induced injury.

Methods: Adult rats underwent transient middle cerebral artery occlusion after atorvastatin pretreatment (5 or 10 mg/ kg/day; po; 30 days) with or without CoQ10 (200 mg/kg/day). After 24 hours ischemic/reperfusion injury, animals were subjected to functional assessments followed by cerebral molecular and histological to detect inflammation, apoptosis and oxidative stress.

Results: Animals dosed with 10 mg/kg presented the worst neurological function and brain damage in the acute phase of stroke injury. CoQ10 supplementation efficiently improved functional deficit and cerebral infarction in all stroke animals, particularly those exhibiting statin toxicity. Such benefits were associated with remarkable anti-inflammatory and anti-apoptotic effects, based on the analyzed tumor necrosis factor-α, interleukin-6, Bax/Bcl2 and cleaved caspase 3/9 immunoblots. Importantly, our fluoro-jade staining data indicated CoQ10 may revert the stroke-induced neurodegeneration. No parallel alteration was detected in stroke-induced oxidative stress as determined by malondialdehyde and 8-oxo-2'-deoxyguanosine levels.

Discussion: These data suggest that all stroke animals may benefit from CoQ10 administration through modulating inflammatory and degenerative pathways. This study provides empirical evidence for potential advantages of CoQ10 supplementation in atorvastatin-receiving patients which may not shadow its antioxidant properties.
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http://dx.doi.org/10.1080/1028415X.2017.1376928DOI Listing
April 2019

Differential impact of treadmill training on stroke-induced neurological disorders.

Brain Inj 2017 12;31(13-14):1910-1917. Epub 2017 Sep 12.

d Department of Physiology , Faculty of Medicine, Tehran University of Medical Sciences , Tehran , Iran.

Objective: Physical exercise contributes to improving stability against nerve injury caused by ischaemic stroke. Here we aimed to preliminarily investigate the effects of continuous endurance training (CET) and high-intensity interval training (HIT) on stroke-associated anxiety, locomotion, neurological assessments and P70S6 Kinase (P70S6K) activation as well. To do this, rats were trained according to HIT and CET protocols for 2 months prior to being subject to middle cerebral artery occlusion surgery.

Methods: Twenty-four hours later behavioural examination was performed by elevated plus maze (EPM) testing, open field and neurological scoring followed by cortical and hippocampal P70S6Ks immunoblotting.

Results: According to the obtained data pre-ischaemic HIT and CET similarly improved neurological performance, anxiety levels and locomotion in EPM and open field tests following ischaemic stroke while there was a remarkable rise in hippocampal and cortical P70S6K activation in the HIT group compared to the CET counterparts.

Conclusion: Behavioral and molecular data suggest that interval training is more beneficial rather than CET, but the distinct mechanisms of CET and HIT on memory are still topics to be discovered.
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http://dx.doi.org/10.1080/02699052.2017.1346287DOI Listing
July 2018

A Search for Mitochondrial Damage in Alzheimer's Disease Using Isolated Rat Brain Mitochondria.

Iran J Pharm Res 2016 ;15(Suppl):185-195

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects regions of the brain that control cognition, memory, language, speech and awareness to one's physical surroundings. The pathological initiation and progression of AD is highly complex and its prevalence is on the rise. In his study, Alzheimer's disease was induced with single injection of amyloid-β (Aβ) peptides (30ng, by stereotaxy) in each hemisphere of the Wistar rat brain. Then memory dysfunction, oxidative stress and apoptosis induced by Aβ peptide were investigated on isolated brain mitochondria obtained from infected rat. Our results showed memory impairment in rats after receiving an Aβ peptide. We also found significant rise (P<0.05) at ROS formation, mitochondrial membrane depolarization, mitochondria swelling, cytochrome c release and significant decrease in ATP/ADP ratio on mitochondria isolated from brain of these memory impaired rats compared with those of untreated control rat group. Activation of caspase-3 the final mediator of apoptosis in the brain homogenate of the memory impaired rats was another justification for occurrence of neuron loss in the experimental model of AD. Our results suggest that oxidative stress and mitochondria mediated apoptosis in brain neurons play very important role in initiation of AD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242364PMC
January 2016

Nanoliposome containing cyclosporine A reduced neuroinflammation responses and improved neurological activities in cerebral ischemia/reperfusion in rat.

Fundam Clin Pharmacol 2017 Apr 28;31(2):185-193. Epub 2016 Oct 28.

Experimental Medicine Research Center, Tehran University of Medical Sciences, Poursina Street, Tehran, 1417613151, Iran.

Cyclosporine A (CsA) is known as a neuroprotective agent against cerebral ischemia/reperfusion (I/R) in animal models. However, the significant therapeutic effects of CsA have been observed in high systemic doses or manipulating the blood-brain barrier, resulting in systemic side effects and toxicity. As the liposome nanocarriers have been developed for efficient delivery of peptide and proteins, liposomal CsA (Lipo-CsA) could improve cerebral (I/R) injuries. In this study, the liposomal CsA formulation (CsA at dose of 2.5 mg/kg) was prepared to assess the brain injury outcomes in 90 min middle cerebral artery occlusion (MCAO) stroke model followed by 48 h reperfusion in treating rats. Five minutes after induction of cerebral ischemia in rats, intravenous (iv) administration of Lipo-CsA significantly (P < 0.001) recovered the infarct size, the brain edema, and the neurological activities compared to corresponding control groups following 48 h I/R. In addition, after 48 h cerebral I/R, Lipo-CsA potentially (P < 0.001) inhibited the inflammation responses including MPO activity and tumor necrosis factor-alpha level in comparison to other groups. In conclusion, the results indicate that the low dose of CsA in liposomal formulation is more effective compared to higher dose of free form of CsA in treatment of ischemic brain in rats.
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http://dx.doi.org/10.1111/fcp.12244DOI Listing
April 2017

Synthesis and Biological Evaluation of Cyclic [Tc]-HYNIC-CGPRPPC as a Fibrin-Binding Peptide for Molecular Imaging of Thrombosis and Its Comparison with [Tc]-HYNIC-GPRPP.

Mol Imaging Biol 2017 04;19(2):256-264

Department of Pharmaceutical Chemistry and Radiopharmacy, School of Pharmacy and PET/CT Unit, Ferdous Nuclear Medicine Center, Dr. Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Vali-e Asr Ave., Niayesh Junction, P.O. Box 14155-6153, Tehran, Iran.

Purpose: Many patients worldwide suffer from cardiovascular diseases for which an underlying factor is thrombosis. Devising a molecular imaging technique for early detection of thrombosis in a clinical setting is highly recommended. Because fibrin is a major constituent of clots and is present in all types of thrombi but absent in circulation, it is a highly specific and sensitive target for molecular imaging of thrombi. It is assumed that cyclization of peptides will improve the receptor binding affinity and stability of the peptide. In the present study, we have developed linear and cyclic fibrin-binding peptides for thrombus imaging and compared their biological properties.

Procedures: Linear HYNIC-GPRPP and cyclic HYNIC-CGPRPPC peptides were synthesized using a standard Fmoc strategy and radiolabeled with Tc-99m. The stability of the radiolabeled peptides in human plasma and their affinity for fibrin and blood clots were determined. Blood clearance and biodistribution were evaluated in rats and mice, respectively. The peptide with the highest affinity was injected to a live rabbit femoral thrombosis model, and scintigraphic images were obtained.

Results: In vitro studies show that peptides are stable in human plasma and have a high affinity for human fibrin. They also demonstrated fast blood clearance in rats and high thrombus uptake in the Balb/c mice femoral thrombosis model. Femoral thrombosis was visualized 30 min postinjection of cyclic peptide in a live rabbit model using single photon emission computed tomography (SPECT)/X-ray computed tomography.

Conclusions: The results indicate that the cyclic peptide is a promising agent for molecular imaging of fibrin using SPECT.
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http://dx.doi.org/10.1007/s11307-016-1004-3DOI Listing
April 2017

Study of Sedative-Hypnotic Effects of Aloe vera L. Aqueous Extract through Behavioral Evaluations and EEG Recording in Rats.

Iran J Pharm Res 2016 ;15(1):293-300

Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

In this study, we investigated the sedative and hypnotic effects of the aqueous extract of Aloe vera on rats. In order to evaluate the overall hypnotic effects of the Aloe vera extract, open field and loss of righting reflex tests were primarily used. The sedative and hypnotic effects of the extract were then confirmed by detection of remarkable raise in the total sleeping time through analysis of electroencephalographic (EEG) recordings of animals. Analysis of the EEG recordings showed that there is concomitant change in Rapid Eye Movement (REM) and None Rapid Eye Movement (NREM) sleep in parallel with the prolonged total sleeping time. Results of the current research show that the extract has sedative-hypnotic effects on both functional and electrical activities of the brain.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986106PMC
September 2016

Association of Long-Term Atorvastatin with Escalated Stroke-Induced Neuroinflammation in Rats.

J Mol Neurosci 2017 Jan 19;61(1):32-41. Epub 2016 Aug 19.

Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, P.O. BOX 19615-1178, Tehran, Iran.

Statins are widely used in high-risk patients to reduce the stroke incidence. However, little has been investigated about the impact of chronic pretreatment with statins on cerebral ischemic insult following defined arterial occlusion. To address this in experimental rats, in the present work, atorvastatin was orally dosed for 1 month to evaluate the outcomes of the subsequent occlusive stroke induced by middle cerebral artery occlusion (MCAO). Our data was suggestive of potential escalating impact of chronic atorvastatin (Atv; 10 mg/kg) on neurological function, but not infarct volume. According to our immunoblotting data, such escalations were consistent with the prominent rise in TNF-α and IL-6 which paralleled with augmented Bax/Bcl2 ratio and Caspase-9 activation; however, these were not enough to worsen acute neurodegeneration determined by Fluoro Jade B staining. Noteworthy, such deteriorating effects were also partly detected in non-ischemic animals. Conclusively, our data are indicative of cerebral proinflammatory effects of chronic Atv which might overwhelm the beneficial pliotropic of the drug and predispose animals' brain to ischemic insult. Further studies on different statins with discrete pharmacokinetic properties are highly suggested to precisely explore stroke outcomes following long term prophylactic treatment particularly in primates.
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http://dx.doi.org/10.1007/s12031-016-0814-8DOI Listing
January 2017

Metformin-induced protection against oxidative stress is associated with AKT/mTOR restoration in PC12 cells.

Life Sci 2016 Mar 10;148:286-92. Epub 2016 Feb 10.

NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Aims: Reactive oxygen species have been recognized to impair cell function through suppressing Akt the well-known pro-survival molecule. Pile of concrete evidence imply metformin as an Insulin sensitizer may enhance Akt/mTOR activity however the significance of Akt/mTOR recruitment has not yet been revealed in metformin induced neuroprotection against oxidative stress.

Main Methods: In the current study using H2O2 induced injury in PC12 cells; we first examined metformin impact on cell death by MTT assay and visual assessment. Metformin pretreated cells were then subjected to immunoblotting as well as real time PCR to find PI3K, Akt, mTOR and S6K concurrent transcriptional and post-transcriptional changes. The proportions of phosphorylated to non-phosphorylated constituents of PI3K/Akt/mTOR/S6K were determined to address their activation upon metformin treatment.

Key Findings: According to cells morphology and MTT data metformin led to significant protection against H2O2 induced injury in 0.1 and 0.5mM concentrations. Metformin induced protection concurred with elevated PI3K/Akt/mTOR/S6K activity as well as enhanced GSH levels. These changes paralleled with a profound decline in the corresponding transcripts as determined by real time PCR.

Significance: Taken together our experimentation supports the hypothesis that Akt/mTOR/S6K cascade may contribute to metformin alleviating effect. The present work while highlighting metformin anti-oxidant characteristics, concludes that Akt/mTOR signaling might be central to the drug's alleviating effects.
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http://dx.doi.org/10.1016/j.lfs.2016.02.024DOI Listing
March 2016

Sphingosin-1-phosphate Receptor 1: a Potential Target to Inhibit Neuroinflammation and Restore the Sphingosin-1-phosphate Metabolism.

Can J Neurol Sci 2015 May 10;42(3):195-202. Epub 2015 Apr 10.

3NeuroBiology Research Center,Shahid Beheshti University of Medical Sciences,Teheran.

Background: Recent evidence suggests that an extreme shift may occur in sphingosine metabolism in neuroinflammatory contexts. Sphingosine 1-phosphate (S1P)-metabolizing enzymes (SMEs) regulate the level of S1P. We recently found that FTY720, a S1P analogue, and SEW2871, a selective S1P receptor 1 (S1P1) agonist, provide protection against neural damage and memory deficit in amyloid beta (Aβ)-injected animals. This study aimed to evaluate the effects of these two analogues on the expression of SMEs as well as their anti-inflammatory roles.

Methods: Rats were treated with intracerebral lipopolysaccharide (LPS) or Aβ. Memory impairment was assessed by Morris water maze and the effects of drugs on SMEs as well as inflammatory markers, TNF- α and COX-II, were determined by immunoblotting.

Results: Aβ and LPS differentially altered the expression profile of SMEs. In Aβ-injected animals, FTY720 and SEW2871 treatments exerted anti-inflammatory effects and restored the expression profile of SMEs, in parallel to our previous findings. In LPS animals however, in spite of anti-inflammatory effects of the two analogues, only FTY720 restored the levels of SMEs and prevented memory deficit.

Conclusion: The observed ameliorating effects of FTY720 and SEW7821 can be partly attributed to the interruption of the vicious cycle of abnormal S1P metabolism and neuro-inflammation. The close imitation of the FTY720 effects by SW2871 in Aβ-induced neuro-inflammation may highlight the attractive role of S1P1 as a potential target to restore S1P metabolism and inhibit inflammatory processes.
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http://dx.doi.org/10.1017/cjn.2015.19DOI Listing
May 2015

Prominence of central sphingosine-1-phosphate receptor-1 in attenuating aβ-induced injury by fingolimod.

J Mol Neurosci 2014 Dec 20;54(4):698-703. Epub 2014 Sep 20.

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

FTY720 (fingolimod), the sphingosine-1-phosphate (S1P) analogue, has been experimentally indicated to exert substantial ameliorating effects in animal models of Alzheimer's disease (AD). The present work aims to answer whether central S1P receptor 1 (S1P1) plays significant role in the impact of fingolimod in AD. To verify the prominence of central FTY720 phosphorylation, DMS (sphingosine kinase inhibitor) was infused intracerebrally in parallel with systemic FTY720 administration to prevent central formation of FTY720-P as the recognized active ligand for S1PRs. The corresponding S1P1 modulation was also investigated using the pharmacological blockage of central S1P1 by W123. Both DMS and W123 were efficiently capable of suppressing FTY720-ameliorating effects in AD animals, either on memory deficit or on COX-II and TNF-α expression. Our data conclude that experimental benefits of FTY720 in the context of AD depend on central S1P1 modulation, as well as on S1P kinase activity in the brain.
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http://dx.doi.org/10.1007/s12031-014-0423-3DOI Listing
December 2014

Fingolimod affects gene expression profile associated with LPS-induced memory impairment.

Exp Brain Res 2014 Nov 7;232(11):3687-96. Epub 2014 Aug 7.

Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.

Lipopolysaccharide is an endotoxin to induce sickness behavior in several animal models to explore the link between immune activation and cognition. Neuroinflammation playing a pivotal role in disease progress is evidently influenced by sphingosine-1-phosphate. As one of the sphingosine analogs in clinical use for multiple sclerosis, fingolimod (FTY720) was shown to substantially affect gene expression profile in the context of AD in our previous experiments. The present study was designed to evaluate the drug efficacy in the context of the mere inflammatory context leading to memory impairment. FTY720 was repeatedly administered for a few days before or after intracerebral lipopolysaccharide (LPS) injection in rats. Animal's brains were then assigned to histological as well as multiplex mRNA assay following memory performance test. Both FTY720 pre-treatment and post-treatment were similarly capable of ameliorating LPS-induced memory impairment as assessed by passive avoidance test. Such amending effects may be partly accountable by the concomitant alterations in transcriptional levels of mitogen-activated protein kinases as well as inflammatory genes determined by QuantiGene Plex analysis. These findings confirming FTY720 application benefits suggest its efficacy may not differ significantly while considered either as a preventive or as a therapeutic approach against neuroinflammation.
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http://dx.doi.org/10.1007/s00221-014-4052-4DOI Listing
November 2014

Dual role of PPAR-γ in induction and expression of behavioral sensitization to cannabinoid receptor agonist WIN55,212-2.

Neuromolecular Med 2013 Sep 21;15(3):523-35. Epub 2013 Jun 21.

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, 19615-1178, Tehran, Iran.

Behavioral sensitization (B.S.) is a pathophysiological animal model for stimulant-induced psychosis and addiction. Accumulated evidence indicates that inflammatory processes are involved in psychostimulants effects in the CNS. Cannabinoids like WIN55,212-2 act as potential activators of PPAR-γ and affects the inflammatory status of the CNS. The purpose of this study is to determine PPAR-γ role in induction and expression of B.S. and the coincident inflammatory responses developed by WIN55,212-2 (WIN). Using open-field test, locomotor activity was monitored in animals treated with intraperitoneal low-dose WIN single or repeated injections. Concurrent striatal COX-2 and TNF-α levels and PPAR-γ activity were determined by immunoblotting assay. Effects of concomitant chronic or acute PPAR-γ pharmacological inhibition (with GW9662) were then investigated on behavioral and biochemical variables. WIN enhanced locomotor activity and while administered chronically augmented cytosolic COX-2 and TNF-α and also PPAR-γ nuclear levels. GW9662 co-administration completely prevented the induction of sensitizing effects of chronic WIN and altered the inflammatory responses. However, the expression of B.S. was intensified with GW9662 as assessed by increased locomotion after WIN challenge following 48 h withdrawal. Neuroinflammation and locomotor excitability in animals received just a single-dose WIN were also escalated with GW9662. Our findings conclude that PPAR-γ could play different key roles during B.S. development by WIN. Although PPAR-γ is mostly known for neuroprotective and anti-inflammatory effects, our data indicate that it mediates the B.S. induction by chronic WIN. However, while the B.S. was induced, PPAR-γ could play a homeostatic role opposing the expressed B.S. escalation.
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http://dx.doi.org/10.1007/s12017-013-8238-xDOI Listing
September 2013

Neurorestorative effect of FTY720 in a rat model of Alzheimer's disease: comparison with memantine.

Behav Brain Res 2013 Sep 15;252:415-21. Epub 2013 Jun 15.

Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.

Alzheimer's disease (AD) as a neurodegenerative brain disorder is the most common cause of dementia. To date, there is no causative treatment for AD and there are few preventive treatments either. The sphingosine-1-phosphate receptor modulator FTY720 (fingolimod) prevents lymphocytes from contributing to an autoimmune reaction and has been approved for multiple sclerosis treatment. In concert with other studies showing the anti-inflammatory and protective effect of FTY720 in some neurodegenerative disorders like ischemia, we have recently shown that FTY720 chronic administration prevents from impairment of spatial learning and memory in AD rats. Here FTY720 was examined on AD rats in comparison to the only clinically approved NMDA receptor antagonist, Memantine. Passive avoidance task showed significant memory restoration in AD animals received FTY720 comparable to Memantine. Upon gene profiling by QuantiGene Plex, this behavioral outcomes was concurrent with considerable alterations in some genes transcripts like that of mitogen activated protein kinases (MAPKs) and some inflammatory markers that may particularly account for the detected decline in hippocampal neural damage or memory impairment associated with AD. From a therapeutic standpoint, our findings conclude that FTY720 may suggest new opportunities for AD management probably based on several modulatory effects on genes involved in cell death or survival.
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http://dx.doi.org/10.1016/j.bbr.2013.06.016DOI Listing
September 2013

Antinociceptive effect of [Met5]enkephalin semicarbazide is not affected by dipeptidyl carboxypeptidase-I.

J Pept Sci 2012 Feb 14;18(2):92-6. Epub 2011 Nov 14.

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Evin 1983963113, Tehran, Iran.

Dipeptidyl carboxypeptidase-I is an enzyme involved in the biological degradation of enkephalins. It has been suggested that C-terminal amidation of enkephalins enhances their resistance to dipeptidyl carboxypeptidase-I-mediated biodegradation. In this study, a novel [Met5]enkephalin amide (MEA) analogue [Met5]enkephalin (ME)-semicarbazide synthesized by another laboratory in our group was assessed for its antinociceptive effects compared with ME-ethylamide, MEA and ME, using tail flick test. To protect the administered drugs from biodegradation, rats were pretreated with peptidase inhibitors including amastatin, phosphoramidon and captopril. Then captopril (dipeptidyl carboxypeptidase-I inhibitor) was deleted from the peptidase inhibitors' combination for evaluating in vivo resistance of the synthetic drugs to dipeptidyl carboxypeptidase-I. According to the results, ME-semicarbazide and MEA were resistant enough to dipeptidyl carboxypeptidase-I to exert their strong antinociception following intrathecal administration even in the absence of captopril, whereas the antinociceptive effects produced by ME-ethylamide (10 nmol) were abolished in rats not pretreated with captopril, indicating that significant amounts of the ME-ethylamide were degraded by dipeptidyl carboxypeptidase-I. Replacement of the amide moiety of MEA with semicarbazide provides a new ME derivative, with high analgesic effects as well as more resistance to dipeptidyl carboxypeptidase-I-mediated biodegradation.
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http://dx.doi.org/10.1002/psc.1420DOI Listing
February 2012