Publications by authors named "Khashayar Afshari"

30 Publications

  • Page 1 of 1

AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma.

J Exp Med 2021 Sep 29;218(9). Epub 2021 Jul 29.

Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.

The STING and absent in melanoma 2 (AIM2) pathways are activated by the presence of cytosolic DNA, and STING agonists enhance immunotherapeutic responses. Here, we show that dendritic cell (DC) expression of AIM2 within human melanoma correlates with poor prognosis and, in contrast to STING, AIM2 exerts an immunosuppressive effect within the melanoma microenvironment. Vaccination with AIM2-deficient DCs improves the efficacy of both adoptive T cell therapy and anti-PD-1 immunotherapy for "cold tumors," which exhibit poor therapeutic responses. This effect did not depend on prolonged survival of vaccinated DCs, but on tumor-derived DNA that activates STING-dependent type I IFN secretion and subsequent production of CXCL10 to recruit CD8+ T cells. Additionally, loss of AIM2-dependent IL-1β and IL-18 processing enhanced the treatment response further by limiting the recruitment of regulatory T cells. Finally, AIM2 siRNA-treated mouse DCs in vivo and human DCs in vitro enhanced similar anti-tumor immune responses. Thus, targeting AIM2 in tumor-infiltrating DCs is a promising new treatment strategy for melanoma.
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http://dx.doi.org/10.1084/jem.20200962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329870PMC
September 2021

Upcoming treatments for morphea.

Immun Inflamm Dis 2021 Jul 17. Epub 2021 Jul 17.

Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Morphea (localized scleroderma) is a rare autoimmune connective tissue disease with variable clinical presentations, with an annual incidence of 0.4-2.7 cases per 100,000. Morphea occurs most frequently in children aged 2-14 years, and the disease exhibits a female predominance. Insights into morphea pathogenesis are often extrapolated from studies of systemic sclerosis due to their similar skin histopathologic features; however, clinically they are two distinct diseases as evidenced by different demographics, clinical features, disease course and prognosis. An interplay between genetic factors, epigenetic modifications, immune and vascular dysfunction, along with environmental hits are considered as the main contributors to morphea pathogenesis. In this review, we describe potential new therapies for morphea based on both preclinical evidence and ongoing clinical trials. We focus on different classes of therapeutics, including antifibrotic, anti-inflammatory, cellular and gene therapy, and antisenolytic approaches, and how these target different aspects of disease pathogenesis.
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http://dx.doi.org/10.1002/iid3.475DOI Listing
July 2021

Antibiotics with therapeutic effects on spinal cord injury: a review.

Fundam Clin Pharmacol 2021 Apr 14;35(2):277-304. Epub 2020 Oct 14.

Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St., Tehran, P. O. Box: 19419-33111, Iran.

Accumulating evidence indicates that a considerable number of antibiotics exert anti-inflammatory and neuroprotective effects in different central and peripheral nervous system diseases including spinal cord injury (SCI). Both clinical and preclinical studies on SCI have found therapeutic effects of antibiotics from different families on SCI. These include macrolides, minocycline, β-lactams, and dapsone, all of which have been found to improve SCI sequels and complications. These antibiotics may target similar signaling pathways such as reducing inflammatory microglial activity, promoting autophagy, inhibiting neuronal apoptosis, and modulating the SCI-related mitochondrial dysfunction. In this review paper, we will discuss the mechanisms underlying therapeutic effects of these antibiotics on SCI, which not only could supply vital information for investigators but also guide clinicians to consider administering these antibiotics as part of a multimodal therapeutic approach for management of SCI and its complications.
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http://dx.doi.org/10.1111/fcp.12605DOI Listing
April 2021

Sumatriptan improves the locomotor activity and neuropathic pain by modulating neuroinflammation in rat model of spinal cord injury.

Neurol Res 2021 Jan 16;43(1):29-39. Epub 2020 Sep 16.

Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences , Tehran, Iran.

Objectives: To investigate the therapeutic effects of sumatriptan in a rat model of spinal cord injury (SCI) and possible anti-inflammatory and analgesic mechanisms underlying this effect.

Methods: Using an aneurysm mini-clip model of contusive SCI, T9-10 laminectomies were performed for 60 male rats. Animals were divided into six experimental groups () as follows: a minocycline administered positive control group, a saline-vehicle negative control group, a sham-operated group, and three experimental groups which received separate doses of sumatriptan (0.1, 0.3 and 1 mg/kg). Behavioural assessments were used to evaluate locomotor activity and neuropathic pain for 28 days. At the end of the study, spinal cord tissues were collected from sacrificed animals for histopathological analysis. Levels of calcitonin gene-related peptide (CGRP) and two pro-inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-1β) were assessed by the enzyme-linked immunosorbent assay (ELISA).

Results: Sumatriptan significantly ( < 0.001) improved the locomotor activity in SCI group. Sumatriptan was also more effective than the positive control, i.e. minocycline (0.3 mg/kg). Additionally, sumatriptan and minocycline similarly attenuated the mechanical and thermal allodynia in SCI ( < 0.001). TNF-α, IL-1β and CGRP levels in sumatriptan- and minocycline-treated groups significantly ( < 0.001) decreased compared to controls. Histopathological analysis also revealed a markedly improvement in hemorrhage followed by inflammatory cell invasion, neuronal vacuolation, and cyst formation in both sumatriptan- and minocycline-treated groups compared to control animals.

Conclusions: Sumatriptan improves functional recovery from SCI through its anti-inflammatory effects and reducing pro-inflammatory and pain mediators.
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http://dx.doi.org/10.1080/01616412.2020.1819090DOI Listing
January 2021

Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways.

World J Gastroenterol 2020 Jun;26(24):3365-3400

Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran.

Inflammatory bowel disease (IBD) refers to a group of disorders characterized by chronic inflammation of the gastrointestinal (GI) tract. The elevated levels of nitric oxide (NO) in serum and affected tissues; mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme; can exacerbate GI inflammation and is one of the major biomarkers of GI inflammation. Various natural and synthetic agents are able to ameliorate GI inflammation and decrease iNOS expression to the extent comparable with some IBD drugs. Thereby, the purpose of this study was to gather a list of natural or synthetic mediators capable of modulating IBD through the NO pathway. Electronic databases including Google Scholar and PubMed were searched from 1980 to May 2018. We found that polyphenols and particularly flavonoids are able to markedly attenuate NO production and iNOS expression through the nuclear factor κB (NF-κB) and JAK/STAT signaling pathways. Prebiotics and probiotics can also alter the GI microbiota and reduce NO expression in IBD models through a broad array of mechanisms. A number of synthetic molecules have been found to suppress NO expression either dependent on the NF-κB signaling pathway (., dexamethasone, pioglitazone, tropisetron) or independent from this pathway (., nicotine, prednisolone, celecoxib, β-adrenoceptor antagonists). Co-administration of natural and synthetic agents can affect the tissue level of NO and may improve IBD symptoms mainly by modulating the Toll like receptor-4 and NF-κB signaling pathways.
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http://dx.doi.org/10.3748/wjg.v26.i24.3365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327787PMC
June 2020

Inhibition of phosphodiesterase IV enzyme improves locomotor and sensory complications of spinal cord injury via altering microglial activity: Introduction of Roflumilast as an alternative therapy.

Int Immunopharmacol 2020 Sep 30;86:106743. Epub 2020 Jun 30.

Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Despite the great search for an effective approach to minimize secondary injury in spinal cord injury (SCI) setting, there have been limited advances. Roflumilast is a selective inhibitor of phosphodiesterase 4 with potent anti-inflammatory properties. Here, we sought to explore Roflumilast efficacy in the improvement of locomotor and sensory deficits of SCI. In an animal setting, 50 male rats were randomly assigned to five groups: an SCI group receiving Placebo, three SCI groups receiving Roflumilast at the doses of 0.25, 0.5, and 1 mg/kg prior to T9 vertebra laminectomy, and a sham-operated group. Locomotor, mechanical, and thermal activities were evaluated for 28 days. At the end of the study, spinal cord samples were taken to assess the relative ratio of microglial subtypes, including M1 and M2, histopathological changes, levels of pro-inflammatory (TNF-α and IL-1β) and anti-inflammatory (IL-10) biomarkers, and cAMP level. Repeated measure analysis revealed significant effect for time-treatment interaction on locomotion [F (24, 270) = 280.7, p < 0.001], thermal sensitivity [F (16, 180) = 4.35, p < 0.001], and mechanical sensitivity [F (16, 180) = 7.96, p < 0.001]. As expected, Roflumilast significantly increased the expression of spinal cAMP. H&E staining exhibited lesser histopathological disruptions in Roflumilast-treated rodents. We also observed a significant reduction in the M1/M2 ratio (p values < 0.001) as well as in pro-inflammatory biomarkers following the administration of Roflumilast to the injured rats. Furthermore, IL-10 level was increased in rodents receiving 1 mg/kg of the reagent. In conclusion, the increased spinal cAMP following Roflumilast therapy might attenuate neuroinflammation via altering microglial activity; therefore, it could be considered as an alternative therapeutic agent for SCI complications.
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http://dx.doi.org/10.1016/j.intimp.2020.106743DOI Listing
September 2020

Targeting Mammalian Target of Rapamycin: Prospects for the Treatment of Inflammatory Bowel Diseases.

Curr Med Chem 2021 ;28(8):1605-1624

Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.

Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview of plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.
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http://dx.doi.org/10.2174/0929867327666200504081503DOI Listing
May 2021

Current Status of M1 and M2 Macrophages Pathway as Drug Targets for Inflammatory Bowel Disease.

Arch Immunol Ther Exp (Warsz) 2020 Apr 1;68(2):10. Epub 2020 Apr 1.

Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.

Chronic inflammation of the gastrointestinal system is mediated by both the immune system activity and homeostasis, mainly through releasing of various cytokines and chemokines, as well as the transmigration of the inflammatory cells to the affected site. In between, macrophages are key mediators of the immune system, nearly located all over the gastrointestinal tract. Macrophages have vital influence on the inflammatory condition with both pro-inflammatory and anti-inflammatory functions. Their polarization status has been linked to numerous metabolic disorders such as inflammatory bowel disease (IBD). The equilibrium between the phenotypes and functions of inflammatory M1 and anti-inflammatory M2 cells is regulated by both extracellular and intracellular stimuli, determining how the disease progresses. Thereby, factors that interchange such balance in the direction of increasing M2 macrophages offer unique approaches for future management of IBD. This study reflects the novel IBD treatment targets via the immune system's pathway, reporting the latest treatments that regulate the M1/M2 macrophages distribution in a way to favor IBD.
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http://dx.doi.org/10.1007/s00005-020-00576-4DOI Listing
April 2020

Comparative Analysis of the Discriminatory Performance of Different Well-Known Risk Assessment Scores for Extended Hepatectomy.

Sci Rep 2020 01 22;10(1):930. Epub 2020 Jan 22.

Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, 69120, Germany.

The aim of this study was to assess and compare the discriminatory performance of well-known risk assessment scores in predicting mortality risk after extended hepatectomy (EH). A series of 250 patients who underwent EH (≥5 segments resection) were evaluated. Aspartate aminotransferase-to-platelet ratio index (APRI), albumin to bilirubin (ALBI) grade, predictive score developed by Breitenstein et al., liver fibrosis (FIB-4) index, and Heidelberg reference lines charting were used to compute cut-off values, and the sensitivity and specificity of each risk assessment score for predicting mortality were also calculated. Major morbidity and 90-day mortality after EH increased with increasing risk scores. APRI (86%), ALBI (86%), Heidelberg score (81%), and FIB-4 index (79%) had the highest sensitivity for 90-day mortality. However, only the FIB-4 index and Heidelberg score had an acceptable specificity (70% and 65%, respectively). A two-stage risk assessment strategy (Heidelberg-FIB-4 model) with a sensitivity of 70% and a specificity 86% for 90-day mortality was proposed. There is no single specific risk assessment score for patients who undergo EH. A two-stage screening strategy using Heidelberg score and FIB-4 index was proposed to predict mortality after major liver resection.
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http://dx.doi.org/10.1038/s41598-020-57748-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976620PMC
January 2020

Possible Involvement of Nitric Oxide in the Antipruritic Effect of Metformin on Chloroquine-Induced Scratching in Mice.

Dermatology 2020 22;236(2):151-159. Epub 2019 Aug 22.

Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran,

Background: Metformin ameliorates non-histamine-mediated itch. We have recently reported that the nitric oxide (NO) pathway is involved in chloroquine (CQ)-induced scratching behavior. Here we investigated the involvement of the NO pathway in the antipruritic effect of metformin on CQ-induced itch.

Methods: Metformin (5-200 mg/kg, given intraperitoneally [i.p.]) was injected 4 h before CQ (400 µg/site, given intradermally [i.d.]) or compound 48/80 (100 µg/site, i.d.). A nonspecific nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 1 and 10 mg/kg, i.p.), or an NO precursor, L-arginine (10 and 100 mg/kg, i.p.) was administered 30 min before injection of CQ. A neural NOS (nNOS) inhibitor, 7-nitroindazole (7-NI; 1 and 10 nmol/site, i.d.) was concurrently administered with CQ. The scratching behavior was recorded for 30 min following the injection of CQ. We studied the changes in skin and spinal nitrite levels after treatments.

Results: Our results showed that metformin (100 and 200 mg/kg) significantly reduced the CQ-induced scratching behavior but not the compound 48/80-induced scratching behavior. L-Arginine inhibited the antipruritic effect of metformin, while L-NAME and 7-NI significantly potentiated the inhibitory effects of a subeffective dose of metformin on the CQ-induced scratching behavior. The skin but not the spinal nitrite level was significantly increased after CQ administration. The elevated cutaneous nitrite level was reversed by effective doses of either metformin or 7-NI, but not by the subeffective doses of metformin + 7-NI.

Conclusion: Acute injection of metformin significantly inhibits CQ-induced scratching behavior. This effect is mediated through inhibition of the NO pathway, especially by inhibiting the dermal nNOS enzyme.
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http://dx.doi.org/10.1159/000501583DOI Listing
February 2021

Sumatriptan Increases Skin Flap Survival through Activation of 5-Hydroxytryptamine 1b/1d Receptors in Rats: The Mediating Role of the Nitric Oxide Pathway.

Plast Reconstr Surg 2019 07;144(1):70e-77e

From the School of Medicine, the Experimental Medicine Research Center, School of Public Health, Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, the Department of Pathology, Dr. Shariati Hospital, and the Department of Pharmacology, Tehran University of Medical Sciences; and the Department of Plastic and Reconstructive Surgery, University of Texas Southwestern Medical Center.

Background: Random pattern skin flaps are applicable for reconstructing any defect in plastic surgery. However, they are difficult to apply because of necrosis. Sumatriptan, a selective 5-hydroxytryptamine 1b/1d agonist, is routinely used to offset acute migraine attacks. Recent studies have suggested that sumatriptan may induce vasodilation at lower concentrations. The authors' aim is to investigate the effect of sumatriptan on skin flap survival and the role of nitric oxide in this phenomenon.

Methods: Seventy-two male Sprague-Dawley rats were divided into eight groups. Increasing doses of sumatriptan (0.1, 0.3, and 1 mg/kg) were given intraperitoneally to three different groups after dorsal random pattern skin flaps were performed. To assess the exact role of 5-hydroxytryptamine 1b/1d receptors, GR-127935 was administered solely and with sumatriptan. N-ω-nitro-L-arginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) was used to evaluate any possible involvement of nitric oxide in this study. All rats were examined 7 days later.

Results: The authors' results demonstrated that flap survival was increased by lower doses of sumatriptan compared to a control group for both 0.3 mg/kg (p = 0.03, mean difference = 32, SE = 8) and 0.1 mg/kg (p = 0.02, mean difference = 26, SE = 8). This protective effect was eliminated by coadministration of GR-127935 or N-ω-nitro-L-arginine methyl ester with sumatriptan. Histopathologic studies revealed a significant increase in capillary count and collagen deposition and a decreased amount of edema, inflammation, and degeneration.

Conclusions: Sumatriptan in lower concentration increases skin flap survival by means of activation of 5-hydroxytryptamine 1b/1d receptors. This effect is mediated through the nitric oxide synthase pathway.
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http://dx.doi.org/10.1097/PRS.0000000000005740DOI Listing
July 2019

Protective effect of minocycline on LPS-induced mitochondrial dysfunction and decreased seizure threshold through nitric oxide pathway.

Eur J Pharmacol 2019 Sep 13;858:172446. Epub 2019 Jun 13.

Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Lipopolysaccharide (LPS) increases inflammatory cytokines of the brain and deregulates the mitochondrial function, thus could increase the seizure susceptibility. Studies have shown that minocycline has neuroprotective and antioxidant properties. In this study, we aimed to evaluate the anticonvulsant properties of minocycline in LPS-treated animals and the possible involvement of nitric oxide and mitochondrial pathways. In a PTZ model of seizure in mice, minocycline was administrated to LPS-treated mice. Then followed by co-injection of its sub-effective dose and NOS inhibitors including 7-Nitroindazole (7-NI), aminoguanidine (AG) and L-N-Nitroarginine methyl ester (L-NAME) to evaluate the changes in seizure threshold and the possible involvement of nitrergic system. Molecular assessments were used to evaluate the effects of each treatment on inflammation and mitochondrial function in the brain. LPS-treated animals had lower seizure threshold compared to intact animals; injection of minocycline (80 mg/kg) to LPS-treated mice reversed this effect. Co-injection of sub-effective doses of minocycline (40 mg/kg) and L-NAME to LPS-treated animals significantly increased seizure threshold. We observed that co-treatment of minocycline and AG dissimilar to 7-NI could increase the seizure threshold of LPS-treated animals. L-arginine reversed the anticonvulsant effect of minocycline. Also, molecular evaluations showed that LPS could increase the ATP levels, GSH levels, and reactive oxygen species formation. However, minocycline at both doses significantly reversed the effect of LPS. Minocycline counteracts the proconvulsant effects of LPS through regulating of mitochondrial function and decreasing of neuro-inflammation. Also, co-administration of minocycline and i-NOS inhibitors could intensify anticonvulsant effects of minocycline.
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http://dx.doi.org/10.1016/j.ejphar.2019.172446DOI Listing
September 2019

Anticonvulsant effect of melatonin through ATP-sensitive channels in mice.

Fundam Clin Pharmacol 2020 Feb 1;34(1):148-155. Epub 2019 Jul 1.

Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

Melatonin is a neurohormone secreted principally by the pineal gland. This molecule has various pharmacological properties including improving immune system, prevent cancer, anti-aging, and anti-oxidant effects. The anticonvulsant effects of melatonin have been proved by previous studies. Adenosine triphosphate (ATP)-sensitive potassium (K ) channels are considered as an important target in the seizure modulation. The aim of the present study was to investigate the anticonvulsant effect of melatonin in pentylenetetrazole (PTZ)-induced seizures in mice, focusing on its ability to regulate K channels. Acute intraperitoneal administration of melatonin (40 and 80 mg/kg) increased clonic seizure threshold induced by intravenous administration of PTZ. Melatonin (40 and 80 mg/kg) increased the latency of clonic seizure and reduced its frequency in mice receiving an intraperitoneal injection of PTZ. Administration of glibenclamide, a K channels blocker, before intravenous injection of PTZ reduced melatonin anticonvulsant effect. Diazoxide and cromakalim, as K channels openers, increased antiseizure effect of melatonin in PTZ model of seizures. These findings suggest that the antiseizure effect of melatonin probably is gained through increasing the opening of K channels.
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http://dx.doi.org/10.1111/fcp.12490DOI Listing
February 2020

Natural flavonoids for the prevention of colon cancer: A comprehensive review of preclinical and clinical studies.

J Cell Physiol 2019 12 13;234(12):21519-21546. Epub 2019 May 13.

Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.

Flavonoids comprise a group of natural polyphenols consisting of more than 5,000 subtypes mostly existing in fruits and vegetables. Flavonoids consumption could potentially attenuate the incidence and recurrence risk of colorectal cancers through their antiperoxidative, antioxidant, and anti-inflammatory effects. In addition, these compounds regulate the mitochondrial function, balance the bacterial flora and promote the apoptosis process in cancerous cells. However, some previous data failed to show the effectiveness of flavonoids in reducing the risk of colorectal cancer. In this study, we have reviewed the efficacy of different flavonoids subtypes on the risk of colon cancer and molecular mechanisms involved in this process in both clinical and animal studies. In addition, we tried to elucidate the potential synergy between these compounds and current colorectal cancer treatments.
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http://dx.doi.org/10.1002/jcp.28777DOI Listing
December 2019

Acute Activation of α7-Nicotinic Receptors by Nicotine Improves Rodent Skin Flap Survival Through Nitrergic System.

Ann Plast Surg 2019 08;83(2):211-216

Cancer Cell Signaling, Turku Center for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.

Background: Recent reports have identified angiogenic, anti-inflammatory, and antioxidant properties of acute treatment with nicotine via activation of nicotinic acetylcholine receptors (nAChRs). In addition, the nitric oxide (NO) pathway is involved in ischemic reperfusion injuries.

Objectives: We investigated the effects of acute pretreatment with nicotine in a rat model of random-pattern skin flap and the potential role of the NO pathway.

Methods: The Sprague-Dawley rats received increasing doses of (-)-nicotine (0.5, 1, 1.5, 2, and 3 mg/kg) before the procedure. Dorsal skin flaps with caudal pedicles were elevated at the midline, and flap survival was evaluated 7 days after surgery. In addition, animals received an α7-nAChR antagonist, methyllycaconitine, with nicotine. Quantitative reverse transcription polymerase chain reaction was also applied to measure the dermal expression of α7-nAChR. Next, a nonselective NO synthase inhibitor, N-nitro-L-arginine methyl ester hydrochloride; a selective inducible NO synthase inhibitor, aminoguanidine; and an NO precursor, L-arginine, were administered with nicotine.

Results: Nicotine at doses of 1, 1.5, and 2 mg/kg significantly increased flap survival, whereas the protective effects of nicotine disappeared at higher doses. Methyllycaconitine completely reversed the protective effects of nicotine and the elevated cutaneous expression of α7-nAChR in nicotine-pretreated rats. In addition, systemic administration of N-nitro-L-arginine methyl ester hydrochloride or aminoguanidine with an effective dose of nicotine caused a significant decrease in flap survival. Conversely, coinjection of a subeffective dose of L-arginine with the subeffective dose of nicotine significantly boosted its protective effects.

Conclusions: Acute pretreatment with nicotine by stimulating the expression and activation of cutaneous α7-nAChR improves skin flap survival, which is partially mediated through modulation of the NO pathway.
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http://dx.doi.org/10.1097/SAP.0000000000001809DOI Listing
August 2019

Evaluation of the pharmacological involvement of ATP-sensitive potassium (K) channels in the antidepressant-like effects of topiramate on mice.

Naunyn Schmiedebergs Arch Pharmacol 2019 07 4;392(7):833-842. Epub 2019 Mar 4.

Experimental Medicine Research Center, Tehran University of Medical Sciences, P.O. Box13145-784, Tehran, Iran.

Acute doses of topiramate (TPM) have been shown to reduce immobility time in the mice forced swimming test (FST) through inhibition of the nitric oxide (NO) pathway. Adenosine triphosphate-sensitive potassium (K) channels are known to have an active role in depression. This study investigates the potential participation of K channels in the antidepressant-like effect of TPM through the stimulatory effects of NO. FST and tail suspension tests (TST) were applied to adult male mice for assessment of the antidepressant-like activity of TPM. Different doses of glibenclamide and cromakalim were also applied in order to investigate the involvement of K channels. Fluoxetine was used as a positive control for evaluation of antidepressant-like effects. In addition, each animal's locomotor activity was evaluated by the open-field test (OFT). TPM (30 mg/kg intraperitoneal (i.p.)) had a significant reductive effect on the immobility behavior similar to fluoxetine (20 mg/kg). Co-administration of sub-effective doses of glibenclamide (1 mg/kg i.p.) and TPM (10 mg/kg i.p.) led to significant synergistic effects in FST and TST. Additionally, the results showed that administration of the sub-effective dose of cromakalim (0.1 and 0.3 mg/kg i.p.) blocked the antidepressant-like effects of TPM (30 mg/kg i.p.) in both tests. These interventions had no impact on the locomotor movement of mice in OFT. This study shows that the antidepressant-like activity of TPM may potentially be mediated by the blocking of the K channels.
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http://dx.doi.org/10.1007/s00210-019-01636-zDOI Listing
July 2019

Activation of ATP-sensitive K-channel promotes the anticonvulsant properties of cannabinoid receptor agonist through mitochondrial ATP level reduction.

Epilepsy Behav 2019 04 16;93:1-6. Epub 2019 Feb 16.

Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Cannabinoid receptor (CBR) agonist could act as a protective agent against seizure susceptibility in animal models of epilepsy. Studies have shown that potassium channels could play a key role in ameliorating neuronal excitability. In this study, we attempted to evaluate how CBRs and Adenosine Tri-Phosphate (ATP)-sensitive potassium channels collaborate to affect seizure susceptibility by changing the clonic seizure threshold (CST). We used male Naval Medical Research Institute (NMRI) mice and treated them with the following drugs: cromakalim (a potassium channel opener, 10 μg/kg), glibenclamide (a potassium channel blocker, 0.03 and 1 mg/kg), 0.5 mg/kg of AM-251 (a selective CB1 antagonist), AM-630 (a selective CB2 antagonist), and 0.5, 3, and 10 mg/kg of WIN 55,212-2 (a nonselective agonist of CBRs); and CST was appraised after each type of administration. Also, we evaluated the ATP level of the hippocampus in each treatment to clarify the interaction between the cannabinoid system and potassium channel. Our results showed that administration of WIN 55,212-2 at 10 mg/kg significantly increased CST (P < 0.001). This change could be reversed by using AM-251(P < 0.001) but not AM-630. Also, either cromakalim (10 μg/kg) or glibenclamide (0.03 and 1 mg/kg) could not significantly affect the CST. In addition, glibenclamide (1 mg/kg) could reverse the anticonvulsant effect of WIN 55,212-2 (10 mg/kg) on CST (P < 0.001). However, the anticonvulsant effect was observed when cromakalim (10 μg/kg) was added to WIN 55,212-2 at its subeffective dose (3 mg/kg) in comparison to single-treated animals. Interestingly, we observed that CB1 agonist could significantly decrease ATP level. In conclusion, CB1 agonist accomplishes at least a part of its anticonvulsant actions through ATP-sensitive potassium channels, probably by decreasing the mitochondrial ATP level to open the potassium channel to induce its anticonvulsant effect.
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http://dx.doi.org/10.1016/j.yebeh.2019.01.025DOI Listing
April 2019

Involvement of opioid system in behavioral despair induced by social isolation stress in mice.

Biomed Pharmacother 2019 Jan 5;109:938-944. Epub 2018 Nov 5.

Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Social isolation stress (SIS) as a type of chronic stress could induce depressive- and anxiety-like behaviors. Our study evaluates the role of opioid system on negative behavioral impacts of SIS in male NMRI mice. We investigated effects of morphine, a nonselective opioid receptor (OR) agonist, naltrexone (NLX), an OR antagonist, naltrindole (NLT), a delta opioid receptor (DOR) antagonist, SNC80, a DOR agonist, U-69593, a kappa opioid receptor (KOR) agonist, nor-Binaltorphimine, a selective KOR antagonist and cyprodime hydrochloride a selective mu opioid receptor (MOR) antagonist on depressive- and anxiety-like behaviors. Using RT-PCR we evaluated ORs gene expression in mice brain. Our findings showed that SIS induced anxiety- and depressive-like behavior in the forced swimming test, open field test, splash test and hole-board test. Moreover, administration of SNC-80 significantly mitigated anxiety- and depressive-like behaviors. NLT decreased grooming-activity in the splash test. Excitingly, administration of agents affecting KOR failed to alter the negative effects of SIS. RT-PCR demonstrated that MOR and KOR gene expression decreased in socially isolated mice; however, SIS did not affect DORs expression. Our findings suggest that SIS at least in part, probably via altering endogenous opioids particularly MORs and KORs but not DORs mediated negative impacts on behavior; also, it could be concluded that DORs might be considered as a novel target for studying depression and anxiety.
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http://dx.doi.org/10.1016/j.biopha.2018.10.144DOI Listing
January 2019

Anti-inflammatory effects of Metformin improve the neuropathic pain and locomotor activity in spinal cord injured rats: introduction of an alternative therapy.

Spinal Cord 2018 Nov 29;56(11):1032-1041. Epub 2018 Jun 29.

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

Study Design: This is an animal study.

Objectives: Metformin is a safe drug for controlling blood sugar in diabetes. It has been shown that metformin improves locomotor recovery after spinal cord injury (SCI). Neuropathic pain is also a disturbing component of SCI. It is indicated that metformin has neuroprotective and anti-inflammatory effects, which attenuate neuropathic pain and hyperalgesia in injured nerves. Thus, we evaluated metformin's therapeutic effects on SCI neuroinflammation and its sensory and locomotor complications. Meanwhile, results were compared to minocycline, an anti-neuroinflammation therapy in SCI.

Setting: Experimental Medicine Research Center, Tehran University of Medical Sciences, Iran METHODS: In an animal model of SCI, 48 male rats were subjected to T9 vertebra laminectomy. Animals were divided into a SHAM-operated group and five treatment groups. The treatments included normal saline as a vehicle control group, minocycline 90 mg/kg and metformin at the doses of 10, 50 and 100 mg/kg. Locomotor scaling, behavioral tests for neuropathic pain and weight changes were evaluated and compared through a 28-days period. At the end of the study, tissue samples were taken to assess neuroinflammatory changes.

Results: Metformin 50 mg/kg improved the locomotors ability (p < 0.001) and decreased sensitivity to mechanical and thermal allodynia (p < 0.01). These results were compatible with minocycline effect on SCI (p > 0.05). While metformin led to weight loss, both metformin and minocycline significantly decreased neuroinflammation in the assessment of cord tissue histopathology, and levels of TNF-α and interleukin-1β (p < 0.001).

Conclusions: Metformin could be considered as an alternative therapeutic agent for SCI, as it potentially attenuates neuroinflammation, sensory and locomotor complications of cord injury.
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http://dx.doi.org/10.1038/s41393-018-0168-xDOI Listing
November 2018

The protective effects of sumatriptan on vincristine - induced peripheral neuropathy in a rat model.

Neurotoxicology 2018 07 26;67:279-286. Epub 2018 Jun 26.

Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Clinical use of vincristine (VCR), an effective chemotherapeutic agent, has been limited due to its peripheral neuropathy toxicity. Sumatriptan, which is an anti-migraine agent is a specific agonist for 5-hydroxytryptamine 1B, 1D (5HT1B, 1D) receptors. Several studies have shown that sumatriptan exerts anti-inflammatory and immunomodulatory properties. This study aimed to investigate the effects of sumatriptan on VCR-induced peripheral neuropathy in a rat model. Male Wistar rats were intraperitoneally injected with VCR and normal saline four times per week for 2 weeks. In the treatment group, sumatriptan (1 mg/kg) was administered intraperitoneally 30 min prior to VCR injection every day. Mortality rate, weight variations and histopathological changes were monitored. Hot plate, tail flick and motor nerve conduction velocity (MNCV) tests were used to evaluate sensory and motor neuropathy. Levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and caspase-3 in the dorsal ganglion root were assessed by quantitative reverse transcription-PCR (qRT-PCR). Moreover, the protein levels of p65 nuclear factor kappa B (NF- B) and phospho-p65 NF- B were examined by Western blot analysis. Co-administration of sumatriptan with VCR significantly reversed alterations in the hot plate, tail flick threshold and sciatic MNCV induced by VCR and also prevented mixed sensory-motor neuropathy, as indicated by better general conditions, behavioral and electrophysiological results. In addition, sumatriptan improved the body weight loss caused by VCR. The mRNA levels of TNF-α, IL-1β and caspase-3 were significantly diminished in the treatment group. These findings were confirmed by histopathological analysis. In conclusion, this study demonstrated that sumatriptan significantly attenuated VCR-induced neuropathy and could be considered as a neuroprotective agent to prevent the VCR-induced neuropathy.
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http://dx.doi.org/10.1016/j.neuro.2018.06.012DOI Listing
July 2018

Cerebellar degeneration in primary Sjӧgren syndrome.

BMJ Case Rep 2018 Jun 6;2018. Epub 2018 Jun 6.

School of Medicine, Tehran University of Medical Sciences, Tehran, The Islamic Republic of Iran.

Neurological manifestations are reported as a consequence of primary Sjӧgren syndrome (PSS). Any part of the brain and peripheral nervous system can be involved in PSS. However, cerebellar degeneration and atrophy associated with PSS have been rarely reported. Our report describes a 22-year-old woman who presented with cerebellar ataxia, arthritis and arthralgia. Evaluation of her symptoms, autoantibodies and salivary gland pathology was in favour of the diagnosis of Sjögren syndrome. Also, her brain MRI revealed cerebellar degeneration. There are only four patients reported to be affected by cerebellar atrophy associated with PSS. Administration of high doses of methylprednisolone and cyclophosphamide leads to substantial improvement in the cerebellar symptoms of this case. In addition, after 2 months of follow-up, the patient's ataxia recovered significantly. It could be concluded that in addition to neurological degenerative disorders, in some cases cerebellar atrophy could also be associated with autoimmune conditions such as PSS.
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http://dx.doi.org/10.1136/bcr-2017-223952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011450PMC
June 2018

Cerebellar degeneration in primary Sjӧgren syndrome.

BMJ Case Rep 2018 Jun 6;2018. Epub 2018 Jun 6.

School of Medicine, Tehran University of Medical Sciences, Tehran, The Islamic Republic of Iran.

Neurological manifestations are reported as a consequence of primary Sjӧgren syndrome (PSS). Any part of the brain and peripheral nervous system can be involved in PSS. However, cerebellar degeneration and atrophy associated with PSS have been rarely reported. Our report describes a 22-year-old woman who presented with cerebellar ataxia, arthritis and arthralgia. Evaluation of her symptoms, autoantibodies and salivary gland pathology was in favour of the diagnosis of Sjögren syndrome. Also, her brain MRI revealed cerebellar degeneration. There are only four patients reported to be affected by cerebellar atrophy associated with PSS. Administration of high doses of methylprednisolone and cyclophosphamide leads to substantial improvement in the cerebellar symptoms of this case. In addition, after 2 months of follow-up, the patient's ataxia recovered significantly. It could be concluded that in addition to neurological degenerative disorders, in some cases cerebellar atrophy could also be associated with autoimmune conditions such as PSS.
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http://dx.doi.org/10.1136/bcr-2017-223952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011450PMC
June 2018

Attenuation of serotonin-induced itch by sumatriptan: possible involvement of endogenous opioids.

Arch Dermatol Res 2018 Mar 19;310(2):165-172. Epub 2018 Jan 19.

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

Serotonin (5-hydroxytryptamine or 5-HT) is a neurotransmitter in itch and impaired serotonin signaling has been linked to a variety of itch conditions. Intradermal injection of 5-HT induces scratching behavior in mice through stimulation of 5-HT receptors. Previous studies have demonstrated that selective 5-HT1B/1D receptors agonists, including sumatriptan, inhibits neurotransmission. We have also reported that sumatriptan suppresses chloroquine-induced itch. Therefore, we investigated if sumatriptan has inhibitory effects on serotonin-induced itch in mice. Here, we show that intradermal and intraperitoneal administration of sumatriptan significantly reduce 5-HT-induced scratching behavior in mice. While intradermal injection of GR-127935, a selective 5-HT1B/1D receptors antagonist, reverses the anti-pruritic effects of sumatriptan. In addition, we show that intradermal and intraperitoneal naltrexone (NTX), a non-specific opioid receptor antagonist, and methylnaltrexone (MNTX), a peripherally acting opioid receptor antagonist, significantly decrease the 5-HT-induced scratching behavior. Additionally, combined treatment with sub-effective doses of sumatriptan and an opioid receptor antagonist, naltrexone, decreases 5-HT-evoked scratching responses. We conclude that sumatriptan inhibits 5-HT-induced itch by activating the peripheral 5-HT1B/1D receptors. Moreover, peripheral opioid receptors have a role in serotonin-induced itch, and anti-pruritic effects of sumatriptan seem to involve the opioid system. These data suggest that 5-HT1B/1D receptors agonists maybe useful to treat a variety of pathologic itch conditions with impaired serotonergic system.
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http://dx.doi.org/10.1007/s00403-018-1809-9DOI Listing
March 2018

Therapeutic efficacy of specific immunotherapy for glioma: a systematic review and meta-analysis.

Rev Neurosci 2018 Jun;29(4):443-461

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr Qarib St, Keshavarz Blvd, Tehran 14194, Iran.

Although different immunotherapeutic approaches have been developed for the treatment of glioma, there is a discrepancy between clinical trials limiting their approval as common treatment. So, the current systematic review and meta-analysis were conducted to assess survival and clinical response of specific immunotherapy in patients with glioma. Generally, seven databases were searched to find eligible studies. Controlled clinical trials investigating the efficacy of specific immunotherapy in glioma were found eligible. After data extraction and risk of bias assessment, the data were analyzed based on the level of heterogeneity. Overall, 25 articles with 2964 patients were included. Generally, mean overall survival did not statistically improve in immunotherapy [median difference=1.51; 95% confidence interval (CI)=-0.16-3.17; p=0.08]; however, it was 11.16 months higher in passive immunotherapy (95% CI=5.69-16.64; p<0.0001). One-year overall survival was significantly higher in immunotherapy groups [hazard ratio (HR)=0.69; 95% CI=0.52-0.92; p=0.01]. As the hazard rate in the immunotherapy approach was 0.83 of the control group, 2-year overall survival was significantly higher in immunotherapy (HR=0.83; 95% CI=0.69-0.99; p=0.04). Three-year overall survival was significantly higher in immunotherapy as well (HR=0.67; 95% CI=0.48-0.92; p=0.01). Overall, median progression-free survival was significantly higher in immunotherapy (standard median difference=0.323; 95% CI=0.110-0.536; p=0.003). However, 1-year progression-free survival was not remarkably different between immunotherapy and control groups (HR=0.94; 95% CI=0.74-1.18; p=0.59). Specific immunotherapy demonstrated remarkable improvement in survival of patients with glioma and could be a considerable choice of treatment in the future. Despite the current promising results, further high-quality randomized controlled trials are required to approve immunotherapeutic approaches as the standard of care and the front-line treatment for glioma.
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http://dx.doi.org/10.1515/revneuro-2017-0057DOI Listing
June 2018

Pharmacological evidence of involvement of nitric oxide pathway in anti-pruritic effects of sumatriptan in chloroquine-induced scratching in mice.

Fundam Clin Pharmacol 2018 Feb 6;32(1):69-76. Epub 2017 Sep 6.

Experimental Medicine Research Center, Tehran University of Medical Sciences, Poorsina St., Enghelab Ave., Tehran, Iran.

Chloroquine (CQ) induces histamine-independent itch in human and mice. We recently reported the role of intradermal nitric oxide (NO)/cyclic guanosine monophosphate pathway in CQ-evoked scratching in mice. Chloroquine stimulates neuronal nitric oxide synthase (nNOS) activity to over-producing NO in the skin. Sumatriptan, a 5-hydroxytryptamine 1b/1d receptors (5-HTR1b/1d) agonist, is involved in pain and used to treat migraine and cluster headaches. According to previous studies, sumatriptan inhibits NOS activity. Thus, we aimed to investigate the effect of sumatriptan on CQ-induced scratching. We used the rostral back model of itch. Chloroquine was injected intradermally into the rostral back of NMRI mice, and the scratching behavior was evaluated by measuring the number of bouts over 30 min. We evaluated the effect of sumatriptan and combination of sumatriptan and a non-selective NO synthase inhibitor, L-N-nitro arginine methyl ester (L-NAME), on the scratching behavior. Additionally, the changes of skin, hippocampus, and cortical nitrite level after different treatments were studied. Intraperitoneal and intradermal sumatriptan attenuates CQ-induced itch which reversed by GR-127935, the selective 5-HTR1b and 5-HTR1d antagonist. Co-administration of subeffective doses of sumatriptan and L-NAME significantly decreases the scratching behavior. Intradermal injection of CQ significantly increases the intradermal nitrite levels while it does not have any significant effects on hippocampal or cortical nitrite concentrations. Likewise, the effective doses of intraperitoneal and intradermal sumatriptan significantly reduce intradermal nitrite levels. We concluded that sumatriptan suppresses CQ-induced itch most likely by activating 5-HT1b/1d receptors. This effect probably mediates through NO pathway.
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http://dx.doi.org/10.1111/fcp.12317DOI Listing
February 2018

Association of peripheral nesfatin-1 with early stage diabetic nephropathy.

Pathophysiology 2017 Mar 13;24(1):17-22. Epub 2016 Dec 13.

Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Background: Nesfatin-1 is a newly found anorectic neuropeptide with potent metabolic regulatory effects that its circulating levels are shown to be elevated in diabetes. We compared serum nesfatin-1 in patients with type 2 diabetes and microalbuminuria (30mg/day≤urinary albumin excretion (UAE) <300mg/day) with their control patients with type 2 diabetes and normoalbuminuria (UAE <30mg/day).

Patients And Methods: In a cross sectional setting, 44 adult patients with type 2 diabetes and microalbuminuria and 44 control patients with type 2 diabetes and normoalbuminuria were evaluated. Serum levels of nesfatin-1 along with demographic, clinical and biochemical factors associated with diabetes was measured.

Results: Mean peripheral concentrations of nesfatin-1 were significantly higher in patients with diabetes who had microalbuminuria compared to normoalbuminuric control patients (175.27±25.96pg/ml vs. 134.66±23.18pg/ml, respectively; p value<0.001). Significant positive correlations were found between circulating nesfatin-1 levels and the following case-mix variables: duration of diabetes, glycated hemoglobin, plasma creatinine, UAE and serum uric acid. In the multivariate logistic regression and after adjustment for a constellation of potentially confounding variables associated with diabetic kidney disease (DKD), circulating nesfatin-1 was the only variable significantly associated with microalbuminuria (odds ratio [95% confidence interval]=1.224 [1.007-1.487], p value=0.042).

Conclusion: In patients with type 2 diabetes, circulating nesfatin-1 appears to be associated with microalbuminuria independent of other established risk factors of DKD. The underlying pathophysiological mechanisms and the prognostic significance of this association remain to be elucidated.
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http://dx.doi.org/10.1016/j.pathophys.2016.12.001DOI Listing
March 2017

Effect of glatiramer acetate on short-term memory impairment induced by lipopolysaccharide in male mice.

Fundam Clin Pharmacol 2016 Aug 8;30(4):347-56. Epub 2016 Jun 8.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Glatiramer acetate (GA) demonstrates neuroprotective, neurogenesis, and anti-inflammatory properties. This study examines the probable protective effect of acute GA on lipopolysaccharide (LPS)-induced memory impairment in male mice and further explores which routes of administration [subcutaneous (s.c.) or intracerebroventricular (i.c.v.)] exert optimum effect. Memory performance was evaluated in two-trial recognition Y-maze and passive-avoidance tasks evaluating special recognition memory and fear memory, respectively. Memory impairment was induced by LPS [100 μg/kg, intraperitoneally (i.p.)], 4 h before training. In Y-maze, GA (10, 2.5, 0.625, 0.153, and 0.03 mg/kg, s.c.; 250 μg/mouse; i.c.v.) was administered 10 min following LPS, and special memory was assayed in Y-maze apparatus. In passive avoidance, LPS (100, 250 μg/kg; i.p.) was injected 4 h before receiving foot shock, and GA (10, 2.5; s.c.) or (250 μg/mouse; i.c.v.) was administered 4 h before the shock. Following 24 h, the fear memory was evaluated. Memory impaired significantly following LPS (100, 250 μg/kg; i.p.) in Y-maze and passive-avoidance tasks, P < 0.001 and P < 0.05, respectively. The data revealed that GA (250 μg/mouse, i.c.v.) and GA (10, 2.5 mg/kg; s.c.) in Y-maze reversed memory impairment (LPS 100 μg/kg, i.p.) (P < 0.01). In passive-avoidance task, GA (2.5, 10 mg/kg; s.c.) reversed LPS-induced impairment and the mice showed significantly longer latency times during the retention trial (P < 0.01). GA improved memory impairment both centrally and systemically. It improved spatial recognition memory increasing the average time in the novel arm and improved fear memory increasing latency time. GA administration improved memory impairment profoundly through both systemic and central routs.
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http://dx.doi.org/10.1111/fcp.12202DOI Listing
August 2016

Effects of combining methylprednisolone with magnesium sulfate on neuropathic pain and functional recovery following spinal cord injury in male rats.

Acta Med Iran 2015 ;53(3):149-57

Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. AND Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Methylprednisolone (MP) has been widely used as a standard therapeutic agent for the treatment of spinal cord injury (SCI). Because of its controversial useful effects, the combination of MP and other pharmacological agents to enhance neuroprotective effects is desirable. Magnesium sulfate (MgSO4) has been shown to have neuroprotective and antihyperalgesic effects. In the present study, we sought to determine the effect of combining MP and MgSO4, on neuropathic pain and functional recovery following spinal cord injury (SCI) in male rats. A total of 48 adult male rats (weight 300-350 g) were used. After laminectomy, complete SCI was achieved by compression of the spinal cord for one minute with aneurysm clips. Single doses of Magnesium sulfate (MgSO4), (600 mg/kg), Methylprednisolone (MP), (30 mg/kg) or combining MgSO4 and MP were injected intraperitoneally. Prior to surgery and during four weeks of study Tail flick latency (TFL) and BBB (Basso-Beattie-Bresnahan) score and the acetone drop test were evaluated. In mean values of BBB score, a significant difference was observed in SCI+veh compared with other groups (P<0.05). Mean TFL also was significantly higher in SCI+veh compared with other groups (P<0.05). Mean acetone drop test score and weight were significantly different in MgSO4, MP and combining MgSO4 and MP  treated groups compared with SCI+veh group (P<0.05). These findings revealed that MP, MgSO4 and combining MgSO4 and MP treatment can attenuate neuropathic pains following SCI in rats include: thermal hyperalgesia and cold allodynia. They also can yield better improvement in motor function and decrease weight loss after SCI in rats compared with the control group.
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September 2015

Postinjury treatment with magnesium sulfate attenuates neuropathic pains following spinal cord injury in male rats.

Behav Pharmacol 2015 Apr;26(3):315-20

aBrain and Spinal Cord Injury Research Center bElectrophysiology Research Center, Neuroscience Institute cDepartment of Physiology, School of Medicine dCancer Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Spinal cord injury (SCI) has a number of severe and disabling consequences including chronic pain. Approximately 40% of patients experience neuropathic pain, which appears to be persistent. Previous studies have demonstrated the neuroprotective effects of magnesium sulfate (MgSO4). We aimed to investigate the effect of MgSO4 on neuropathic pains following SCI in male rats. Thirty-two adult male rats (weight 300-350 g) were used. After laminectomy, a complete SCI was induced by compression of the spinal cord for 1 min with an aneurysm clip. A single dose of 300 or 600 mg/kg MgSO4 was injected intraperitoneally. Tail-flick latency and acetone drop test scores were evaluated before surgery and once a week for 4 weeks after surgery. Rats in groups SCI+Mg300 and SCI+Mg600 showed significantly higher mean tail-flick latencies and lower mean scores in the acetone test compared with those in the SCI+veh group 4 weeks after surgery (P<0.05). These findings revealed that systemic single-dose administration of MgSO4 can attenuate thermal hyperalgesia and cold allodynia induced by SCI in rats.
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http://dx.doi.org/10.1097/FBP.0000000000000103DOI Listing
April 2015

Lithium protects against spinal cord injury in rats: role of nitric oxide.

J Neurol Surg A Cent Eur Neurosurg 2014 Nov 7;75(6):427-33. Epub 2013 Nov 7.

Brain and Spinal Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Objective: Lithium improves locomotor scores after spinal cord injury (SCI) in rats. However, the underlying mechanisms are unknown. Herein, we assess the role of nitric oxide (NO) in this action.

Methods: The first set of experiments were performed to determine a dose of lithium that effectively improves locomotor scores in rats with SCI. Therefore, rats received different doses of lithium chloride (1, 4, 10, and 20 mg/kg intraperitoneally) or saline 1 hour before SCI. In the next step, the role of NO in the effect of lithium on SCI was investigated. For this purpose, rats were co-treated with an effective dose of lithium (20 mg/kg 1 hour before SCI) and a noneffective dose of Nω-nitro-L-arginine methyl ester (L-NAME, a nonselective NO synthase inhibitor; 15 mg/kg intraperitoneally 30 minutes before SCI). SCI was induced by compressing the T9 spinal segment with an aneurysmal clip for 60 seconds in anesthetized rats. Locomotor scores were determined at 1, 3, 5, 7, 14, 21, and 28 days after SCI. Plasma lithium levels were measured 12 hours after SCI. Spinal histopathologies were examined 30 days after SCI.

Results: Lithium (20 mg/kg) significantly improved locomotor scores and decreased histopathologic spinal damage. l-NAME (15 mg/kg) reversed the beneficial effects of lithium. The 20-mg/kg dose of lithium resulted in a 0.68 ± 0.02 mEq/L plasma lithium concentration, which is lower than the therapeutic level in humans (0.8-1.2 mEq/L).

Conclusion: Lithium protects against SCI through an NO-dependent mechanism.
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http://dx.doi.org/10.1055/s-0033-1345098DOI Listing
November 2014
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