Publications by authors named "Hamed Shafaroodi"

84 Publications

Involvement of nNOS, and α1, α2, β1, and β2 Subunits of Soluble Guanylyl Cyclase Genes Expression in Anticonvulsant Effect of Sumatriptan on Pentylenetetrazole-Induced Seizure in Mice.

Iran J Pharm Res 2020 ;19(4):181-192

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

Epileptic seizure is phenomenon of abnormal synchronous neuronal discharge of a set of neurons in brain as a result of neuronal excitation. Evidence shows the nitric oxide (NO) involvement in neuronal excitability. Moreover, the role of cyclic guanosine monophosphate (cGMP) activation in seizure pathogenesis is well-established. Sumatriptan is a selective agonist of 5-Hydroxytryptamine1B/D auto-receptor, has been reassessed for its neuroprotection. This study was aimed to explore the anticonvulsant effect of sumatriptan through possible involvement of NO-cGMP pathway in mice. For this purpose, the protective effect of sumatriptan on PTZ-induced clonic seizure threshold (CST) was measured using NO-cGMP pathway inhibitors including N(G)-nitro-L-arginine (L-NNA, 1, 5, and 10 mg/kg), 7-nitroindazole (7-NI, 30, 45, and 60 mg/kg), aminoguanidine (AG, 30, 50, and 100 mg/kg), methylene blue (MB, 0.1, 0.5, and 1 mg/kg) and sildenafil (5, 10, and 20 mg/kg). The involvement of nitrergic system was further confirmed by measurement of nitrite levels by Griess reaction. The gene expression of neuronal nitric oxide synthase (nNOS) and subunits of soluble guanylyl cyclase (sGC) was studied using qRT-PCR analysis. Acute administration of sumatriptan (1.2 and 0.3 mg/kg) in combination with subeffective doses of NOS, sGC, and phosphodiesterase 5 inhibitors significantly reversed the PTZ-induced CST ( 0.001). The nitrite level in prefrontal cortex was significantly attenuated by sumatriptan ( ≤ 0.01). Furthermore, sumatriptan downregulated the PTZ-induced mRNA expression of nNOS ( ≤ 0.01), α1 ( ≤ 0.001), α2 ( ≤ 0.05), and β1 ( ≤ 0.05) genes in cerebral cortex of mice. In conclusion, the anticonvulsant activity of sumatriptan at least, in part, is mediated through inhibiting NO-cGMP pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22037/ijpr.2020.112594.13844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019868PMC
January 2020

Glatiramer acetate attenuates depressive/anxiety-like behaviors and cognitive deficits induced by post-weaning social isolation in male mice.

Psychopharmacology (Berl) 2021 Apr 2. Epub 2021 Apr 2.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.

Rationale: Major depressive disorder (MDD) is a debilitating disorder with adverse effects on mood, memory, and quality of life.

Objectives: In this study, the antidepressant potential of glatiramer acetate (GA), a drug used in the management of multiple sclerosis, was investigated in acute and chronic models of depression in male mice. The acute antidepressant screening was performed with the forced swim (FST) and tail suspension (TST) tests. In the chronic phase, post-weaning social isolation (SI) was used to induce depressive-/anxiety-like behaviors.

Methods: Mice were reared in two different groups of social (SG) and isolated (IG) for 4 weeks. IG mice were treated with 0.5, 1.0, and 2.0 mg/kg of GA for the last 2 weeks of the SI period. Animals were assessed by the behavioral tests of depression, anxiety, learning, and memory, and hippocampal brain-derived neurotrophic factor (BDNF) level was measured.

Results: The acute tests confirmed the antidepressant potential of GA. In the chronic phase, GA could reduce immobility time in FST (P < 0.05), increase exploration activity in open field test (P < 0.05), increase open arms duration (P < 0.05) and entries in elevated plus maze (P<0.001), and improve memory and learning in passive avoidance test (P < 0.05). The BDNF level was increased in IG mice and decreased in IG mice treated with GA.

Conclusions: Our results showed that GA improved depressive-/anxiety-like behaviors and cognitive dysfunction of SI reared mice without increasing the BDNF level which may be associated with other mechanisms of actions of GA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-021-05836-5DOI Listing
April 2021

Glatiramer acetate treatment inhibits inflammatory responses and improves survival in a mice model of cecal ligation and puncture-induced sepsis.

J Basic Clin Physiol Pharmacol 2021 Feb 9. Epub 2021 Feb 9.

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

Objectives: Sepsis is a clinical crisis which has been considered as one of the important causes of mortality across the world. We hypothesized that modulation of hyper-inflammatory phase of sepsis pathophysiology can lead to protective effects on survival outcome. Glatiramer acetate (GA) is a neuroprotective drug commonly used in multiple sclerosis (MS). GA is characterized by immunom activity via regulation of innate and adaptive immunity. This study was designed to evaluate the acute treatment with GA on initial inflammatory response-induced mortality in septic mice.

Methods: Cecal ligation and puncture (CLP) model was operated on male mice as a model of Polymicrobial sepsis. GA was administrated intraperitoneally after the sepsis induction at doses of 0.5, 1, and 2 mg/kg in three treatment groups. To investigate the effect of GA on short-term survival, septic mice were observed during 72 h after CLP. Serum levels of TNF-α, IL-1β, and IL-6 as pro-inflammatory cytokines and also IL-10 as a critical anti-inflammatory cytokine were analysed. To consider sepsis-induced acute kidney injury, renal functional biomarkers and histopathological changes was assessed.

Results: GA treatment significantly improved survival rate at doses of 1, and 2 mg/kg. Survival improvement was accompanied by remarkable reduction in the pro-inflammatory cytokines and enhanced production of IL-10. GA showed to have protective effects on renal function as well.

Conclusions: Immunomodulatory and anti-inflammatory properties of GA resulted in increase in survival rate and decrease in inflammatory markers in mice model of cecal ligation and puncture-induced sepsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/jbcpp-2020-0303DOI Listing
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/fcp.12605DOI Listing
April 2021

5-[Aryloxypyridyl (or nitrophenyl)]-4H-1,2,4-triazoles as novel flexible benzodiazepine analogues: Synthesis, receptor binding affinity and lipophilicity-dependent anti-seizure onset of action.

Bioorg Chem 2021 Jan 24;106:104504. Epub 2020 Nov 24.

Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14176, Iran.

A new series of 5-(2-aryloxy-4-nitrophenyl)-4H-1,2,4-triazoles and 5-(2-aryloxy-3-pyridyl)-4H-1,2,4-triazoles, possessing C-3 thio or alkylthio substituents, was synthesized and evaluated for their benzodiazepine receptor affinity and anti-seizure activity. These analogues revealed similar to significantly superior affinity to GABA/benzodiazepine receptor complex (IC values of 0.04-4.1 nM), relative to diazepam as the reference drug (IC value of 2.4 nM). To determine the onset of anti-seizure activity, the time-dependent effectiveness of i.p. administration of compounds on pentylenetetrazole induced seizure threshold was studied and a very good relationship was observed between the lipophilicity (cLogP) and onset of action of studied analogues (r = 0.964). The minimum effective dose of the compounds, determined at the time the analogues showed their highest activity, was demonstrated to be 0.025-0.1 mg/kg, relative to diazepam (0.025 mg/kg).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2020.104504DOI Listing
January 2021

Lithium reverses the effect of opioids on eNOS/nitric oxide pathway in human umbilical vein endothelial cells.

Mol Biol Rep 2020 Sep 4;47(9):6829-6840. Epub 2020 Sep 4.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.

The main challenge of pain management with opioids is development of acute and chronic analgesic tolerance. Several studies on neuronal cells have focused on the molecular mechanisms involved in tolerance such as cyclic AMP (cAMP) activation, and nitric oxide (NO) pathway. However, the effects of opioids on non-neuronal cells and tolerance development have been poorly investigated. Lithium chloride is a glycogen synthase kinase 3β (GSK-3β) inhibitor and exert its effects through modulation of nitric oxide pathway. In this study we examined the effect of lithium on acute/chronic morphine and methadone administration in endothelial cells which express mu opioid receptors. Human umbilical vein endothelial cells (HUVECs) were treated with different doses of morphine, methadone, and lithium for six and 48 h. Then we evaluated cell viability, nitrite and cyclic AMP levels, as well as the expression of endothelial nitric oxide synthase (eNOS) protein using Immunocytochemistry (ICC) assay and phosphorylated GSK-3β enzyme by western blot analysis in cells. Both chronic morphine and methadone treatment increased NO level and eNOS expression in HUVECs. Morphine induced cAMP overproduction after 48 h exposure with cells. Lithium pretreatment (10 mM) in both morphine and methadone received groups significantly reduced nitrite and cAMP levels as well as eNOS expression as compared to the control. The decreased amount of phospho GSK-3β due to the opioid exposure was increased following lithium treatment. Tolerance like pattern may occur in non-neuronal cells with opioid receptors and this study clearly revealed the attenuation of morphine and methadone tolerance like behavior by lithium treatment in HUVECs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11033-020-05740-9DOI Listing
September 2020

Aripiprazole prevents from development of vincristine-induced neuropathic nociception by limiting neural NOS overexpression and NF-kB hyperactivation.

Cancer Chemother Pharmacol 2020 09 14;86(3):393-404. Epub 2020 Aug 14.

Experimental Medicine Research Center, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.

Purpose: Increased nitric oxide (NO) synthesis and NF-kB activation have been shown as critical players in the pathophysiology of vincristine-induced peripheral neuropathy. Consistently, neural nitric oxide synthase (nNOS) inhibitors alleviated the neuropathic pain. Previous studies demonstrated that aripiprazole is capable of modulating NO synthesis and also has been reported its modulatory effect on NF-kB activity.

Methods: Aripiprazole was administered daily to the male Wistar rats at the same time with establishing neuropathic model by I.P. injection of vincristine every 2 days, over 2 weeks. Efficacy of aripiprazole in suppressing the development of neuropathy was evaluated by assessing changes in body weight, mechanical threshold, withdrawal latency, sciatic nerve conduction velocity (SNCV), and compound motor action potential (CMAP) characteristics. Expression of nNOS and NF-kB activation were evaluated by western blotting RESULTS: Rats receiving aripiprazole during neuropathy establishment period demonstrated a normal weight gain pattern, a significantly higher mechanical withdrawal threshold, and SNCV compared to vincristine-treated group. Furthermore, the amplitude and area of CMAP were significantly higher in aripiprazole group. Western blotting demonstrated a significantly reduced expression of nNOS and NF-kB activation in dorsal root ganglia of aripiprazole co-treated rats.

Conclusion: In conclusion, aripiprazole effectively prevents from vincristine-induced neuropathy by limiting nNOS overexpression and NF-kB hyperactivation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-020-04127-8DOI Listing
September 2020

Interaction of morphine tolerance with pentylenetetrazole-induced seizure threshold in mice: The role of NMDA-receptor/NO pathway.

Epilepsy Behav 2020 11 2;112:107343. Epub 2020 Aug 2.

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:

N-methyl-d-aspartate receptor (NMDA-R)/nitric oxide (NO) pathway is involved in the intensification of the analgesic effect of opioids and the reduction of the intensity of opioids tolerance and dependence. In the current study, we investigated the involvement of NMDA-R/NO pathway in chronic morphine-treated mice in both the development of tolerance to the analgesic effect of morphine and in pentylenetetrazole (PTZ)-induced seizure threshold. Chronic treatment with morphine (30 mg/kg) exhibited increased seizure resistance in morphine-induced tolerant mice. The development of morphine tolerance was withdrawn when used concomitantly with NOS inhibitors and NMDA-R antagonist, suggesting that the development of tolerance to the anticonvulsant effect of morphine (30 mg/kg) is mediated through the NMDA-R/NO pathway. A dose-dependent biphasic seizure modulation of morphine was demonstrated in the acute treatment with morphine; acute treatment at a dose of 0.5 mg/kg shows the anticonvulsant effect and at a dose of 30 mg/kg shows proconvulsant effect. However, a different pattern was observed in the mice treated chronically with morphine: they demonstrated tolerance in the tail-flick test; five consecutive days of chronic treatment with a high dose of morphine (30 mg/kg) showed anticonvulsant effect while a low dose of morphine (0.5 mg/kg) showed a proconvulsant effect. The anticonvulsant effect of morphine was inhibited completely by the concomitant administration of NO synthase (NOS) inhibitors including nonspecific NOS inhibitor (L-NAME, 10 mg/kg), inducible NOS inhibitor (aminoguanidine, 50 mg/kg), and neuronal NOS inhibitor (7-nitroindazole (7-NI), 15 mg/kg) for five consecutive days. Besides, five days injection of NMDA-R antagonist (MK-801, 0.05 mg/kg) significantly inhibited the anticonvulsant effect of morphine on the PTZ-induced clonic seizures. The results revealed that chronic treatment with morphine leads to the development of tolerance in mice, which in turn may cause an anticonvulsant effect in a high dose of morphine via the NMDA-R/NO pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2020.107343DOI Listing
November 2020

Effect of Essential Oil of Zhumeria majdae on Morphine Tolerance and Dependence in Mice.

Chin J Integr Med 2020 Sep 27;26(9):683-687. Epub 2020 Jul 27.

Department of Pharmacognosy, Faculty of Pharmacy and Pharmaceutical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.

Objective: To evaluate the effects of Zhumeria majdae essential oil (ZMEO) on morphine dependence and tolerance in mice.

Methods: ZMEO (10, 20, and 40 mg/kg) and clonidine (0.1 mg/kg) as the positive control were injected intraperitoneally (i.p.). The effect of ZMEO and clonidine on the dependence were evaluated by counting the number of jumps induced by naloxone (5 mg/kg) while the tolerance was evaluated by the tail-flick test.

Results: ZMEO at the dose of 10 mg/kg during the development period led to a significant inhibition of morphine tolerance (P<0.01), while it led to reduced morphine dependence with the doses of 20 and 40 mg/kg. ZMEO at two dose levels of 20 and 40 mg/kg indicated significant antinociceptive activity (P>0.01), and significantly reduced the withdrawal signs (number of jumps) of mice (P>0.01).

Conclusions: ZMEO had significant effects on morphine tolerance and dependence. The linalool rich essential oil of Z. majdae plays a major role in the reduction of tolerance and dependence induced by morphine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11655-020-3424-9DOI Listing
September 2020

Involvement of 5-HT1B/1D receptors in the inflammatory response and oxidative stress in intestinal ischemia/reperfusion in rats.

Eur J Pharmacol 2020 Sep 20;882:173265. Epub 2020 Jun 20.

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

Acute mesenteric ischemia (AMI) is caused by an abrupt cessation of blood flow to the small intestine. Reperfusion is the return of blood flow to the ischemic bowel. Intestinal ischemia/reperfusion (I/R) leads to the formation of reactive oxygen species, local inflammatory response, and may lead to the patient's death. Pre-treatment of the intestinal may reduce the high mortality associated with AMI. 5-Hydroxytryptamine 1B (5-HT1B) and 5-HT1D receptors have anti-inflammatory and neuroprotective effects in different experimental studies. We aimed to investigate the potential involvement of these receptors in intestinal I/R injury. Firstly, we assessed the expression and localization of 5-HT1B and 5-HT1D receptors in the enteric nervous system using an immunofluorescence-based method. Intestinal I/R in rats was induced by 30 min occlusion of superior mesenteric artery and reperfusion for 2 h. Rats were randomly divided in different control and I/R groups (n = 6) receiving either vehicle, sumatriptan (5-HT1B/1D receptors agonist; 0.1 mg/kg), GR127,935 (5-HT1B/1D receptors antagonist; 0.1 mg/kg) and combination of sumatriptan (0.1 mg/kg) + GR127,935 (0.1 mg/kg) before determination of biochemical and histological parameters. In the enteric nervous system, 5-HT1B and 5-HT1D receptors were expressed 17% and 11.5%, respectively. Pre-treatment with sumatriptan decreased 5-hydroxytryptamine (5HT) level by 53%, and significantly decreased calcitonin gene-related peptide (CGRP) levels, lipid pereoxidation, neutrophil infiltration, and level of pro-inflammatory markers in the serum. Histopathologic studies also showed a remarkable decrease in intestinal tissue injury. These findings suggest that sumatriptan may inhibit intestinal injury induced by I/R through modulating the inflammatory response by activation of 5-HT1B/1D receptors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2020.173265DOI Listing
September 2020

Anticonvulsant Activity of Essential Oil From Leaves of Zhumeria majdae (Rech.) in Mice: The Role of GABA Neurotransmission and the Nitric Oxide Pathway.

Clin Transl Sci 2020 07 8;13(4):785-797. Epub 2020 Apr 8.

Department of Pharmacognosy, Faculty of Pharmacy and Pharmaceutical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.

The essential oil from the leaves of Zhumeria majdae Rech. (ZMEO) has been shown to have several beneficial effects in the clinic. In this work we examined the anticonvulsant activities of ZMEO in an experimental mouse model of seizure and aimed to identify any possible underlying mechanisms. ZMEO (5, 10, 20, and 40 mg/kg intraperitoneally (i.p.)) or diazepam, as the reference anticonvulsant drug (25, 50 and 100 µg/kg i.p.), were administered 60 minutes prior to pentylenetetrazol (PTZ) injection (intravenously (i.v.) or i.p.) and changes in threshold, latency, and frequency of clonic seizure were examined. The PTZ i.p.-induced model of seizure was also applied for examining the protective effects of ZMEO pretreatment against PTZ-induced mortality. In some studies, the anticonvulsant effect of the combination of diazepam and ZMEO was also studied. The protective effects of ZMEO against hindlimb tonic extensions (HLTEs) were also examined by maximal electroshock (MES) seizure testing. The γ-aminobutyric acid (GABA)ergic mechanism and nitric oxide (NO) pathway involvement in anticonvulsant activity of ZMEO were assessed by pretreating animals with flumazenil, N -nitro-L-arginine methyl ester (L-NAME), aminoguanidine, and L-arginine in a PTZ-induced model of seizure. Administration of 20 mg/kg ZMEO significantly increased chronic seizure threshold and latency while reducing frequency of convulsions and mortality in the PTZ-induced model. In the doses studied, ZMEO could not protect mice from HLTE and mortality induced by MES. Pretreatment with L-arginine and diazepam potentiated the anticonvulsant effects of ZMEO, whereas pretreatment with L-NAME, aminoguanidine, and flumazenil reversed anticonvulsant activity. The anticonvulsant activity of ZMEO may be mediated in part through a GABAergic mechanism and the NO signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cts.12767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359939PMC
July 2020

Glatiramer acetate attenuates renal ischemia reperfusion injury in rat model.

Exp Mol Pathol 2020 02 4;112:104329. Epub 2019 Nov 4.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, P.O. Box 13145-784, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, P.O. Box 13145-784, Iran. Electronic address:

Chronic renal failure can ultimately lead to kidney transplantation. Renal transplantation is associated with ischemia-reperfusion injury (I/R). The subsequent processes of kidney I/R can lead to irreversible damages to the kidney tissue. Glatiramer acetate is an immunomodulatory drug for the treatment of multiple sclerosis (MS) and the anti-inflammatory effects of this drug have already been proven in some inflammatory models. The purpose of this study was to evaluate the protective effects of Glatiramer on reducing the damages arising from kidney ischemia-reperfusion. In this study, 35 Wistar rats were used which divided into 5 groups: sham, control (I/R), I/R + Glatiramer 0.5 mg/kg, I/R + Glatiramer 1 mg/kg, I/R + Glatiramer 2 mg/kg. Renal arteries were clamped bilaterally for 45 min, then the clamps were removed and the reperfusion process continued to 24 h. In the following, serum and kidneys were separated for analysis. In the control group, serum levels of LDH, inflammatory factor TNF-α and renal functional markers such as BUN and Creatinine were remarkably increased, but in the treatment groups, especially in Glatiramer 2 mg/kg received group, a significant decrease in these factors was observed. Tissue concentration of MDA was reduced following Glatiramer treatment. Besides, Glatiramer attenuated the increased kidney level of NF-κB protein using immunohistochemical assay. NFkB migration to the nucleolus increases inflammatory cytokines production. The anti-inflammatory factor, IL-10, in serum was significantly increased in the treatment group of Glatiramer 2 mg/kg. Furthermore, Glatiramer decreased renal tissue injury score according to the histopathological study. These results demonstrate that Glatiramer may play protective effects in kidney ischemia-reperfusion injury by reducing inflammatory and oxidative damages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yexmp.2019.104329DOI Listing
February 2020

The effects of acute sumatriptan treatment on renal ischemia/reperfusion injury in rat and the possible involvement of nitric oxide.

Can J Physiol Pharmacol 2020 Apr 11;98(4):252-258. Epub 2019 Oct 11.

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

Renal ischemia/reperfusion (I/R) injury is a common pathological condition. Studies reported renal toxicity following administration of triptans, which are commonly used for treating migraine headaches. To investigate the effects of sumatriptan and the molecular mechanisms involved in renal I/R injury in rats, ischemia was induced by bilateral clamping of renal pedicles followed by 24 h of reperfusion. Sumatriptan was administered in three different doses (5, 10, and 20 mg/kg) before I/R injury induction. Biochemical and histopathological changes were evaluated. The contribution of nitric oxide in modulating the effects of sumatriptan was determined by administrating aminoguanidine at 50 mg/kg 60 min before I/R injury. The tissue level of nitrite, superoxide dismutase (SOD), and malondialdehyde (MDA) were measured. Sumatriptan at 10 and 20 mg/kg increased the serum level of creatinine (Cr) and blood urea nitrogen (BUN) significantly. There was also a significant increase in nitrite level of animals that received 10 mg/kg sumatriptan. Co-administration of sumatriptan with aminoguanidine significantly decreased the BUN and Cr. Depletion of SOD level ( < 0.05) and elevation of serum levels of MDA ( < 0.001) indicated the involvement of oxidative stress in sumatriptan adverse effects. Overall, the administration of sumatriptan intensified renal I/R injury through activation of inducible nitric oxide synthase and oxidative responses in rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1139/cjpp-2019-0301DOI Listing
April 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000501583DOI Listing
February 2021

Lead Poisoning in Opium-Addicted Subjects, Its Correlation with Pyrimidine 5'-Nucleotidase Activity and Liver Function Tests.

Int J Prev Med 2019 5;10:36. Epub 2019 Mar 5.

Tehran University of Medical Sciences (TUMS), Tehran, Iran.

Background: Lead may be added to the opium by drug smugglers. It can cause elevated blood lead level (BLL) in opium-addicted patients. Erythrocyte pyrimidine 5'-nucleotidase (P5N) activity is susceptible to high BLL. The aim of this study was to find out whether opium-addicted patients show erythropathy and elevated liver enzymes explainable by high BLL and decreased P5N activity.

Methods: Forty orally opium-addicted subjects and 40 normal healthy volunteers were enrolled in this study. BLL was measured in whole blood specimens using atomic absorption spectrometry instrumentation. Enzymatic activity, protein amount of P5N, and erythrocyte purine/pyrimidine ratio were determined. Blood films were analyzed for the presence of basophilic stippling of red cells and hemolytic anemia. The level of liver function enzymes was measured.

Results: The mean BLL for opium-addicted patients was significantly higher than control group ( < 0.001). On the contrary, P5N activity showed a valid decrease in opium-addicted patients when compared with control group ( < 0.001). In line with repressed P5N activity, erythrocyte purine/pyrimidine ratio in patients was lower than control group ( < 0.001). A statistically significant reverse correlation was found between BLL and P5N activity ( < 0.05, = -0.85). The prevalence of both basophilic stippling ( < 0.001, = 6.62) and hemolytic anemia ( < 0.001, = 6.52) in study population was significantly associated with elevated BLL. We could not find any significant correlation between serum level of liver enzymes and BLL.

Conclusions: Opium-addicted patients in Tehran, Iran, are at high risk of lead poisoning which may result in hematologic problems and possibly hepatic damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/ijpvm.IJPVM_490_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425880PMC
March 2019

Novel fused 1,2,3-triazolo-benzodiazepine derivatives as potent anticonvulsant agents: design, synthesis, in vivo, and in silico evaluations.

Mol Divers 2020 Feb 20;24(1):179-189. Epub 2019 Mar 20.

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

A novel series of 1,2,3-triazolo-benzodiazepine derivatives 6a-o has been synthesized and evaluated in vivo for their anticonvulsant activities using by pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures in mice. The synthetic approach started with diazotizing 2-aminobenzoic acids 1 to produce 2-azidobenzoic acids 2. Next, reaction of the latter compounds with propargylamine 3, benzaldehyde 4, and isocyanides 5 led to the formation of the title compounds 6a-o, in good yields. All the synthesized compounds exhibited high anticonvulsant activity in the PTZ test, comparable to or better than the standard drug diazepam. Among the tested compounds, N-(tert-butyl)-2-(9-chloro-6-oxo-4H-[1,2,3]triazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl)-2-(3-bromophenyl)acetamide 6h was the most potent compound in this assay. Moreover, compounds 6i and 6k showed excellent activity in MES test. Loss of the anticonvulsant effect of compound 6h in the presence of flumazenil in the PTZ test and appropriate interaction of this compound in the active site of benzodiazepine (BZD)-binding site of GABA receptor confirm involvement of BZD receptors in the anticonvulsant activity of compound 6h. A novel series of 1,2,3-triazolo-benzodiazepine derivatives 6a-o have been synthesized and evaluated in vivo for their anticonvulsant activities using by pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures in mice. All the synthesized compounds exhibited high anticonvulsant activity, comparable to or better than the standard drug diazepam in the PTZ test and compounds 6i and 6k showed excellent activity in MES test. Flumazenil test and in silico docking study confirm involvement of benzodiazepine receptors in the anticonvulsant activity of these compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11030-019-09940-9DOI Listing
February 2020

The protective effect of acute pantoprazole pretreatment on renal ischemia/reperfusion injury in rats.

Fundam Clin Pharmacol 2019 Aug 21;33(4):405-411. Epub 2019 Feb 21.

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

Renal ischemia/reperfusion injury (IRI), which occurs in many pathological conditions, is associated with high rate of morbidity and mortality. Activation of inflammatory responses and oxidative stress contribute to induce organ damage following IRI. Pantoprazole, a proton pump inhibitor, which is mostly prescribed for gastroesophageal reflux disease (GERD) has been shown to exert anti-inflammation effects. In order to evaluate the effects of pantoprazole on renal ischemia/reperfusion injury, four different doses of pantoprazole (4.5, 9, 18, and 36 mg/kg) were administered 30 min before the induction of IRI in male Wistar rats. Serum concentration of creatinine and blood urea nitrogen (BUN) were measured to assess renal function. Histopathological changes, malondialdehyde (MDA) level and toll-like receptor 4 (TLR-4) expression in renal tissue were determined and compared to control group. The results revealed that pretreatment with 18 and 36 mg/kg of pantoprazole leads to the significant decline in serum creatinine and BUN levels and the severity of necrosis grade in comparison with control group (P < 0.05). Pantoprazole also reduced the MDA level and TLR-4 expression in renal tissue. In summary, pantoprazole attenuates renal injury following ischemia/reperfusion. This effect is mediated partially through inhibition of oxidative stress and TLR-4 signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/fcp.12451DOI Listing
August 2019

Acute foot-shock stress decreased seizure susceptibility against pentylenetetrazole-induced seizures in mice: Interaction between endogenous opioids and cannabinoids.

Epilepsy Behav 2018 10 28;87:25-31. Epub 2018 Aug 28.

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

Background: Stressful conditions affect the brain's neurotransmission and neural pathways that are involved in seizure susceptibility. Stress alters the intensity and/or frequency of seizures. Although evidence indicates that chronic stress exerts proconvulsant effects and acute stress has anticonvulsant properties, the underlying mechanisms which mediate these effects are not well understood. In the present study, we assessed the role of endogenous opioids, endocannabinoids, as well as functional interaction between opioid and cannabinoid systems in the anticonvulsant effects of acute foot-shock stress (FSS) against pentylenetetrazole (PTZ)-induced seizures in mice.

Methods: Prolonged intermittent FSS was chosen as an acute stress model. Seizure threshold was determined after 30 min of stress induction in male Naval Medical Research Institute (NMRI) mice (20-30 g). Opioid and cannabinoid receptor antagonists were administered before animal placement in the FSS apparatus.

Results: Acute FSS significantly decreased seizure susceptibility in animals. The administration of the cannabinoid receptor 1 (CB) antagonist, AM251, completely blocked the anticonvulsant effect of acute FSS at the doses of 1 pg/kg-100 μg/kg but not at 1 fg/kg. Pretreatment with the nonspecific opioid receptor antagonist, naltrexone (NTX), significantly inhibited the anticonvulsant effects of acute FSS at 1 and 2 mg/kg but not at 0.3 mg/kg. However, coadministration of the subeffective doses of AM251 (1 fg/kg) and NTX (0.3 mg/kg) reversed the anticonvulsant effects of acute FSS.

Conclusions: Opioid and cannabinoid systems are involved in the anticonvulsant effects of acute FSS, and these neurotransmission systems interact functionally in response to acute FSS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2018.06.035DOI Listing
October 2018

2, 5-Disubstituted Phthalimides: Design, Synthesis and Anticonvulsant Activity in scPTZ and MES Models.

Curr Comput Aided Drug Des 2018 ;14(4):310-321

Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.

Introduction: In this study, fifteen new 2,5-disubstituted analgouges of phthalimide were designed and synthesized using the appropriate synthetic route to evaluate anticonvulsant activity against the Maximal Electroshock (MES) and subcutaneous Pentylenetetrazole (scPTZ) compare to phenytoin as a positive control. The structures of the synthesized compounds were confirmed by FTIR, H-NMR, C-NMR and MASS spectroscopy.

Methods: All the tested compounds were found to be effective in the PTZ model at dose of 60 mg/kg and most of the compounds showed protection against MES test indicative of their ability to inhibit the seizure spread at all dose ranges. Compound 3 illustrated the best efficacy among all compounds and showed more potency than phenytoin in clonic seizure and was potent as phenytoin in tonic seizure.

Results & Discussion: Using a model of the Na channel, these derivatives were docked in the active site. Docking studies displayed that all synthesized compounds have more negative binding energy compare to reference drug and inhibition-constant less than phenytoin that means they can block the receptor more efficiently and usually form hydrophobic interactions or hydrogen bond interaction frequently with the domains I, II, III and rarely with domain IV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1573409914666180516115450DOI Listing
January 2019

Docking, Synthesis and Anticonvulsant Activity of N-substituted Isoindoline-1,3-dione.

Iran J Pharm Res 2017 ;16(2):586-595

Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.

A series of compounds related to ameltolide were studied for anticonvulsant potential in the subcutaneous pentylenetetrazol (sc Ptz) test in mice. These compounds were synthesized and characterized by TLC followed by IR and HNMR. screening data acquired indicate that most of analogs have the ability to protect against PTZ-induced seizure. Phenytoin (PHT) was employed as the reference prototype antiepileptic drug. All compounds exerted their maximal effects 30 min after administration. Out of the 6 compounds, compound 2 at 40 mg/Kg dose is more potent than phenytoin (reference drug) on clonic seizure. Using a model of the open pore of the Na channel, docking study was performed by AutoDock 4.2 program. Docking study has revealed that these compounds are stabilized through at least one hydrogen bond rises from ketone of phthalimide and residue Thr-87 of domain G of sodium channel.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603866PMC
January 2017

N-arylmethylideneaminophthalimide: Design, Synthesis and Evaluation as Analgesic and Anti-inflammatory Agents.

Mini Rev Med Chem 2019 ;19(8):679-687

Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Research Center, Tehran University of Medical Sciences, Iran.

Background And Objective: N-aryl derivatives of phthalimide and 4-nitro phthalimide have demonstrated cyclooxygenase inhibitory activity. Also, they possess excellent analgesic and antiinflammatory activity. In this work, a new series of N-arylmethylideneamino derivatives of phthalimide and 4-nitro phthalimide were designed and synthesized.

Methods: The designed compounds were synthesized by condensation of the appropriate aldehyde and N-aminophthalimide in ethanol at room temperature at PH around 3. Their analgesic and antiinflammatory activity were evaluated by acetic acid-induced pain test and carrageenan-induced paw edema test in mice and rats, respectively.

Results And Conclusion: The details of the synthesis and chemical characterization of the analogs are described. In vivo screening showed compounds 3a, 3b, 3f and 3h were the most potent analgesic compounds. In addition, compounds 3a, 3c, 3d, 3e and 3j indicated comparable anti-inflammatory activity to indomethacin as a reference drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389557518666180424101009DOI Listing
June 2019

Prognostic value of cortisol and thyroid function tests in poisoned patients admitted to toxicology ICU.

World J Emerg Med 2018 ;9(1):51-55

Pharmaceutical Sciences Branch, Islamic Azad University (IAUPS), Tehran, Iran.

Background: Prognostic value of cortisol and thyroid function tests (TFTs) has previously been evaluated in medical ICUs. We aimed to evaluate prognostic efficacy of cortisol and TFTs in critically ill poisoned patients admitted to toxicology intensive care unit (ICU).

Methods: In a prospective study of consecutively enrolled subjects admitted to the toxicology ICU, lab analyses included TFTs (total T3 and T4 as well as TSH) and cortisol levels drawn between 8 am-10 am during period of the first 24 hours post-ingestion/exposure. Simplified Acute Physiology Score II (SAPS II) and Acute Physiology and Chronic Health Evaluation II (APACHE II) were recorded. All scores were compared to detect the best prognostic factor. Type of poisoning was also included.

Results: In 200 patients evaluated, 129 were male and mean age was 31 years. In general, SAPS II, T4, and cortisol could prognosticate death. After regression analysis, only cortisol had such efficacy (=0.04; =1.06; 95%=1.05-1.08; cut-off=42 µg/dL; sensitivity=70%; specificity=82%). Between aluminium phosphide (ALP)- and non ALP-poisoned patients, level of consciousness, mean arterial pressure, and cortisol level could prognosticate death in ALP poisoning (all <0.001 in both uni and multivariate analyses). Median (interquartile range; IQR) GCS was 7 (6, 10) and 15 (8, 15) in non-ALP and ALP-poisoned patients (<0.003). SAPS II and APACHE II could not prognosticate death at all.

Conclusion: Cortisol best prognosticated outcomes for subjects admitted to the toxicology ICU. Its level is higher in ALP-poisoned patients probably due to the higher stress while they remain conscious till the final stages of toxicity and are aware of deterioration of their clinical condition or may be due to their significantly lower blood pressures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5847/wjem.j.1920-8642.2018.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717377PMC
January 2018

Novel derivatives of phthalimide with potent anticonvulsant activity in PTZ and MES seizure models.

Iran J Basic Med Sci 2017 Apr;20(4):430-437

Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.

Objectives: Phthalimide-based derivatives have anticonvulsant activity like as phenytoin by inhibition of sodium channel. In our previously research we mentioned about some phthalimide derivatives as potent anticonvulsant agents.

Materials And Methods: Fourteen analogs of 2-substituted phthalimide pharmacophore were synthesized and then were evaluated for the anticonvulsant activities in pentylenetetrazole-induced seizures (PTZ) and maximal electroshock seizure (MES) models.

Results: The screening results showed that all the analogs have the ability to protect against the maximal electroshock and PTZ. The compounds 3 and 9 elevated clonic seizure thresholds at 30 min which were more active than the standard medicine phenytoin. Compounds 3, 6, 7, 11, 13 and 14 with 100% protection were the most potent ones in tonic seizure. The most potent compound in the both PTZ and MES models was compound 3. Using a model of the open pore of sodium channel, all of the compounds were docked. Results of docking showed that the ligands interacted mainly with residues II-S6 of NaV1.2 by making hydrogen bonds and have additional hydrophobic interactions with other domains in the channel's inner pore.

Conclusion: Some of these compounds are more potent than phenytoin simultaneously in the clonic and tonic seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22038/IJBMS.2017.8586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425926PMC
April 2017

Aripiprazole prevents renal ischemia/reperfusion injury in rats, probably through nitric oxide involvement.

Eur J Pharmacol 2017 Oct 19;813:17-23. Epub 2017 Jul 19.

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

Renal ischemia/reperfusion (I/R) injury is strongly related to morbidity and mortality. Oxidative stress, inflammation, and apoptosis play key roles in renal dysfunction following renal I/R. Aripiprazole is an atypical antipsychotic which used for the treatment of schizophrenia and bipolar disorder. Recent studies have reported aripiprazole as displaying certain anti-inflammatory effects. Regarding the underlying mechanisms of renal ischemia-reperfusion, therefore, nephroprotective effects might be predicted to be seen with aripiprazole. I/R injury was induced by bilateral clamping of the renal pedicles (45min) followed by reperfusion (24h). The mechanism of aripiprazole-mediated nephroprotection was explored by a combined use of aripiprazole and L-NAME (non-selective nitric oxide synthase inhibitor). Animals were given aripiprazole (2.5, 5, 10 and 20mg/kg) intraperitoneally, 30min before ischemia. L-NAME was administered before the aripiprazole injection. Serum creatinine and blood urea nitrogen were assessed after 24h of reperfusion. Serum levels of malondialdehyde (MDA), TNF-α and IL-1β were measured for rats treated with aripiprazole. The extent of necrosis was measured by the stereology method. Ischemia/reperfusion caused significant renal dysfunction and marked renal injury. Aripiprazole reduced creatinine and blood urea nitrogen. Serum levels of MDA, IL-1β and TNF-α were significantly lower in the aripiprazole group. Aripiprazole treatment also decreased the volume of kidney necrosis. The administration of L-NAME reversed the renoprotective effect of aripiprazole on BUN and creatinine, but enhanced the anti-necrotic effect of aripiprazole. The results show that a single dose of aripiprazole significantly improved renal function following ischemia/reperfusion injury - probably through the involvement of nitric oxide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2017.07.032DOI Listing
October 2017

Creatine Revealed Anticonvulsant Properties on Chemically and Electrically Induced Seizures in Mice.

Iran J Pharm Res 2016 ;15(4):843-850

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

Creatine exerts beneficial effects on a variety of pathologies in which energy metabolism and oxidative stress play an etiological role. Creatine supplements have shown beneficial effects on neurological disorders including Parkinson׳s disease, Huntington›s disease, amyotrophic lateral sclerosis, as well as Alzheimer›s disease and stroke. However, the potential benefits of creatine for patients with convulsive disorders remain poorly defined. While some authors did not suggest any anti- or pro-convulsant roles for creatine treatment, others suggest that creatine may be an anticonvulsant agent. In this study, we investigated the effects of creatine on seizures in mice. Three models were used to explore the role of creatine on seizures in mice including intravenous pentylenetetrazole (PTZ), intraperitoneal PTZ, and electroshock models. Acute creatine treatment (10, 20, 40 and 80 mg/Kg) significantly increased the clonic seizure threshold in the intravenous PTZ model. Sub-chronic administration of creatine (10 and 20 mg/Kg) revealed a significant anticonvulsant effect in intravenous PTZ model. Acute creatine administration (10, 20 and 40 mg/Kg) significantly decreased the frequency of clonic seizures in the intraperitoneal PTZ model. Besides, acute creatine (40 and 80 mg/Kg) decreased the incidence of tonic seizures after electroshock. In conclusion, creatine exerts anticonvulsant effects in three seizure models; therefore, it may act as a potential drug to help patients with convulsions. However, further investigations should be done to clarify these results more.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316263PMC
January 2016

The Possible Role of Nitric Oxide and Oxidative Stress in the Enhanced Apoptosis of Cardiac Cells in Cirrhotic Rats.

Acta Med Iran 2017 Jan;55(1):29-34

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

 Cirrhosis has been related with hyperdynamic circulation, manifesting as increased cardiac output and decreased systemic vascular resistance. In the present study we examined the cirrhosis outcome on apoptosis of rat hearts. We also tried to explore the role of nitric oxide (NO) and oxidative stress in the probable changed apoptosis of cirrhotic hearts. Twenty eight days after ligation of bile duct, heart tissues were tested for apoptosis. The extent of malondialdehyde (MDA), and the activities of catalase (CAT), glutathione peroxidase (GSHPx) and superoxide dismutase (SOD) have been calculated in heart tissues. The cirrhotic hearts exhibited structural defects and greater apoptosis. Chronic treatment of cirrhotic rats with L-NAME, a non-selective inhibitor of NO synthase, inhibited heart structural defects and reduced apoptosis of hearts. We also showed that cirrhotic rat hearts had an enhanced level of MDA and reduced activities of CAT, GSHPx and SOD. When the animals were treated by L-NAME chronically, the MDA level reduced and activities of CAT, GSHPx and SOD augmented in cirrhotic heart. In conclusion, increased apoptosis of cirrhotic hearts probably happen due to NO overproduction and increased oxidative stress in hearts of cirrhotic rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2017

Activation of cannabinoid receptors elicits antidepressant-like effects in a mouse model of social isolation stress.

Brain Res Bull 2017 04 1;130:200-210. Epub 2017 Feb 1.

Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box, 13145-784, Tehran, Iran. Electronic address:

Social isolation stress (SIS) paradigm is a chronic stress procedure able to induce profound behavioral and neurochemical changes in rodents and evokes depressive and anxiety-like behaviors. Recent studies demonstrated that the cannabinoid system plays a key role in behavioral abnormalities such as depression through different pathways; however, there is no evidence showing a relation between SIS and the cannabinoid system. This study investigated the role of the cannabinoid system in depressive-like behavior and anxiety-like behavior of IC animals. For this purpose, NMRI mice were treated with WIN55, 212-2 (non-selective cannabinoid receptor agonist) and AM-251 (cannabinoid receptor type 1 antagonist) and AM-630 (cannabinoid receptor type 2 antagonist). We found that behavioral abnormality followed by SIS was mitigated after administration of WIN55, 212-2. Also, depressive-like effects induced by SIS were significantly increased following administration of AM-251 and AM-630. Co-administration of cannabinoid receptor antagonists (AM-251 and AM-630), significantly reversed the antidepressant effect of WIN55, 212-2 in IC animals. Our findings suggest that the cannabinoid system is involved in depressive-like behaviors induced by SIS. We showed that activation of cannabinoid receptors (type 1 and 2) could mitigate depression-like behavior induced by SIS in a mouse model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainresbull.2017.01.018DOI Listing
April 2017

Design and Synthesis of 2-(Arylmethylideneamino) Isoindolines as New Potential Analgesic and Anti-Inflammatory Agents: A Molecular Hybridization Approach.

Curr Pharm Des 2016 ;22(37):5760-5766

Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, 19419, Iran.

Phthalimide and hydrazine pharmacophores have been demonstrated to be inhibitors of cyclooxygenases (COX) and lipoxygenases (LOX) and to possess a marked analgesic and anti-inflammatory activity. A new group of hybrid analogs of phthalimide and hydrazine (2-(arylmethylideneamino) isoindolines), possessing a variety of substituents (OMe, OH, NO2, Cl, and F) at different positions of the aryl ring, were synthesized and their analgesic and anti-inflammatory effects were evaluated. In vivo screening showed that all the analogs possessed analgesic and anti-inflammatory activity and compounds 10g, 10h and 10e were the most potent as analgesic and compounds 10b, 10c and 10i were the most potent as anti-inflammatory agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1381612822666160701072127DOI Listing
December 2017

Atorvastatin attenuates the antinociceptive tolerance of morphine via nitric oxide dependent pathway in male mice.

Brain Res Bull 2016 07 2;125:173-80. Epub 2016 Jul 2.

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:

The development of morphine-induced antinociceptive tolerance limits its therapeutic efficacy in pain management. Atorvastatin, or competitive inhibitor of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase, is mainstay agent in hypercholesterolemia treatment. Beyond the cholesterol-lowering activity, exploration of neuroprotective properties of this statin indicates its potential benefit in central nervous disorders. The aim of the present study was to assess the effects of atorvastatin in development and expression of morphine-induced analgesic tolerance in male mice and probable involvement of nitric oxide. Chronic and acute treatment with atorvastatin 10 and 20mg/kg, respectively, could alleviate morphine tolerance in development and expression phases. Chronic co-administration of nitric oxide synthase (NOS) inhibitors including L-NAME (non selective NOS inhibitor; 2mg/kg), aminoguanidine (selective inducible NOS inhibitor; 50mg/kg) and 7-NI (selective neuronal NOS inhibitor; 15mg/kg) with atorvastatin blocked the protective effect of atorvastatin in tolerance reversal. Moreover, reversing the atorvastatin effect was also observed in acute simultaneous treatment of L-NAME (5mg/kg) and aminoguanidine (100mg/kg) with atorvastatin. Co-treatment of guanylyl cyclase inhibitor, ODQ (chronic dose: 10mg/kg and acute dose: 20mg/kg) was associated with prevention of atorvastatin anti-tolerance properties. Our results revealed that the atorvastatin modulating role in morphine antinociceptive tolerance is mediated at least in part via nitric oxide in animal pain models of hot plate and tail flick.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainresbull.2016.07.002DOI Listing
July 2016

The interaction between morphine and propranolol in chemical and electrical seizure models of mice.

Neurol Res 2016 Feb 26;38(2):166-76. Epub 2016 Feb 26.

c Department of Pharmacology, School of Medicine , Shiraz University of Medical Sciences , Shiraz , Iran.

Objectives: Morphine and propranolol have different effects on seizure. Several studies have shown interaction between adrenergic and opioid systems in different models. In this study, interaction between morphine and propranolol in different seizure models was examined in mice.

Methods: In this study, three seizure models, including intravenous pentylenetetrazole (PTZ), intraperitoneal PTZ and electroshock, were examined in mice. Animals were injected with different doses of morphine or propranolol in the 60th and 45th min, before seizure induction, respectively.

Results: Acute administration of propranolol or lower doses of morphine induced an anticonvulsant effect in intravenous PTZ, intraperitoneal PTZ and electroshock-induced seizure models; on the contrary, higher doses of morphine exert proconvulsant effects in all three models. Also additive anticonvulsant effect of propranolol and lower doses of morphine was observed in all examined models. The additive anti-seizure effect of propranolol and lower doses of morphine was blocked by naltrexone in intraperitoneal PTZ model. Moreover, the anticonvulsant effect of propranolol was inhibited by naltrexone in intraperitoneal PTZ seizure model of mice. Propranolol restrained the proconvulsant effects in higher doses of morphine in clonic seizures of intravenous and intraperitoneal PTZ models.

Discussion: In conclusion, we believe that this is the first study that has indicated the interaction of propranolol and lower doses of morphine in the anticonvulsant effects in three seizure models of intravenous PTZ, intraperitoneal PTZ and electroshock. The involvement of μ-opioid receptor in this interaction was also demonstrated. Simultaneously, we showed the interaction between propranolol and higher doses of morphine in proconvulsant effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01616412.2015.1136779DOI Listing
February 2016