Publications by authors named "Vahid Nikoui"

27 Publications

  • Page 1 of 1

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

Antidepressant-like effect of ethanol in mice forced swimming test is mediated via inhibition of NMDA/nitric oxide/cGMP signaling pathway.

Alcohol 2021 May 11;92:53-63. Epub 2021 Feb 11.

Department of Pharmacology, School of Medicine, 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:

There is evidence for a dramatic relationship between depression and alcohol consumption. Depressed patients may abuse ethanol because this agent reduces the symptoms of depression. In the current study, we aimed to investigate the NMDA/nitric oxide/cGMP pathway in the antidepressant-like effect of ethanol in an animal model of behavioral despair. Animals were subjected to locomotor activity in an open-field test separately, followed by a forced swimming test. During the forced swimming test (FST), ethanol (2 and 2.5 g/kg) significantly decreased the immobility time without altering the locomotor activity of animals. The antidepressant-like effect of ethanol (2.5 g/kg) was reversed by co-administration of N-methyl-D-aspartate (NMDA, 75 mg/kg), L-arginine (750 mg/kg), or sildenafil (5 mg/kg). In contrast, co-administration of MK-801 (0.05 mg/kg), ketamine (1 mg/kg), and ifenprodil (0.5 mg/kg) as antagonists of NMDAR, and NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), 7-nitroindazole (7-NI, 30 mg/kg), and methylene blue (10 mg/kg) as inhibitors of nitric oxide synthase (NOS), or 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (20 mg/kg), a nitric oxide/cyclic-guanosine monophosphate (NO-cGMP) inhibitor, with a subeffective dose of ethanol (1.5 g/kg), significantly decreased the immobility time in the FST. Furthermore, injection of ethanol 2.5 g/kg alone or 1.5 g/kg with a 7-NI subeffective dose, significantly decreased the nitrite levels in the hippocampus and prefrontal cortex. Hence, it is concluded that blockade of NMDA receptors and the nitric oxide/cyclic-guanosine monophosphate (NO-cGMP) pathway might be involved in the antidepressant-like effect of ethanol in mice.
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http://dx.doi.org/10.1016/j.alcohol.2021.01.005DOI Listing
May 2021

Licofelone, a dual cyclooxygenase/5-lipoxygenase inhibitor, reverses endotoxin-induced impaired atrial chronotropic responsiveness to cholinergic stimulation in rats.

Eur J Pharmacol 2020 Nov 16;887:173569. Epub 2020 Sep 16.

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:

Evidence show that endotoxemia is linked with tachycardia. The exact mechanism of tachycardia is not well-understood, but it seems that impaired cardiac chronotropic responsiveness to cholinergic stimulation plays a role in this phenomenon. The aim of this experiment was to study the effect of licofelone as a dual cyclooxygenase (COX)/5-lipoxygenase (5-LOX) inhibitor in modulation of atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats, compared with hydrocortisone and indomethacin in in vitro and in vivo studies. Rats were injected by either of lipopolysaccharide (LPS) or saline. The isolated atria were incubated with licofelone, hydrocortisone, or indomethacin in an organ bath set up. In a separate experiment, rats were injected with licofelone, hydrocortisone, or indomethacin prior to isolation of the atria. Then, in both experiments, chronotropic responsiveness to cumulative concentrations of carbacholine in organ bath was recorded. LPS injection decreased the chronotropic responsiveness to cholinergic stimulation in both in vitro and in vivo experiments, significantly (P < 0.0001), while either incubation of isolated atria with licofelone (a dual COX/5-LOX inhibitor) or injection of licofelone to animals could reverse it, completely (P < 0.01). Hydrocortisone (phospholipase A and COX-2 inhibitor) in vitro and in vivo (P < 0.001, P < 0.05, respectively) as well as indomethacin (COX inhibitor) in vitro and in vivo (P < 0.05, P < 0.01, respectively) exerted some lesser effects. Our data revealed that in endotoxemic rats, chronotropic hyporesponsiveness to cholinergic stimulation was modulated by the dual COX/5-LOX inhibitor licofelone, and this effect is comparable with hydrocortisone and indomethacin.
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http://dx.doi.org/10.1016/j.ejphar.2020.173569DOI Listing
November 2020

A review on qualifications and cost effectiveness of induced pluripotent stem cells (IPSCs)-induced cardiomyocytes in drug screening tests.

Arch Physiol Biochem 2020 Aug 12:1-12. Epub 2020 Aug 12.

Department of Biochemistry and Molecular Biophysics, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.

Human induced pluripotent stem cells (hIPSCs) have initiated a higher degree of successes in disease modelling, preclinical evaluation of drug therapy and pharmaco-toxicological testing. Since the discovery of iPSCs in 2006, many advanced techniques have been introduced to differentiate iPSCs to cardiomyocytes, which have been progressively improved. The disease models from iPSC-induced cardiomyocytes (iPSC-CM) have been successfully helping to study a variety of cardiac diseases such as long QT syndrome, drug-induced long QT, different cardiomyopathies related to mutations in mitochondria or desmosomal proteins and other rare genetic diseases. IPSC-CMs have also been used to screen the role of chemicals in cardiovascular drug discovery and individualisation of drug dosages. In this review, the quality of current procedures for characterisation and maturation of iPSC-CM lines will be discussed. Also, we will focus on time efficiency and cost of standard differentiation methods after reprogramming.
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http://dx.doi.org/10.1080/13813455.2020.1802600DOI Listing
August 2020

Hepatoprotective effects of phosphatidylserine liposomes on carbon tetrachloride-induced hepatotoxicity in rats.

J Cell Biochem 2019 Feb 15. Epub 2019 Feb 15.

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

It has been proposed carbon tetrachloride (CCl ) intoxication due to the production of free radicals and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) overload results hepatotoxicity. Phosphatidylserine (PS) has shown antioxidant activity in numerous studies. Therefore, this study was aimed to investigate the effects of PS liposomes treatment against the CCl -induced hepatotoxicity in a rat model. Male Wistar rats were treated with PS (10 mg/kg, oral) or phosphatidylcholine liposomes (PC) (10 mg/kg, oral) for 3 days before CCl (2 ml/kg; ip once on the third day) injection. The serum level of ALT, AST, and ALP were measured. Also, antioxidant assays were performed. Administration of PS with CCl significantly inhibited alterations in the serum levels of AST, ALP ( P < 0.01), and ALT ( P < 0.001) compared with control group. Furthermore, measurement of malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) levels indicated that PS significantly reduced reactive oxygen species. The results of the present study showed the hepatoprotective effects of PS against CCl -induced hepatotoxicity in rats.
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http://dx.doi.org/10.1002/jcb.28464DOI Listing
February 2019

Cardiac chronotropic hypo-responsiveness and atrial fibrosis in rats chronically treated with lithium.

Auton Neurosci 2019 01 7;216:46-50. Epub 2018 Sep 7.

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

Lithium is a widely used mood-stabilizing agent; however, it causes a variety of cardiovascular side effects including sinus node dysfunction. In this study we explored the potential adverse effects of lithium on cardiac chronotropic responsiveness, atrial tissue histology and gene expression in rats that were chronically treated with therapeutic doses of lithium. Male Wistar albino rats were given lithium chloride (2.5 g/kg) orally for 2 or 3 months. Following treatment, the atria were isolated and spontaneously beating rate and chronotropic responsiveness to β-adrenergic stimulation was evaluated in an organ bath. Development of cardiac fibrosis was examined by histological methods. The expression of atrial Col1a1 (collagen I, alpha 1) and β-arrestin2 was also assessed using quantitative RT-PCR. Treatment with lithium induced a significant hypo-responsiveness to adrenergic stimulation (P < 0.001) and caused fibrosis in the atrial tissue of treated rats. In addition, the expression of atrial Col1a1 mRNA was significantly increased in atrial tissues of lithium-treated animals, while β-arrestin2 mRNA expression did not show a significant difference compared with control animals. Altogether, these findings indicate that cardiac chronotropic hypo responsiveness and associated cardiac fibrosis are side effects of chronic lithium treatment. Moreover, it seems that lithium treatment does not influence β-arrestin2 mRNA expression.
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http://dx.doi.org/10.1016/j.autneu.2018.09.002DOI Listing
January 2019

The role of nitric oxide-cGMP pathway in selegiline antidepressant-like effect in the mice forced swim test.

Pharmacol Rep 2018 Sep 13;70(5):1015-1022. Epub 2018 May 13.

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

Background: Considering the pivotal role of nitric oxide (NO) pathway in depressive disorders, the aim of the present study was to investigate the antidepressant-like effect of selegiline in mice forced swimming test (FST), and possible involvement of NO-cyclic guanosine monophosphate (cGMP) pathway in this action.

Methods: After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. All drugs were given intraperitoneally (ip).

Results: Selegiline (10 mg/kg) decreased the immobility time in the FST similar to fluoxetine (20 mg/kg). Pretreatment with l-arginine (NO precursor, 750 mg/kg) or sildenafil (a phosphodiesterase 5 inhibitor, 5 mg/kg) significantly reversed the selegiline anti-immobility effect. Sub-effective dose of selegiline (1 mg/kg) showed a synergistic antidepressant effect with NG-nitro-l-arginine methyl ester (L-NAME, inhibitor of NO synthase, 10 mg/kg) or 7-nitroindazole (specific neuronal NO synthase inhibitor, 30 mg/kg), but not with aminoguanidine (specific inducible NO synthase inhibitor, 50 mg/kg). Pretreatment of mice with methylene blue (an inhibitor of NO synthase and soluble guanylyl cyclase, 10 mg/kg) significantly produced a synergistic response with the sub-effective dose of selegiline. Neither of the drugs changed the locomotor activity. Also, hippocampal and prefrontal cortex (PFC) nitrite content was significantly lower in selegiline-injected mice compared to saline-administrated mice. Also, co-injection of 7-nitroindazole with selegiline produced a significant reduction in hippocampal or PFC nitrite contents.

Conclusions: It is concluded that selegiline possesses antidepressant-like effect in mice FST through inhibition of l-arginine-NO-cyclic guanosine monophosphate pathway.
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http://dx.doi.org/10.1016/j.pharep.2018.05.004DOI Listing
September 2018

The role of nitric oxide-cGMP pathway in selegiline antidepressant-like effect in the mice forced swim test.

Pharmacol Rep 2018 Oct 13;70(5):1015-1022. Epub 2018 May 13.

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

Background: Considering the pivotal role of nitric oxide (NO) pathway in depressive disorders, the aim of the present study was to investigate the antidepressant-like effect of selegiline in mice forced swimming test (FST), and possible involvement of NO-cyclic guanosine monophosphate (cGMP) pathway in this action.

Methods: After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4min was evaluated. All drugs were given intraperitoneally (ip).

Results: Selegiline (10mg/kg) decreased the immobility time in the FST similar to fluoxetine (20mg/kg). Pretreatment with l-arginine (NO precursor, 750mg/kg) or sildenafil (a phosphodiesterase 5 inhibitor, 5mg/kg) significantly reversed the selegiline anti-immobility effect. Sub-effective dose of selegiline (1mg/kg) showed a synergistic antidepressant effect with NG-nitro-l-arginine methyl ester (L-NAME, inhibitor of NO synthase, 10mg/kg) or 7-nitroindazole (specific neuronal NO synthase inhibitor, 30mg/kg), but not with aminoguanidine (specific inducible NO synthase inhibitor, 50mg/kg). Pretreatment of mice with methylene blue (an inhibitor of NO synthase and soluble guanylyl cyclase, 10mg/kg) significantly produced a synergistic response with the sub-effective dose of selegiline. Neither of the drugs changed the locomotor activity. Also, hippocampal and prefrontal cortex (PFC) nitrite content was significantly lower in selegiline-injected mice compared to saline-administrated mice. Also, co-injection of 7-nitroindazole with selegiline produced a significant reduction in hippocampal or PFC nitrite contents.

Conclusions: It is concluded that selegiline possesses antidepressant-like effect in mice FST through inhibition of l-arginine-NO-cyclic guanosine monophosphate pathway.
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http://dx.doi.org/10.1016/j.pharep.2018.05.004DOI Listing
October 2018

Nitric oxide involvement in additive antidepressant-like effect of agmatine and lithium in mice forced swim test.

Psychiatry Res 2018 08 15;266:262-268. Epub 2018 Mar 15.

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

Lithium is still the main agent in the management of mood disorders such as depression. Likewise, agmatine protects the central nervous system (CNS) against depression. The aim of the present study was to examine the possible additive antidepressant-like effect of agmatine and lithium in mice forced swim test (FST) as well as exploration of the probable involvement of nitric oxide (NO) pathway in this response. Results showed that pretreatment with a subeffective dose of agmatine (0.01 mg/kg) augmented the antidepressant-like effect of lithium subeffective dose (3 mg/kg) (P < 0.001). L-NG-nitroarginine methyl ester (L-NAME, nonspecific nitric oxide synthase [NOS] inhibitor) at doses of 10 and 30 mg/kg, and 7-nitroindazole (7-NI, neuronal NOS inhibitor) at doses of 15 and 30 mg/kg potentiated the antidepressant-like effect of the subeffective combination of lithium (3 mg/kg) and agmatine (0.001 mg/kg) (P < 0.001, P < 0.01, respectively). However, various doses of aminoguanidine (25 and 50 mg/kg, inducible NOS inhibitor) failed to alter the immobility time of the same combination (P > 0.05). Moreover, pretreatment with subeffective doses of L-arginine (substrate for NOS, 300 and 750 mg/kg) reversed the augmenting antidepressant-like effect of agmatine (0.01 mg/kg) on lithium (3 mg/kg) (P < 0.001). Our results revealed that agmatine enhances the antidepressant-like effects of lithium and the NO pathway might mediate this phenomenon. In addition, constitutive NOS plays a dramatic role in this response.
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http://dx.doi.org/10.1016/j.psychres.2018.03.010DOI Listing
August 2018

Involvement of IL-1β and IL-6 in antiarrhythmic properties of atorvastatin in ouabain-induced arrhythmia in rats.

Immunopharmacol Immunotoxicol 2018 Jun 28;40(3):256-261. Epub 2018 Feb 28.

e Razi Drug Research Center , Iran University of Medical Sciences , Tehran , Iran.

Purpose: Evidence show that statins possess wide beneficial cardioprotective and anti-inflammatory effects; therefore, in the present experiment, we investigated the antiarrhythmic properties of atorvastatin in ouabain-induced arrhythmia in isolated rat atria and the role of several inflammatory cytokines in this effect.

Materials And Methods: Male rats were pretreated with either of atorvastatin (10 mg/kg) or vehicle, orally once daily for 6 weeks. After induction of anesthesia, we isolated the atria and after incubation with ouabain, time of onset of arrhythmia and asystole as well as atrial beating rate and contractile force were recorded. We also measured the atrial levels of IL-1β, IL-6, and TNF-α after the injection of ouabain to animals.

Results: Pretreatment with atorvastatin significantly delayed the onset of arrhythmia and asystole compared with vehicle-treated group (p < .01, p < .001, respectively). Incubation of ouabain boosted both atrial beating rate and contractile force in vehicle-treated group (p < .05), while these responses in atorvastatin-treated group were not significant (p > .05). Injection of ouabain elevated the atrial levels of IL-1β, IL-6, and TNF-α, while pretreatment of animals with atorvastatin could reverse the ouabain-induced increase in atrial IL-1β and IL-6 (p < .01 and p < .05, respectively).

Conclusions: It is concluded that observed antiarrhythmic effects of atorvastatin might be attributed to modulation of some inflammatory cytokines, at least IL-1β and IL-6.
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http://dx.doi.org/10.1080/08923973.2018.1440592DOI Listing
June 2018

Cromakalim, a Potassium Channel Opener, Ameliorates the Organophosphate and Carbamate-Induced Seizure in Mice.

Acta Med Iran 2018 Jan;56(1):14-20

Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. AND Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Organophosphates (OPs) and carbamates are acetylcholine esterase inhibitors (AChEIs), which can cause seizure and lethality. Anticonvulsant properties of potassium channel openers including cromakalim have been determined in previous studies. In the present experiment, the possible effect of cromakalim on the convulsion and death induced by OPs and carbamates was studied in mice. Dichlorvos (an OP, 50 mg/kg) and physostigmine (a carbamate, 2 mg/kg) were used to induce seizure in animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg was injected 30 min before dichlorvos and physostigmine, and 5 min before glibenclamide (a potassium channel blocker, 1 mg/kg) administration. All injections were performed intraperitoneally. After drugs administration, the onset of convulsion, death, the severity of seizure, and rate of mortality were investigated. Results revealed that both dichlorvos and physostigmine induced seizure activity and lethality in 100% of the animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg significantly increased the latency of both seizure and death (P<0.05). Also, cromakalim decreased the mortality rate induced by dichlorvos and physostigmine (P<0.05). On the other hand, glibenclamide blocked all aspects of the anticonvulsant effect of cromakalim (P<0.05). This study revealed for the first time that cromakalim (a KATP channel opener) diminishes the seizure and death induced by dichlorvos and physostigmine in mice, and introduces a new aspect to manage the patients who suffer from OPs/carbamates-induced seizure.
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January 2018

The potassium channel blocker, dalfampridine diminishes ouabain-induced arrhythmia in isolated rat atria.

Arch Physiol Biochem 2019 Feb 1;125(1):25-29. Epub 2018 Feb 1.

e Razi Drug Research Center , Iran University of Medical Sciences , Tehran , Iran.

The aim of the present experiment was to investigate the possible antiarrhythmic effects of dalfampridine in ouabain-induced arrhythmia in rats. Twenty-four male rats including the control and dalfampridine-incubated (100 µM to 10 mM) ouabain-stimulated (40 µM) groups were used. After induction of anesthesia, the atria were isolated and the time of onset of arrhythmia and asystole were recorded. The contractile force of atria was also measured. Dalfampridine at concentration of 1 mM significantly postponed the onset of arrhythmia and asystole compared to control group (p ≤ .05). Ouabain significantly increased the atrial beating rate in control group (p ≤ .05), while pretreatment of isolated atria with dalfampridine reversed this effect. Incubation of isolated atria with ouabain did not alter the contractile force in both control- and dalfampridine-treated groups (p > .05). It is concluded that dalfampridine might possess antiarrhythmic properties in reducing the atrial arrhythmias.
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http://dx.doi.org/10.1080/13813455.2018.1430158DOI Listing
February 2019

Evaluation of propylene glycol nanoliposomes containing curcumin on burn wound model in rat: biocompatibility, wound healing, and anti-bacterial effects.

Drug Deliv Transl Res 2017 10;7(5):654-663

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

Curcumin is an effective wound healing agent in burn therapy, but due to its low bioavailability, it is required to be formulated for topical therapy. Liposomal nanocarriers are developed as stable and efficient dermal delivery systems. In this study, we prepared curcumin-propylene glycol liposomes (Cur-PgL) to treat animals subjected to second degree burns. The characterization tests confirmed the production of monodisperse nanoliposomes of average size of about 145 nm with high entrapment efficiency percentage and a sustained release behavior. TEM analysis of nanocarriers showed no aggregation in long time storage up to 60 days. The biocompatibility of the Cur-PgL formulation was evaluated by ISO standards. We found that Cur-PgL 0.3% was the effective dose in injured rats without any side effects on intact skin. The cytotoxicity of the Cur-PgL 0.3% nanovesicles was also assessed on human dermal fibroblast (HDF) cells. The results showed no detectable cytotoxicity, but considerable cytotoxicity was observed in higher concentration of 1.5 and 3 mg/ml of free and PgL forms of curcumin. Eight days of application of Cur-PgL on burned rats resulted in a significant (P<0.001) recovery of wound repair parameters, and after 18 days, wound contraction occurred significantly (P < 0.001) compared to the other groups. The antibacterial activity of the Cur-PgL formulation was found to be similar to the silver sulfadiazine (SSD) cream 1% regarding the inhibition of the bacterial growth. In conclusion, the low dose of curcumin nanoliposomal formulation efficiently improved injuries and infections of burn wounds and it can be considered in burn therapy.
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http://dx.doi.org/10.1007/s13346-017-0405-4DOI Listing
October 2017

Possible involvement of ATP-sensitive potassium channels in the antidepressant-like effects of gabapentin in mouse forced swimming test.

Can J Physiol Pharmacol 2017 Jul 29;95(7):795-802. Epub 2017 Jan 29.

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

Gabapentin as an anticonvulsant drug also has beneficial effects in treatment of depression. Previously, we showed that acute administration of gabapentin produced an antidepressant-like effect in the mouse forced swimming test (FST) by a mechanism that involves the inhibition of nitric oxide (NO). Considering the involvement of NO in adenosine triphosphate (ATP)-sensitive potassium channels (K), in the present study we investigated the involvement of K channels in antidepressant-like effect of gabapentin. Gabapentin at different doses (5-10 mg/kg) and fluoxetine (20 mg/kg) were administrated by intraperitoneal route, 60 and 30 min, respectively, before the test. To clarify the probable involvement of K channels, mice were pretreated with K channel inhibitor or opener. Gabapentin at dose 10 mg/kg significantly decreased the immobility behavior of mice similar to fluoxetine (20 mg/kg). Co-administration of subeffective dose (1 mg/kg) of glibenclamide (inhibitor of K channels) with gabapentin (3 mg/kg) showed a synergistic antidepressant-like effect. Also, subeffective dose of cromakalim (opener of K channels, 0.1 mg/kg) inhibited the antidepressant-like effect of gabapentin (10 mg/kg). None of the treatments had any impact on the locomotor movement. Our study, for the first time, revealed that antidepressant-like effect of gabapentin in mice is mediated by blocking the K channels.
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http://dx.doi.org/10.1139/cjpp-2016-0292DOI Listing
July 2017

Streptozotocin induced oxidative stress, innate immune system responses and behavioral abnormalities in male mice.

Neuroscience 2017 01 10;340:373-383. Epub 2016 Nov 10.

Zanjan Applied Pharmacology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran; Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran. Electronic address:

Recent evidence indicates the involvement of inflammatory factors and mitochondrial dysfunction in the etiology of psychiatric disorders such as anxiety and depression. To investigate the possible role of mitochondrial-induced sterile inflammation in the co-occurrence of anxiety and depression, in this study, we treated adult male mice with the intracerebroventricular (i.c.v.) infusion of a single low dose of streptozotocin (STZ, 0.2mg/mouse). Using valid and qualified behavioral tests for the assessment of depressive and anxiety-like behaviors, we showed that STZ-treated mice exhibited behaviors relevant to anxiety and depression 24h following STZ treatment. We observed that the co-occurrence of anxiety and depressive-like behaviors in animals were associated with abnormal mitochondrial function, nitric oxide overproduction and, the increased activity of cytosolic phospholipase A (cPLA) in the hippocampus. Further, STZ-treated mice had a significant upregulation of genes associated with the innate immune system such as toll-like receptors 2 and 4. Pathological evaluations showed no sign of neurodegeneration in the hippocampus of STZ-treated mice. Results of this study revealed that behavioral abnormalities provoked by STZ, as a cytotoxic agent that targets mitochondria and energy metabolism, are associated with abnormal mitochondrial activity and, consequently the initiation of innate-inflammatory responses in the hippocampus. Our findings highlight the role of mitochondria and innate immunity in the formation of sterile inflammation and behaviors relevant to anxiety and depression. Also, we have shown that STZ injection (i.c.v.) might be an animal model for depression and anxiety disorders based on sterile inflammation.
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http://dx.doi.org/10.1016/j.neuroscience.2016.11.003DOI Listing
January 2017

The effect of nitrazepam on depression and curiosity in behavioral tests in mice: The role of potassium channels.

Eur J Pharmacol 2016 Nov 9;791:369-376. Epub 2016 Sep 9.

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:

Evidence show that gamma-aminobutyric acid (GABA) receptors are involved in depression, so the aim of this study was to investigate the effect of nitrazepam as agonist of GABA receptors on depression and curiosity in male mice and the role of potassium channel in antidepressant-like response. For this purpose, we studied the antidepressant-like properties of fluoxetine, nitrazepam, glibenclamide, and cromakalim by both forced swimming test (FST) and tail suspension test (TST). Animals were injected by various doses of nitrazepam (0.05, 0.1, and 0.5mg/kg). Nitrazepam at dose of 0.5mg/kg significantly decreased the immobility time compared to control group in both FST and TST. Fluoxetine also showed such a response. Co-administration of nitrazepam (0.05mg/kg) with glibenclamide in TST (1mg/kg) and in FST (0.3, 1mg/kg) also showed antidepressant-like response. Beside, cromakalim (0.1mg/kg) could reverse the antidepressant-like effect of nitrazepam (0.5mg/kg) in both FST and TST, while cromakalim and glibenclamide alone could not change the immobility time compared to control group (P>0.05). The hole-board test revealed that nitrazepam at doses of 0.5 and 0.1mg/kg could increase the activity of the animal's head-dipping and boost the curiosity and exploration behavior of mice. The results of this study revealed that nitrazepam may possess antidepressant-like properties and this effect is dependent to potassium channels in both FST and TST.
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http://dx.doi.org/10.1016/j.ejphar.2016.09.017DOI Listing
November 2016

Possible involvement of ATP-sensitive potassium channels in the antidepressant-like effect of baclofen in mouse forced swimming test.

Pharmacol Rep 2016 Dec 22;68(6):1214-1220. Epub 2016 Jul 22.

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

Background: Previous study confirmed that the acute treatment with baclofen by inhibition of the l-arginine-nitric oxide (NO) pathway diminished the immobility behavior in the forced swimming test (FST) of mice. Considering the involvement of NO in adenosine triphosphate (ATP)-sensitive potassium channels (K), in the present study we investigated the involvement of K channels in antidepressant-like effect of baclofen in the forced swimming test (FST).

Methods: After assessment of locomotor behavior in the open-field test (OFT), FST was applied for evaluation of the antidepressant-like activity of baclofen in mice. Baclofen at different doses (0.1, 0.3, and 1mg/kg) and fluoxetine (20mg/kg) were administrated by intraperitoneal (ip) route, 30min before the FST or OFT. To clarify the probable involvement of K channels, after determination of sub-effective doses of glibenclamide as a K channel blocker and cromakalim, as an opener of these channels, they were co-administrated with the sub-effective and effective doses of baclofen, respectively.

Results: Baclofen at dose 1mg/kg significantly decreased the immobility behavior of mice similar to fluoxetine (20mg/kg). Co-administration of gelibenclamide sub-effective dose (1mg/kg) with baclofen (0.1mg/kg) showed a synergistic antidepressant-like effect in the FST. Also, sub-effective dose of cromakalim (0.1mg/kg) inhibited the antidepressant-like effect of baclofen (1mg/kg) in the FST. All aforementioned treatments had not any impact on the locomotor movement of mice in OFT.

Conclusions: Our study for the first time revealed that antidepressant-like effect of baclofen on mice is K-dependent, and baclofen seems that exert this effect by blocking the K channels.
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http://dx.doi.org/10.1016/j.pharep.2016.07.006DOI Listing
December 2016

Pharmacological evidence for the involvement of the NMDA receptor and nitric oxide pathway in the antidepressant-like effect of lamotrigine in the mouse forced swimming test.

Biomed Pharmacother 2016 Aug 14;82:713-21. Epub 2016 Jun 14.

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

Lamotrigine is an anticonvulsant agent that shows clinical antidepressant properties. The aim of the present study was to investigate the involvement of N-methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) synthesis in possible antidepressant-like effect of lamotrigine in forced swimming test (FST) in mice. Intraperitoneal administration of lamotrigine (10mg/kg) decreased the immobility time in the FST (P<0.01) without any effect on locomotor activity in the open-field test (OFT), while higher dose of lamotrigine (30mg/kg) reduced the immobility time in the FST (P<0.001) as well as the number of crossings in the OFT. Pretreatment of animals with NMDA (75mg/kg), l-arginine (750mg/kg, a substrate for nitric oxide synthase [NOS]) or sildenafil (5mg/kg, a phosphodiesterase [PDE] 5 inhibitor) reversed the antidepressant-like effect of lamotrigine (10mg/kg) in the FST. Injection of l-nitroarginine methyl ester (l-NAME, 10mg/kg, a non-specific NOS inhibitor), 7-nitroindazole (30mg/kg, a neuronal NOS inhibitor), methylene blue (20mg/kg, an inhibitor of both NOS and soluble guanylate cyclase [sGC]), or MK-801 (0.05mg/kg), ketamine (1mg/kg), and magnesium sulfate (10mg/kg) as NMDA receptor antagonists in combination with a sub-effective dose of lamotrigine (5mg/kg) diminished the immobility time of animals in the FST compared with either drug alone. None of the drugs produced significant effects on the locomotor activity in the OFT. Based on our findings, it is suggested that the antidepressant-like effect of lamotrigine might mediated through inhibition of either NMDA receptors or NO-cGMP synthesis.
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http://dx.doi.org/10.1016/j.biopha.2016.05.035DOI Listing
August 2016

Protective Effects of Lithium on Sumatriptan-Induced Memory Impairment in Mice.

Acta Med Iran 2016 Apr;54(4):226-32

Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. AND Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Lithium is a drug used for the treatment of bipolar disorder. It has several mechanisms of action, and recently it is shown that lithium can antagonize the 5-HT1B/1D serotonin receptors. Sumatriptan is a 5-HT1B/1D receptor agonist used for the treatment of cluster headaches and migraine which might cause memory impairment as a potential side effect. In this study, effects of lithium on sumatriptan-induced memory impairment have been determined in a two-trial recognition Y-maze and passive avoidance tests. Male mice weighing 25-30 g were divided into several groups randomly. In Y-maze test, effects of lithium (1,5,10,20,40,80 mg/kg) and sumatriptan (1,5,10 mg/kg) were assessed on memory acquisition, then lithium (0.1,1,10 mg/kg) and sumatriptan (1,10 mg/kg) were studied in passive avoidance test. Effects of lithium (1mg/kg) on sumatriptan (10 mg/kg)-induced memory impairment were studied in both of tests. The present study demonstrated that sumatriptan impaired memory in Y-maze and passive avoidance tests (P<0.05, P<0.01, respectively). Lithium did not show any significant effect on memory function compared to saline-treated control group in both tests (P>0.05), but significantly reversed sumatriptan-induced memory impairment in Y-maze and passive avoidance tests (P<0.001, P<0.05, respectively). It is concluded that lithium reverses the sumatriptan-induced memory impairment probably through 5-HT1B/1D receptors antagonism.
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April 2016

Involvement of Inflammatory Cytokines in Antiarrhythmic Effects of Clofibrate in Ouabain-Induced Arrhythmia in Isolated Rat Atria.

Adv Pharmacol Sci 2016 10;2016:9128018. Epub 2016 Feb 10.

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

Considering the cardioprotective and anti-inflammatory properties of clofibrate, the aim of the present experiment was to investigate the involvement of local and systemic inflammatory cytokines in possible antiarrhythmic effects of clofibrate in ouabain-induced arrhythmia in rats. Rats were orally treated with clofibrate (300 mg/kg), and ouabain (0.56 mg/kg) was administered to animals intraperitoneally. After induction of anesthesia, the atria were isolated and the onset of arrhythmia and asystole was recorded. The levels of inflammatory cytokines in atria were also measured. Clofibrate significantly postponed the onset of arrhythmia and asystole when compared to control group (P ≤ 0.05 and P ≤ 0.01, resp.). While ouabain significantly increased the atrial beating rate in control group (P ≤ 0.05), same treatment did not show similar effect in clofibrate-treated group (P > 0.05). Injection of ouabain significantly increased the atrial and systemic levels of all studied inflammatory cytokines (P ≤ 0.05). Pretreatment with clofibrate could attenuate the ouabain-induced elevation of IL-6 and TNF-α in atria (P ≤ 0.01 and P ≤ 0.05, resp.), as well as ouabain-induced increase in IL-6 in plasma (P ≤ 0.05). Based on our findings, clofibrate may possess antiarrhythmic properties through mitigating the local and systemic inflammatory factors including IL-6 and TNF-α.
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http://dx.doi.org/10.1155/2016/9128018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764719PMC
March 2016

Involvement of opioid system in antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251 after physical stress in mice.

Clin Exp Pharmacol Physiol 2016 Feb;43(2):203-12

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

Cannabinoid inverse agonists possess antidepressant-like properties, but the mechanism of this action is unknown. Numerous studies have reported the interaction between opioid and cannabinoid pathways. In this study, acute foot-shock stress was used in mice to investigate the involvement of the opioid pathway in the antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251. Stress was induced by intermittent foot-shock stimulation for 30 min. Then, using the forced swimming test (FST) and tail suspension test (TST), the immobility time was measured. Results show that the immobility time was significantly prolonged in animals subjected to foot-shock stress, compared with non-stressed controls (P < 0.01). Also, the serum corticosterone level was significantly increased after stress induction (P < 0.001). Administration of AM-251 (0.5 and 0.3 mg/kg, intraperitoneally (i.p.)), significantly decreased the immobility time of stressed mice in the FST (P < 0.001 and P < 0.01, respectively) and TST (P < 0.01 and P < 0.05, respectively). The lowest dose of AM-251 (0.1 mg/kg), naltrexone (0.3 mg/kg), and morphine (1.0 mg/kg) did not show any significant effect on stressed animals (P > 0.05). Co-administration of AM-251 with sub-effective dose of naltrexone decreased the effective dose of this cannabinoid inverse agonist, to 0.1 mg/kg (P < 0.01). On the other hand, administration of the sub-effective dose of morphine reversed the anti-immobility effect of AM-251 (0.5 mg/kg; P < 0.001). In conclusion, the present study for the first time reveals the possible role of opioid signalling in the antidepressant-like properties of AM-251 in a foot-shock stress model.
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http://dx.doi.org/10.1111/1440-1681.12518DOI Listing
February 2016

The role of PPAR-gamma receptor in pruritus.

Eur J Pharmacol 2015 Sep 6;762:322-5. Epub 2015 Jun 6.

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:

Recent studies have clarified the novel mediators and neuronal pathways involved in itch transmission, which might result in introduction of new therapies for management of pruritus in the near future. Involvement of peroxisome proliferator-activated receptor (PPAR) signaling in the pathogenesis of skin diseases was suggested in recent experiments. PPAR-γ agonists, thiazolidinediones, which are used in the treatment of diabetes mellitus, have been recently shown to diminish pruritus not only in animal models, but also in patients suffering from psoriasis; nevertheless, the role of PPAR-γ receptors in the pruritus is not well understood. In this perspective, a brief overview on the function of PPAR signaling in the pathogenesis of skin disorders as well as the involvement of PPAR-γ impact on pruritus is argued. Detecting the relationship between PPAR-γ signaling and itching could lead to the emergence of novel therapies for management of pruritus in a wide range of dermatological and systemic disorders.
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http://dx.doi.org/10.1016/j.ejphar.2015.06.009DOI Listing
September 2015

Mesenteric artery responsiveness to acetylcholine and phenylephrine in cirrhotic rats challenged with endotoxin: the role of TLR4.

Can J Physiol Pharmacol 2015 Jun 5;93(6):475-83. Epub 2015 Mar 5.

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

Cirrhosis is associated with vascular dysfunction and endotoxemia. These experiments were designed to investigate the hypothesis that the administration of a low-dose of lipopolysaccharide (LPS) worsens vascular dysfunction in rats subjected to bile-duct ligation (BDL), and to determine whether LPS initiates changes in vascular Toll-like receptor 4 (TLR4) expression. Four weeks after BDL, the animals were given an intraperitoneal injection of either saline or LPS (1.0 mg/kg body mass). Three hours later, the superior mesenteric artery was isolated, perfused, and then subjected to the vasoconstriction and vasodilatation effects of phenylephrine and acetylcholine, respectively. Our results show that phenylephrine-induced vasoconstriction decreased in the cirrhotic vascular bed (BDL rats) compared with the vascular bed of the sham-operated animals, and that the LPS injections in the cirrhotic (BDL) rats worsened this response. LPS injection administered to the sham-operated animals had no such effect. On the other hand, both the BDL procedure and the LPS injection increased acetylcholine-induced vasorelaxation, but LPS administration to the BDL rats had no effect on this response. The mRNA levels of TLR4 did not change, but immunohistochemical studies showed that TLR4 localization switched from the endothelium to vascular smooth muscle cells following chronic BDL. In conclusion, acute endotoxemia in cirrhotic rats is associated with hyporesponsiveness to phenylephrine and tolerance to the effects of acetylcholine. Altered localization of TLR4 may be responsible for these effects.
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http://dx.doi.org/10.1139/cjpp-2014-0515DOI Listing
June 2015

Prostaglandin F₂α modulates atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats.

Eur J Pharmacol 2015 Feb 18;748:149-56. Epub 2014 Oct 18.

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

Endotoxemia induces various physiological adaptive responses such as tachycardia. There is evidence to show that inflammatory tachycardia might be linked to a direct action of prostanoids on the cardiac pacemaker cells. Recent reports have indicated that systemic inflammation may uncouple of cardiac pacemaker from cholinergic neural control in experimental animals; however, the exact mechanism of this phenomenon is uncertain. This study was aimed to explore the hypothesis that prostanoids modulate atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats. Male albino rats were given intraperitoneal injection of either saline or lipopolysaccharide (LPS, 1 mg/kg). 3 h after saline or LPS injection, the atria were isolated and chronotropic responsiveness to cholinergic stimulation was evaluated in an organ bath. The expression of atrial cyclooxygenases (COX)-1, COX-2 and COX-3 mRNA was assessed by quantitative real-time RT-PCR and cytosocalcium-dependent phospholipase A₂ (cPLA₂) activity was measured in the atria. The expression of atrial COX-2 mRNA and cPLA₂ activity increased significantly in endotoxemic atria (P<0.05). Incubation with prostaglandin F₂α (PGF₂α, 100 pM) could significantly decrease chronotropic response to cholinergic stimulation in vitro. Likewise, LPS injection could induce a significant hyporesponsiveness to cholinergic stimulation, and incubation of isolated atria with either indomethacin (5 µM) or AL-8810 (a PGF₂α antagonist, 10 µM) could reverse it (P<0.01, P<0.05, respectively), while SQ29548 (a thromboxane A₂ antagonist, 10 nM) was failed (P>0.05). Our data showed that PGF₂α may contribute to the atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats.
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http://dx.doi.org/10.1016/j.ejphar.2014.10.019DOI Listing
February 2015

Teratogenic effects of coadministration of fluoxetine and olanzapine on rat fetuses.

Adv Pharmacol Sci 2014 15;2014:132034. Epub 2014 Jan 15.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Pour Sina Street, Qods Street, Keshavarz Boulevard, Tehran 1417613151, Iran.

Objective. Depression during pregnancy is a relatively common problem. Since little is known about the teratogenic effects of concomitant administration of fluoxetine and olanzapine during the organogenesis period, the aim of the present study was to evaluate the teratogenic effects of coadministration of fluoxetine and olanzapine on rat fetuses. Method. Forty-two pregnant rats were divided into seven groups, randomly. The first group received 0.5 mL of normal saline as the control. The second and third groups received fluoxetine at doses of 9 mg/kg and 18 mg/kg, respectively. Olanzapine was injected at 3 mg/kg and 6 mg/kg to the fourth and fifth groups, respectively. The sixth group received 9 mg/kg fluoxetine and 3 mg/kg olanzapine. Finally, the seventh group was administrated with fluoxetine and olanzapine at 18 mg/kg and 6 mg/kg, respectively. Drugs were injected intraperitoneally between day eight and day 15 of the pregnancy. On the 17th day of pregnancy, the fetuses were removed and micro-/macroscopically studied. Results. Fetuses of rats receiving high doses of these drugs showed a significant rate of cleft palate development, premature eyelid opening and torsion anomalies, compared to the control group (P ≤ 0.01). It is concluded that these drugs can lead to teratogenicity, so their concomitant use during pregnancy should be avoided, or if necessary their doses must be decreased.
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http://dx.doi.org/10.1155/2014/132034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914285PMC
February 2014

The Study of Analgesic Effects of Leonurus cardiaca L. in Mice by Formalin, Tail Flick and Hot Plate Tests.

Int Sch Res Notices 2014 1;2014:687697. Epub 2014 Sep 1.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran.

Leonurus cardiaca, commonly known as motherwort, is a member of the Lamiaceae family. It has a number of interesting biological activities, for example, sedative and hypotensive, antioxidant, anti-inflammatory, and antimicrobial activities. The aim of the present study was to investigate the effect of alcoholic extract of aerial part of Leonurus cardiaca on nociceptive response using formalin, tail flick, and hot plate tests in mice. The acute treatment of mice with an ethanolic extract at doses of 500 and 250 mg/kg by intraperitoneal administration produced a significant antinociceptive in the first and second phases of formalin test, respectively. The hot plate and tail flick tests showed an increase in the antinociceptive effect at dose 500 mg/kg. These results suggest that Leonurus cardiaca possesses central and peripheral antinociceptive actions.
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http://dx.doi.org/10.1155/2014/687697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897125PMC
July 2016

The role of clomipramine in potentiating the teratogenic effects of caffeine in pregnant rats: a histopathological study.

ScientificWorldJournal 2013 4;2013:382434. Epub 2013 Nov 4.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Keshavarz Boulevard, Tehran 1417613151, Iran.

Since little is known about the teratogenic effects of clomipramine used concurrently with caffeine during the organogenesis period, the aim of this study was to test the teratogenic effects of a coadministration of caffeine and clomipramine on rat fetuses. We divided 42 pregnant rats into seven groups, randomly. The first group (control) received 0.5 mL of normal saline. Clomipramine was injected at 40 mg/kg and 80 mg/kg to the second and third groups, respectively. The fourth and fifth groups received caffeine in doses of 60 mg/kg and 120 mg/kg, respectively. The sixth group received a combination of 40 mg/kg clomipramine and 60 mg/kg caffeine, and the seventh group was given clomipramine and caffeine at 80 mg/kg and 120 mg/kg, respectively. The fetuses were removed on the 17th day of pregnancy and studied in terms of microscopic and macroscopic morphological features. Fetuses of rats receiving high doses of caffeine or combinations of caffeine and clomipramine showed a significant rate of cleft palate development, open eyelids, mortality, torsion anomalies, shrinkage of skin, and subcutaneous haemorrhage (P ≤ 0.001). This study concludes that caffeine in high doses or the simultaneous administration of caffeine and clomipramine leads to teratogenicity.
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http://dx.doi.org/10.1155/2013/382434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835609PMC
June 2014