Publications by authors named "Kiarash Riazi"

33 Publications

Risk stratification of patients with nonalcoholic fatty liver disease using a case identification pathway in primary care: a cross-sectional study.

CMAJ Open 2020 Apr-Jun;8(2):E370-E376. Epub 2020 May 15.

Division of Gastroenterology and Hepatology (Shaheen, Riazi, Kaplan, Burak, Swain), Department of Medicine, University of Calgary; EFW Radiology group (Medellin, Bhayana, Park); Alberta Health Services (Jiang, Schaufert); Community Primary Care, Alberta Health Services (Sargious), Calgary, Alta.

Background: Identification of patients with nonalcoholic fatty liver disease (NAFLD) with advanced liver fibrosis in primary care remains an unmet need. Our primary objective was to implement a pathway driven by shear wave elastography (SWE) to facilitate risk stratification of patients with NAFLD within primary care and evaluate whether SWE assessment can reduce referrals of patients with NAFLD at low risk for fibrosis to hepatology.

Methods: A multidisciplinary NAFLD clinical care pathway was codeveloped by hepatologists, radiologists and primary care physicians in Calgary to provide access to SWE-based screening of patients with NAFLD risk factors in primary care. The study outcome measures were estimated NAFLD-related referrals to the hepatology service in Calgary after implementation of the NAFLD pathway and characteristics of patients with NAFLD at risk for advanced fibrosis. The NAFLD pathway was implemented in January 2018 and was made available to all primary care physicians in the Calgary Health Zone. Patients with NAFLD who had liver stiffness (SWE value ≥ 8.0 kPa) or an inconclusive assessment were referred to hepatology. A serum liver fibrosis score was also measured with the fibrosis-4 (FIB-4) index, and performance of an FIB-4 index score of 1.30 or greater to risk stratify patients with NAFLD was evaluated. Demographic, clinical and laboratory characteristics of study groups were compared.

Results: Between March and October 2018, 2084 patients with suspected NAFLD were evaluated. Nonalcoholic fatty liver disease was confirmed by ultrasonography in 1958 (94.1%). A majority of the cohort had elevated liver enzyme values (1028 [52.5%]) and obesity (body mass index ≥ 30) (1063/1764 [60.3%]). Most patients with NAFLD (1791 [91.5%]) had an SWE value less than 8.0 kPa and were not referred to hepatology. Sixty-seven patients (3.4%) had an SWE value of 8.0 kPa or more, and 100 (5.1%) had an inconclusive SWE; these patients were referred to hepatology. Using an FIB-4 index score cut-off of 1.30 would have led to hepatology referral of 396/1251 patients (31.6%).

Interpretation: Implementation of a primary care-accessible SWE pathway for patients with NAFLD facilitated fibrosis risk stratification and greatly reduced hepatology referrals. Using the FIB-4 index score alone would led to higher rates of referral of patients with NAFLD.
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http://dx.doi.org/10.9778/cmajo.20200009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239637PMC
February 2021

Dietary Patterns and Components in Nonalcoholic Fatty Liver Disease (NAFLD): What Key Messages Can Health Care Providers Offer?

Nutrients 2019 Nov 26;11(12). Epub 2019 Nov 26.

Department of Medicine, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, AB T2N 4Z6, Canada.

Nonalcoholic fatty liver disease (NAFLD) is a rising epidemic worldwide and will be the leading cause of cirrhosis, hepatocellular carcinoma, and liver transplant within the next decade. NAFLD is considered as the hepatic manifestation of metabolic syndrome. Behaviors, such as a sedentary lifestyle and consuming a Western diet, have led to substantial challenges in managing NAFLD patients. With no curative pharmaceutical therapies, lifestyle modifications, including dietary changes and exercise, that ultimately lead to weight loss remain the only effective therapy for NAFLD. Multiple diets, including low-carbohydrate, low-fat, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean (MD) diets, have been evaluated. NAFLD patients have shown better outcomes with a modified diet, such as the MD diet, where patients are encouraged to increase the consumption of fruits and vegetables, whole grains, and olive oil. It is increasingly clear that a personalized approach to managing NAFLD patients, based on their preferences and needs, should be implemented. In our review, we cover NAFLD management, with a specific focus on dietary patterns and their components. We emphasize the successful approaches highlighted in recent studies to provide recommendations that health care providers could apply in managing their NAFLD patients.
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http://dx.doi.org/10.3390/nu11122878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950597PMC
November 2019

Modulation of the anticonvulsant effect of swim stress by agmatine.

Epilepsy Behav 2018 01 22;78:142-148. Epub 2017 Dec 22.

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

Agmatine is an endogenous l-arginine metabolite with neuroprotective effects in the stress-response system. It exerts anticonvulsant effects against several seizure paradigms. Swim stress induces an anticonvulsant effect by activation of endogenous antiseizure mechanisms. In this study, we investigated the interaction of agmatine with the anticonvulsant effect of swim stress in mice on pentylenetetrazole (PTZ)-induced seizure threshold. Then we studied the involvement of nitric oxide (NO) pathway and endogenous opioid system in that interaction. Swim stress induced an anticonvulsant effect on PTZ seizures which was opioid-independent in shorter than 1-min swim durations and opioid-dependent with longer swims, as it was completely reversed by pretreatment with naltrexone (NTX) (10mg/kg), an opioid receptor antagonist. Agmatine significantly enhanced the anticonvulsant effect of opioid-independent shorter swim stress, in which a combination of subthreshold swim stress duration (45s) and subeffective dose of agmatine (1mg/kg) revealed a significantly higher seizure threshold compared with either one. This effect was significantly reversed by NO synthase inhibitor N-nitro-l-arginine (L-NAME (Nω-Nitro-L-arginine methyl ester), 5mg/kg), suggesting an NO-dependent mechanism, and was unaffected by NTX (10mg/kg), proving little role for endogenous opioids in the interaction. Our data suggest that pretreatment of animals with agmatine acts additively with short swim stress to exert anticonvulsant responses, possibly by mediating NO pathway.
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http://dx.doi.org/10.1016/j.yebeh.2017.11.005DOI Listing
January 2018

Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation.

J Neurosci 2015 Mar;35(12):4942-52

Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Peripheral inflammatory diseases are often associated with behavioral comorbidities including anxiety, depression, and cognitive dysfunction, but the mechanism for these is not well understood. Changes in the neuronal and synaptic functions associated with neuroinflammation may underlie these behavioral abnormalities. We have used a model of colonic inflammation induced by 2,4,6-trinitrobenzenesulfonic acid in Sprague Dawley rats to identify inflammation-induced changes in hippocampal synaptic transmission. Hippocampal slices obtained 4 d after the induction of inflammation revealed enhanced Schaffer collateral-induced excitatory field potentials in CA1 stratum radiatum. This was associated with larger-amplitude mEPSCs, but unchanged mEPSC frequencies and paired-pulse ratios, suggesting altered postsynaptic effects. Both AMPA- and NMDA-mediated synaptic currents were enhanced, and analysis of AMPA-mediated currents revealed increased contributions of GluR2-lacking receptors. In keeping with this, both transcripts and protein levels of the GluR2 subunit were reduced in hippocampus. Both long-term potentiation (LTP) and depression (LTD) were significantly reduced in hippocampal slices taken from inflamed animals. Chronic administration of the microglial/macrophage activation inhibitor minocycline to the inflamed animals both lowered the level of the cytokine tumor necrosis factor α in the hippocampus and completely abolished the effect of peripheral inflammation on the field potentials and synaptic plasticity (LTP and LTD). Our results reveal profound synaptic changes caused by a mirror microglia-mediated inflammatory response in hippocampus during peripheral organ inflammation. These synaptic changes may underlie the behavioral comorbidities seen in patients.
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http://dx.doi.org/10.1523/JNEUROSCI.4485-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705378PMC
March 2015

P-selectin-mediated monocyte-cerebral endothelium adhesive interactions link peripheral organ inflammation to sickness behaviors.

J Neurosci 2013 Sep;33(37):14878-88

Immunology Research Group and Gastrointestinal Research Group, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, and Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.

Sickness behaviors, such as fatigue, mood alterations, and cognitive dysfunction, which result from changes in central neurotransmission, are prevalent in systemic inflammatory diseases and greatly impact patient quality of life. Although, microglia (resident cerebral immune cells) and cytokines (e.g., TNFα) are associated with changes in central neurotransmission, the link between peripheral organ inflammation, circulating cytokine signaling, and microglial activation remains poorly understood. Here we demonstrate, using cerebral intravital microscopy, that in response to liver inflammation, there is increased monocyte specific rolling and adhesion along cerebral endothelial cells (CECs). Peripheral TNFα-TNFR1 signaling and the adhesion molecule P-selectin are central mediators of these monocyte-CEC adhesive interactions which were found to be closely associated with microglial activation, decreased central neural excitability and sickness behavior development. Similar monocyte-CEC adhesive interactions were also observed in another mouse model of peripheral organ inflammation (i.e., 2,4-dinitrobenzene sulfonic acid-induced colitis). Our observations provide a clear link between peripheral organ inflammation and cerebral changes that impact behavior, which can potentially allow for novel therapeutic interventions in patients with systemic inflammatory diseases.
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http://dx.doi.org/10.1523/JNEUROSCI.1329-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705165PMC
September 2013

Increased excitability and molecular changes in adult rats after a febrile seizure.

Epilepsia 2013 Apr 7;54(4):e45-8. Epub 2013 Jan 7.

Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

Both early life inflammation and prolonged febrile seizures have been associated with increased excitation in the adult brain. We hypothesized this may be due in part to changes in the cation-chloride cotransporter system. Rat pups received saline or lipopolysaccharide/kainic acid (LPS/KA) resulting in inflammation, followed by a behavioral febrile seizure (FS) in approximately 50% of rats. Adult animals from the saline, inflammation, or inflammation + FS groups underwent the following: (1) in vitro electrophysiologic studies; (2) Western blotting or polymerase chain reaction; or (3) application of the Na-K-Cl cotransporter 1 (NKCC1) blocker bumetanide to determine its effect on reversing increased excitability in vitro. The inflammation and inflammation + FS groups demonstrated increased excitability in vitro and increased hippocampal protein expression of NR2B and GABAA α5 receptor subunits and mRNA expression of NKCC1. The inflammation + FS group also had decreased protein expression of GluR2 and GABAA α1 receptor subunits and mRNA and protein expression of KCC2. Bumetanide decreased in vitro 4-aminopyridine-induced inter-ictal activity in the inflammation and inflammation + FS groups. The results demonstrate early-life inflammation with or without a behavioral FS can lead to long-lasting molecular changes and increased excitability in the adult rat hippocampus, although some changes are more extensive when inflammation is accompanied by behavioral seizure activity. Bumetanide is effective in reversing increased excitability in vitro, providing evidence for a causal role for cation-chloride cotransporters and suggesting this drug may prove useful for treating epilepsy that develops after a FS.
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http://dx.doi.org/10.1111/epi.12061DOI Listing
April 2013

Cytokines and brain excitability.

Front Neuroendocrinol 2012 Jan 27;33(1):116-25. Epub 2011 Dec 27.

Hotchkiss Brain Institute, Alberta Children's Hospital Research Institute, Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Health Sciences Centre, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1.

Cytokines are molecules secreted by peripheral immune cells, microglia, astrocytes and neurons in the central nervous system. Peripheral or central inflammation is characterized by an upregulation of cytokines and their receptors in the brain. Emerging evidence indicates that pro-inflammatory cytokines modulate brain excitability. Findings from both the clinical literature and from in vivo and in vitro laboratory studies suggest that cytokines can increase seizure susceptibility and may be involved in epileptogenesis. Cellular mechanisms that underlie these effects include upregulation of excitatory glutamatergic transmission and downregulation of inhibitory GABAergic transmission.
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http://dx.doi.org/10.1016/j.yfrne.2011.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547977PMC
January 2012

Seizure susceptibility alteration through 5-HT(3) receptor: modulation by nitric oxide.

Seizure 2010 Jan 25;19(1):17-22. Epub 2009 Nov 25.

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

There is some evidence that epileptic seizures could be induced or increased by 5-hydroxytryptamine (5-HT) attenuation, while augmentation of serotonin functions within the brain (e.g. by SSRIs) has been reported to be anticonvulsant. This study was performed to determine the effect of selective 5-HT(3) channel/receptor antagonist granisetron and agonist SR57227 hydrochloride on the pentylenetetrazole (PTZ)-induced seizure threshold in mice. The possible interaction of this effect with nitrergic system was also examined using the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) and the NO precursor l-arginine. SR57227 (10mg/kg, i.p.) significantly increased the seizure threshold compared to control group, while high dose granisetron (10mg/kg, i.p.) proved proconvulsant. Co-administration of sub-effective doses of the 5-HT(3) agonist with l-NAME (5 and 60mg/kg, i.p., respectively) exerted a significant anticonvulsive effect, while sub-effective doses of granisetron (3mg/kg) was observed to have a proconvulsive action with the addition of l-arginine (75mg/kg, i.p.). Our data demonstrate that enhancement of 5-HT(3) receptor function results in as anticonvulsant effect in the PTZ-induced seizure model, and that selective antagonism at the 5-HT(3) receptor yields proconvulsive effects. Furthermore, the NO system may play a role in 5-HT(3) receptor function.
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http://dx.doi.org/10.1016/j.seizure.2009.10.006DOI Listing
January 2010

Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability.

Epilepsy Res 2010 Mar 4;89(1):34-42. Epub 2009 Oct 4.

Hotchkiss Brain Institute, Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada T2N 4N1.

Inflammation is an important factor in the pathophysiology of seizure generation and epileptogenesis. While the role of CNS inflammation is well acknowledged as an important factor in seizure pathophysiology, less is known about the role of peripheral inflammation. Systemic inflammation induces a mirror inflammatory response in the brain that might have transient or long-term effects on seizure susceptibility. The focus of our laboratory research is the study of the interaction of systemic inflammatory events with neuronal excitability and seizure susceptibility. In this paper we provide a review of our findings and discuss possible mechanisms.
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http://dx.doi.org/10.1016/j.eplepsyres.2009.09.004DOI Listing
March 2010

The interaction of sildenafil with the anticonvulsant effect of diazepam.

Eur J Pharmacol 2009 Sep 10;617(1-3):79-83. Epub 2009 Jul 10.

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

In order to assess the role of nitric oxide/cyclicGMP signaling pathway in the anticonvulsant effect of benzodiazepines, we studied the potential interaction of a phosphodiesterase type 5 inhibitor, sildenafil with the effect of diazepam on a mouse model of clonic seizures induced by intravenous infusion of GABA antagonist, pentylenetetrazole (PTZ). Administration of sildenafil (10 mg/kg; per se effective on seizure threshold) could abolish the anticonvulsive effect of diazepam, and a subeffective dose (5 mg/kg), when added to NO precursor L-arginine (50 mg/kg) could cause the same effect. Conversely, subeffective doses of diazepam (0.02 mg/kg) and NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 5 mg/kg), administered together, reversed the proconvulsive effect of sildenafil. Our findings indicate that the enhancement of NO/cGMP signaling pathway by sildenafil attenuates the anticonvulsant effect of the benzodiazepine prototype, diazepam. This suggests that the effects of facilitating GABA(A)-mediated inhibition and modulating NO pathways are additive and there might be a role for NO pathway in benzodiazepine effect against PTZ-induced seizures in mice.
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http://dx.doi.org/10.1016/j.ejphar.2009.06.061DOI Listing
September 2009

Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone.

Epilepsy Res 2009 Feb 6;83(2-3):261-4. Epub 2008 Dec 6.

Department of Pharmacology, School of Pharmacy, Medical Sciences/University of Tehran, Tehran, Iran.

Summary: The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a mouse model of clonic seizures induced by pentylenetetrazole, and whether ultra-low doses of the opioid receptor antagonist naltrexone which selectively block G(s) opioid receptors were capable of preventing the observed tolerance. The results showed that the morphine anticonvulsant effect could be subject to tolerance after repeated administration. Both the development and expression of tolerance were inhibited by ultra-low doses of naltrexone, suggesting the possible involvement of G(s)-coupled opioid receptors in the development of tolerance to the anticonvulsant effect of morphine.
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http://dx.doi.org/10.1016/j.eplepsyres.2008.10.011DOI Listing
February 2009

Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation.

Proc Natl Acad Sci U S A 2008 Nov 27;105(44):17151-6. Epub 2008 Oct 27.

Hotchkiss Brain Institute and Snyder Institute of Infection, Immunity, and Inflammation, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.

Peripheral inflammation leads to a number of centrally mediated physiological and behavioral changes. The underlying mechanisms and the signaling pathways involved in these phenomena are not yet well understood. We hypothesized that peripheral inflammation leads to increased neuronal excitability arising from a CNS immune response. We induced inflammation in the gut by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) to adult male rats. To examine the excitability of the brain in vivo, we administered pentylenetetrazole (PTZ; a GABAergic antagonist) intravenously to evoke clonic seizures. Rats treated with TNBS showed increased susceptibility to PTZ seizures that was strongly correlated with the severity and progression of intestinal inflammation. In vitro hippocampal slices from inflamed, TNBS-treated rats showed increased spontaneous interictal burst firing following application of 4-aminopyridine, indicating increased intrinsic excitability. The TNBS-treated rats exhibited a marked, reversible inflammatory response within the hippocampus, characterized by microglial activation and increases in tumor necrosis factor alpha (TNFalpha) levels. Central antagonism of TNFalpha using a monoclonal antibody or inhibition of microglial activation by i.c.v. injection of minocycline prevented the increase in seizure susceptibility. Moreover, i.c.v. infusion of TNFalpha in untreated rats for 4 days also increased seizure susceptibility and thus mimicked the changes in seizure threshold observed with intestinal inflammation. Our finding of a microglia-dependent TNFalpha-mediated increase in CNS excitability provides insight into potential mechanisms underlying the disparate neurological and behavioral changes associated with chronic inflammation.
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http://dx.doi.org/10.1073/pnas.0806682105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579393PMC
November 2008

Effect of acute and chronic photoperiod modulation on pentylenetetrazole-induced clonic seizure threshold in mice.

Epilepsy Res 2008 Nov 26;82(1):64-69. Epub 2008 Sep 26.

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

Changes in circadian rhythms have been shown to alter seizure susceptibility and anticonvulsant properties of drugs. The present study attempts to elucidate the effect of acute and chronic light/dark (LD) cycle alterations on pentylenetetrazol-induced clonic seizure threshold (CST) in male NMRI mice. The acute effect was tested by comparing the effects of abrupt 6-h phase shifts that resulted in 6-h and 18-h photoperiods, during the 24-h period before CST determination, with the controls that were maintained on 12h/12h LD cycle. In order to test the effect of chronic LD cycle alteration on CST, three groups of mice were maintained on 12h/12h, 6h/18h and 18h/6h LD cycles for 2 weeks prior to CST testing. The effect of administration of exogenous melatonin (5, 10 and 20mg/kg, i.p.) was also assessed on LD cycle related changes of CST. The results indicate that acute photoperiod change from 12h/12h to 18h/6h LD cycle lowers CST, while keeping animals under shorter photoperiod does not produce a significant effect. The pro-convulsant effect of acute increase in light period is reversed by a single injection of melatonin (10 and 20mg/kg). Animals chronically maintained on both shorter and longer photoperiods show a significant decrease in CST compared to animals under 12h/12h LD cycle. However, in both groups chronic administration of melatonin (20mg/kg) reversed the effect of LD cycle alteration on CST. In conclusion, our data demonstrate that acute increase and chronic modulation of the photoperiod increase seizure susceptibility in mice. Moreover, the pro-convulsant effect of LD cycle alteration could be reversed by exogenous melatonin administration.
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http://dx.doi.org/10.1016/j.eplepsyres.2008.07.006DOI Listing
November 2008

Role of nitric oxide in the anticonvulsive effect of progesterone.

Epilepsy Behav 2008 Nov 30;13(4):579-84. Epub 2008 Aug 30.

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

Described here is an investigation of the potential interaction of the nitric oxide signaling pathway with the anticonvulsant effects of progesterone. In ovariectomized Swiss mice, the threshold for seizures induced by intravenous infusion of pentylenetetrazole was determined after treatment with progesterone (25, 50, or 75 mg/kg, given subcutaneously 6h before seizure testing) or vehicle. Progesterone induced significant anticonvulsive activity at moderate (50 mg/kg) and high (75 mg/kg) doses. This effect of progesterone was abolished by the NO precursor compound L-arginine (200 mg/kg). Moreover, when subeffective doses of progesterone (25 mg/kg) and the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (10 mg/kg) were injected, a strong anticonvulsant effect was observed. These findings suggest a potential role for NO signaling as an anticonvulsant target in females.
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http://dx.doi.org/10.1016/j.yebeh.2008.07.011DOI Listing
November 2008

Postnatal inflammation increases seizure susceptibility in adult rats.

J Neurosci 2008 Jul;28(27):6904-13

Epilepsy and Brain Circuits Program, Hotchkiss Brain Institute, Department of Neuroscience, University of Calgary, Calgary, Alberta, Canada.

There are critical postnatal periods during which even subtle interventions can have long-lasting effects on adult physiology. We asked whether an immune challenge during early postnatal development can alter neuronal excitability and seizure susceptibility in adults. Postnatal day 14 (P14) male Sprague Dawley rats were injected with the bacterial endotoxin lipopolysaccharide (LPS), and control animals received sterile saline. Three weeks later, extracellular recordings from hippocampal slices revealed enhanced field EPSP slopes after Schaffer collateral stimulation and increased epileptiform burst-firing activity in CA1 after 4-aminopyridine application. Six to 8 weeks after postnatal LPS injection, seizure susceptibility was assessed in response to lithium-pilocarpine, kainic acid, and pentylenetetrazol. Rats treated with LPS showed significantly greater adult seizure susceptibility to all convulsants, as well as increased cytokine release and enhanced neuronal degeneration within the hippocampus after limbic seizures. These persistent increases in seizure susceptibility occurred only when LPS was given during a critical postnatal period (P7 and P14) and not before (P1) or after (P20). This early effect of LPS on adult seizures was blocked by concurrent intracerebroventricular administration of a tumor necrosis factor alpha (TNFalpha) antibody and mimicked by intracerebroventricular injection of rat recombinant TNFalpha. Postnatal LPS injection did not result in permanent changes in microglial (Iba1) activity or hippocampal cytokine [IL-1beta (interleukin-1beta) and TNFalpha] levels, but caused a slight increase in astrocyte (GFAP) numbers. These novel results indicate that a single LPS injection during a critical postnatal period causes a long-lasting increase in seizure susceptibility that is strongly dependent on TNFalpha.
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http://dx.doi.org/10.1523/JNEUROSCI.1901-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547980PMC
July 2008

The nonadrenergic noncholinergic-mediated relaxation of corpus cavernosum was impaired in chronic lithium-treated rats: improvement with l-arginine.

Eur J Pharmacol 2008 May 29;586(1-3):300-5. Epub 2008 Feb 29.

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

One-third of lithium-treated men complain from sexual dysfunction, although the exact mechanisms of which are not yet known. In this study we investigated the effect of chronic lithium (LiCl, 600 mg/l for 30 days) administration on the neurogenic relaxation of isolated rat corpus cavernosum. The corporal strips were precontracted with phenylephrine and electrical field stimulation (EFS) was applied to obtain relaxation. Relaxation to EFS was significantly (P<0.001) impaired in LiCl-treated rats. The nitric oxide (NO) synthase inhibitor Nomega-nitro-l-arginine methyl ester (l-NAME; 100 microM) inhibited the relaxation to EFS in both LiCl-treated and control rats. The NO precursor l-arginine, at per se noneffective concentration (0.1 mM), significantly (P<0.001) enhanced the EFS-induced relaxation of LiCl-treated corporal strips. The relaxation responses to the NO donor sodium nitroprusside were similar between two groups. These data demonstrate that chronic lithium treatment could impair the NO-mediated neurogenic relaxation of rat corpus cavernosum which could be prevented by l-arginine.
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http://dx.doi.org/10.1016/j.ejphar.2008.02.054DOI Listing
May 2008

Seizure susceptibility alteration following reversible cholestasis in mice: Modulation by opioids and nitric oxide.

Eur J Pharmacol 2008 Feb 23;580(3):322-8. Epub 2007 Nov 23.

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

There is an increasing body of evidence that the central nervous system is affected by cholestatic liver disorders. Cholestasis has been shown to result in a decreased seizure propensity which is believed to be mediated by an increased opioidergic tone and nitric oxide (NO) signaling pathway. In this study, we used a reversible chemically-induced cholestasis model in mice to investigate the changes in seizure susceptibility. The cholestasis was induced by intragastric administration of alpha-naphthylisothiocyanate (ANIT) (100 mg/kg) or vehicle (corn oil). The threshold to generalized clonic seizures induced by timed intravenous infusion of pentylenetetrazole (PTZ) was used as an index of seizure propensity. The role of opioid receptors and NO pathway in the changes of seizure threshold, and the responsiveness to the anticonvulsant effect of opioid agonist, morphine, during and after the resolution of cholestasis was studied in this reversible paradigm of cholestatic disease. A significant increase in cholestasis-related biochemical markers as well as in clonic seizure threshold was observed; it was maximal at day 3 after cholestasis induction and slowly decreased to normal thereafter. Seizure threshold rise was inhibited by chronic administration of the opioid antagonist naltrexone or acute administration of N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO production. Co-administration of subeffective doses of L-NAME and naltrexone showed an additive effect. Injection of an anticonvulsant dose of morphine on day 7 after cholestasis induction did not increase seizure threshold, suggestive of a downregulation of receptors even after cholestasis resolution. These data shows that ANIT-induced cholestasis leads to a reversible increased resistance to PTZ-induced seizures through an opioid/NO-mediated pathway, and is probably accompanied by downregulation of opioid receptors.
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http://dx.doi.org/10.1016/j.ejphar.2007.11.018DOI Listing
February 2008

Melatonin enhances the anticonvulsant and proconvulsant effects of morphine in mice: role for nitric oxide signaling pathway.

Epilepsy Res 2007 Jul 28;75(2-3):138-44. Epub 2007 Jun 28.

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

Melatonin has different interactions with opioids including enhancing their analgesic effect and reversal of opioid tolerance and dependence. Opioids are known to exert dose-dependent anti- and proconvulsant effects in different experimental seizure paradigms. This study investigated the effect of melatonin on biphasic modulation of seizure susceptibility by morphine, in mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. We further investigated the involvement of the nitric oxidergic pathway in this interaction, using a nitric oxide synthase inhibitor, NG-nitro-L-arginine-methyl-ester (L-NAME). Melatonin exerted anticonvulsant effect with doses as high as 40-80 mg/kg, but with a dose far bellow that amount (10 mg/kg), it potentiated both the anticonvulsant and proconvulsant effects of morphine on the PTZ-induced clonic seizures. Possible pharmacokinetic interaction of melatonin and morphine cannot be ruled out in the enhancement of two opposing effects of morphine on seizure threshold. L-NAME (1 mg/kg) reversed the anticonvulsant property of the combination of melatonin (10 mg/kg) plus morphine (0.5 mg/kg). Moreover, L-NAME (5 mg/kg) blocked the enhancing effect of melatonin (10 mg/kg) on proconvulsant activity of morphine (60 mg/kg). Our results indicate that co-administration of melatonin enhances both anti- and proconvulsant effects of morphine via a mechanism that may involve the nitric oxidergic pathway.
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http://dx.doi.org/10.1016/j.eplepsyres.2007.05.002DOI Listing
July 2007

Effect of low-dose aspirin therapy on implantation rate in women undergoing in-vitro fertilization cycles.

Saudi Med J 2007 May;28(5):732-6

Department of Endocrinology and Female Infertility, Royan Institute, Tehran University of Medical Sciences, Tehran, Iran.

Objective: To determine the effect of low-dose aspirin on ovarian response, implantation and pregnancy rates in patients undergoing in-vitro fertilization (IVF) cycles.

Methods: We performed a randomized analysis of 145 infertile women with a mean+/-SD age of 29.6 +/- 4.47 years who underwent cycles of IVF. Patients received 100 mg of aspirin (n=72) or placebo (n=73) daily. This study was conducted in Royan Institute, Tehran, Iran from April 2002 to January 2004. Aspirin was started on the 21st of their preceding menstrual cycle and it was continued until menstruation or a negative pregnancy test. Pregnant women received the medication until 12 weeks of pregnancy. The main outcome measures were number of follicles >or=15 mm, number of oocytes retrieved, serum E2 levels, cancellation rate, Ovarian Hyperstimulation Syndrome (OHSS) occurrence, number of embryos transferred, and implantation and pregnancy rates.

Results: There were statistically significant differences between the treatment group and the control group in the number of follicles (7.4 +/- 4.1 versus 9.0 +/- 4.8) and OHSS occurrence (5.6% versus 23.3%) but not in the other measures.

Conclusion: The addition of aspirin low dose (100 mg/daily) to the standard long protocol for oocyte retrieval did not improve implantation and pregnancy rates in unselected patients undergoing IVF cycles.
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May 2007

Opioid system blockade decreases collagenase activity and improves liver injury in a rat model of cholestasis.

J Gastroenterol Hepatol 2007 Mar;22(3):406-13

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

Background: Following bile duct ligation (BDL) endogenous opioids accumulate in plasma and play a role in the pathophysiology and manifestation of cholestasis. Evidence of centrally mediated induction of liver injury by exogenous opioid agonist administration, prompts the question of whether opioid receptor blockade by naltrexone can affect cholestasis-induced liver injury.

Methods: Cholestasis was induced by BDL and cholestatic and sham-operated rats received either naltrexone or saline for 7 consecutive days. On the 7th day, liver samples were collected for determining matrix metalloproteinase-2 (MMP-2) activity, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) content and blood samples were obtained for measuring plasma nitrite/nitrate and liver enzyme activities.

Results: Naltrexone-treated BDL animals had a significant reduction in plasma enzyme activity and nitrite/nitrate level. Liver SAM : SAH ratio and SAM level improved by naltrexone treatment in cholestatic animals compared to saline-treated BDL ones. Naltrexone treatment in BDL rats led to a decrease in the level of liver MMP-2 activity, which had already increased during cholestasis.

Conclusion: Opioid receptor blockade improved the degree of liver injury in cholestasis, as assessed by plasma enzyme and liver MMP-2 activities. The beneficial effect of naltrexone may be due to its ability to increase liver SAM level and restore the SAM : SAH ratio.
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http://dx.doi.org/10.1111/j.1440-1746.2006.04260.xDOI Listing
March 2007

Nitric oxide involvement in estrous cycle-dependent changes of the behavioral responses of female rats in the elevated plus-maze test.

Behav Brain Res 2007 Mar 4;178(1):10-7. Epub 2007 Jan 4.

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

Nitric oxide (NO)/cGMP pathway is known as a mediator in anxiety modulation. In this study, we assessed the involvement of NO pathway in the estrous cycle-related changes of anxiety level in rat. By using elevated plus-maze test, we studied the changes of serum nitrate and nitrite (NO(x)) levels in comparison to the estrous cycle-dependent changes of anxiety state. Then, we tested the effects of nitric oxide synthase (NOS) inhibitor, L-NAME (10, 60mg/kg, i.p.), and the NO precursor, l-arginine (100mg/kg, i.p.) on anxiety modulatory properties of exogenous ovarian hormones in ovariectomized (OVX) rats. Compared with other cycle phases and with OVX rats, cycling rats spent more time in open arms and had lower levels of serum NO(x) levels during metestrous while they spent less time in open arms and had lower levels of serum NO(x) levels during proestrous. In OVX rats, L-NAME (60mg/kg, i.p.) exerted anxiolytic effect while l-arginine showed no effect. In comparison with corn oil-treated controls, estradiol benzoate (10microg/kg, subcutaneously (s.c.)) significantly increased the serum NO(x) level and exerted anxiogenic effect, which was dose-dependently inhibited by L-NAME but was not changed by l-arginine. In contrast, progesterone (25mg/kg, s.c.) significantly decreased the serum NO(x) level and exerted anxiolytic effect, which was abolished by l-arginine but was not affected by L-NAME. These findings suggest that NO system might be involved in the estrous cycle-related changes of anxiety level, probably by mediating the effect of ovarian sex hormones.
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http://dx.doi.org/10.1016/j.bbr.2006.11.045DOI Listing
March 2007

The proconvulsant effect of sildenafil in mice: role of nitric oxide-cGMP pathway.

Br J Pharmacol 2006 Apr;147(8):935-43

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

Recent evidence indicates that sildenafil may exert some central effects through enhancement of nitric oxide (NO)-mediated effects. NO is known to have modulatory effects on seizure threshold, raising the possibility that sildenafil may alter seizure susceptibility through NO-mediated mechanisms. This study was performed to examine whether sildenafil influences the threshold of clonic and/or generalized tonic seizures through modulation of nitric oxide (NO)-cGMP pathway. The effect of sildenafil (1-40 mg kg(-1)) was investigated on clonic seizures induced by intravenous administration of GABA antagonists pentylenetetrazole (PTZ) and bicuculine and on generalized tonic seizures induced by intraperitoneal administration of high dose PTZ in male Swiss mice. The interaction of sildenafil-induced effects with NO-cGMP pathway was examined using nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), NOS substrate L-arginine, NO donor, sodium nitroprusside (SNP) and guanylyl cyclase inhibitor methylene blue (MB). Sildenafil induced a dose-dependent proconvulsant effect in both models of clonic, but not generalized tonic type of seizures. Pretreatment with either MB or L-NAME inhibited the proconvulsant effect of sildenafil, indicating the mediation of this effect by NO-cGMP pathway. In addition, a subeffective dose of sildenafil induced an additive proconvulsant effect when combined with either L-arginine or SNP. Sildenafil induces a proconvulsant effect on clonic seizure threshold that interacts with both exogenously and endogenously released NO and may be linked to activation of NO-cGMP pathway.
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http://dx.doi.org/10.1038/sj.bjp.0706680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760711PMC
April 2006

Involvement of nitric oxide pathway in the acute anticonvulsant effect of melatonin in mice.

Epilepsy Res 2006 Feb 10;68(2):103-13. Epub 2006 Jan 10.

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

Melatonin, the major hormone produced by the pineal gland, is shown to have anticonvulsant effects. Nitric oxide (NO) is a known mediator in seizure susceptibility modulation. In the present study, the involvement of NO pathway in the anticonvulsant effect of melatonin in pentylenetetrazole (PTZ)-induced clonic seizures was investigated in mice. Acute intraperitoneal administration of melatonin (40 and 80 mg/kg) significantly increased the clonic seizure threshold induced by intravenous administration of PTZ. This effect was observed as soon as 1 min after injection and lasted for 30 min with a peak effect at 3 min after melatonin administration. Combination of per se non-effective doses of melatonin (10 and 20 mg/kg) and nitric oxide synthase (NOS) substrate L-arginine (30, 60 mg/kg) showed a significant anticonvulsant activity. This effect was reversed by NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg), implying an NO-dependent mechanism for melatonin effect. Pretreatment with L-NAME (30 mg/kg) and N(G)-nitro-L-arginine (L-NNA, 10 mg/kg) inhibited the anticonvulsant property of melatonin (40 and 80 mg/kg) and melatonin 40 mg/kg, respectively. Specific inducible NOS (iNOS) inhibitor aminoguanidine (100 and 300 mg/kg) did not affect the anticonvulsant effect of melatonin, excluding the role of iNOS in this phenomenon, while pretreatment of with 7-NI (50 mg/kg), a preferential neuronal NOS inhibitor, reversed this effect. The present data show an anticonvulsant effect for melatonin in i.v. PTZ seizure paradigm, which may be mediated via NO/L-arginine pathway by constitutively expressed NOS.
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http://dx.doi.org/10.1016/j.eplepsyres.2005.09.057DOI Listing
February 2006

Contribution of endogenous opioids and nitric oxide to papillary muscle contractile impairment in cholestatic rats.

Eur J Pharmacol 2005 Oct 13;523(1-3):93-100. Epub 2005 Oct 13.

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

Attenuated responsiveness to adrenoceptor stimulation has been proposed as an important factor underlying cardiovascular complications of cholestasis. We examined isolated papillary muscle responsiveness to alpha (phenylephrine) and beta-adrenoceptor (isoproterenol) agonists in 7-day bile duct-ligated rats. We investigated the role of nitric oxide (NO) and endogenous opioids in papillary muscle hyporesponsiveness to isoproterenol stimulation. In order to evaluate the effect of NO and endogenous opioids, animals were treated with chronic subcutaneous injections of N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg/day) or naltrexone (20 mg/kg/day), or isolated papillary muscles were exposed acutely to the same drugs (10(-4) and 10(-6) M, respectively) in an organ bath. The basal contractile force of papillary muscle, +dT/dtmax and -dT/dtmax, was significantly decreased in bile duct-ligated rats compared to sham-operated ones (P<0.05, for each value). The concentration-response curve for phenylephrine and isoproterenol demonstrated a reduced maximum effect in bile duct-ligated rats compared to the sham-operated group (P<0.01 and 0.05, respectively). Basal contractile abnormalities of bile duct-ligated rats were corrected by L-NAME or naltrexone treatment, either acute or chronic. While chronic L-NAME treatment resulted in a left-ward shift (P<0.05), it had no effect on the maximum effect in bile duct-ligated rats. Acute L-NAME treatment did not influence isoproterenol responsiveness. Acute and chronic naltrexone treatment resulted in partial and complete correction of the hyporesponsiveness of bile duct-ligated rats, respectively (P<0.05). This investigation demonstrates that the papillary muscles of 7-day bile duct ligated-rats have an impaired basal contractility and hyporesponsiveness to both alpha and beta-adrenoceptor stimulation. It also provides evidence for the involvement of increased opioidergic tone and NO overproduction in cholestasis-induced cardiac impairment.
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http://dx.doi.org/10.1016/j.ejphar.2005.08.057DOI Listing
October 2005

Endometriosis may contribute to oocyte retrieval-induced pelvic inflammatory disease: report of eight cases.

J Assist Reprod Genet 2005 Aug;22(7-8):307-9

Royan Institute of Fertility, Tehran, Iran.

Purpose: Pelvic inflammatory disease is a rare complication of transvaginal oocyte retrieval. It results in failure of assisted reproductive procedure.

Patients: During a 6-year period, 5958 transvaginal ultrasound-guided oocyte retrievals resulted in 10 cases of acute pelvic inflammatory disease (0.12%).

Results: Eight of the 10 patients were diagnosed infertile because of endometriosis. Two patients had mild ovarian, three had stage III, and two had stage IV endometriosis. One patient had a 3-4 cm ovarian endometrioma. After treatment, no mortality was encountered among the 10 patients, although none of them conceived.

Conclusion: This observation supports the previous reports that endometriosis can raise the risk of pelvic inflammatory disease after oocyte retrieval. More vigorous antibiotic prophylaxis and better vaginal preparation are recommended when oocyte pickup is performed in patients with endometriosis.
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http://dx.doi.org/10.1007/s10815-005-6003-2DOI Listing
August 2005

The synergistic anticonvulsant effect of agmatine and morphine: possible role of alpha 2-adrenoceptors.

Epilepsy Res 2005 Jun;65(1-2):33-40

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

Recent demonstrations of the anticonvulsant properties of agmatine suggest it may be considered as a potential adjunct for protection against seizure. We investigated the possibility of an additive anticonvulsant effect between low doses of agmatine and morphine. The thresholds for the clonic seizures induced by the intravenous administration of gamma-aminobutyric acid (GABA)-antagonist, pentylenetetrazole (PTZ) were assessed in mice. Morphine at lower doses (1-3mg/kg) increased and at higher doses (30, 60 mg/kg) decreased the seizure threshold. Pretreatment with a per se non-effective dose of agmatine (1mg/kg) potentiated the anticonvulsant effect of morphine. The combination of subeffective doses of agmatine and morphine led to potent anticonvulsant effects. The pro-convulsant effect of morphine was attenuated by agmatine. Yohimbine with a dose (1mg/kg) incapable of affecting seizure threshold reversed the effect of agmatine on both anticonvulsant and pro-convulsant effects of morphine. These results suggest that agmatine potentiates the anticonvulsant effect of morphine and alpha 2-adrenoceptors may be involved in this effect.
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http://dx.doi.org/10.1016/j.eplepsyres.2005.04.003DOI Listing
June 2005

Homocysteine alterations in experimental cholestasis and its subsequent cirrhosis.

Life Sci 2005 Apr;76(21):2497-512

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

Homocysteine (Hcy), an intermediate in methionine metabolism, has been proposed to be involved in hepatic fibrogenesis. Impaired liver function can alter Hcy metabolism. The aim of the present study was to determine plasma Hcy alterations in acute obstructive cholestasis and the subsequent biliary cirrhosis. Cholestasis was induced by bile duct ligation and sham-operated and unoperated rats were used as controls. The animals were studied on the days 7th, 14th, 21st and 28th after the operation. Plasma Hcy, cysteine, methionine, nitric oxide (NO) and liver S-adenosyl-methionine (SAM), S-adenosyl-homocysteine (SAH), SAM to SAH ratio and glutathione were measured. Chronic L-NAME treatment was also included in the study. Plasma Hcy concentrations were transiently elevated by the day 14th after bile duct ligation (P < 0.01) and subsequently returned to control levels. Similar relative fluctuations in plasma Hcy were observed in BDL rats after intraperitoneal methionine overload. Plasma methionine, cysteine and nitrite and nitrate were significantly increased after bile duct ligation. SAM to SAH ratio was diminished by the 1st week of cholestasis and remained significantly decreased throughout the study. These events were accompanied by a decrease in GSH to GSSG ratio in the liver. Chronic L-NAME treatment improved SAM to SAH ratio and prevented the elevation of plasma Hcy and methionine (P < 0.05) while couldn't influence the other parameters. In conclusion, this study demonstrates alterations in plasma Hcy and liver SAM and SAH contents in precirrhotic stages and in secondary biliary cirrhosis, for the first time. In addition, we observed that plasma Hcy concentrations in BDL rats follow a distinct pattern of alteration from what has been previously reported in other models of cirrhosis. NO overproduction may contribute to plasma Hcy elevation and liver SAM depletion after cholestasis.
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http://dx.doi.org/10.1016/j.lfs.2004.12.009DOI Listing
April 2005

Lithium inhibits the modulatory effects of morphine on susceptibility to pentylenetetrazole-induced clonic seizure in mice: involvement of a nitric oxide pathway.

Brain Res 2004 Dec;1029(1):48-55

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

Lithium has been reported to inhibit opioid-induced properties. The present study examined the effect of acute and chronic administration of lithium chloride (LiCl) on morphine's biphasic modulation of susceptibility to pentylenetetrazole (PTZ)-induced clonic seizure in mice. We also examined the possible involvement of nitric oxide (NO) pathway in lithium effect. Both acute (0.1 and 1 mg/kg) and chronic (same doses, 21 consecutive days) administration of LiCl completely inhibited the anticonvulsant and proconvulsant effects of morphine (at doses 1 and 30 mg/kg, respectively). A very low and per se noneffective dose of LiCl (0.05 mg/kg) significantly inhibited both phases of morphine effect when administered concomitant with a noneffective low dose of naloxone (0.1 mg/kg). The NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) at a per se noneffective dose of 0.3 mg/kg potentiated the inhibitory effects of low doses of LiCl (0.01 and 0.05 mg/kg) on both phases of morphine effect. l-arginine, a NO synthase substrate, at a per se noneffective dose of 30 mg/kg reversed the inhibitory effects of lithium (1 mg/kg). Lithium is capable of antagonizing both modulatory effects of morphine on seizure susceptibility even at relatively low doses. These inhibitory effects of lithium may also involve NO synthesis.
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http://dx.doi.org/10.1016/j.brainres.2004.09.018DOI Listing
December 2004

Obstructive cholestasis alters intestinal transit in mice: role of opioid system.

Life Sci 2004 Dec;76(4):397-406

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

Acute cholestasis is associated with increased activity of the endogenous opioid system. It is also known that opioid receptor agonists like morphine decrease the intestinal transit. The purpose of the present study was to investigate the effect of cholestasis on the small intestine transit and the possible involvement of opioid system in this phenomenon in mice. Cholestasis was induced by bile duct-ligation and intestinal transit was measured with charcoal meal and calculation of percent of transit through small intestine. The effect of chronic administration of naltrexone and acute pretreatment with morphine on intestinal transit was evaluated in bile duct-ligated (BDL) as well as unoperated (CTL) and sham-operated (SHAM) animals. The plasma alkaline phosphatase and alanine aminotransferase activities were also measured. A significant decrease in small intestine transit (%transit) was observed in BDL mice compared to SHAM animals, which was prominent even after 24 h of cholestasis. Chronic pretreatment with an opioid receptor antagonist, naltrexone, (10 mg/kg, i.p for 2, 4 or 6 days) completely restored the cholestasis-induced decrease in %transit to that of control animals. Although the acute administration of morphine (2 mg/kg, s.c.) 20 min before charcoal feeding caused a significant decrease in the intestinal transit of CTL and SHAM animals, it did not decrease the %transit of BDL animals on the day 5 after operation. Our findings show that acute cholestasis is associated with a prominent decrease in small intestine transit in mice and opioid receptors maybe involved in this phenomenon.
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http://dx.doi.org/10.1016/j.lfs.2004.09.002DOI Listing
December 2004

Sex and estrus cycle differences in the modulatory effects of morphine on seizure susceptibility in mice.

Epilepsia 2004 Sep;45(9):1035-42

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

Purpose: To evaluate the effects of sex and estrus cycle on biphasic anticonvulsant and proconvulsant modulation of seizure threshold by morphine.

Methods: The threshold for the clonic seizures (CST) induced by acute intravenous administration of gamma-aminobutyric acid (GABA)-antagonist pentylenetetrazole (PTZ) was assessed in male and female mice. Estrus cycle was assessed by vaginal smears. The effect of removing circulating sex hormones was assessed by gonadectomy.

Results: At baseline, diestrus females had a higher CST compared with males and estrus females. Morphine at lower doses (0.5-3 mg/kg) had a significant anticonvulsant effect in males and estrus females compared with that in vehicle-treated controls, whereas female mice in diestrus phase showed a relative subsensitivity to this effect. Morphine at higher doses (30 and 60 mg/kg) significantly decreased CST in males and diestrus females, with less relative effect in estrus mice. In both phases, morphine exerted stronger effects in males compared with females. Ovariectomy brought the baseline CST to the male level and resulted in significant expression of both phases of morphine effect but did not abolish the sex difference in responsiveness to morphine.

Conclusions: The biphasic modulation of seizure threshold is subject to both constitutive sex differences in sensitivity to morphine and hormonal fluctuations during the estrus cycle.
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http://dx.doi.org/10.1111/j.0013-9580.2004.69903.xDOI Listing
September 2004