Publications by authors named "Ahmad R Dehpour"

76 Publications

Role of Nitric Oxide in Neurodegeneration: Function, Regulation, and Inhibition.

Curr Neuropharmacol 2021 ;19(2):114-126

Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 1435916471, Iran.

Reactive nitrogen species (RNS) and reactive oxygen species (ROS), collectively known as reactive oxygen and nitrogen species (RONS), are the products of normal cellular metabolism and interact with several vital biomolecules including nucleic acid, proteins, and membrane lipids and alter their function in an irreversible manner which can lead to cell death. There is an imperative role for oxidative stress in the pathogenesis of cognitive impairments and the development and progression of neural injury. Elevated production of higher amounts of nitric oxide (NO) takes place in numerous pathological conditions, such as neurodegenerative diseases, inflammation, and ischemia, which occur concurrently with elevated nitrosative/oxidative stress. The enzyme nitric oxide synthase (NOS) is responsible for the generation of NO in different cells by conversion of Larginine (Arg) to L-citrulline. Therefore, the NO signaling pathway represents a viable therapeutic target. Naturally occurring polyphenols targeting the NO signaling pathway can be of major importance in the field of neurodegeneration and related complications. Here, we comprehensively review the importance of NO and its production in the human body and afterwards highlight the importance of various natural products along with their mechanisms against various neurodegenerative diseases involving their effect on NO production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1570159X18666200429001549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033982PMC
January 2021

Anti-tumor activity of neratinib, a pan-HER inhibitor, in gastric adenocarcinoma cells.

Eur J Pharmacol 2019 Nov 28;863:172705. Epub 2019 Sep 28.

Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Gastric adenocarcinoma (GAC), the most common malignancy of the stomach, is the fourth most common and the second cause of cancer-related death worldwide. Although HER family plays a cardinal role in tumorigenesis of GAC, trastuzumab is the only approved anti-HER drug for this malignancy and development of resistance to trastuzumab is inevitable. Additionally, single-targeted HER inhibitors have demonstrated limited activity in GAC. Hence, there is a pressing need to devise more efficacious anti-HER therapeutic strategies. Here, we examined the anti-tumor activity of neratinb, a pan-HER inhibitor, on GAC cells. Anti-proliferative effects of neratinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and anoikis resistance and wound healing assays were carried out to examine the effects of neratinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) analyses were applied to further investigate the anti-tumor activity of neratinib. We found that neratinib sensitized GAC cells to 5FU, carboplatin and oxaliplatin. Moreover, we found that neratinib was synergistic with trametinib (an approved MEK inhibitor) and foretinib (a c-MET inhibitor) and potentiated radio-sensitivity of GAC cells. Furthermore, we found that neratinib diminished GAC cell proliferation along with downregulation of FOXM1 and its targets. Additionally, neratinib induced apoptosis along with upregulation of pro-apoptotic and downregulation of anti-apoptotic genes. Treatment with neratinib attenuated invasive ability of GAC cells as shown by reduced anoikis resistance, downregulation of EMT markers, and reduced width in scratch assay. Our findings indicate that neratinib provides the therapeutic potential in the treatment of GAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2019.172705DOI Listing
November 2019

The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells.

Cell Oncol (Dordr) 2019 Aug 25;42(4):491-504. Epub 2019 Apr 25.

Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Purpose: Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells.

Methods: Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib.

Results: We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal.

Conclusions: Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13402-019-00448-wDOI Listing
August 2019

Targeting Hedgehog signaling pathway: Paving the road for cancer therapy.

Pharmacol Res 2019 03 11;141:466-480. Epub 2019 Jan 11.

Department of Pharmacology, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran.

The Hedgehog pathway is essential for embryonic development but also for tissue and organ homeostasis in adult organisms. Activation of this pathway leads to the expression of target genes involved in proliferation, angiogenesis and stem cell self-renewal. Moreover, abnormal persistence of Hedgehog signaling is directly involved in a wide range of human cancers. Development of novel strategies targeting the Hedgehog pathway has become a subject of increased interest in anticancer therapy. These data are sustained by pre-clinical studies demonstrating that Hedgehog pathway inhibitors could represent an effective strategy against a heterogeneous panel of malignancies. Limited activity in other tumor types could be explained by the existence of crosstalk between the Hedgehog pathway and other signaling pathways that can compensate for its function. This review describes the Hedgehog pathway in detail, with its physiological roles during embryogenesis and adult tissues, and summarizing the preclinical evidence on its inhibition, the crosstalk between Hedgehog and other cancer-related pathways and finally the potential therapeutic effects of emerging compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2019.01.014DOI Listing
March 2019

Inhibition of bromodomain and extraterminal domain reduces growth and invasive characteristics of chemoresistant ovarian carcinoma cells.

Anticancer Drugs 2018 11;29(10):1011-1020

Hematology/Oncology and Stem Cell Transplantation Research Center.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination are the major reasons for low survival rate in the patients. The bromodomain and extraterminal domain (BET) proteins are known as epigenetic 'readers,' and their inhibitors are novel epigenetic strategies for cancer treatment. Accumulating body of evidence indicates that epigenetic modifications have critical roles in development of EOC, and overexpression of the BET family is a key step in the induction of important oncogenes. Here, we examined the mechanistic activity of I-BET151, a pan-inhibitor of the BET family, in therapy-resistant EOC cells. Our findings showed that I-BET151 diminished cell growth, clonogenic potential, and induced apoptosis. I-BET151 inhibited cell proliferation through down-modulation of FOXM1 and its targets aurora kinase B and cyclin B1. I-BET151 attenuated migration and invasion of the EOC cells by down-regulation of epithelial-mesenchymal transition markers fibronectin, ZEB2, and N-cadherin. I-BET151 synergistically enhanced cisplatin chemosensitivity by down-regulation of survivin and Bcl-2. Our data provide insights into the mechanistic activity of I-BET151 and suggest that BET inhibition has potential as a therapeutic strategy in therapy-resistant EOC. Further in vivo investigations on the therapeutic potential of I-BET151 in EOC are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CAD.0000000000000681DOI Listing
November 2018

Targeting mTORs by omega-3 fatty acids: A possible novel therapeutic strategy for neurodegeneration?

Pharmacol Res 2018 09 7;135:37-48. Epub 2018 Jul 7.

Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 14359-16471, Iran. Electronic address:

Neurodegenerative diseases (NDs) such as Parkinson's (PD), Alzheimer's (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) cause significant world-wide morbidity and mortality. To date, there is no drug of cure for these, mostly age-related diseases, although approaches in delaying the pathology and/or giving patients some symptomatic relief have been adopted for the last few decades. Various studies in recent years have shown the beneficial effects of omega-3 poly unsaturated fatty acids (PUFAs) through diverse mechanisms including anti-inflammatory effects. This review now assesses the potential of this class of compounds in NDs therapy through specific action against the mammalian target of rapamycin (mTOR) signaling pathway. The role of mTOR in neurodegenerative diseases and targeted therapies by PUFAs are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2018.07.004DOI Listing
September 2018

Targeting mTORs by omega-3 fatty acids: A possible novel therapeutic strategy for neurodegeneration?

Pharmacol Res 2018 09 7;135:37-48. Epub 2018 Jul 7.

Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 14359-16471, Iran. Electronic address:

Neurodegenerative diseases (NDs) such as Parkinson's (PD), Alzheimer's (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) cause significant world-wide morbidity and mortality. To date, there is no drug of cure for these, mostly age-related diseases, although approaches in delaying the pathology and/or giving patients some symptomatic relief have been adopted for the last few decades. Various studies in recent years have shown the beneficial effects of omega-3 poly unsaturated fatty acids (PUFAs) through diverse mechanisms including anti-inflammatory effects. This review now assesses the potential of this class of compounds in NDs therapy through specific action against the mammalian target of rapamycin (mTOR) signaling pathway. The role of mTOR in neurodegenerative diseases and targeted therapies by PUFAs are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2018.07.004DOI Listing
September 2018

Blockade of nuclear factor-κB (NF-κB) pathway inhibits growth and induces apoptosis in chemoresistant ovarian carcinoma cells.

Int J Biochem Cell Biol 2018 06 19;99:1-9. Epub 2018 Mar 19.

Hematology/oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Epithelial ovarian cancer (EOC) has exhibited marginal improvement in survival rate, despite advances in surgical debulking and chemotherapy regimens. Although the majority of EOC patients achieve a clinical remission after induction therapy, over 80% relapse and succumb to chemoresistant disease. In this regard, it is of paramount importance to elucidate molecular mechanisms and signaling pathways which promote therapy resistance in EOC in order to devise novel and more effective treatment strategies. In this study, we showed that activation of nuclear factor-κB (NF-κB) is significantly higher in therapy-resistant EOC cells compared to chemosensitive counterparts, which was positively associated with resistance to cisplatin, carboplatin, paclitaxel and erlotinib. Bay 11-7082, a highly selective NF-κB inhibitor, reduced cell proliferation, clonogenicity and anoikis resistance in the therapy-resistant EOC cells and induced apoptotic cell death. Moreover, Bay 11-7082 decreased the expression of pro-survival, inflammatory and metastatic genes and synergistically increased anti-proliferative efficacy of cisplatin, carboplatin, paclitaxel and erlotinib. Altogether, these findings suggest that NF-κB is an attractive therapeutic target in EOC to be exploited in translational oncology and Bay 11-7082 is a potential anti-cancer drug to overcome chemoresistance and inhibit proliferation of the EOC cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biocel.2018.03.015DOI Listing
June 2018

The expression, localization and function of α7 nicotinic acetylcholine receptor in rat corpus cavernosum.

J Pharm Pharmacol 2017 Dec 24;69(12):1754-1761. Epub 2017 Aug 24.

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

Objectives: Alpha7 nicotinic acetylcholine receptor (α7-nAChR), an emerging pharmacological target for a variety of medical conditions, is expressed in the most mammalian tissues with different effects. So, this study was designed to investigate the expression, localization and effect of α7-nAChR in rat corpus cavernosum (CC).

Methods & Key Findings: Reverse transcription polymerase chain reaction (RT-PCR) revealed that α7-nAChR was expressed in rat CC and double immunofluorescence studies demonstrated the presence of α7-nAChR in corporal neurons. The rat CC segments were mounted in organ bath chambers and contracted with phenylephrine (0.1 μm -300 μm) to investigate the relaxation effect of electrical field stimulation (EFS,10 Hz) assessed in the presence of guanethidine (adrenergic blocker, 5 μm) and atropine (muscarinic cholinergic blocker, 1 μm) to obtain non-adrenergic non-cholinergic (NANC) response. Cumulative administration of nicotine significantly potentiated the EFS-induced NANC relaxation (-log EC50 = 7.5 ± 0.057). Whereas, the potentiated NANC relaxation of nicotine was significantly inhibited with different concentrations of methyllycaconitine citrate (α7-nAChR antagonist, P < 0.05) in preincubated strips. L-NAME (non-specific nitric oxide synthase inhibitor, 1 μm) completely blocked the neurogenic relaxation induced by EFS plus nicotine.

Conclusion: To conclude α7-nAChR is expressed in rat CC and modulates the neurogenic relaxation response to nicotine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jphp.12806DOI Listing
December 2017

Fas Receptor Activation by Endogenous Opioids Is A New Mechanism for Cardiomyopathy in Cirrhotic Rats.

J Clin Exp Hepatol 2017 Jun 17;7(2):107-114. Epub 2016 Oct 17.

Department of Pathology, Tehran University of Medical sciences (TUMS), Tehran, Iran.

Background: Cirrhosis, a common consequence of chronic liver inflammation is associated with various cardiovascular dysfunctions which are called cirrhotic cardiomyopathy (CC). Among the various possible causes of CC, apoptosis is considered to have a pivotal role.

Objectives: To explore the contribution of endogenous opioids in the apoptosis process in a rat model of CC.

Material And Methods: Four genes were selected to cover both intrinsic and extrinsic pathways of apoptosis. Cardiac samples from 4 groups of rats were evaluated. Two groups were cirrhotic through bile duct ligation (BDL) receiving either naltrexone (BDL-naltrexone) or saline (BDL-saline), two others were normal rats as sham groups receiving either naltrexone (sham-naltrexone) or saline (sham-saline). Expression level of BCL2, Caspase3, Fas and FasL was explored in all groups using reverse transcriptase real-time PCR.

Results: BDL-saline group showed significant over-expression of BCL2, caspase3 and Fas. BCL2 expression was 1.44 ( < 0.001) and caspasse3 was 1.35 ( < 0.001) times higher than sham-saline group, Fas was also overexpressed 1.3 ( < 0.001) times higher than BDL-naltrexone group and 1.91 ( < 0.001) compared to sham-naltrexone group. Caspase3 expression was 1.35 ( < 0.001) folds higher than sham-naltrexone group. The expression pattern of FasL revealed no statistically significant change among study groups.

Conclusion: Fas molecule enrollment during CC is a novel finding. Fas molecule is activated during cirrhosis through elevated levels of endogenous opioids. This pathway is one of the leading causes of CC. Our findings also demonstrated the protective role of naltrexone as opioids antagonist on cardiomyocytes in a rat model of CC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jceh.2016.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478937PMC
June 2017

Dacomitinib, a pan-inhibitor of ErbB receptors, suppresses growth and invasive capacity of chemoresistant ovarian carcinoma cells.

Sci Rep 2017 06 23;7(1):4204. Epub 2017 Jun 23.

Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination of EOC cells are the major reasons for low survival rate. Targeting signal transduction pathways which promote therapy resistance and metastatic dissemination is the key to successful treatment. Members of the ErbB family of receptors are over-expressed in EOC and play key roles in chemoresistance and invasiveness. Despite this, single-targeted ErbB inhibitors have demonstrated limited activity in chemoresistant EOC. In this report, we show that dacomitinib, a pan-ErbB receptor inhibitor, diminished growth, clonogenic potential, anoikis resistance and induced apoptotic cell death in therapy-resistant EOC cells. Dacominitib inhibited PLK1-FOXM1 signalling pathway and its down-stream targets Aurora kinase B and survivin. Moreover, dacomitinib attenuated migration and invasion of the EOC cells and reduced expression of epithelial-to-mesenchymal transition (EMT) markers ZEB1, ZEB2 and CDH2 (which encodes N-cadherin). Conversely, the anti-tumour activity of single-targeted ErbB agents including cetuximab (a ligand-blocking anti-EGFR mAb), transtuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small-molecule tyrosine kinase inhibitor) were marginal. Our results provide a rationale for further investigation on the therapeutic potential of dacomitinib in treatment of the chemoresistant EOC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-04147-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482808PMC
June 2017

Anti-tumour activity of tivozanib, a pan-inhibitor of VEGF receptors, in therapy-resistant ovarian carcinoma cells.

Sci Rep 2017 04 6;7:45954. Epub 2017 Apr 6.

Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy. Despite initial therapeutic response, the majority of advanced-stage patients relapse and succumb to chemoresistant disease. Overcoming drug resistance is the key to successful treatment of EOC. Members of vascular endothelial growth factor (VEGF) family are overexpressed in EOC and play key roles in its malignant progression though their contribution in development of the chemoresistant disease remains elusive. Here we show that expression of the VEGF family is higher in therapy-resistant EOC cells compared to sensitive ones. Overexpression of VEGFR2 correlated with resistance to cisplatin and combination with VEGFR2-inhibitor apatinib synergistically increased cisplatin sensitivity. Tivozanib, a pan-inhibitor of VEGF receptors, reduced proliferation of the chemoresistant EOC cells through induction of G2/M cell cycle arrest and apoptotic cell death. Tivozanib decreased invasive potential of these cells, concomitant with reduction of intercellular adhesion molecule-1 (ICAM-1) and diminishing the enzymatic activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-2 (MMP-2). Moreover, tivozanib synergistically enhanced anti-tumour effects of EGFR-directed therapies including erlotinib. These findings suggest that the VEGF pathway has potential as a therapeutic target in therapy-resistant EOC and VEGFR blockade by tivozanib may yield stronger anti-tumour efficacy and circumvent resistance to EGFR-directed therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep45954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382685PMC
April 2017

Blockade of vascular endothelial growth factor receptors by tivozanib has potential anti-tumour effects on human glioblastoma cells.

Sci Rep 2017 03 13;7:44075. Epub 2017 Mar 13.

Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro. Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep44075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347040PMC
March 2017

Effects of oleuropein on pentylenetetrazol-induced seizures in mice: involvement of opioidergic and nitrergic systems.

J Nat Med 2017 Apr 19;71(2):389-396. Epub 2017 Jan 19.

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

Oleuropein, a well-known olive polyphenol, has been shown to mediate neuroprotection in Alzheimer's disease and cerebral ischemia. We investigated the effects of oleuropein on pentylenetetrazole (PTZ)-induced seizures in male NMRI mice, with diazepam as the standard drug. We also examined the possible involvement of opioidergic/nitrergic pathways in the probable effects of oleuropein. Intraperitoneal (i.p.) administration of different doses of oleuropein (10, 20 and 30 mg/kg) significantly increased the seizure threshold 60 min prior to induction of seizure, in a dose-dependent manner. Administration of naltrexone (10 mg/kg, i.p.), an opioid receptor antagonist, completely reversed the anticonvulsant effects of oleuropein (10 mg/kg). On the other hand, the anticonvulsant effect of oleuropein (10 mg/kg) was blocked by a non-effective dose of nonspecific inhibitor of nitric oxide synthase (NOS), L-NAME (1 and 10 mg/kg, i.p) and a selective inhibitor of neuronal NOS, 7-nitroindazole (30 mg/kg, i.p.). However, the nitric oxide precursor, L-arginine (30 and 60 mg/kg, i.p.) potentiated the anticonvulsant activity of oleuropein (10 mg/kg). A selective inducible NOS inhibitor, aminoguanidine (100 mg/kg, i.p.) did not change the anticonvulsant activity of oleuropein. It seems that the opioidergic system and constitutive neuronal NOS may be involved in the anticonvulsant properties of oleuropein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11418-017-1071-zDOI Listing
April 2017

Nitric oxide mediates effects of acute, not chronic, naltrexone on LPS-induced hepatic encephalopathy in cirrhotic rats.

Can J Physiol Pharmacol 2017 Jan 7;95(1):16-22. Epub 2016 Aug 7.

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

Recent studies suggest endogenous opioids and nitric oxide (NO) are involved in the pathophysiology of hepatic encephalopathy (HE). In this study, the interaction between the opioid receptor antagonist and NO was investigated on lipopolysaccharide (LPS)-induced HE in cirrhotic rats. Male rats were divided in the sham- and bile duct ligation (BDL)-operated groups. Animals were treated with saline; naltrexone (10 mg/kg, i.p.); or L-NAME (3 mg/kg, i.p.), alone or in combination with naltrexone. To induce HE, LPS (1 mg/kg, i.p.) was injected 1 h after the final drug treatment. HE scoring, hepatic histology, and plasma NO metabolites levels and mortality rate were recorded. Deteriorated level of consciousness and mortality after LPS administration significantly ameliorated following both acute and chronic treatment with naltrexone in cirrhotic rats. However, acute and chronic administration of L-NAME did not change HE scores in cirrhotic rats. The effects of acute but not chronic treatment of naltrexone on HE parameters were reversed by L-NAME. Plasma NO concentrations elevated in BDL rats, which were decreased after acute and chronic treatment by naltrexone or L-NAME, significantly. We suggest both acute and chronic treatment with naltrexone improved LPS-induced HE. But, only acute treatment with naltrexone may affect through NO pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1139/cjpp-2016-0188DOI Listing
January 2017

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

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

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

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

Download full-text PDF

Source
http://dx.doi.org/10.1111/fcp.12244DOI Listing
April 2017

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

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

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

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

Download full-text PDF

Source
http://dx.doi.org/10.1111/fcp.12202DOI Listing
August 2016

Hassan Farsam (1932-2016).

Acta Med Iran 2016 Feb;54(2):83-4

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

View Article and Find Full Text PDF

Download full-text PDF

Source
February 2016

Increased Salivary Nitrite and Nitrate Excretion in Rats with Cirrhosis.

Acta Med Iran 2015 Nov;53(11):669-75

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

Increased nitric oxide (NO) formation is mechanistically linked to pathophysiology of the extrahepatic complications of cirrhosis. NO is formed by either enzymatic or non-enzymatic pathways. Enzymatic production is catalyzed by NO synthase (NOS) while entero-salivary circulation of nitrate and nitrite is linked to non-enzymatic formation of NO under acidic pH in the stomach. There is no data on salivary excretion of nitrate and nitrite in cirrhosis. This study was aimed to investigate salivary levels of nitrate and nitrite in a rat model of biliary cirrhosis. Cirrhosis was induced by bile duct ligation (BDL). Four weeks after the operation, submandibular ducts of anesthetized BDL and control rats were cannulated with polyethylene microtube for saliva collection. Assessment of pH, nitrite and nitrate levels was performed in our research. We also investigated NOS expression by real time RT-PCR to estimate eNOS, nNOS and iNOS mRNA levels in the submandibular glands. Salivary pH was significantly lower in BDL rats in comparison to control animals. We also observed a statistically significant increase in salivary levels of nitrite as well as nitrate in BDL rats while there was no elevation in the mRNA expression of nNOS, eNOS, and iNOS in submandibular glands of cirrhotic groups. This indicates that an increased salivary level of nitrite/nitrate is less likely to be linked to increased enzymatic production of NO in the salivary epithelium. It appears that nitrate/nitrite can be transported from the blood stream by submandibular glands and excreted into saliva as entero-salivary circulation, and this mechanism may have been exaggerated during cirrhosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
November 2015

The effect of endotoxin on heart rate dynamics in diabetic rats.

Auton Neurosci 2015 May 2;189:83-6. Epub 2015 Jan 2.

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

The effect of endotoxin on heart rate variability (HRV) was assessed in diabetic and controls rats using a telemetric system. Endotoxin induced a reduction in sample entropy of cardiac rhythm in control animals. However, this effect was significantly blunted in streptozotocin-induced diabetic rats. Since uncoupling of cardiac pacemaker from cholinergic control is linked to reduced HRV in endotoxemia, chronotropic responsiveness to cholinergic stimulation was assessed in isolated atria. Endotoxemia was associated with impaired responsiveness to carbacholine in control rats. However, endotoxemia did not impair cholinergic responsiveness in diabetic atria. These findings corroborates with development of endotoxin tolerance in diabetic rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autneu.2014.12.006DOI Listing
May 2015

Effects of D-penicillamine on pentylenetetrazole-induced seizures in mice: involvement of nitric oxide/NMDA pathways.

Epilepsy Behav 2014 Oct 29;39:42-7. Epub 2014 Aug 29.

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

Besides the clinical applications of penicillamine, some reports show that use of D-penicillamine (D-pen) has been associated with adverse effects such as seizures. So, the purpose of this study was to evaluate the effects of D-pen on pentylenetetrazole (PTZ)-induced seizures in male NMRI mice. It also examined whether N-methyl-D-aspartate (NMDA) receptor/nitrergic system blockage was able to alter the probable effects of D-pen. Different doses of D-pen (0.1, 0.5, 1, 10, 100, 150, and 250 mg/kg) were administered intraperitoneally (i.p.) 90 min prior to induction of seizures. D-Penicillamine at a low dose (0.5 mg/kg, i.p.) had anticonvulsant effects, whereas at a high dose (250 mg/kg, i.p.), it was proconvulsant. Both anti- and proconvulsant effects of D-pen were blocked by a single dose of a nonspecific inhibitor of nitric oxide synthase (NOS), L-NAME (10 mg/kg, i.p.), and a single dose of a specific inhibitor of neuronal nitric oxide synthase (nNOS), 7-nitroindazole (30 mg/kg, i.p.). A selective inhibitor of iNOS, aminoguanidine (100 mg/kg, i.p.), had no effect on these activities. An NMDA receptor antagonist, MK-801 (0.05 mg/kg, i.p.), alters the anti- and proconvulsant effects of D-pen. The results of the present study showed that the nitric oxide system and NMDA receptors may contribute to the biphasic effects of D-pen, which remain to be clarified further.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2014.07.013DOI Listing
October 2014

Does hepatic vagus nerve modulate the progression of biliary fibrosis in rats?

Auton Neurosci 2014 Oct 17;185:67-75. Epub 2014 Jul 17.

Department of Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address:

Recent studies have shown that vagus nerve activation inhibits cytokine production in a variety of non-neural cells though activation of α7 nicotinic acetylcholine receptor (α7nAChR). Since chronic inflammation plays a pivotal role in liver fibrosis, this study was designed to investigate the role of hepatic vagus nerve in the progression of hepatic fibrosis in rats. Cirrhosis was induced by chronic ligation of the bile duct. Hepatic hydroxyproline level, portal pressure, serum transaminase level, hepatic TIMP-1 (tissue inhibitor of metalloproteinase-1) and MCP-1 (monocyte chemoattractant peptide-1) expression were measured in order to assess the progression of liver cirrhosis. α7nAChR expression was assessed using RT-PCR as well as immunostaining. RT-PCR analysis of the liver showed that α7nAChR mRNA is expressed in rat liver. Immunostaining study demonstrated that hepatic α7nAChR is mainly expressed in the hepatocytes of cirrhotic liver with minimum α7nAChR expression in biliary epithelium or myofibroblasts. Bile duct ligation was associated with portal hypertension, increased hepatic hydroxyproline level as well as TIMP-1 and MCP-1 expression in the liver. However neither selective hepatic vagotomy nor methyllycaconitine (an α7nAChR antagonist) could significantly affect development of portal hypertension or hepatic fibrosis in rats. Selective hepatic vagotomy could only attenuate serum aspartate aminotransferase level in bile duct ligated rats but did not have a significant effect on hepatic inflammation as assessed by MCP-1 mRNA expression. Our study provides evidence against a crucial role for the hepatic vagus nerve as an intrinsic protective mechanism in modulation of hepatic fibrosis in a rat model of biliary cirrhosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autneu.2014.07.005DOI Listing
October 2014

Activation of central muscarinic receptor type 1 prevents development of endotoxin tolerance in rat liver.

Eur J Pharmacol 2014 Oct 4;740:436-41. Epub 2014 Jul 4.

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

Endotoxin tolerance is a mechanism in which cells receiving low doses of endotoxin, enter a transient phase with less inflammatory response to the next endotoxin challenges. Central nervous system is known to modulate systemic inflammation through activation of the cholinergic system; however, the role of central anti-inflammatory pathway in pathophysiology of hepatic endotoxin tolerance is unknown. Our study was designed to assess the effect central muscarinic type 1 receptor (M1) activation on development of endotoxin tolerance in rat liver. Endotoxin tolerance was induced by daily intraperitoneal injection of endotoxin (1 mg/kg) for 5 days. Animals were randomly divided into two groups which received intracerebroventricular injection of either MCNA-343 (an M1 agonist, 5 ng/kg) or saline 1h after intraperitoneal injection of saline or endotoxin. The responsiveness to endotoxin was assessed by measuring hepatic MCP-1 (monocyte chemotactic protein-1), iNOS (inducible nitric oxide synthase) and TNF-α (tumor necrosis-α) mRNA expression 3h after intraperitoneal administration of endotoxin using quantitative RT-PCR. A significant reduction in hepatic expression of MCP-1, iNOS and TNF-α was observed in rats with 5 days endotoxin challenge in comparison with rats given a single dose of endotoxin. There was no significant difference in hepatic expression of MCP-1, iNOS or TNF-α between acute and chronic LPS-treated groups in rats given MCNA-343. Central MCNA-343 stimulation could prevent the induction of hepatic endotoxin tolerance in animals receiving repeated doses of endotoxin. This indicates that M1 cholinergic receptor activation in the central nervous system can modulate endotoxin tolerance in rat liver.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2014.06.050DOI Listing
October 2014

Opioid receptors blockade modulates apoptosis in a rat model of cirrhotic cardiomyopathy.

Ann Med Health Sci Res 2014 May;4(3):404-9

Department of Pharmacology, Tehran University of Medical Science, Tehran, Iran.

Background: Cirrhosis is a common consequence of chronic liver inflammation is known to be associated with various manifestation of cardiovascular dysfunction, which has been introduced as a cirrhotic cardiomyopathy. Some possible pathogenic mechanisms has been reported and still more details should be explored.

Aim: The present study is the first study to explore the contribution of endogenous opioids in the apoptosis process in a rat model of cirrhotic cardiomyopathy.

Materials And Methods: Cirrhosis was induced in rats by bile duct ligation (BDL) and resection. Cardiomyopathy was confirmed using trichrome staining for fibrosis. Naltrexone, an opioid antagonist was administered for 29(1) days. Apoptosis was detected using terminal transferase deoxyuridine triphosphate nick end labeling assay with some modification. Statistical evaluation of data was performed using analysis of variance test. P < 0.05 was considered to be statistically significant.

Results: Left ventricular (LV) wall thickness was significantly (P < 0.001) lower in the BDL group than the sham group, either receiving naltrexone or saline. No significant difference was seen in LV wall thickness or LV end diastolic diameter in BDL group receiving either saline or naltrexone. The apoptosis density of cardiac specimens of sham operated and BDL rats were dramatically different from each other. The cardiac specimens of BDL rats contained multiple apoptotic cells. In saline treated samples (BDL-saline vs. sham-saline), apoptosis density was significantly increased in BDL-saline group (P < 0.001). Cardiomyocyte apoptosis was significantly decreased in the BDL-naltrexone group compared to BDL-saline group (P < 0.001). There was no significant change in apoptosis density in sham groups receiving either naltrexone or saline.

Conclusion: Apoptosis occurs during cirrhotic cardiomyopathy and endogenous opioid receptors blockade using naltrexone decreases its amount, but cardiac function may not be improved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/2141-9248.133468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071742PMC
May 2014

The effect of endotoxin on the controllability of cardiac rhythm in rats.

Physiol Meas 2014 Mar 30;35(3):339-49. Epub 2014 Jan 30.

Department of Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Decreased heart rate variability (HRV) has both diagnostic and prognostic value in patients with sepsis. However, it is not known whether reduced HRV in sepsis reflects an altered input from the autonomic nervous system or a remodeling of the cardiac pacemaker cells by inflammatory mediators. The present study aimed to investigate the effect of endotoxin on the heart rate dynamics of a denervated isolated heart in rats. Saline or endotoxin was injected into rats and their hearts were isolated and perfused. Atrial electrical activity was recorded and memory length in the time-series was assessed using inverse statistical analysis. Memory was defined as a statistical feature that lasts for a period of time and distinguishes the time-series from a random process. Endotoxaemic hearts exhibited a prolonged memory compared to the controls with respect to observing rare events. This indicates that a sudden decelerating event could potentially affect the cardiac rhythm of an endotoxaemic heart for a longer time than the controls. The prolongation of memory is indirectly linked to a reduced controllability in a complex system; therefore our data may provide evidence for a reduced controllability in cardiac rhythm following endotoxaemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/0967-3334/35/3/339DOI Listing
March 2014

The increased gastroprotective effect of pioglitazone in cholestatic rats: role of nitric oxide and tumour necrosis factor alpha.

Int J Exp Pathol 2014 Feb;95(1):78-85

Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

The prevalence of gastric ulcers is high in cholestatic patients, but the exact mechanism of this increased frequency remains uncertain. It has been shown that pioglitazone accelerates the healing of pre-existing gastric ulcers. The present study was designed to investigate the effect of pioglitazone, on the gastric mucosal lesions in cholestatic rats. Cholestasis was induced by surgical ligation of common bile duct and sham-operated rats served as control. Different groups of sham and cholestatic animals received solvent or pioglitazone (5, 15, 30 mg/kg) for 7 days. On the day eight rats were killed after oral ethanol administration and the area of gastric lesions was measured. The serums of rats were also collected to determine serum levels of tumour necrosis factor alpha (TNF-α), IL-1β and bilirubin. The ethanol-induced gastric mucosal damage was significantly more severe in cholestatic rats than sham-operated ones. Pretreatment with pioglitazone dose-dependently attenuated gastric lesions induced by ethanol in both sham and cholestatic rats, but this effect was more prominent in cholestatic ones. The effect of pioglitazone was associated with a significant fall in serum levels of TNF-α in cholestatic rats. L-NAME, a non-selective nitric oxide synthase (NOS) inhibitor, and decreased pioglitazone-induced gastroprotective effect in cholestatic rats, while aminoguanidine, a selective inducible NOS inhibitor, potentiated pioglitazone-induced gastroprotective effect in the cholestatic rats. Chronic treatment with pioglitazone exerts an enhanced gastroprotective effect on the stomach ulcers of cholestatic rats compared to sham rats probably due to constitutive NOS induction and/or inducible NOS inhibition and attenuating release of TNF-α.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/iep.12067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919651PMC
February 2014

The role of α7 nicotinic acetylcholine receptor in modulation of heart rate dynamics in endotoxemic rats.

PLoS One 2013 10;8(12):e82251. Epub 2013 Dec 10.

Department of Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Previous reports have indicated that artificial stimulation of the vagus nerve reduces systemic inflammation in experimental models of sepsis. This phenomenon is a part of a broader cholinergic anti-inflammatory pathway which activates the vagus nerve to modulate inflammation through activation of alpha7 nicotinic acetylcholine receptors (α7nACHR). Heart rate variability represents the complex interplay between autonomic nervous system and cardiac pacemaker cells. Reduced heart rate variability and increased cardiac cycle regularity is a hallmark of clinical conditions that are associated with systemic inflammation (e.g. endotoxemia and sepsis). The present study was aimed to assess the role of α7nACHR in modulation of heart rate dynamics during systemic inflammation. Systemic inflammation was induced by injection of endotoxin (lipopolysaccharide) in rats. Electrocardiogram and body temperature were recorded in conscious animals using a telemetric system. Linear and non-linear indices of heart rate variability (e.g. sample entropy and fractal-like temporal structure) were assessed. RT-PCR and immunohistochemistry studies showed that α7nACHR is expressed in rat atrium and is mainly localized at the endothelial layer. Systemic administration of an α7nACHR antagonist (methyllycaconitine) did not show a significant effect on body temperature or heart rate dynamics in naïve rats. However, α7nACHR blockade could further reduce heart rate variability and elicit a febrile response in endotoxemic rats. Pre-treatment of endotoxemic animals with an α7nACHR agonist (PHA-543613) was unable to modulate heart rate dynamics in endotoxemic rats but could prevent the effect of endotoxin on body temperature within 24 h experiment. Neither methyllycaconitine nor PHA-543613 could affect cardiac beating variability of isolated perfused hearts taken from control or endotoxemic rats. Based on our observations we suggest a tonic role for nicotinic acetylcholine receptors in modulation of heart rate dynamics during systemic inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0082251PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858293PMC
September 2014

Quantifying memory in complex physiological time-series.

PLoS One 2013 5;8(9):e72854. Epub 2013 Sep 5.

Computational Physical Sciences Research Laboratory, School of Nano-Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran.

In a time-series, memory is a statistical feature that lasts for a period of time and distinguishes the time-series from a random, or memory-less, process. In the present study, the concept of "memory length" was used to define the time period, or scale over which rare events within a physiological time-series do not appear randomly. The method is based on inverse statistical analysis and provides empiric evidence that rare fluctuations in cardio-respiratory time-series are 'forgotten' quickly in healthy subjects while the memory for such events is significantly prolonged in pathological conditions such as asthma (respiratory time-series) and liver cirrhosis (heart-beat time-series). The memory length was significantly higher in patients with uncontrolled asthma compared to healthy volunteers. Likewise, it was significantly higher in patients with decompensated cirrhosis compared to those with compensated cirrhosis and healthy volunteers. We also observed that the cardio-respiratory system has simple low order dynamics and short memory around its average, and high order dynamics around rare fluctuations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072854PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764113PMC
June 2014

Nitric oxide mediates the beneficial effect of chronic naltrexone on cholestasis-induced memory impairment in male rats.

Behav Pharmacol 2013 Jun;24(3):195-206

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

Recent studies suggest an augmentation of endogenous opioids following bile duct ligation (BDL) and their pivotal role in the pathophysiology of cholestasis. In this study, the effect of naltrexone, an opioid receptor antagonist, was determined on cholestasis-induced memory impairment and the possible involvement of nitric oxide (NO) in this effect. Male Albino-Wistar rats were randomized to sham-operated and BDL-operated groups. In each group, animals were treated for up to 28 days with saline; naltrexone (10 mg/kg); naltrexone and N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective nitric oxide synthase (NOS) inhibitor (3, 10 mg/kg); naltrexone and aminoguanidine, an inducible NOS inhibitor (100 mg/kg); or methylnaltrexone, a peripherally acting opioid receptor antagonist (3 mg/kg, intraperitoneal). Spatial recognition memory was determined in a Y-maze task on the day before surgery and days 7, 14, 21, and 28 after surgery. Memory performance was impaired 14 days after BDL in cholestatic rats and was significantly reversed by chronic treatment with naltrexone at days 14, 21, and 28 after BDL. On day 21 after BDL, chronic L-NAME produced only a nonsignificant decrease in the beneficial effect of naltrexone, whereas on day 28, chronic administration of both L-NAME and aminoguanidine significantly reversed this effect of naltrexone. It is therefore shown in this study that naltrexone improves BDL-induced memory deficit in rats. We conclude that the memory impairment in cholestatic rats might be because of an increase in the level of endogenous opioids and that naltrexone improved the spatial recognition memory by antagonizing opioid receptors. The observation that the procognitive effect of naltrexone is counteracted either by general inhibition of NOS enzymes or by selective inhibition of inducible NOS suggests the nitrergic pathway as a probable mechanism involved in the amelioration of spatial recognition memory by naltrexone in BDL rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FBP.0b013e3283618a8cDOI Listing
June 2013