Publications by authors named "Ghorbangol Ashabi"

43 Publications

Tannic acid protects aged brain against cerebral hypoperfusion via modulation of Nrf2 and inflammatory pathways.

Neurosci Lett 2021 Sep 22;765:136263. Epub 2021 Sep 22.

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

Current study purposed to investigate the neuroprotective effects of Tannic Acid (TA) on mild chronic cerebral hypoperfusion model in rats. Male Wistar rats were subjected to permanent Unilateral Common Carotid Artery Occlusion (UCCAO), followed by TA treatment (0.05% w/v) in drinking water for one month. Nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO-1), heme oxygenase-1 (HO-1), factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, blood triglyceride, blood glucose, and liver enzymes' activity were detected after the experimental period. Also, behavioral tests, hematoxylin and eosin (H&E) staining, and PET scan were performed after treatment. Post-treatment of TA improved locomotion and memory function (P < 0.001), and reduced neural cell death (P < 0.001) in the treatment group compared to UCCAO rats. Furthermore, long-term TA treatment significantly increased the levels of Nrf2 (P < 0.001), NQO-1 (P < 0.001), and HO-1 (P < 0.001) in the hippocampus of the treatment group compared to the UCCAO group. TA consumption in the treatment group applied its anti-inflammatory effects via reducing the activity of NF-κB and TNF-α in comparison with the UCCAO group (P < 0.001 for both). Blood triglyceride, blood glucose, and liver enzymes did not change considerably in the groups (P > 0.05). The current results indicate that long-term post-treatment of TA exhibits protective effects against memory deficit and motor dysfunction. The cellular mechanism of TA in hypoperfused rats might be associated with the activation of antioxidant pathways, especially the Nrf2 pathway, and suppressing inflammatory factors like NF-κB and TNF-α.
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http://dx.doi.org/10.1016/j.neulet.2021.136263DOI Listing
September 2021

How cytosolic compartments play safeguard functions against neuroinflammation and cell death in cerebral ischemia.

Metab Brain Dis 2021 Oct 26;36(7):1445-1467. Epub 2021 Jun 26.

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Ischemic stroke is the second leading cause of mortality and disability globally. Neuronal damage following ischemic stroke is rapid and irreversible, and eventually results in neuronal death. In addition to activation of cell death signaling, neuroinflammation is also considered as another pathogenesis that can occur within hours after cerebral ischemia. Under physiological conditions, subcellular organelles play a substantial role in neuronal functionality and viability. However, their functions can be remarkably perturbed under neurological disorders, particularly cerebral ischemia. Therefore, their biochemical and structural response has a determining role in the sequel of neuronal cells and the progression of disease. However, their effects on cell death and neuroinflammation, as major underlying mechanisms of ischemic stroke, are still not understood. This review aims to provide a comprehensive overview of the contribution of each organelle on these pathological processes after ischemic stroke.
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http://dx.doi.org/10.1007/s11011-021-00770-zDOI Listing
October 2021

Dimethyl fumarate protects the aged brain following chronic cerebral hypoperfusion-related ischemia in rats in Nrf2-dependent manner.

Nutr Neurosci 2021 Jun 19:1-11. Epub 2021 Jun 19.

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

It has been stated that chronic cerebral hypoperfusion (CCH) markedly prompts neuronal damage and affects cognition. Dimethyl fumarate (DMF), a nuclear erythroid 2-related factor 2 (Nrf2) activator, represents a class of molecules exhibiting neuroprotection. We explored the effect of DMF on CCH using a model of permanent left common carotid occlusion. The left common carotid artery was occluded and then DMF (100mg.kg) was orally administrated three times per week for four consecutive weeks. Behavioral rests, PET imaging and Hematoxylin and Eosin staining, were examined and also, the hippocampal level of inflammatory, Nrf2 antioxidant, neuronal plasticity and apoptotic factors were determined using Western blot analysis and related ELISA kits. The neurological deficit scores were significantly reduced in the treatment group compared with the CCH group (<0.001). DMF decreased the novel object recognition index (NOR) compared with the CCH group, while CCH + DMF increased the NOR compared with the CCH group (<0.001). CCH + DMF reduces the ratio of Bax/Bcl2 and capase-3 activity in comparison to the CCH group (<0.001). Treatment with DMF increased Nrf2, NAD(P)H dehydrogenase-1 and Heme oxygenase-1 and decreased Tumor necrosis factor α and Nuclear factor-κB density compared with the CCH group (<0.001). A significant increase in brain-derived neurotrophic factor and c-fos was found in DMF-treated rats compared with the CCH group (<0.001). Also, retinoic acid inhibits Nrf2 activation via DMF and increases inflammatory factors in hypoperfused rats' hippocampus compared with the CCH group (<0.001). Long-term DMF treatment induces the Nrf2 pathway and has beneficial effects on memory and motility in CCH.
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http://dx.doi.org/10.1080/1028415X.2021.1940429DOI Listing
June 2021

Highlighting the protective or degenerative role of AMPK activators in dementia experimental models.

CNS Neurol Disord Drug Targets 2021 May 26. Epub 2021 May 26.

Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

AMP-activated protein kinase (AMPK) is a serine/threonine kinase and a driving or deterrent factor in the development of neurodegenerative diseases and dementia. AMPK affects intracellular proteins like the mammalian target of rapamycin (mTOR). Peroxisome proliferator-activated receptor-γ coactivator 1-α (among others) contributes to a wide range of intracellular activities based on its downstream molecules such as energy balancing (ATP synthesis), extracellular inflammation, cell growth, and neuronal cell death (such as apoptosis, necrosis, and necroptosis). Several studies have looked at the dual role of AMPK in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington disease (HD) but the exact effect of this enzyme on dementia, stroke, and motor neuron dysfunction disorders has not been elucidated yet. In this article, we review current research on the effects of AMPK on the brain to give an overview of the relationship. More specifically, we review the neuroprotective or neurodegenerative effects of AMPK or AMPK activators like metformin, resveratrol, and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside on neurological diseases and dementia, which exert through the intracellular molecules involved in neuronal survival or death.
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http://dx.doi.org/10.2174/1871527320666210526160214DOI Listing
May 2021

Probiotic Supplementation Improved Capecitabine Protective Effect against Gastric Cancer Growth in Male BALB/c Mice.

Nutr Cancer 2021 14;73(10):2089-2099. Epub 2020 Oct 14.

Department of Pathology, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.

The gastric cancer (GC) is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Herein, we studied the effects of probiotics () on subcutaneous implantation of xenograft GC. Moreover, the effect of probiotics () was compared with the capecitabine drug as known used drug against GC. Human GC tissue was obtained from patients with gastric adenocarcinoma and grafted into mice armpit. Probiotic () was given to animals by gavage 2 weeks prior to GC and 4 weeks after GC induction. Also, capecitabine was orally added through feeding tube at the last week of treatment procedure. All grafted animals received cyclosporine a day before the surgery and during the study period to prevent graft rejection. Capecitabine-probiotic complex reduced the size of the axillary implanted GC when compared with control group. Furthermore, combination of capecitabine and probiotic increased apoptotic and necrotic responses in the grafted tumor, blood cells (red blood cells, white blood cells, and platelet counts) in comparison with capecitabine. Probiotic () administration effectively improved the therapeutic index and outcomes, and also, improved the therapeutic effects of the capecitabine.
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http://dx.doi.org/10.1080/01635581.2020.1832237DOI Listing
October 2021

High-protein and low-calorie diets improved the anti-aging Klotho protein in the rats' brain: the toxic role of high-fat diet.

Nutr Metab (Lond) 2020 15;17:86. Epub 2020 Oct 15.

Department of Physiology, School of Medicine, Tehran University of Medical Sciences, P.O.box: 1417613151, Tehran, Iran.

Background: In the current study, our specific aim was to characterize the Klotho protein and expression levels in the hippocampus and prefrontal cortex of old rats treated with different diets (high-fat, high-protein, low-calorie, high-protein and low-calorie).

Methods: Rats were treated with high-fat, high-protein, low-calorie, low-calorie high-protein diets for 10 weeks and then behavioral and molecular assessments were evaluated.

Results: Statistical analysis showed the percentage of open arm time was increased in the high-protein, low-calorie and low-calorie high-protein groups compared with old control (old-C) rats. The percentage of open arm entries was increased in the low-calorie and low-calorie high-protein group compared with old-C rats. The body weight and serum triglyceride were decreased in the low-calorie and low-calorie high-protein groups in comparison to control old rats. Low-calorie and low-calorie high-protein treatments statistically enhanced caspase-3 level compared with old-C rats in the hippocampus and prefrontal cortex. Treatment of old rats with high-protein, low-calorie and low-calorie high-protein could increase Klotho-α level compared with control old rats. The levels of Klotho-α, c-fos and brain-derived neurotrophic factors were decreased in the low-calorie high-protein group in Klotho inhibitor's presence compared with the low-calorie high-protein group.

Conclusion: According to our findings, Klotho-α level was reduced in old rats. Low-calorie, high-protein and particularly low-calorie high-protein diets increased this protein level and consequently increased neuronal plasticity and improved memory function.

Graphic Abstract:
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http://dx.doi.org/10.1186/s12986-020-00508-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559193PMC
October 2020

Toxic effect of calcium/calmodulin kinase II on anxiety behavior, neuronal firing and plasticity in the male offspring of morphine-abstinent rats.

Behav Brain Res 2020 10 22;395:112877. Epub 2020 Aug 22.

Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Pharmacology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran. Electronic address:

Studies have shown that epigenetic changes such as alteration in histone acetylation and DNA methylation in various brain regions play an essential role in anxiety behavior. According to the critical role of calcium/calmodulin protein kinaseII (CaMKII) in these processes, the present study examined the effect of CaMKII inhibitor (KN93) on neuronal activity and level of c-fos in the amygdala and nucleus accumbens (NAC) in the offspring of morphine-exposed parents. Adult male and female Wistar rats received morphine orally (for 21 days). After the washout period (10 days), rats were mated with either drug-naïve or morphine-exposed rats. KN93 was microinjected into the brain of male offspring. The anxiety-like behavior, the neuronal firing rate in the NAC and the amygdala and level of c-fos were assessed by related techniques. Data showed the offspring with one and/or two morphine-abstinent parent(s) had more anxiety-like behavior than the control group. However, the administration of KN-93 decreased anxiety in the offspring of morphine-exposed rats compared with saline-treated groups. The expression level of the c-fos was not significantly altered by the inhibition of CaMKII in the amygdala, but the c-fos level was reduced in the NAC. The neuronal firing rate of these groups was associated with an increase in the amygdala in comparison to the saline groups but was decreased in the NAC. Results showed that CaMKII had a role in anxiety-like behavior in the offspring of morphine-exposed parents, and changes in neuronal firing rate and c-fos level in the NAC might be involved in this process.
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http://dx.doi.org/10.1016/j.bbr.2020.112877DOI Listing
October 2020

Repeated Administration of Baclofen Modulates TRPV-1 Channel Expression by PKC Pathway in Dorsal Root Ganglia of Spinal Cord in a Morphine Tolerance Model of Rats

Iran Biomed J 2020 11 21;24(6):379-85. Epub 2020 Jun 21.

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

Background: Tolerance and dependence to anti-nociceptive effect of morphine restricted its use. Nowadays co-administration of morphine and other drugs suggests diminishing this tolerance. Baclofen is one of the drugs that may be beneficial in the attenuation of tolerance to morphine. Studies have shown that changes in transient receptor potential vanilloid type 1 (TRPV-1) expression during administration of morphine have a pivotal role in developing morphine tolerance. Therefore, the effect of baclofen on TRPV-1 expression during chronic administration of morphine was investigated in this study.

Methods: A total of 48 rats were divided into four groups of control, morphine single injection, morphine tolerance, and morphine tolerance + baclofen. To induce morphine tolerance in rats, animals received 10 mg/kg of i.p. morphine sulfate once a day for 10 days. In the treatment group, baclofen (0.5 mg/kg) was injected for 10 days, before morphine injection. Finally, to evaluate baclofen treatment on morphine analgesia and hyperalgesia, thermal hyperalgesia and formalin test were used. TRPV-1 and protein kinase C (PKC) expression and protein production in DRG of spinal cord were then evaluated by real-time PCR and Western blot.

Results: In baclofen treatment group, thermal hyperalgesia and formalin test improved in comparison with morphine tolerance group. In morphine tolerance group, both TRPV-1/PKC gene expression and protein levels increased in comparison with the control group. However, following the baclofen treatment, the TRPV-1 and PKC levels decreased.

Conclusion: Baclofen can enhance anti-nociceptive effect of morphine by modulating TRPV-1 channel and PKC activity.
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http://dx.doi.org/10.29252/ibj.24.6.374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601548PMC
November 2020

Adipose-Derived Mesenchymal Stem Cells and Conditioned Medium Attenuate the Memory Retrieval Impairment During Sepsis in Rats.

Mol Neurobiol 2020 Sep 19;57(9):3633-3645. Epub 2020 Jun 19.

Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, 1417613151, Iran.

In this study, we hypothesized that sepsis induction impairs memory retrieval in rats while transplanted mesenchymal stem cells (MSCs) and MSC-conditioned medium (MSC-CM) application are capable of attenuating those complications. MSCs were obtained from adipose tissue of rats and at the second culture passage; MSCs and MSC-CM were collected. Rats were randomly divided into four experimental groups: sham, CLP, MSC, and MSC-CM. Sepsis was induced by cecal ligation and puncture (CLP) model in the CLP, MSC, and MSC-CM groups. The MSC group received 1 × 10 MSCs/rat (i.p., 2 h after CLP surgery); the MSC-CM rats received the conditioned medium (CM) from 1 × 10 MSCs intraperitoneally 2 h after sepsis induction. Novel object recognition test, sepsis score, and blood pressure measurement were performed 24 h after the treatments. The right hippocampus was taken for western blot analysis. CLP rats showed a significantly higher sepsis score and systolic blood pressure. They also had a significant increase in the phosphorylated form of CAMKII-α, cleaved caspase 3 and Bax/Bcl2 ratio, and a reduction in c-fos protein in the hippocampus tissue samples compared with the sham group. MSC transplantation and MSC-CM administration significantly decreased the mean sepsis score and prevented sepsis-induced attenuation of blood pressure compared with the CLP rats. Animals in the MSC and MSC-CM groups showed a better memory retrieval, attenuation in phosphorylated form of CAMKII-α, cleaved caspase 3 and Bax/Bcl ratio, and an increase in c-fos protein expression compared with the CLP group. It seems that CAMKII and c-fos are inversely involved in regulating memory processes in hippocampus. Phosphorylated form of CaMKII-α overexpression may impair the ability of object recognition. Our findings confirmed that MSC-CM application has more advantages compared with transplanted MSCs and may be offered as a promising therapy for inflammatory diseases such as severe sepsis.
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http://dx.doi.org/10.1007/s12035-020-01991-6DOI Listing
September 2020

Effect of morphine exposure on novel object memory of the offspring: The role of histone H3 and ΔFosB.

Brain Res Bull 2020 03 17;156:141-149. Epub 2020 Jan 17.

Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran. Electronic address:

It has been demonstrated that alteration in histone acetylation in the regions of the brain involved in the reward which may have an important role in morphine addiction. It is well established that epigenetic changes prior to birth influence the function and development of the brain. The current study was designed to evaluate changes in novel object memory, histone acetylation and ΔFosB in the brain of the offspring of morphine-withdrawn parents. Male and female Wistar rats received morphine orally for 21 following days. After ten days of abstinent, they were prepared for mating. The male offspring of the first parturition were euthanized on postnatal days 5, 21, 30 and 60. The novel object recognition (NOR) test was performed on adult male offspring. The amount of acetylated histone H3 and ΔFosB were evaluated in the prefrontal cortex (PFC) and hippocampus using western blotting. Obtained results indicated that the discrimination index in the NOR test was decreased in the offspring of morphine-withdrawn parents as compared with morphine-naïve offspring. In addition, the level of acetylated histone H3 was decreased in the PFC and hippocampus in the offspring of morphine-withdrawn parents during lifetime (postnatal days 5, 21, 30 and 60). In the case of ΔFosB, it also decreased in these regions in the morphine-withdrawn offspring. These results demonstrated that parental morphine exposure affects NOR memory, and decreased the level of histone H3 acetylation and ΔFosB in the PFC and hippocampus. Taken together, the effect of morphine might be transmitted to the next generation even after stop consuming morphine.
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http://dx.doi.org/10.1016/j.brainresbull.2020.01.011DOI Listing
March 2020

Oxidative stress enzymes are changed in opioid abusers and multidrug abusers.

J Clin Neurosci 2020 Feb 8;72:365-369. Epub 2020 Jan 8.

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

The current study was designed to measure malondialdehyde level (MDA), super oxide dismutase (SOD) activity and COX-2 protein level in the prefrontal cortex (PFC) of drug-abusers. A total of 101 male drug abusers and 13 control subjects were gathered from the Iranian Legal Medicine center, Kahrizak, Tehran. Kind of death was determined by forensic pathologists, and the kind of drugs of abuse was detected using hair analysis. The medial prefrontal cortex (mPFC), lateral prefrontal cortex (lPFC), and orbitofrontal cortex (OFC) were dissected and were kept at -80 °C, until starting the assays. Our results indicated that the level of MDA was increased in the mPFC, lPFC and OFC of pure-opioid and multi-drug abusers compared with the control group. The SOD activity was reduced in the mPFC, lPFC and OFC of abusers in comparison to the control group. The protein level of COX-2 was decreased in the mPFC and lPFC of multi-drug abusers compared with the control group. This elevation in oxidative stress might be due to the increase of dopamine (as a consequence of drug abuse) or the direct effect of opioids and other drugs of abuse on oxidative agents. Antioxidant agents may be useful in preventing the damaging effect of oxidative agents in the brain of drug-addicted persons.
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http://dx.doi.org/10.1016/j.jocn.2019.12.064DOI Listing
February 2020

Long-term NaHS administration reduces oxidative stress and apoptosis in a rat model of left-side varicocele.

Andrologia 2020 Mar 3;52(2):e13496. Epub 2019 Dec 3.

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

The main aim of this study was to assay the testicular H S levels in the varicocele rat model and then to investigate the protective effects of NaHS on morphometric changes, sperm parameters, oxidative stress and apoptosis markers in rat's testis. D,L-propargylglycine (PAG) was administrated to show the effects of cystathionine γ-lyase enzyme (CSE) inhibition in the varicocele. Rats were assigned to four groups: (a) Sham, (b) varicocele, (c) varicocele + PAG and (d) varicocele + NaHS. Animals in varicocele + NaHS group received 30 µmol/L NaHS in drinking water for 56 days. In the varicocele + PAG group, animals received PAG 19 mg/kg twice a week. Morphometric assessment, oxidative stress markers, testicular H S levels, sperm parameters, TUNEL assay and expression of Bax/Bcl2 were evaluated at the end of experiment. Testicular H S levels were significantly decreased in varicocele group. NaHS significantly improved sperm parameters, morphometric characteristics and oxidative stress compared to varicocele group. Oxidative stress status deteriorated in the PAG group compared to the varicocele group. This study showed that a low testicular H S level might play a critical role in male infertility. Thus, NaHS administration may be a promising treatment strategy for male infertility in varicocele. In addition, CSE may not be the only important enzyme in testicular H S production.
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http://dx.doi.org/10.1111/and.13496DOI Listing
March 2020

Parental morphine exposure affects repetitive grooming actions and marble burying behavior in the offspring: Potential relevance for obsessive-compulsive like behavior.

Eur J Pharmacol 2019 Dec 3;865:172757. Epub 2019 Nov 3.

Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran. Electronic address:

Family, adoption and twin studies have highlighted the significant role of heritable influences on individual differences in opioid addiction. Meanwhile, obsessive-compulsive disorder (OCD) is a disorder wherein the individual experiences recurring thoughts that cause irrational fears and anxiety. In the present study, adult male and female rats received morphine solution for 21 days and were drug-free for 10 days. Offspring were used in 4 distinct groups; (1) paternal morphine-exposed, (2) maternal morphine-exposed, (3) maternal and paternal morphine-exposed, and (4) drug-naïve subjects. We assessed the grooming behavior and marble burying test as an indicator of obsessive-compulsive behavior. To clarify the mechanisms underlying these changes, the mRNA level of BDNF, the phosphorylation level of CREB and the protein level of D2 dopamine receptor (DR) were evaluated in the nucleus accumbens (NAc). The grooming behavior in male offspring with one or two morphine-abstinent parent(s) increased compared with the offspring of drug naïve rats. In addition, the offspring of morphine-exposed parents buried more marbles when compared with the offspring of drug-naïve parents. Also, the BDNF mRNA was down-regulated in the NAC. However, the levels of phospho-CREB and D2 DR were elevated. Previous studies indicated that exposure to morphine in adulthood enhances the risk of psychiatric disorders in offspring. OCD is one the comorbid disorders with addiction and increases the risk of substance abuse disorder in patients. In this survey, we found that morphine exposure in parents before gestation can encourage obsessive-compulsive behavior in offspring.
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http://dx.doi.org/10.1016/j.ejphar.2019.172757DOI Listing
December 2019

Activation of D1-like dopamine receptors is involved in the impairment of spatial memory in the offspring of morphine-abstinent rats.

Neurosci Res 2020 Sep 17;158:37-46. Epub 2019 Oct 17.

Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Pharmacology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran. Electronic address:

Accumulating evidence suggests that epigenetic mechanisms play an essential role in the formation and maintenance of memory as well as addiction. In this study, we examined the role of D1-like dopamine receptor (D1 DR) on spatial memory in the offspring of morphine-abstinent rats. Adult male and female rats received morphine orally for 21 days and were drug-free for ten days. The rats were prepared to mate and the offspring were divided into four groups: offspring of drug-naïve parents, offspring of maternal morphine-exposed, offspring of paternal morphine-exposed, and PME + MME group. Saline or SCH23390 was injected into the hippocampus and prefrontal (PFC), and the Morris Water Maze task was performed. Afterward, the rats were sacrificed, and phosphorylated-CREB (p-CREB) was assessed using Western blotting. The data obtained from saline-treated offspring indicated that spatial memory was deteriorated in the offspring of morphine-abstinent parents compared with the control which improved when they received SCH23390. The level of p-CREB also decreased in the hippocampus, while it increased in the PFC and hippocampus after SCH23390 administration. Our results suggested that morphine exposure before conception could induce impairment in spatial memory in the offspring. Since D1 DR was up-regulated in the PFC of the offspring, blocking D1 DR led to improved memory deficit in the offspring of morphine-abstinent rats. Improvement of memory is correlated to p-CREB level in the hippocampus and PFC.
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http://dx.doi.org/10.1016/j.neures.2019.10.003DOI Listing
September 2020

Age-related difference in protective effect of early post-conditioning on ischemic brain injury: possible involvement of MAP-2/Synaptophysin role.

Metab Brain Dis 2019 12 30;34(6):1771-1780. Epub 2019 Aug 30.

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

Brain Ischemia/Reperfusion (I/R) injury leads to the failure of the microtubules function and neuronal death. Ischemic post-conditioning is defined as a series of rapid alternating interruptions of blood flow in the first seconds of reperfusion. In the present study, the caspase-3, Microtubule-Associated Protein-2 (MAP-2), Protein Kinase C α (PKCα), c-fos, and synaptophysin were evaluated in the hippocampus of focal I/R post-conditioning model in a time -dependent study in aged and young rats. Adult and aged rats were subjected to right MCAO for 30 min and post-conditioned (10 s) for 3 cycles. Sensory-motor tests were performed, and locomotion and anxiety-like behavior were evaluated. Molecular tests were done by detection kit, RT-PCR, and Western blotting techniques. Ninety-six hours after I/R post-conditioning, neurological signs, locomotion, anxiety-like behavior, and ischemic area were improved in young rats compared to 6 h after I/R post-conditioning (P < 0.001). Caspase-3 activity declined in the hippocampus and cortex of I/R post-conditioned young rats in 96 h after I/R post-conditioning compared with 6 h after I/R post-conditioning (P < 0.001). Also, MAP-2 mRNA, MAP-2 protein level, PKCα, c-fos and synaptophysin protein levels were enhanced during post-conditioning in young rats in 96 h after I/R post-conditioning compared with 6 h after induction of I/R post-conditioning. The results of the present study suggested that, early post-conditioning might be considered as a candidate for therapeutic methods against I/R in the adult animals not aged rats. Moreover, inhibition of cell death in post-conditioned ischemic rats was found to be regulated by some neuroprotective molecules as well as MAP-2 and c-fos in young rats. Graphical abstract Graphical abstract representing the post-conditioning (PC) treatment timeline in adult and old rats.
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http://dx.doi.org/10.1007/s11011-019-00484-3DOI Listing
December 2019

Possible involvement of nucleus accumbens D1-like dopamine receptors in the morphine-induced condition place preference in the offspring of morphine abstinent rats.

Life Sci 2019 Sep 1;233:116712. Epub 2019 Aug 1.

Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Pharmacology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran. Electronic address:

Aims: Previous researches demonstrated that genetics and environment are two essential factors to prone individuals to drug abuse. Our previous data showed that dopaminergic system changed in the offspring of morphine-abstinent rats. In the present study, we evaluated whether blocking the D1-like dopamine receptors (DR) in the nucleus accumbens (NAC) affect the rewarding effect of morphine in the offspring of morphine-abstinent rats.

Main Methods: In the study, male and female Wistar rats received morphine orally for 21 days. Ten days after last morphine administration, animals prepared to mate either with a morphine abstinent or a drug-naive rat. Adult male offspring were chosen for further evaluation. SCH23390 (0.01 μg/rat) was administrated intra-NAC during the conditioning phase in the CPP paradigm (morphine 7.5 mg/kg).

Key Findings: Obtained data showed that morphine administration (7.5 mg/kg) did not induce conditioning in the offspring of the morphine-abstinent parent(s) (p < 0.001) compared with the control group. However, when SCH23390 injected in the NAC during the induction phase, the offspring of morphine-abstinent rats were conditioned with the same dose of morphine.

Significance: Previous studies showed that the offspring of morphine-abstinent rats are more prone to opioid consumption, and also developed tolerance to the rewarding effect of morphine. Current data indicated that blockade of D1-like DR in the NAC could prevent morphine-induced tolerance in these offspring. Therefore, inhibition of D1-like DR in the NAC might be a new candidate against morphine-reinforcing effect in the offspring of morphine-abstinent parent(s).
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http://dx.doi.org/10.1016/j.lfs.2019.116712DOI Listing
September 2019

Radiation-Induced Dual Oxidase Upregulation in Rat Heart Tissues: Protective Effect of Melatonin.

Medicina (Kaunas) 2019 Jun 27;55(7). Epub 2019 Jun 27.

Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran.

: Radiation-induced heart injury can lead to increased risk of heart failure, attack, and ischemia. Some studies proposed IL-4 and IL-13 as two important cytokines that are involved in late effects of ionizing radiation. On the other hand, these cytokines may, through upregulation of and , induce chronic oxidative stress, inflammation, and fibrosis. In this study, we evaluated the upregulation of and pathways in hearts following chest irradiation in rats and then detected possible attenuation of them by melatonin. : Twenty male Wistar rats were divided into four groups: (1) control; (2) melatonin treated (100 mg/kg); (3) radiation (15 Gy gamma rays); (4) melatonin treated before irradiation. All rats were sacrificed after 10 weeks and their heart tissues collected for real-time PCR (RT-PCR), ELISA detection of IL-4 and IL-13, as well as histopathological evaluation of macrophages and lymphocytes infiltration. : Results showed an upregulation of IL-4, , , and . The biggest changes were for and . Treatment with melatonin before irradiation could attenuate the upregulation of all genes. Melatonin also caused a reduction in IL-4 as well as reverse infiltration of inflammatory cells. : and may be involved in the late effects of radiation-induced heart injury. Also, via attenuation of these genes, melatonin can offer protection against the toxic effects of radiation on the heart.
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http://dx.doi.org/10.3390/medicina55070317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680718PMC
June 2019

Sorafenib-loaded PAMAM dendrimer attenuates liver fibrosis and its complications in bile-duct-ligated rats.

Can J Physiol Pharmacol 2019 Aug 9;97(8):691-698. Epub 2019 May 9.

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

We assessed the effect of sorafenib-loaded polyamidoamine (PAMAM) dendrimer on liver fibrosis induced by bile duct ligation (BDL). Male Wistar rats were divided into 9 groups: intact, sham, DMSO + BDL, BDL, sorafenib (30 mg/kg), sorafenib (60 mg/kg), PAMAM + BDL, sorafenib (30 mg/kg) + PAMAM + BDL, sorafenib (60 mg/kg) + PAMAM + BDL. BDL was induced and then rats were treated daily with sorafenib and (or) PAMAM for 4 weeks. Improvement of liver was detected via assessment of ascites formation, collagen deposition, liver blood flow, vascular endothelial growth factor level, and blood cells count. Sorafenib-loaded PAMAM dendrimer in both 30 and 60 mg/kg doses reduced ascites formation, reduced collagen deposition, and improved drug-induced hematological side effects of sorafenib alone in comparison with sorafenib-alone treatment. Sorafenib-loaded PAMAM dendrimer increased liver blood flow compared with sorafenib-received groups. Sorafenib-loaded PAMAM dendrimer reduced BDL-induced liver injury compared with sorafenib-received groups. Moreover, sorafenib-loaded PAMAM dendrimer decreased vascular endothelial growth factor level in serum and liver tissue in comparison with sorafenib-received groups. Sorafenib-loaded PAMAM dendrimer profoundly improved the therapeutic effects of sorafenib in BDL rats.
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http://dx.doi.org/10.1139/cjpp-2019-0141DOI Listing
August 2019

Parental morphine exposure enhances morphine (but not methamphetamine) preference and increases monoamine oxidase-B level in the nucleus accumbens.

Behav Pharmacol 2019 08;30(5):435-445

Iranian National Center for Addiction Studies.

Opioid addiction is one of the most crucial issues in the world. Opioid abuse by parents makes children more prone to many psychological disorders such as drug addiction. Therefore, this study was carried out to examine the effect of morphine exposure 10 days before gestation on morphine and methamphetamine preference in male offspring. Adult Wistar rats (male and female) received morphine orally for 21 days and were drug free for 10 days. Thereafter, they were allowed to mate with either a morphine-abstinent or drug-naive rat. The male offspring were tested for morphine and methamphetamine preference with a three-bottle choice test. Moreover, the rewarding effects of morphine and methamphetamine were evaluated using a conditioned place preference test. To determine the mechanisms underlying these changes, monoamine oxidase-B (MAO-B) level was measured in the nucleus accumbens (NAC). Offspring of morphine-abstinent mothers and offspring of both-abstinent parents were found to consume morphine more than those of other groups, but in the case of methamphetamine, there were no differences. In addition, the offspring of morphine-abstinent parent(s) did not condition with a high dose of morphine in the conditioned place preference test. Administration of methamphetamine induced conditioning at different doses in controls and offspring of one or two morphine-abstinent parent(s), and there were no effects of parental morphine exposure on the dose of methamphetamine that was required for conditioning. Moreover, the level of MAO-B was increased in the NAC of offspring of morphine-abstinent parents as compared with the control group. These results demonstrate that offspring of a morphine-abstinent mother and a drug-naive father and offspring of two morphine-abstinent parents were more susceptible to opioid but not methamphetamine addiction. Moreover, parental morphine consumption did not have any effect on the reinforcing effect of methamphetamine in their offspring but induced morphine tolerance in the offspring. Although the level of MAO-B was elevated in the NAC, this did not correlate with the methamphetamine preference in offspring.
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http://dx.doi.org/10.1097/FBP.0000000000000465DOI Listing
August 2019

NMDA receptors of blood lymphocytes anticipate cognitive performance variations in healthy volunteers.

Physiol Behav 2019 03 13;201:53-58. Epub 2018 Dec 13.

Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Institute for Cognitive Science Studies (ICSS), Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran. Electronic address:

Working memory (WM) system, temporarily stores information and uses this information for complex cognitive tasks. WM connects memory, emotional feelings and perception. Evidence compelling that N-methyl d-aspartate receptor (NMDAR) expression relatively affect WM performance in animal models. It has been suggested some peripheral blood lymphocyte's (PBL) receptors are similar with neuronal receptors in the brain, so we measured PBL's receptors changes as a marker of the neuronal receptor. In this study, we examined one hundred adult men with Wisconsin Card Sorting Test (WCST) as a tool for primary screening for executive function (EF) which include WM. Then, we selected fifty individuals with high and low WCST scores. With digit span and symmetry span tasks, we screened 20 samples for high WM group and 19 samples for low WM group. After separating PBL, we measured mRNA expression level changes in NMDAR subunits with Reverse transcription-polymerase chain reaction method. We demonstrated that GluN2D increased and GluN3A decreased in individuals with high WM compared with the low WM (P < .01 and P < .001, respectively). The expression levels of GluN2A, GluN2B, and GluN3B were not altered between two groups (P > .05). Modifying the PBL receptors could be future approaches to defend memory loss and concentrate the senses over WM-related processes in physiological and pathological statuses. We hypothesized that increasing in GluN2 subunits and decreasing in GluN3 subunits led to improving current via NMDAR and subsequently affect WM.
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http://dx.doi.org/10.1016/j.physbeh.2018.12.015DOI Listing
March 2019

Morphine exposure before conception affects anxiety-like behavior and CRF level (in the CSF and plasma) in the adult male offspring.

Brain Res Bull 2019 01 29;144:122-131. Epub 2018 Nov 29.

Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran. Electronic address:

It has been proven that exposure to some drugs even before gestation had transgenerational effects. To investigate the changes which induced by parental morphine exposure before gestation; mainly the anxiety-like behavior, Corticotropin Releasing Factor (CRF) level in the CSF and plasma, CRF Receptor 1 (CRFR1), and the level of protein kinase C (PKC-α) were evaluated in the male offspring. Male and female Wistar rats were exposed to morphine for 21 following days. Ten days after last drug exposure, animals were prepared for mating in 4 distinct groups as follow: drug-naïve female and male (used as control), drug-naïve female and morphine-abstinent male, drug-naïve male and morphine-abstinent female, and morphine abstinent male and female. Offspring were subjected to assess anxiety-like behavior (using elevated plus maze test). CSF and plasma were gathered, and the CRF level was evaluated by ELISA. Using real-time PCR, the CRFR1 level in the brain was evaluated. Results showed that anxiety-like behavior increased in the offspring of morphine-abstinent parent(s) compared with the control group. CRF level in the plasma and CSF also increased in the litter of morphine-abstinent parent(s). CRFR1 mRNA level was upregulated in the brain of offspring with one and/or two morphine-abstinent parent(s). Furthermore, the level of PKC-α was decreased in the brain of offspring which had one and/or two morphine-abstinent parent(s). Taken together, our findings indicated that morphine exposure even before gestation induced transgenerational effects via dysregulation of HPA axis which results in anxiety in the adult male offspring.
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http://dx.doi.org/10.1016/j.brainresbull.2018.11.022DOI Listing
January 2019

Alteration of dopamine receptors subtypes in the brain of opioid abusers: A postmortem study in Iran.

Neurosci Lett 2018 11 27;687:169-176. Epub 2018 Sep 27.

Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Dopamine is the most important neurotransmitter which is involved in reward and addiction. Repeated drug exposure can induce some adaptive changes in the molecular and cellular function of the mesolimbic dopaminergic system. Since the essential role of dopamine in the pathophysiology of drug addiction is proven, the changes in dopamine receptors level in the brain of opioid abusers and matched control subjects were investigated. Fifty-six opioid abusers and thirteen control subjects were obtained from Legal Medicine Center. The cause of death and the postmortem interval were determined by forensic pathologists. mRNA expression and protein level of dopamine receptors in the ventral tegmental area (VTA), nucleus accumbens (NAC) and amygdala were assessed. The mRNA and protein level of DRD1 increased in the VTA, NAC and amygdala of opioid abusers. DRD2 protein level increased in the VTA, NAC and amygdala of opioid abusers when compared with the control. DRD3 level decreased in all the brain regions except in the amygdala of opioid abusers in comparison with the control group. DRD4 mRNA level increased only in the amygdala of opioid abusers. There were no significant changes in the protein and mRNA levels of DRD4 in the VTA and NAC. In mRNA and protein level of DRD5, it followed the same pattern like DRD1. The current data suggest that adaptive changes in mRNA and protein level of dopamine receptors occurred in the brain of opioid abusers and the variations depended on the brain region.
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http://dx.doi.org/10.1016/j.neulet.2018.09.043DOI Listing
November 2018

Preventing morphine reinforcement with high-frequency deep brain stimulation of the lateral hypothalamic area.

Addict Biol 2019 07 8;24(4):685-695. Epub 2018 May 8.

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

Deep brain stimulation (DBS) has been proposed as a promising intervention for patients with treatment-refractory substance use disorder. Here, we investigated if high-frequency DBS in the lateral hypothalamic area (LHA) could affect drug-induced reinforcement. Rats were bilaterally implanted with bipolar stimulation electrodes in the LHA and trained to the morphine conditioned place preference. DBS (monophasic square pulses, 130 Hz, 100-microsecond pulse duration and 150 μA) was applied during the morphine-pairing trials (30 minutes daily for 4 days) or drug-free postconditioning test (15 minutes) to determine its effect on the acquisition or expression of morphine reward, respectively. LHA DBS during morphine-conditioning trials blocked subsequent preference for the drug-associated context. In contrast, DBS in the postconditioning phase failed to inhibit expression of morphine-induced conditioned place preference. These results were further controlled by ruling out significant changes by DBS in physical performance and anxiety-like behavior as measured by an open field test and by precluding anhedonia-like behavior as measured by sucrose consumption test. Our results suggest that LHA DBS can prevent development of morphine reward without diminishing the motivation for naturally rewarding stimuli. Therefore, the LHA could be a potential target for research in the field of DBS-based treatment of intractable substance use disorder. Further studies will be necessary to assess the translatability of these findings to the clinic.
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http://dx.doi.org/10.1111/adb.12634DOI Listing
July 2019

Is the Nociception Mechanism Altered in Offspring of Morphine-Abstinent Rats?

J Pain 2018 05 31;19(5):529-541. Epub 2018 Jan 31.

Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

To investigate the effect of parental drug abuse on children, nociception, electrophysiological alteration, mRNA expression of opioid receptors, and expression of certain intracellular proteins in offspring of morphine-abstinent rats were studied. Adult male and female animals received water-soluble morphine for 21 days. Ten days after the last morphine administration, animals were placed for mating in 4 groups as follows: healthy (drug naive) female and male, morphine-abstinent female and healthy male, morphine-abstinent male and healthy female, morphine-abstinent male and morphine-abstinent female. Their adult male offspring were tested for nociception, neuronal discharge in nucleus accumbens (NAC) and prefrontal cortex (PFC). Our results showed that nociception in male offspring of all morphine-abstinent parent(s) groups was significantly reduced, compared with the control group. In the offspring of morphine-abstinent parent(s) groups, sensitivity to the antinociceptive effect of morphine was enhanced in chronic as well as in acute phases of the formalin test. Neuronal electrical activity reduced in the offspring of the morphine-exposed parent(s) in NAC as well as PFC regions. Moreover, our findings show that opioid receptors' expressions (µ, κ, and δ) increased in NAC of the litter of morphine-abstinent parent(s), compared with the control group. In addition, the expression of κ receptors was remarkably increased in the PFC in morphine-abstinent parent group, relative to the control group. The phosphorylated levels of extracellular regulated kinase 1/2 and cyclic adenosine monophosphate responsive element binding protein were significantly higher in the offspring of the morphine-abstinent parent(s) than the control group in the NAC. Our results indicated that endogenous opioid is altered in offspring of the morphine-exposed parent(s) and that heritage has a major role.

Perspective: This study showed that nociception was reduced in offspring of morphine-abstinent rat(s) and also these litters had a low level of neuronal firing rate, and enhanced opioid receptors expression, especially in the NAC. Because these offspring are more sensitive to the analgesic effect of morphine, clinicians should consider this issue to manage the dosage of morphine for treating pain in children with an abstinent parent(s).
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http://dx.doi.org/10.1016/j.jpain.2017.12.268DOI Listing
May 2018

Differential impact of treadmill training on stroke-induced neurological disorders.

Brain Inj 2017 12;31(13-14):1910-1917. Epub 2017 Sep 12.

d Department of Physiology , Faculty of Medicine, Tehran University of Medical Sciences , Tehran , Iran.

Objective: Physical exercise contributes to improving stability against nerve injury caused by ischaemic stroke. Here we aimed to preliminarily investigate the effects of continuous endurance training (CET) and high-intensity interval training (HIT) on stroke-associated anxiety, locomotion, neurological assessments and P70S6 Kinase (P70S6K) activation as well. To do this, rats were trained according to HIT and CET protocols for 2 months prior to being subject to middle cerebral artery occlusion surgery.

Methods: Twenty-four hours later behavioural examination was performed by elevated plus maze (EPM) testing, open field and neurological scoring followed by cortical and hippocampal P70S6Ks immunoblotting.

Results: According to the obtained data pre-ischaemic HIT and CET similarly improved neurological performance, anxiety levels and locomotion in EPM and open field tests following ischaemic stroke while there was a remarkable rise in hippocampal and cortical P70S6K activation in the HIT group compared to the CET counterparts.

Conclusion: Behavioral and molecular data suggest that interval training is more beneficial rather than CET, but the distinct mechanisms of CET and HIT on memory are still topics to be discovered.
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http://dx.doi.org/10.1080/02699052.2017.1346287DOI Listing
July 2018

Exercise training with concomitant nitric oxide synthase inhibition improved anxiogenic behavior, spatial cognition, and BDNF/P70S6 kinase activation in 20-month-old rats.

Appl Physiol Nutr Metab 2018 Jan 30;43(1):45-53. Epub 2017 Aug 30.

e Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, PO box 141761-3151, Tehran, Iran.

This study aimed to investigate the effect of exercise and nitric oxide synthase (NOS) inhibition on memory, anxiety, and protein levels of brain-derived neurotrophic factor (BDNF) and P70S6 kinase (P70S6K). Twenty-month-old rats were divided into 6 groups: a control group, 2 groups treated with l-nitro-arginine methyl ester (L-NAME) (25 or 100 mg/kg) for 63 days, 2 groups treated with L-NAME (25 or 100 mg/kg) for 63 days plus 2 months of exercise, and 1 group treated with exercise. Behavioral tests were conducted to determine the anxiolytic and memory-improving role of exercise and NOS inhibition. BDNF, P70S6K, and cleaved caspase-3 protein levels in the hippocampus and prefrontal cortex were evaluated by Western blotting. Exercise and L-NAME (25 mg/kg) or their combination had an anxiolytic effect and improved spatial memory in old rats compared with the control or exercised group, respectively. Exercise and treatment with a low dose of L-NAME (25 mg/kg) each increased BDNF and P70S6K in the hippocampus and prefrontal cortex compared with levels in control rats. In comparison with exercise alone, co-treatment with exercise and a low dose of L-NAME (25 mg/kg) also increased BDNF and P70S6K in the hippocampus. The neuronal level of cleaved caspase-3 was reduced in the L-NAME (25 mg/kg) + exercise group compared with the exercised group. The L-NAME (100 mg/kg) + exercise treatment had no positive behavioral or molecular effects compared with exercise alone. The protective role of NOS inhibition and aerobic exercise against aging is probably modulated via BDNF and P70S6K in the brain.
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http://dx.doi.org/10.1139/apnm-2017-0313DOI Listing
January 2018

NMDA receptor adjusted co-administration of ecstasy and cannabinoid receptor-1 agonist in the amygdala via stimulation of BDNF/Trk-B/CREB pathway in adult male rats.

Brain Res Bull 2017 04 3;130:221-230. Epub 2017 Feb 3.

Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran; Institute for Cognitive Science Studies (ICSS), Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran; Medical Genomics Research Center, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran. Electronic address:

Consumption of cannabinoid receptor-1 (CB-1) agonist such as cannabis is widely taken in 3,4- methylenedioxymethamphetamine (MDMA) or ecstasy users; it has been hypothesized that co-consumption of CB-1 agonist might protect neurons against MDMA toxicity. N-methyl-d-aspartate (NMDA) receptors regulate neuronal plasticity and firing rate in the brain through Tyrosine-kinase B (Trk-B) activation. The molecular and electrophysiological association among NMDA and MDMA/Arachidonylcyclopropylamide (ACPA, a selective CB-1 receptor agonist) co-consumption was not well-known. Here, neuronal spontaneous activity, Brain-derived neurotrophic factor (BDNF), Trk-B and cAMP response element binding protein (CREB) phosphorylation levels were recognized in ACPA and MDMA co-injected rats. Besides, we proved the role of NMDA receptor on MDMA and ACPA combination on neuronal spontaneous activity and Trk-B/BDNF pathway in the central amygdala (CeA). Male rats were anesthetized with intra-peritoneal injections of urethane; MDMA, D-2-amino-5-phosphonopentanoate (D-AP5, NMDA receptor antagonist) were injected into CeA. ACPA was administrated by intra-cerebroventricular injection. Thirty minutes following injections, neuronal firing rate was recorded from CeA. Two hours after drug injection, amygdala was collected from brain for molecular evaluations. Single administration of MDMA and/or ACPA reduced firing rates compared with sham group in the CeA dose-dependently. Injection of D-AP5, ACPA and MDMA reduced firing rate compared with sham group (P<0.001). Interestingly, injection of ACPA+MDMA enhanced BDNF, Trk-B and CREB phosphorylation compared with MDMA groups. D-AP5, ACPA and MDMA co-injection decreased BDNF, Trk-B and CREB phosphorylation levels compared with ACPA+MDMA in the amygdala (P<0.01). Probably, NMDA receptors are involved in the protective role of acute MDMA+ACPA co-injection via BDNF/Trk-B/CREB pathways.
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http://dx.doi.org/10.1016/j.brainresbull.2017.01.020DOI Listing
April 2017

Subchronic metformin pretreatment enhances novel object recognition memory task in forebrain ischemia: behavioural, molecular, and electrophysiological studies.

Can J Physiol Pharmacol 2017 Apr 4;95(4):388-395. Epub 2016 Nov 4.

d Medical School, Alborz University of Medical Sciences, Karaj, Iran.

Metformin exerts its effect via AMP-activated protein kinase (AMPK), which is a key sensor for energy homeostasis that regulates different intracellular pathways. Metformin attenuates oxidative stress and cognitive impairment. In our experiment, rats were divided into 8 groups; some were pretreated with metformin (Met, 200 mg/kg) and (or) the AMPK inhibitor Compound C (CC) for 14 days. On day 14, rats underwent transient forebrain global ischemia. Data indicated that pretreatment of ischemic rats with metformin reduced working memory deficits in a novel object recognition test compared to group with ischemia-reperfusion (I-R) (P < 0.01). Pretreatment of the I-R animals with metformin increased phosphorylated cyclic-AMP response element-binding protein (pCREB) and c-fos levels compared to the I-R group (P < 0.001 for both). The level of CREB and c-fos was significantly lower in ischemic rats pretreated with Met + CC compared to the Met + I-R group. Field excitatory postsynaptic potential (fEPSP) amplitude and slope was significantly lower in the I-R group compared to the sham operation group (P < 0.001). Data showed that fEPSP amplitude and slope was significantly higher in the Met + I-R group compared to the I-R group (P < 0.001). Treatment of ischemic animals with Met + CC increased fEPSP amplitude and slope compared to the Met + I-R group (P < 0.01). We unravelled new aspects of the protective role of AMPK activation by metformin, further emphasizing the potency of metformin pretreatment against cerebral ischemia.
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http://dx.doi.org/10.1139/cjpp-2016-0260DOI Listing
April 2017

The involvement of protein kinase G inhibitor in regulation of apoptosis and autophagy markers in spatial memory deficit induced by Aβ.

Fundam Clin Pharmacol 2016 Aug 6;30(4):364-75. Epub 2016 Apr 6.

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

The role of nitric oxide/protein kinase G (NO/PKG) in neurodegenerative disorders is controversial in different circumstances. PKG affects neurons both by itself and as a result of increased NO concentration. In this study, we examined the influence of PKG on spatial memory by intrahippocampal administration of three different concentrations of KT5823 as a PKG inhibitor. Morris water maze (MWM) was used for evaluation of behavioral alterations. We also measured the apoptosis and autophagy markers as two probable interfering pathways with PKG signaling by Western blot method. We found that in Aβ-pretreated rats, intrahippocampus infusions of 2.5, 5, and 10 μm/side of KT5823 led to a significant reduction in escape latency and traveled distance comparing to Aβ-treatment group. Our molecular findings indicated that KT5823 could induce autophagy and attenuate apoptotic markers at distinct doses. Here, we can conclude that in addition to other parameters, apoptosis, and autophagy in part have damaging and protective roles, respectively, in PKG signaling mechanisms. As autophagy-related proteins lose their functions in neurodegenerative diseases, we can suggest that autophagy can be one of the therapeutic aims for remedy of Alzheimer's disease.
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http://dx.doi.org/10.1111/fcp.12196DOI Listing
August 2016

Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: the role of the AMPK/BDNF/P70SK signalling pathway.

Pharm Biol 2016 Oct 9;54(10):2211-9. Epub 2016 Mar 9.

e Physiology Research Center and Department of Physiology, School of Medicine , Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran.

Context Metformin induced AMP-activated protein kinase (AMPK) and protected neurons in cerebral ischaemia. Objective This study examined pretreatment with metformin and activation of AMPK in molecular and behavioral levels associated with memory. Materials and methods Rats were pretreated with metformin (200 mg/kg) for 2 weeks and 4-vessels occlusion global cerebral ischaemia was induced. Three days after ischaemia, memory improvement was done by passive avoidance task and neurological scores were evaluated. The amount of Brain-Derived Neurotropic Factor (BDNF) and phosphorylated and total P70S6 kinase (P70S6K) were measured. Results Pretreatment with metformin (met) in the met + ischaemia/reperfusion (I/R) group reduced latency time for enter to dark chamber compared with the sham group (p < 0.001) and increased latency time compared with the I/R group (p < 0.001). Injection of Compound C (CC) (as an AMPK inhibitor) concomitant with metformin reduced latency time in I/R rats compared with the I/R + met group (p < 0.05). Neurological scores were reduced in met treated rats compared with the sham group. Pretreatment with metformin in I/R animals reduced levels of pro-BDNF compared with the I/R group (p < 0.001) but increased that compared with the sham group (p < 0.001). The level of pro-BDNF decreased in the met + CC + I/R group compared with the met + I/R group (p < 0.01). Pretreatment with metformin in I/R animals significantly increased P70S6K compared with the I/R group (p < 0.001). Conclusion Short-term memory in ischaemic rats treated with metformin increased step-through latency; sensory-motor evaluation was applied and a group of ischaemia rats that were pretreated with metformin showed high levels of BDNF, P70S6K that seemed to be due to increasing AMPK.
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http://dx.doi.org/10.3109/13880209.2016.1150306DOI Listing
October 2016
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