Publications by authors named "Mehrdad Roghani"

125 Publications

Differential Effect of Amyloid Beta1-40 on Short-term and Long-term Plasticity in Dentate Gyrus of a Rat Model of Alzheimer Disease.

Basic Clin Neurosci 2020 Jul-Aug;11(4):517-524. Epub 2020 Jul 1.

Neurophysiology Research Center, Shahed University, Tehran, Iran.

Introduction: Synaptic plasticity is inappropriately affected by neurodegenerative diseases, including Alzheimer Disease (AD). In this study, we examined the effect of intrahippocampal amyloid-beta (Aβ1-40) on dentate gyrus Long-term Potentiation (LTP) and presynaptic short-term plasticity in a rat model of AD.

Methods: The experimental groups in this research included the control with no treatment, sham-operated receiving the vehicle (normal saline), and Aβ-lesioned groups. For modeling AD, aggregated Aβ1-40 (10 μg/2 μl on each side) was injected into the hippocampal CA1. Three weeks later, Population Spike (PS) amplitude and slope ratios were determined at different Inter-pulse Intervals (IPI) of 10, 20, 30, and 50 ms as a valid indicator of the short-term presynaptic facilitation and/or depression. In addition, PS amplitude and slope were taken as an index of long-term synaptic plasticity after application of High-frequency Stimulation (HFS) to induce LTP in the medial perforant-dentate gyrus pathway.

Results: No significant differences were noted amongst the experimental groups regarding fEPSP slope and paired-pulse indices as indicators of short-term plasticity. In contrast, fEPSP slope and PS amplitude significantly decreased following the application of HFS in Aβ-injected group. In addition, there was no significant difference between the control and sham-operated groups regarding the mentioned parameters.

Conclusion: Findings of this study clearly demonstrated that microinjection of Aβ1-40 into the CA1 could impair LTP in dentate gyrus but could not modify short-term plasticity.
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http://dx.doi.org/10.32598/bcn.9.10.190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878034PMC
July 2020

Dual Profile of Environmental Enrichment and Autistic-Like Behaviors in the Maternal Separated Model in Rats.

Int J Mol Sci 2021 Jan 25;22(3). Epub 2021 Jan 25.

Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.

Background: Environmental Enrichment (EE) has been suggested as a possible therapeutic intervention for neurodevelopmental disorders such as autism. Although the benefits of this therapeutic method have been reported in some animal models and human studies, the unknown pathophysiology of autism as well as number of conflicting results, urge for further examination of the therapeutic potential of EE in autism. Therefore, the aim of this study was to examine the effects of environmental enrichment on autism-related behaviors which were induced in the maternal separation (MS) animal model.

Material And Methods: Maternally separated (post-natal day (PND) 1-14, 3h/day) and control male rats were at weaning (PND21) age equally divided into rats housed in enriched environment and normal environment. At adolescence (PND42-50), the four groups were behaviorally tested for direct social interaction, sociability, repetitive behaviors, anxiety behavior, and locomotion. Following completion of the behavioral tests, the blood and brain tissue samples were harvested in order to assess plasma level of brain derived neurotrophic factor (BDNF) and structural plasticity of brain using ELISA and stereological methods respectively.

Results: We found that environmental enrichment reduced repetitive behaviors but failed to improve the impaired sociability and anxiety behaviors which were induced by maternal separation. Indeed, EE exacerbated anxiety and social behaviors deficits in association with increased plasma BDNF level, larger volume of the hippocampus and infra-limbic region and higher number of neurons in the infra-limbic area ( < 0.05). : We conclude that environmental enrichment has a significant improvement effect on the repetitive behavior as one of the core autistic-like behaviors induced by maternal separation but has negative effect on the anxiety and social behaviors which might have been modulated by BDNF.
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http://dx.doi.org/10.3390/ijms22031173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865216PMC
January 2021

Melatonin reverses cognitive deficits in streptozotocin-induced type 1 diabetes in the rat through attenuation of oxidative stress and inflammation.

J Chem Neuroanat 2021 Mar 1;112:101902. Epub 2020 Dec 1.

Neurophysiology Research Center, Shahed University, Tehran, Iran. Electronic address:

Uncontrolled diabetes mellitus (DM) is linked to attentional deficits and cognition deterioration. The neurohormone melatonin is an endogenous synchronizer of circadian rhythms with multiple protective properties. This research was designed to assess its effect against learning and memory decline in streptozotocin (STZ)-induced diabetic rats. Rats were assigned to control, melatonin-treated control, diabetic, and melatonin-treated diabetic groups. Melatonin was administered i.p. at a dose of 10 mg/kg/day for 47 days. Treatment of diabetic rats with melatonin reversed decline of spatial recognition memory in Y maze, performance of rats in novel object discrimination, and retention and recall in passive avoidance tasks. Furthermore, melatonin appropriately attenuated hippocampal malondialdehyde (MDA) and reactive oxygen species (ROS) and improved superoxide dismutase (SOD) activity and improved mitochondrial membrane potential (MMP) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) with no significant effect on nitrite, glutathione (GSH) and catalase activity. Besides, hippocampal level of acetylcholinesterase (AChE), glial fibrillary acidic protein (GFAP), nuclear factor-kappaB (NF-κB), interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) decreased following melatonin treatment. There was also a reduction of dendritic spines of pyramidal neurons of hippocampal CA1 area in diabetic group that was significantly alleviated upon melatonin treatment. Melatonin could ameliorate learning and memory disturbances in diabetic rats through mitigation of cholinesterase activity, astrocytes, oxidative stress and inflammation and also via upregulation of some antioxidants in addition to its prevention of dendritic spine loss.
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http://dx.doi.org/10.1016/j.jchemneu.2020.101902DOI Listing
March 2021

Ellagic acid ameliorates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis: Involvement of NLRP3 and pyroptosis.

J Chem Neuroanat 2021 Jan 17;111:101891. Epub 2020 Nov 17.

Neurophysiology Research Center, Shahed University, Tehran, Iran. Electronic address:

Multiple sclerosis (MS) is presented as the most common autoimmune and demyelinating neurological disorder with incapacitating complications and with no definite therapy. Most treatments for MS mainly focus on attenuation of its severity and recurrence. To model MS reliably to study pathogenesis and efficacy of possible chemicals, experimental autoimmune encephalomyelitis (EAE) condition is induced in rodents. Ellagic acid is a neuroprotective polyphenol that can protect against demyelination. This study was planned and conducted to assess its possible beneficial effect in MOG-induced EAE model of MS with emphasis on uncovering its modes of action. Ellagic acid was given p.o. (at doses of 10 or 50 mg/kg/day) after development of clinical signs of MS to C57BL/6 mice immunized with MOG. Results showed that ellagic acid can ameliorate severity of the disease and partially restore tissue level of TNFα, IL-6, IL-17A and IL-10. Besides, ellagic acid lowered tissue levels of NLRP3 and caspase 1 in addition to its mitigation of neuroinflammation, demyelination and axonal damage in spinal cord specimens of EAE group. As well, ellagic acid treatment prevented reduction of MBP and decreased GFAP and Iba1 immunoreactivity. Taken together, ellagic acid can decrease severity of EAE via amelioration of astrogliosis, astrocyte activation, demyelination, neuroinflammation and axonal damage that is partly related to its effects on NLRP3 inflammasome and pyroptotic pathway.
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http://dx.doi.org/10.1016/j.jchemneu.2020.101891DOI Listing
January 2021

Netrin-1 protects the SH-SY5Y cells against amyloid beta neurotoxicity through NF-κB/Nrf2 dependent mechanism.

Mol Biol Rep 2020 Dec 18;47(12):9271-9277. Epub 2020 Nov 18.

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

Many evidence confirms that amyloid beta 1-42 fragment (Aβ) causes neuroinflammation, oxidative stress, and cell death, which are related to progressive memory loss, cognitive impairments and mental disorders that will lead to Alzheimer's disease (AD) progression. Netrin-1, as a member of the laminins, has been proved to inhibit apoptosis and inflammation outside of nervous system, in addition to having a vital role in morphogenesis and neurogenesis of neural system. This study was designed to assess the protective effects of netrin-1 in SH-SY5Y human neuroblastoma cell line exposed to Aβ and to explore some mechanisms that underlie netrin-1 effects. Cultured SH-SY5Y neuroblast-like cells were treated with netrin-1 prior to Aβ exposure and the effects were assessed by MTT and ELISA assay kits. Netrin- 1 pretreatment of Aβexposed SH-SY5Y human neuroblastoma cells attenuated Aβ induced toxic effects, increased cell viability and partially restored levels of 3 inflammatory and oxidative stress biomarkers including: nuclear factor erythroid 2-like 2 (Nrf2), tumor necrosis factor alpha (TNFα) and nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB). Based on the findings of this study, netrin-1 represents a promising therapeutic bio agent to abrogate cellular inflammation and reactive oxygen species (ROS) activation induced by Aβ in the SH-SY5Y cell model of AD.
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http://dx.doi.org/10.1007/s11033-020-05996-1DOI Listing
December 2020

Fetal Hypothyroidism Impairs Aortic Vasorelaxation Responses in Adulthood: Involvement of Hydrogen Sulfide and Nitric Oxide Cross talk.

J Cardiovasc Pharmacol 2021 Feb;77(2):238-244

Neurophysiology Research Center, Shahed University, Tehran, Iran.

Abstract: Thyroid hormones have a wide range of effects on growth, differentiation, evolution, metabolism, and physiological function of all tissues, including the vascular bed. In this study, the effect of fetal hypothyroidism on impairment of aortic vasorelaxation responses in adulthood was investigated with emphasis on possible involvement of hydrogen sulfide (H2S)/nitric oxide interaction. Two groups of female rats were selected. After mating and observation of vaginal plaque, one group received propylthiouracil (200 ppm in drinking water) until the end of pregnancy and another group had no propylthiouracil treatment during the fetal period. In adult rats, aortic relaxation responses to l-arginine and GYY4137 were assessed in the presence or absence of Nω-nitro-L-arginine methyl ester hydrochloride and dl-propargylglycine in addition to the biochemical measurement of thyroid hormones and some related factors. Obtained findings showed a lower vasorelaxation response for GYY4137 and l-arginine in the fetal hypothyroidism group, and preincubation with Nω-nitro-L-arginine methyl ester hydrochloride or dl-propargylglycine did not significantly aggravate this weakened relaxation response. In addition, aortic levels of sirtuin 3, endothelial nitric oxide synthase, cystathionine gamma-lyase, and H2S were significantly lower in the fetal hypothyroidism group. Meanwhile, no significant changes were obtained regarding serum levels of thyroid hormones including free triiodothyronine;, total triiodothyronine, free thyroxine, total thyroxine, and thyroid-stimulating hormone in adult rats. It can be concluded that hypothyroidism in the fetal period has inappropriate effects on the differentiation and development of vascular bed with subsequent functional abnormality that persists into adulthood, and part of this vascular abnormality is mediated through weakened interaction and/or cross talk between H2S and nitric oxide.
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http://dx.doi.org/10.1097/FJC.0000000000000948DOI Listing
February 2021

Combination therapy with dipeptidyl peptidase-4 and P2X7 purinoceptor inhibitors gives rise to antiepileptic effects in rats.

J Chem Neuroanat 2020 12 5;110:101855. Epub 2020 Oct 5.

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

Objective(s): Although the available therapeutic agents alleviate the symptoms in patients with temporal lobe epilepsy (TLE), these antiepileptic drugs do not provide adequate control of seizures in 30-40 % of patients. This study was conducted to evaluate anti-epileptic effects of simultaneous inhibition of dipeptidyl peptidase-4 and P2 × 7 purinoceptors in Kainate treated rats.

Materials And Methods: Brilliant Blue G)BBG(, linagliptin)lin(and lin + BBG were administrated 30 min prior to induction of the intrahippocampal kainate model of epilepsy in male Wistar rats. In the case of valproic acid group, the animals intraperitoneally received valproic acid for 7 consecutive days prior to induction of the model. We carried out histological evaluations, monitoring of behavior, recording of intracranial electroencepholography (IEEG), and determination of astrogliosis and DNA fragmentation using ELISA methods.

Results: Our results showed that BBG and lin combination therapy had better effects on decrease in astrogliosis, DNA fragmentation and cognitive disturbances than ones whereas its effects on neuronal survival and seizure severity was similar to only BBG or lin. Likewise, the effects of lin + BBG on decrease in DNA fragmentation and cognitive disturbances were better than valproic acid group.

Conclusion: Our findings suggest that simultaneous inhibition of dipeptidyl peptidase-4 and P2 × 7 purinoceptors might more efficiently provide protection against progression of the kainate-induced TLE in rats.
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http://dx.doi.org/10.1016/j.jchemneu.2020.101855DOI Listing
December 2020

The Association Between Circulating Klotho and Dipeptidyl Peptidase-4 Activity and Inflammatory Cytokines in Elderly Patients With Alzheimer Disease.

Basic Clin Neurosci 2020 May-Jun;11(3):349-357. Epub 2020 May 1.

Neurophysiology Research Center, Shahed University, Tehran, Iran.

Introduction: Klotho and Dipeptidyl Peptidase-4 (DPP4) are two proteins that modulate inflammatory pathways. We investigated the association between circulating klotho and DPP4 activity and their relationship with inflammatory cytokines, miR-29a, and miR-195 in Alzheimer Disease (AD).

Methods: This study was conducted on 16 AD patients and 16 healthy age-matched controls. Plasma levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β, interleukin-6 (IL-6), klotho, and DPP4 were measured by enzyme-linked immunosorbent assay. Plasma expression of miR-29a and miR-195 were also measured and compared by a real-time polymerase chain reaction.

Results: There was a significant increase in TNF-α (p=0.006), IL-1β (p=0.012), and IL-6 (p=0.012) levels in the AD subjects compared with controls. Also, we found a decrease in plasma levels of klotho and an increase in plasma levels of DPP4 in the AD group that was not significant compared with the controls. Lower expression of miR-29a (P=0.009) and higher expression of miR-195 (P=0.003) were observed in the AD group that was significant than controls. Further analysis showed a negative correlation between klotho and plasma levels of IL-6 (r=-0.58, p=0.01). Also, there was a positive correlation between plasma DPP4 activity and TNF-α levels (r=0.50, P=0.04) and IL-1β (r=0.62, P=0.01). Likewise, plasma klotho concentration showed a negative correlation with the age of AD subjects (r=-0.56, P=0.02).

Conclusion: TNF-α, IL-1β, and IL-6 are involved in AD pathophysiology, and dysregulation of DPP4 and klotho may be associated with the inflammatory response of AD. Down-regulation of miR-29a and up-regulation of miR-195 indicated the role of miRNAs in the AD process.
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http://dx.doi.org/10.32598/bcn.11.2.1747.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502192PMC
May 2020

Exogenous Ghrelin Could Not Ameliorate 3,4-methylenedioxymethamphetamine-induced Acute Liver Injury in The Rat: Involved Mechanisms.

Iran J Pharm Res 2020 ;19(1):343-354

Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is often abused by youth as a recreational drug. MDMA abuse is a growing problem in different parts of the world. An important adverse consequence of the drug consumption is hepatotoxicity of different intensities. However, the underlying mechanism of this toxicity has not been completely understood. Ghrelin is a gut hormone with growth hormone stimulatory effect. It expresses in liver, albeit at a much lower level than in stomach, and exerts a hepatoprotective effect. In this study, we investigated hepatotoxicity effect of MDMA alone and its combination with ghrelin as a hepatoprotective agent. MDMA and MDMA+ ghrelin could transiently increase serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) followed by tissue necrosis. However, they could significantly decrease liver tumor necrosis factor-a (TNF-±) in both treatment groups. Unexpectedly, in MDMA treated rats, Bax, Bcl-xl, Bcl-2, Fas, Fas ligand (Fas-L), caspase 8, cytochrome c, caspase 3 gene expression, and DNA fragmentation were nearly unchanged. In addition, apoptosis in MDMA+ ghrelin group was significantly reduced when compared with MDMA treated animals. In all, MDMA could transiently increase serum transaminases and induce tissue necrosis and liver toxicity. Ghrelin, however, could not stop liver enzyme rise and MDMA hepatotoxicity. MDMA hepatotoxicity seems to be mediated via tissue necrosis than apoptotic and inflammatory pathways. Conceivably, ghrelin as an anti-inflammatory and anti-apoptotic agent may not protect hepatocytes against MDMA liver toxicity.
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http://dx.doi.org/10.22037/ijpr.2020.1100940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462488PMC
January 2020

Sinomenine Alleviates Murine Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis through Inhibiting NLRP3 Inflammasome.

J Mol Neurosci 2021 Feb 19;71(2):215-224. Epub 2020 Aug 19.

Neurophysiology Research Center, Shahed University, Tehran, Iran.

Multiple sclerosis (MS) is known as a chronic neuroinflammatory disorder typified by an immune-mediated demyelination process with ensuing axonal damage and loss. Sinomenine is a natural alkaloid with different therapeutic benefits, including anti-inflammatory and immunosuppressive activities. In this study, possible beneficial effects of sinomenine in an MOG-induced model of MS were determined. Sinomenine was given to MOG-immunized C57BL/6 mice at doses of 25 or 100 mg/kg/day after onset of MS clinical signs till day 30 post-immunization. Analyzed data showed that sinomenine reduces severity of the clinical signs and to some extent decreases tissue level of pro-inflammatory cytokines IL-1β, IL-6, IL-18, TNFα, IL-17A, and increases level of anti-inflammatory IL-10. In addition, sinomenine successfully attenuated tissue levels of inflammasome NLRP3, ASC, and caspase 1 besides its reduction of intensity of neuroinflammation, demyelination, and axonal damage and loss in lumbar spinal cord specimens. Furthermore, immunoreactivity for MBP decreased and increased for GFAP and Iba1 after MOG-immunization, which was in part reversed upon sinomenine administration. Overall, sinomenine decreases EAE severity, which is attributed to its alleviation of microglial and astrocytic mobilization, demyelination, and axonal damage along with its suppression of neuroinflammation, and its beneficial effect is also associated with its inhibitory effects on inflammasome and pyroptotic pathways; this may be of potential benefit for the primary progressive phenotype of MS.
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http://dx.doi.org/10.1007/s12031-020-01637-1DOI Listing
February 2021

The Effect of Myrtus communis Aqueous Extract-Containing Gel on Wound Healing in Streptozotocin-Induced Diabetic Rats.

Curr Drug Discov Technol 2020 Jul 12. Epub 2020 Jul 12.

Neurophysiology Research Center, Shahed University, Tehran. Iran.

Background: The medicinal plant Myrtus communis L. (Myrtle) has been medicinal properties including antiinflammatory and wound healing in Persian Medicine.

Objective: The objective of this study was to explore the wound healing potential of the local application of a gel containing aqueous extract of the plant berry in streptozotocin (STZ)-induced diabetic rats.

Methods: Seven days after diabetes establishment, full-thickness excision skin wounds were made in normal and diabetic rats and treated groups received topical application of a gel containing 6% aqueous extract of myrtle berries for 3 weeks. The rate of wound healing and the level of epidermal and dermal maturation in the wound tissue were determined.

Results: The results showed that after 3 and 7 days of wound injury, the gel significantly improved wound healing by accelerating epidermal and dermal maturation in diabetic rats with no significant effect in control group. However, the wounds of all groups almost completely healed after 3 weeks.

Conclusion: These results demonstrate that aqueous extract of myrtle possesses a definite wound healing potential in diabetic condition. Our present findings may suggest the use of topical myrtle berries aqueous extract gel 6% to treat and manage intractable diabetic wounds.
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http://dx.doi.org/10.2174/1570163817666200712163956DOI Listing
July 2020

Anti-aging Klotho Protects SH-SY5Y Cells Against Amyloid β1-42 Neurotoxicity: Involvement of Wnt1/pCREB/Nrf2/HO-1 Signaling.

J Mol Neurosci 2021 Jan 5;71(1):19-27. Epub 2020 Jul 5.

Neurophysiology Research Center, Shahed University, Tehran, Iran.

Alzheimer's disease (AD) is considered a prevalent neurological disorder with a neurodegenerative nature in elderly people. Oxidative stress and neuroinflammation due to amyloid β (Aβ) peptides are strongly involved in AD pathogenesis. Klotho is an anti-aging protein with multiple protective effects that its deficiency is involved in development of age-related disorders. In this study, we investigated the beneficial effect of Klotho pretreatment at different concentrations of 0.5, 1, and 2 nM against Aβ1-42 toxicity at a concentration of 20 μM in human SH-SY5Y neuroblastoma cells. Our findings showed that Klotho could significantly and partially restore cell viability and decrease reactive oxygen species (known as ROS) and improve superoxide dismutase activity (SOD) in addition to reduction of caspase 3 activity and DNA fragmentation following Aβ1-42 challenge. In addition, exogenous Klotho also reduced inflammatory biomarkers consisting of nuclear factor-kB (NF-kB), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in Aβ-exposed cells. Besides, Klotho caused downregulation of Wnt1 level, upregulation of phosphorylated cyclic AMP response element binding (pCREB), and mRNA levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) with no significant alteration of epsilon isoform of protein kinase C (PKCε) after Aβ toxicity. In summary, Klotho could alleviate apoptosis, oxidative stress, and inflammation in human neuroblastoma cells after Aβ challenge and its beneficial effect is partially exerted through appropriate modulation of Wnt1/pCREB/Nrf2/HO-1 signaling.
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http://dx.doi.org/10.1007/s12031-020-01621-9DOI Listing
January 2021

Autistic-like behaviours and associated brain structural plasticity are modulated by oxytocin in maternally separated rats.

Behav Brain Res 2020 09 11;393:112756. Epub 2020 Jun 11.

Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Centre for Perinatal Medicine and Health, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Early psycho-social experiences influence the developing brain and possible onset of various neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD). ASD is characterized by a variety of brain abnormalities, including alteration of oxytocin receptors in the brain. Recently, early life adverse experiences, such as maternal separation (MS), have been shown to constitute risk factors for ASD in preclinical studies. Therefore, the main aims of the current study were to i) explore the association between onset of autistic-like behaviours and molecular/structural changes in the brain following MS, and ii) evaluate the possible beneficial effects of oxytocin treatment on the same parameters.

Method And Material: Male rats were exposed to the maternal separation from post-natal day (PND) 1 to PND14. After weaning, daily injections of oxytocin (1 mg/kg, ip) were administered (PND 22-30), followed by examination of autism-related behaviours at adolescence (PND 42-50). Brain structural plasticity was examined using stereological methods, and the plasma level of brain derived neurotrophic factor (BDNF) was analysed using ELISA.

Results: We found that maternal separation induced autistic-like behaviours, which was associated with increase in the hippocampal CA1 stratum radiatum (CA1.SR) volume. In addition, we observed increase in the infralimbic brain region volume and in the number of the pyramidal neurons in the same brain region. Maternal separation significantly increased the plasma BDNF levels. Treatment with oxytocin improved autistic like behaviours, normalized the number of neurons and the volume of the infralimbic region as well as the plasma BDNF level (p < 0.05).

Conclusion: Maternal separation induced autistic-like behaviours, brain structural impairment together with plasma BDNF level abnormality, which could be improved by oxytocin treatment.
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http://dx.doi.org/10.1016/j.bbr.2020.112756DOI Listing
September 2020

Diosgenin Attenuates Cognitive Impairment in Streptozotocin-Induced Diabetic Rats: Underlying Mechanisms.

Neuropsychobiology 2021 11;80(1):25-35. Epub 2020 Jun 11.

Neurophysiology Research Center, Shahed University, Tehran, Iran,

Objective: Prolonged diabetes mellitus causes impairments of cognition and attentional dysfunctions. Diosgenin belongs to a group of steroidal saponins with reported anti-diabetic and numerous protective properties. This research aimed to assess the effect of diosgenin on beneficially ameliorating learning and memory decline in a rat model of type 1 diabetes caused by streptozotocin (STZ) and to explore its modes of action including involvement in oxidative stress and inflammation.

Methods: Rats were assigned to one of four experimental groups, comprising control, control under treatment with diosgenin, diabetic, and diabetic under treatment with diosgenin. Diosgenin was given daily p.o. (40 mg/kg) for 5 weeks.

Results: The administration of diosgenin to the diabetic group reduced the deficits of functional performance in behavioral tests, consisting of Y-maze, passive avoidance, radial arm maze, and novel object discrimination tasks (recognitive). Furthermore, diosgenin treatment attenuated hippocampal acetylcholinesterase activity and malon-dialdehyde, along with improvement of antioxidants such as superoxide dismutase and glutathione. Meanwhile, the hippocampal levels of inflammatory indicators, namely interleukin 6, nuclear factor-κB, toll-like receptor 4, tumor necrosis factor α, and astrocyte-specific biomarker glial fibrillary acidic protein, were lower and, on the other hand, tissue levels of nuclear factor (erythroid-derived 2)-related factor 2 were elevated upon diosgenin administration. Besides, the mushroom-like spines of the pyramidal neurons of the hippocampal CA1 area decreased in the diabetic group, and this was alleviated following diosgenin medication.

Conclusions: Taken together, diosgenin is capable of ameliorating cognitive deficits in STZ-diabetic animals, partly due to its amelioration of oxidative stress, inflammation, astrogliosis, and possibly improvement of cholinergic function in addition to its neuroprotective potential.
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http://dx.doi.org/10.1159/000507398DOI Listing
June 2020

The Effect of Rosmarinic Acid on Apoptosis and nNOS Immunoreactivity Following Intrahippocampal Kainic Acid Injections in Rats.

Basic Clin Neurosci 2020 Jan-Feb;11(1):41-48. Epub 2020 Jan 1.

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

Introduction: Kainic Acid (KA) is an ionotropic glutamate receptor agonist. KA can induce neuronal overactivity and excitotoxicity. Rosmarinic Acid (RA) is a natural polyphenolic compound with antioxidant, anti-apoptotic, anti-neurodegenerative, and anti-inflammatory properties. This study aimed to assess the effect of RA on apoptosis, nNOS-positive neurons number, as well as Mitogen-Activated Protein Kinase (MAPK) and Cyclooxygenase-2 (COX-2) immunoreactivity, following intrahippocampal Kainic acid injection in rats.

Methods: The study rats were randomly assigned to three groups of sham, KA (KA was injected into the right side of the hippocampus) and KA+RA (a dose of 10 mg/kg/day through a gavage needle for one week before KA injection). Then, histopathological changes, including apoptosis [Terminal Deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay], nNOS-positive neurons number, as well as COX-2 and MAPK immunoreactivity were evaluated in the hippocampus.

Results: In the RA pretreated group, nNOS-positive neurons and TUNEL-positive cells were significantly reduced compared to the KA group (P<0.05). COX-2and MAPK immunoreactivity demonstrated no significant changes compared to the KA group. They indicated a significant higher reactivity for COX-2 (P<0.01) and MAPK (P<0.005) versus the sham group.

Conclusion: RA had neuroprotective effects, compared to KA, through reduced apoptosis and nNOS-positive neurons, but not MAPK and COX-2.
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http://dx.doi.org/10.32598/bcn.9.10.340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253813PMC
January 2020

S-allyl cysteine, an active ingredient of garlic, attenuates acute liver dysfunction induced by lipopolysaccharide/ d-galactosamine in mouse: Underlying mechanisms.

J Biochem Mol Toxicol 2020 May 26:e22518. Epub 2020 May 26.

Neurophysiology Research Center, Shahed University, Tehran, Iran.

In the present study, beneficial effect of S-allyl cysteine (SAC) was evaluated in the lipopolysaccharide/d-galactosamine (LPS/d-Gal) model of acute liver injury (ALI). To mimic ALI, LPS and d-Gal (50 μg/kg and 400 mg/kg, respectively) were intraperitoneally administered and animals received SAC per os (25 or 100 mg/kg/d) for 3 days till 1 hour before LPS/d-Gal injection. Pretreatment of LPS/d-Gal group with SAC-lowered activities of alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase and partially reversed inappropriate alterations of hepatic oxidative stress- and inflammation-related biomarkers including liver reactive oxygen species, malondialdehyde, and hepatic activity of the defensive enzyme superoxide dismutase, ferric reducing antioxidant power (FRAP), toll-like receptor-4 (TLR4), cyclooxygenase 2, NLR family pyrin domain containing 3 (NLRP3), caspase 1, nuclear factor κB (NF-κB), interleukin 1β (IL-1β), IL-6, tumor necrosis factor-α, and myeloperoxidase activity. Additionally, SAC was capable to ameliorate apoptotic biomarkers including caspase 3 and DNA fragmentation. In summary, SAC can protect liver against LPS/d-Gal by attenuation of neutrophil infiltration, oxidative stress, inflammation, apoptosis, and pyroptosis which is partly linked to its suppression of TLR4/NF-κB/NLRP3 signaling.
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http://dx.doi.org/10.1002/jbt.22518DOI Listing
May 2020

Neuroprotective and anticonvulsant effects of sinomenine in kainate rat model of temporal lobe epilepsy: Involvement of oxidative stress, inflammation and pyroptosis.

J Chem Neuroanat 2020 10 8;108:101800. Epub 2020 May 8.

Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Oxidative stress, inflammation and pyroptosis are three of the most important mechanisms in the pathophysiology of temporal lobe epilepsy (TLE). Most people with TLE are refractory to the existing drugs. Sinomenine has shown neuroprotective effects through counteracting oxidative stress, inflammation and pyroptosis. In this study, we evaluated the effect of sinomenine on seizure behavior, oxidative stress, inflammation and pyroptosis markers in addition to its neuroprotective potential in intrahippocampal kainate-induced rat model of TLE. For this purpose, male rats (n = 60) were randomly divided into five groups, i.e., sham, kainate (lesion) with an intrahippocampal injection of kainate, kainate groups receiving sinomenine at doses of 30 or 50 mg/kg, and kainate group receiving valproic acid at a dose of 200 mg/kg (as the positive control). Our obtained data showed that sinomenine administration at a dose of 50 mg/kg can significantly decreases severity of seizures and incidence of status epilepticus (SE), hippocampal aberrant MFS and DNA fragmentation and prevents reduction of neuronal density. It also significantly restored level of ROS, MDA, HO-1 and SOD but its effect on GSH level was not significant. Additionally, sinomenine at a dose of 50 mg/kg partially counteracted the increase of NF-κB, TLR 4, TNFα, GFAP and caspase 1. These results suggest that sinomenine has anticonvulsant and neuroprotective effects by reducing hippocampal oxidative stress, inflammation, pyroptosis and apoptosis in intrahippocampal kainate model of TLE.
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http://dx.doi.org/10.1016/j.jchemneu.2020.101800DOI Listing
October 2020

Protective effect of diosgenin on LPS/D-Gal-induced acute liver failure in C57BL/6 mice.

Microb Pathog 2020 Sep 7;146:104243. Epub 2020 May 7.

Neurophysiology Research Center, Shahed University, Tehran, Iran.

Acute liver failure (ALF) is a deadly clinical syndrome, which leads to a rapid loss of normal liver function. Diosgenin is a natural steroidal sapogenin found in various plant families. Various studies have shown that diosgenin have therapeutic or preventive effect in various diseases such as cancer, cardiovascular disorders, type 2 diabetes, and neurodegenerative disorders. In this study, we evaluated effects of diosgenin on mice model of ALF. Animal model of ALF was induced by intraperitoneal injection of lipopolysaccharide (LPS)/d-galactosamine (D-Gal). The male C57BL/6 mice were randomly divided into 3 groups: control group, LPS/D-Gal group, and LPS/D-Gal + diosgenin group (50 mg/kg). Mice in the LPS/D-Gal group received a combination of LPS (50 μg/kg) and D-Gal (400 mg/kg) intraperitoneally. LPS/D-Gal + diosgenin group received diosgenin twice orally 24 h and 1 h before receiving LPS/D-Gal. Markers of liver injury including ALT, AST and ALP were measured in blood samples in addition to determination of oxidative stress and inflammatory markers including MDA, nitrite, ROS, catalase, SOD, Nrf2, IL-1β, IL-6, TLR4, TNF-α and NF-κB in hepatic tissue. Administration of diosgenin could greatly reduce serum levels of ALT, AST, and ALP. Besides, hepatic levels of MDA, ROS, IL-1β, IL-6, TLR4, TNF-α, and NF-κB significantly decreased and SOD activity and Nrf2 level increased in comparison with the LPS/D-Gal group. In addition, myeloperoxidase activity as a marker of neutrophil infiltration decreased following diosgenin administration. In summary, diosgenin led to reduction of liver injury indices and oxidative stress and inflammatory events and diosgenin has probably hepatoprotecive effects in ALF.
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http://dx.doi.org/10.1016/j.micpath.2020.104243DOI Listing
September 2020

Lactation ameliorates neurobehavioral outcomes in the ischemic rat dams.

J Matern Fetal Neonatal Med 2020 Feb 26:1-9. Epub 2020 Feb 26.

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

Cardiac arrest and stroke as a life-threatening event that may occur in throughout the female life, especially during pregnancy or after delivery. Previous studies demonstrated that cerebral ischemia during pregnancy or the puerperium is a rare occurrence but is associated with significant mortality and high morbidity. This study was designed to assess the effects of pregnancy and lactation on behavioral deficits, neural density, and angiogenesis in rat dams undergoing global ischemia. Thirty-two female Wistar rats were divided into four groups: virgin-Sham (Vir-Sham) group, virgin-ischemic (Vir-Isc) group, pregnancy-lactation-sham (P-L-Sham) group, and pregnancy-lactation-ischemic (P-L-Isc) group. Global brain ischemia was induced in ischemic groups by using the 2-vessel occlusion (2-VO) model at the end of lactation phase. Seven days after 2-VO, anxiety-like signals and passive avoidance memory tests were assessed in animals. We found that the lactation significantly improved memory and reduced anxiety-like signals in P-L-Isc group as compared with Vir-Isc group. Moreover, angiogenesis and neural density significantly increased in the P-L-Isc group as compared with the Vir-Isc group. This finding for the first time indicated that lactation protects the maternal brain against ischemic insult partly through promoting angiogenesis and neurogenesis.
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http://dx.doi.org/10.1080/14767058.2020.1731796DOI Listing
February 2020

The effects simultaneous inhibition of dipeptidyl peptidase-4 and P2X7 purinoceptors in an in vivo Parkinson's disease model.

Metab Brain Dis 2020 03 3;35(3):539-548. Epub 2020 Feb 3.

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

Loss of dopaminergic neurons following Parkinson's disease (PD) diminishes quality of life in patients. The present study was carried out to investigate the protective effects of simultaneous inhibition of dipeptidyl peptidase-4 (DPP-4) and P2X7 purinoceptors in a PD model and explore possible mechanisms. The 6-hydroxydopamine (6-OHDA) was used as a tool to establish PD model in male Wister rats. The expressions of SIRT1, SIRT3, mTOR, PGC-1α, PTEN, P53 and DNA fragmentation were evaluated by ELISA assay. Behavioral impairments were determined using apomorphine-induced rotational and narrow beam tests. Dopamine synthesis and TH-positive neurons were detected by tyrosine hydroxylase (TH) immunohistochemistry. Neuronal density was determined by Nissl staining. OHDA-lesioned rats exhibited behavioral impairments that reversed by BBG, lin and lin + BBG. We found significant reduced levels of SIRT1, SIRT3, PGC-1α and mTOR in both mid brain and striatum from OHDA-lesioned rats that reversed by BBG, lin and lin + BBG. Likewise, significant increased levels of PTEN and P53 were found in both mid brain and striatum from OHDA-lesioned rats that was reversed by BBG, lin and lin + BBG. TH-positive neurons and neuronal density were markedly reduced OHDA-lesioned rats that reversed by BBG, lin and lin + BBG. Collectively, our results showed protective effects of simultaneous inhibition of DPP-4 and P2X7 purinoceptors in a rat model of PD can be linked to targeting SIRT1/SIRT3, PTEN-mTOR pathways. Moreover, our findings demonstrated that simultaneous inhibition of DPP-4 and P2X7 purinoceptors might have stronger effect on mitochondrial biogenesis compared to only one.
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http://dx.doi.org/10.1007/s11011-020-00538-xDOI Listing
March 2020

Isorhamnetin exerts neuroprotective effects in STZ-induced diabetic rats via attenuation of oxidative stress, inflammation and apoptosis.

J Chem Neuroanat 2019 12 4;102:101709. Epub 2019 Nov 4.

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

Objective: Isorhamnetin, a derivative of quercetin, exerts antioxidant and anti-inflammatory effects in different diseases, and we examined its protective effects against diabetes-related changes in the brain.

Methods: A single dose of a freshly prepared solution of streptozotocin (STZ) (60 mg/kg body weight) was intraperitoneally injected to establish STZ-induced diabetic model in male Wistar rats. The animals were randomly divided into four groups: control, control + isorhamnetin, diabetic, diabetic + isorhamnetin. Isorhamnetin at a dose of 10 mg/kg body weight was intraperitoneally administrated once a day for 12 weeks. Formalin and tail immersion tests were performed to evaluate the severity of pain. Astrogliosis markers such as GFAP and APO-E4, DNA fragments, MDA level, and TNFα expressions were evaluated using ELISA assay. Neuronal density in the hippocampus region was evaluated using Nissl staining. The method of Ellman and fluorescent probe 2, 7-dichlorofluorescein diacetate (DCFH-DA) was used to measure brain acetyl-cholinesterase activity and detect reactive nitrogen and oxygen species (RNS and ROS), respectively.

Results: Isorhamnetin reduced pain, blood glucose levels, and increased body weight significantly compared to control. Moreover, isorhamnetin inhibited astroglial activation, acetyl-cholinesterase activity, oxidative stress, apoptosis, and inflammation.

Conclusion: These findings suggested that isorhamnetin has potential effects as neuroprotective agents against diabetes-related changes in the brain.
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http://dx.doi.org/10.1016/j.jchemneu.2019.101709DOI Listing
December 2019

Safranal, an active ingredient of saffron, attenuates cognitive deficits in amyloid β-induced rat model of Alzheimer's disease: underlying mechanisms.

Metab Brain Dis 2019 12 17;34(6):1747-1759. Epub 2019 Aug 17.

Neurophysiology Research Center, Shahed University, Tehran, Iran.

Alzheimer's disease (AD) is the most prevalent neurodegenerative amyloid disorder with progressive deterioration of cognitive and memory skills. Despite many efforts, no decisive therapy yet exists for AD. Safranal is the active constituent of saffron essential oil with antioxidant, anti-inflammatory, and anti-apoptotic properties. In this study, the possible beneficial effect of safranal on cognitive deficits was evaluated in a rat model of AD induced by intrahippocampal amyloid beta (Aβ). Safranal was daily given p.o. (0.025, 0.1, and 0.2 ml/kg) post-surgery for 1 week and finally learning and memory were evaluated in addition to assessment of the involvement of oxidative stress, inflammation, and apoptosis. Findings showed that safranal treatment of amyloid β-microinjected rats dose-dependently improved cognition in Y-maze, novel-object discrimination, passive avoidance, and 8-arm radial arm maze tasks. Besides, safranal attenuated hippocampal level of malondialdehyde (MDA), reactive oxygen species (ROS), protein carbonyl, interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor α (TNFα), nuclear factor-kappa B (NF-kB), apoptotic biomarkers including caspase 3 and DNA fragmentation, glial fibrillary acidic protein (GFAP), myeloperoxidase (MPO), and acetylcholinesterase (AChE) activity and improved superoxide dismutase (SOD) activity and mitochondrial membrane potential (MMP) with no significant effect on nitrite, catalase activity, and glutathione (GSH). Furthermore, safranal prevented CA1 neuronal loss due to amyloid β. In summary, safranal treatment of intrahippocampal amyloid beta-microinjected rats could prevent learning and memory decline via neuronal protection and at a molecular level through amelioration of apoptosis, oxidative stress, inflammation, cholinesterase activity, neutrophil infiltration, and also by preservation of mitochondrial integrity.
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http://dx.doi.org/10.1007/s11011-019-00481-6DOI Listing
December 2019

Troxerutin exerts neuroprotection against lipopolysaccharide (LPS) induced oxidative stress and neuroinflammation through targeting SIRT1/SIRT3 signaling pathway.

Metab Brain Dis 2019 10 16;34(5):1505-1513. Epub 2019 Jul 16.

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

This study was conducted to clarify the potential mechanisms of Troxerutin neuroprotection against Lipopolysaccharide (LPS) induced oxidative stress and neuroinflammation through targeting the SIRT1/SIRT3 signaling pathway. To establish a model, a single dose of LPS (500μg/kg body weight) was injected to male Wistar rats intraperitoneally. Troxerutin (100 mg/kg body weight) was injected intraperitoneally for 5 days after induction of the model. Cognitive and behavioral evaluations were performed using Y-maze, single-trial passive avoidance, and novel object recognition tests. The expression of inflammatory mediators, SIRT1/SIRT3, and P53 was measured using the ELISA assay. Likewise, the expression levels of SIRT1/SIRT3 and NF-κB were determined using Western blot assay. Brain acetyl-cholinesterase activity was determined by utilizing the method of Ellman. Reactive oxygen species (ROS) was detected using Fluorescent probe 2, 7-dichlorofluorescein diacetate (DCFH-DA). Furthermore, malondialdehyde (MDA) levels were determined. A single intraperitoneal injection of LPS was led to ROS production, acute neuroinflammation, apoptotic cell death, and inactivation of the SIRT1/SIRT3 signaling pathway. Likewise, ELISA assay demonstrated that post-treatment with Troxerutin considerably suppressed LPS-induced acute neuroinflammation, oxidative stress, apoptosis and subsequently memory impairments by targeting SIRT1/SIRT3 signaling pathway. Western blot assay confirmed ELISA results about SIRT1/SIRT3 and NF-κB proteins. These results suggest that Troxerutin can be a suitable candidate to treat neuroinflammation caused by neurodegenerative disorders.
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http://dx.doi.org/10.1007/s11011-019-00454-9DOI Listing
October 2019

Klotho Ameliorates Cellular Inflammation via Suppression of Cytokine Release and Upregulation of miR-29a in the PBMCs of Diagnosed Alzheimer's Disease Patients.

J Mol Neurosci 2019 Sep 13;69(1):157-165. Epub 2019 Jun 13.

Neurophysiology Research Center, Shahed University, Tehran, Iran.

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by neural inflammation and oxidative stress. In the current study, the protective effects of klotho and linagliptin treatment on human peripheral blood mononuclear cells (PBMCs) of AD patients and healthy controls (HCs) are assessed through measurement of inflammatory cytokines, signaling proteins, and miRNA expression. Sixteen diagnosed AD patients and sixteen HCs were enrolled in the study. Blood samples were obtained and PBMCs were isolated. PBMCs were treated with klotho at different concentrations (0.5, 1, and 2 nM) and linagliptin (50 μM). The concentration of interleukin-1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), epsilon isoform of protein kinase C (PKCε), phosphorylated cyclic AMP response element binding (pCREB), and Wnt1 were measured by ELISA. The expression of miR-29a and miR-195 was detected by real-time PCR. The results showed that klotho significantly reduced IL-1β, IL-6, and TNF-α levels in both groups of the experiment. Linagliptin also remarkably reduced TNF-α levels in the AD group. Moreover, klotho caused the downregulation of Wnt1 in the PBMCs of both groups and the upregulation of the pCREB in HCs. Meanwhile, klotho induced miR-29a expression in the PBMCs of HCs, while miR-29a expression was induced in the AD group by klotho and linagliptin. The current findings revealed that klotho alleviates inflammation in human PBMCs, probably through the suppression of inflammatory cytokines and the upregulation of miR-29a, and part of its beneficial effect is mediated through appropriate modulation of the Wnt1/pCREB signaling cascade. In addition, linagliptin exerts protective effects by reducing TNF-α and inducing miR-29a expression in PBMCs.
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http://dx.doi.org/10.1007/s12031-019-01345-5DOI Listing
September 2019

Effects of resin extract on motor dysfunction and brain oxidative stress in an experimental model of Parkinson's disease.

Avicenna J Phytomed 2019 May-Jun;9(3):281-290

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

Objective: oleo-gum resin (frankincense) exerted antioxidant and anti-inflammatory effects against several diseases, such as; asthma, rheumatoid arthritis and irritable bowel syndrome. In the current study, the influences of resin extract on motor dysfunction and oxidative stress markers were investigated in the intrastriatal 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD).

Materials And Methods: The animals were randomly assigned to sham, lesion (6-OHDA), and three lesion groups treated with ethyl alcoholic extract of at doses of 125, 250 and 500 mg/kg for 3 weeks. The neurotoxin 6-OHDA (12.5 µg) was microinjected into the left striatum to induce PD in male rats. Motor behavior was assessed by rotational and elevated narrow beam tests. Oxidative stress markers were measured in striatal and midbrain homogenates.

Results: There was a significant increase in contralateral rotations in 6-OHDA group versus sham group (p<0.001), and treatment with resin extract at doses of 125 and 250 mg/kg significantly decreased the rotations in comparison to 6-OHDA group (p<0.001 and p<0.001, respectively). The 6-OHDA group also showed considerable elevation in the latency to initiate crossing (p<0.001) and the total time (p<0.001) on narrow beam test. Moreover, treatment with extract at doses of 125, 250 and 500 mg/kg caused a significant reduction in the latency and total time (p<0.001, p<0.001, and p<0.01, respectively). Biochemical analysis showed no significant difference in oxidative stress markers levels among the groups.

Conclusion: Our findings suggest that resin extract acts as an anti-inflammatory and antioxidant agent that protects nigrostriatal dopaminergic neurons and improve motor impairments in PD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526039PMC
May 2019

Assessment of the protective effect of KN-93 drug in systemic epilepsy disorders induced by pilocarpine in male rat.

J Cell Biochem 2019 09 9;120(9):15906-15914. Epub 2019 May 9.

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

Background And Aims: Epileptic seizures occur as a consequence of a sudden imbalance between the stimuli and inhibitors within the network of cortical neurons in favor of the stimulus. One of the drugs that induce epilepsy is pilocarpine. Systemic injection of pilocarpine affects on muscarinic receptors. Increasing evidence has addressed the implication of KN-93 by blocking Ca /calmodulin-dependent protein kinase II (CaMKII), suppressing oxidative stress and inflammation, and also reducing neuron decay. So, we aimed to evaluate the potential preventive effects of KN-93 in systemic epilepsy disorders induced by pilocarpine.

Materials And Methods: In this animal study, male rats were divided into five groups including treatment group (KN-93 with the dose of 5 mM/10 µL dimethyl sulfoxide (DMSO) before inducing epilepsy by 380 mg/kg pilocarpine) KN-93 group (received 5 mM KN-93), control group, epilepsy group (received 380 mg/kg pilocarpine Intraperitoneal), and sham group (received 10 µL DMSO). Oxidative stress was assessed by measuring its indicators including the concentration of malondialdehyde (MDA), nitrite, glutathione (GSH), as well as the antioxidant activity of catalase. In addition, serum levels of proinflammatory mediators including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were determined.

Results: Pretreatment with KN-93 significantly reduced oxidative stress index by reducing the concentration of MDA, nitrite, and increasing the level of GSH. In addition, low concentrations of TNF-α and IL-1β were observed in hippocampus supernatant of KN-93 pretreated rats in comparison with the pilocarpine groups. Moreover, administration of KN-93 improved neuronal density and attenuated the seizure activity and behavior.

Conclusions: Overall, our findings suggest that KN-93 can effectively suppress oxidative stress and inflammation. Furthermore, KN-93 is able to attenuate seizure behaviors by preventing its effects on neuron loss, so, it is valuable for the treatment of epileptic seizures.
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http://dx.doi.org/10.1002/jcb.28864DOI Listing
September 2019

Diosgenin ameliorates testicular damage in streptozotocin-diabetic rats through attenuation of apoptosis, oxidative stress, and inflammation.

Int Immunopharmacol 2019 May 19;70:37-46. Epub 2019 Feb 19.

Neurophysiology Research Center, Department of Physiology, Shahed University, Tehran, Iran. Electronic address:

Diabetes mellitus (DM) is a prevalent metabolic disorder that is associated with development of some complications in male reproductive system including testicular damage, sexual dysfunction, abnormal spermatogenesis, and infertility. Diosgenin is a natural steroidal saponin with anti-diabetic, anti-oxidative, and anti-inflammatory effects. This research study was undertaken to explore the protective effect of diosgenin against diabetes-induced testicular damage in the rat. Ten days following streptozotocin (STZ; i.p.), diosgenin was daily administered for 6 weeks (p.o.). Diosgenin administration to diabetic rats significantly improved body weight and lowered serum glucose. In addition, diosgenin-treated diabetic group had a significantly lower level of malondialdehyde (MDA), protein carbonyl, greater level of glutathione (GSH), and higher activity of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) in addition to testicular improvement of ferric reducing antioxidant power (FRAP). Furthermore, diosgenin significantly improved serum insulin and testosterone level and alleviated testicular markers of inflammation including tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) in diabetic rats. Moreover, apoptotic markers including caspase 3 activity, Annexin V, and DNA fragmentation decreased, mitochondrial membrane potential (MMP) accentuated, and myeloperoxidase (MPO) activity as a biomarker of neutrophil infiltration decreased in diosgenin-treated diabetic group. Additionally, diosgenin was capable to improve sperm count, motility, and viability in addition to prevention of damage to seminiferous tubules in diabetic animals. Collectively, diosgenin ameliorates testicular damage in DM, at least via partial suppression of apoptosis, oxidative stress, inflammation, and neutrophil infiltration and also via partial restoration of mitochondrial integrity.
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http://dx.doi.org/10.1016/j.intimp.2019.01.047DOI Listing
May 2019

S-allyl cysteine protects against lipopolysaccharide-induced acute kidney injury in the C57BL/6 mouse strain: Involvement of oxidative stress and inflammation.

Int Immunopharmacol 2019 Apr 18;69:19-26. Epub 2019 Jan 18.

Neurophysiology Research Center, Department of Physiology, Shahed University, Tehran, Iran. Electronic address:

Sepsis is a serious and life-threatening medical condition with a higher rate of patients' morbidity and mortality and with complications such as acute kidney injury (AKI). S-allyl cysteine (SAC) is the active constituent of the medicinal plant garlic (Allium sativum) with multiple beneficial effects including anti-inflammatory and antioxidant properties. In this research, we tried to determine the protective effect of SAC pretreatment in a mouse model of AKI. To induce AKI, lipopolysaccharide (LPS) was injected once (10 mg/kg, i.p.) and SAC was administered at doses of 25, 50, or 100 mg/kg (p.o.) 1 h before LPS. Treatment of LPS-challenged C56BL/6 animals with SAC lowered serum level of creatinine and blood urea nitrogen (BUN), partially restored renal oxidative stress-related biomarkers including malondialdehyde (MDA), glutathione (GSH), and activity of superoxide dismutase (SOD) and catalase in addition to improvement of mitochondrial membrane potential (MMP). Furthermore, SAC was capable to bring renal nuclear factor-kappaB (NF-κB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX2), tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), Annexin V, and DNA fragmentation partially back to their control levels. Additionally, SAC pretreatment was capable to exert a protective effect, as shown histologically by lower tubular injury and pathologic changes in the kidney. In summary, SAC is capable to alleviate LPS-induced AKI through mitigation of renal oxidative stress, inflammation, and apoptosis in addition to preservation of mitochondrial integrity and its favorable effect exhibits a dose-dependent pattern.
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http://dx.doi.org/10.1016/j.intimp.2019.01.026DOI Listing
April 2019

Huperzine A ameliorates cognitive dysfunction and neuroinflammation in kainic acid-induced epileptic rats by antioxidant activity and NLRP3/caspase-1 pathway inhibition.

Clin Exp Pharmacol Physiol 2019 Apr 10;46(4):360-372. Epub 2019 Feb 10.

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

Temporal lobe epilepsy (TLE) is one of the most prevalent types of epilepsy in human. Huperzine A (Hup-A) has been reported to possess antioxidative and anti-inflammatory properties; however, its role in TLE induced by kainic acid has not been determined. The current study investigated the protective effects of Hup-A (0.1 mg/kg) in kainic acid-induced model of TLE in the rat. In the current study, it was found that Hup-A significantly prevented the seizure intensity and learning and memory deterioration which was assessed by Morris water maze (MWM) and novel object recognition task (NOR). Additionally, Hup-A inhibited oxidative stress, inflammation, and acetylcholinesterase activity (AChE). In addition, catalase and superoxide dismutase (SOD) activities increased after Hup-A treatment, while malondialdehyde (MDA) and nitrite levels significantly reduced. Regarding inflammation, this drug decreased kainic acid-induced NLRP3 expression in microglial cells and caspase-1 activity in hippocampal tissue, possibly through diminishing oxidative stress. Taken together, our data showed that Hup-A could be a potential protective substance to ameliorate seizure severity and some memory deficits related to epilepsy via attenuating neuroinflammation and protection of neurons.
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http://dx.doi.org/10.1111/1440-1681.13064DOI Listing
April 2019

Protective effect of sesamin in lipopolysaccharide-induced mouse model of acute kidney injury via attenuation of oxidative stress, inflammation, and apoptosis.

Immunopharmacol Immunotoxicol 2018 Oct 29;40(5):423-429. Epub 2018 Nov 29.

d Department of Physiology, Neurophysiology Research Center , Shahed University , Tehran , Iran.

Context: Acute kidney injury (AKI) is considered a major public health concern in today's world. Sepsis-induced AKI is large as a result of exposure to lipopolysaccharide (LPS) that is the major outer membrane component of Gram-negative bacteria. Sesamin is the main lignan of sesame seeds with multiple protective effects.

Objective: In this research, we tried to demonstrate the protective effect of sesamin pretreatment in LPS-induced mouse model of AKI.

Methods: LPS was injected at a single dose of 10 mg/kg (i.p.) and sesamin was given p.o. at doses of 25, 50, or 100 mg/kg, one hour prior to LPS.

Results: Treatment of LPS-challenged mice with sesamin reduced serum level of creatinine and blood urea nitrogen (BUN) and returned back renal oxidative stress-related parameters including glutathione (GSH), malondialdehyde (MDA), and activity of catalase and superoxide dismutase (SOD). Moreover, sesamin alleviated inappropriate changes of renal nuclear factor-kappaB (NF-κB), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX2), tumor necrosis factor α (TNFα), interleukin-6, DNA fragmentation (an apoptotic index), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, sesamin diminished magnitude of kidney tissue damage due to LPS.

Conclusion: In summary, sesamin could dose-dependently abrogate LPS-induced AKI via attenuation of renal oxidative stress, inflammation, and apoptosis.
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http://dx.doi.org/10.1080/08923973.2018.1523926DOI Listing
October 2018