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Physiology And Pharmacology (24765236) 28(4)pp. 419-429
Introduction: It is known that glial cells are crucial for memory formation. Glial cells and neurons interconnect via gap junction channels made of connexin (Cx) proteins. Glial connexins were shown to be involved in memory formation. However, the expression profile of different glial connexins was not measured during memory consolidation. Cx43 and Cx30 are expressed in astrocytes, whereas Cx32 is expressed in oligodendrocytes. We quantified the messenger RNA (mRNA) levels of the hippocampal Cx30, Cx32, and Cx43 throughout the consolidation stage of fear or spatial memory. Methods: Male Wistar rats were distributed into eight groups of four each. To assess the spatial or fear memory consolidation, the Morris water maze and passive avoidance task were utilized. At different time intervals (one, three, and twenty-four hours) following the training sessions, rats were sacrificed and the hippocampi were isolated and frozen instantly in liquid nitrogen. A quantitative real-time polymerase chain reaction (PCR) was employed to measure mRNA levels of the target genes. Results: The results revealed that Cx43 and Cx32 downregulated significantly, one or three hours after training in the inhibitory avoidance model. In the Morris water maze, Cx43 expression was upregulated three hours after training. The expression of Cx30 did not exhibit significant alterations in either of the experimental assays. Conclusion: The results indicate the crucial, but differential role of the hippocampal Cx32 and Cx43 during fear or spatial memory consolidation. The exact outcomes of these potential changes need to be clarified. © 2024, Iranian Society of Physiology and Pharmacology. All rights reserved.
Beheshti, S. ,
Ershadi, S. ,
Zamani, F. ,
Azimzadeh, M. ,
Wesal, M.W. Epilepsy Research (09201211) 197
Ghrelin is a peptide, which has been shown to affect seizures. However, there is not a consensus about its real impact on the control of seizure severity. We assessed the influence of intra-amygdala injections of a ghrelin receptor (GHSR) antagonist, as well as a GHSR inverse agonist on the electrical kindling-induced seizures. Two unipolar electrodes and a tripolar electrode twisted with a guide cannula were implanted in the skull surface or the basolateral amygdala of adult male rats, respectively. A rapid electrical kindling protocol was applied for kindling epileptogenesis. The stimulations were applied until rats showed three consecutive stage five seizures. Each rat was considered as its control. D-Lys-3-GHRP-6 (1, 12.5, and 25 μg/rat) or [D-Arg, D-phe, D-Trp, heu] substance P (D-SP) (50, 500 and 5000 ng/rat) as the GHSR antagonist or inverse agonist were injected into the basolateral amygdala. Seizure parameters including after-discharge duration (ADD), stage five duration (S5D), and seizure stage (SS) were documented thirty minutes following administration of the drugs or saline. Antagonism of the GHSR in the amygdala, significantly increased seizure induction in the kindled rats, in a dose-dependent manner, and induced spontaneous seizures leading to status epilepticus. Conversely, D-SP had a dose-dependent anticonvulsant activity, indicated by decreased ADD and S5D. The results show that GHSR inverse agonism suppressed seizure severity in the rat amygdala kindling model, whereas GHSR antagonism made seizures more severe. Therefore, when considering the ghrelin system to modulate seizures, it is crucial to note the differential impact of various GHSR ligands. © 2023 Elsevier B.V.
Epilepsy Research (09201211) 189
Numerous studies have shown that the ghrelin hormone is involved in epileptic conditions. However, the profile of ghrelin or its functional receptor mRNAs in seizure-susceptible brain areas was not assessed during epileptogenesis. Here, we measured the expression levels of the hippocampal ghrelin or its receptor mRNAs during electrical kindling-induced epileptogenesis. The study was conducted on twenty adult male Wistar rats. One tri-polar and two uni-polar electrodes were stereotaxically implanted in the baso-lateral amygdala or skull surface, respectively. Animals were divided into four groups, consisting of two sham groups (sham1 and sham2), and two other groups, which were partially or fully kindled. After the establishment of partial or full kindling, the hippocampi of the animals and that of the corresponding sham groups were removed. A quantitative real-time PCR technique was used to measure the expression levels of ghrelin or its functional receptor mRNAs. The results indicated that the expression levels of ghrelin did not alter in either of the partially or fully kindled rats compared to the corresponding sham groups. Ghrelin receptor (ghrelinR) down regulated, significantly in the fully-kindled rats, compared to sham2 group. Meanwhile, the mRNA expression levels of ghrelinR did not change in partially-kindled rats compared to sham1 group. The outcomes of the current study highlight the crucial, unknown impact of the hippocampal ghrelinR through the development of electrical kindling epileptogenesis, and points out the importance of ghrelinR as a goal to adjust epileptogenic progression. © 2022 Elsevier B.V.
Mirshafiei, Marziehsadat ,
Mirshafiei M. ,
Yazdi, A. ,
Beheshti, S. Iranian Journal Of Basic Medical Sciences (20083874) 26(8)pp. 966-971
Objective(s): Hepatic encephalopathy inducescognitivedisturbances. Patients showneuroinflammation due to accumulation of toxic substances. Frankincense has neuroprotective and anti-inflammatory properties. Accordingly, we intended to evaluate the impact of frankincense on memory performance, inflammation, and the amount of hippocampal neurons in bile duct-ligated rats.Materials and Methods: The bile duct was ligated in three groups of adult male Wistar rats (BDL groups). In two of these groups, frankincense was administered (100 or 200 mg/kg; by gavage) starting from one week before surgery to 28 days after surgery. The third BDL group received saline. In the sham group, the bile duct was not ligated and the animals received saline. Twenty-eight days after surgery, spatial memory was evaluated by the Morris water maze test. Five rats from each group were sacrificed to measure the expression of the hippocampal tumor necrosis factor-alpha (TNF-& alpha;). Three rats from each group were perfused to determine the amount of hippocampal neurons.Results: Bile duct ligation impaired memory acquisition, while frankincense amended it. Bile duct ligation significantly increased the expression of TNF-& alpha;. Frankincense reduced TNF-& alpha; in BDL rats, significantly. The number of neurons in the hippocampal CA1 and CA3 areas was significantly lower in the BDL group and in the group that received frankincense (100 mg/kg) equated to the sham group. Frankincense (200 mg/kg) augmented the amount of neurons in the CA1 area, slightly and in the CA3 area, significantly.Conclusion: The results indicate the anti-inflammatory and neuroprotective effects of frankincense in bile duct ligation-induced hepatic encephalopathy.
Keimasi, M. ,
Salehifard, K. ,
Shahidi, M. ,
Esmaeili, F. ,
Mirshah jafar esfahani, N. ,
Beheshti, S. ,
Amirsadri, M. ,
Naseri, F. ,
Keimasi, M. ,
Ghorbani, N. Frontiers in Pharmacology (16639812) 13
Memory impairment is one of the main complications of Alzheimer’s disease (AD). This condition can be induced by hyper-stimulation of N-Methyl-D-aspartate receptors (NMDARs) of glutamate in the hippocampus, which ends up to pyramidal neurons determination. The release of neurotransmitters relies on voltage-gated calcium channels (VGCCs) such as P/Q-types. Omega-lycotoxin-Gsp2671e (OLG1e) is a P/Q-type VGCC modulator with high affinity and selectivity. This bio-active small protein was purified and identified from the Lycosa praegrandis venom. The effect of this state-dependent low molecular weight P/Q-type calcium modulator on rats was investigated via glutamate-induced excitotoxicity by N-Methyl-D-aspartate. Also, Electrophysiological amplitude of field excitatory postsynaptic potentials (fEPSPs) in the input–output and Long-term potentiation (LTP) curves were recorded in mossy fiber and the amount of synaptophysin (SYN), synaptosomal-associated protein, 25 kDa (SNAP-25), and synaptotagmin 1(SYT1) genes expression were measured using Real-time PCR technique for synaptic quantification. The outcomes of the current study suggest that OLG1e as a P/Q-type VGCC modulator has an ameliorative effect on excitotoxicity-induced memory defects and prevents the impairment of pyramidal neurons in the rat hippocampus. Copyright © 2022 Keimasi, Salehifard, Shahidi, Esmaeili, Mirshah Jafar Esfahani, Beheshti, Amirsadri, Naseri, Keimasi, Ghorbani, Mofid and Moradmand.
Psychopharmacology (00333158) 239(2)pp. 479-487
Studies have shown the anti-seizure properties of the ghrelin hormone in different models of epilepsy. Nevertheless, the role of the endogenous ghrelin is unknown in the electrical kindling model of epilepsy. In this study, we evaluated the effect of the antagonism of the ghrelin receptors in the brain of fully kindled rats. Adult male Wistar rats weighing 300 g were used. Animals were stereotaxically implanted with two uni-polar electrodes in the skull surface and a tri-polar electrode in the basolateral amygdala, and a guide cannula in the left lateral ventricle. Animals underwent a rapid kindling protocol. After showing three consecutive stages of five seizures, the animals were considered fully kindled. D-Lys-3-GHRP-6 (1, 50, and 100 μg/rat) was injected intracerebroventricularly (i.c.v.) in the kindled animals. Each rat was considered as its control and received a single dose of D-Lys-3-GHRP-6. Seizure parameters including after discharge duration (ADD), seizure stage (SS), stage four latency (S4L), and stage five duration (S5D) were recorded. The paired t test indicated a significant increase in seizure induction. D-Lys-3-GHRP-6 (1 μg/rat; i.c.v.) prolonged ADD in the kindled rats, significantly. D-Lys-3-GHRP-6 (50 and 100 μg/rat; i.c.v.) induced spontaneous seizures, which led to status epilepticus in the kindled rats. The results indicate that the antagonism of the ghrelin functional receptors prolongs seizures and induces status epilepticus in the kindling model of epilepsy, and propose that the endogenous ghrelin signaling has crucial antiepileptic properties. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Neuroscience Letters (18727972) 782
Studies have shown that brain histamine has a role in seizure pathophysiology. Histamine acts by four distinct receptor subtypes (H1R–H4R). Previous reports signified the anticonvulsant activity of histamine H3R antagonists. We evaluated the effect of intra-amygdala injection of pitolisant the H3R inverse agonist on seizures induced by the electrical kindling model of epilepsy. Eighteen adult male rats with an approximate weight of 300 g were used. A tri-polar electrode twisted with the guide cannula, and two monopolar electrodes were implanted into the basolateral amygdala or the surface of the skull using stereotaxic surgery. One week after surgery, the threshold was determined in the animals. Twenty-four hours afterward, the animals received six stimuli daily with the threshold intensity until the generation of three consecutive stages five seizures. Then, saline, and 24 h later, pitolisant at three doses (1, 10, and 100 μg) were injected into the amygdala in distinct rats. Thirty minutes after injection of the drug or its solvent, seizure parameters including after-discharge duration (ADD), seizure stage (SS), and stage five duration (S5D) were recorded. Data analysis indicated that pitolisant reduced S5D at all doses, significantly. Pitolisant at the dose of 100 µg also decreased ADD and SS, significantly. However, pitolisant at the doses of 1 and 10 µg did not change ADD and SS. The dose–response curves showed that the anticonvulsant activity of pitolisant changed in a dose-dependent manner. In conclusion, the results confirmed the powerful anticonvulsant effects of pitolisant in the electrical kindling model of epilepsy. © 2022 Elsevier B.V.
Behavioural Brain Research (18727549) 408
Ghrelin is a peptide, secreted mainly from the stomach. But, it is also produced in the brain. Studies have confirmed the positive impact of ghrelin on memory formation. However, the expression levels of ghrelin or its receptors were not measured in the brain during the process of memory formation. The probable alteration in the expression levels of ghrelin or its receptors in the brain during memory formation can be a reason for the contribution of its signaling in this process. We quantified the gene expression levels of ghrelin and its receptors in the hippocampus during fear and spatial memory consolidation. Thirty- nine adult male Wistar rats weighing 180−220 g were utilized. Memory consolidation was evaluated using the inhibitory avoidance task and Morris water maze. Rats were euthanized at different times (1, 3, and 24 h) post-training and their hippocampi were removed and freezed directly in liquid nitrogen. Quantitative real-time polymerize chain reaction (PCR) was used to quantify the messenger ribonucleic acid (mRNA) expression levels of the hippocampal ghrelin and its receptors. The mRNA levels of ghrelin exhibited a significant increase, 24 h post-training in the inhibitory avoidance task, while its receptor levels were down-regulated. Also, the mRNA expression levels of the hippocampal ghrelin were not changed significantly during memory consolidation in the Morris water maze, while its receptor showed a significant increase, 24 h post-training. The results show a differential profile of the expression levels of the hippocampal ghrelin or its receptor mRNA during fear or spatial memory consolidation. This proposes that a local increase in the hippocampal ghrelin or its receptor levels might be crucial for fear, and spatial memory consolidation. However, due to the small sample sizes, it is worth noting the preliminary nature of the conclusions in the present study. © 2021 Elsevier B.V.
2025 29th International Computer Conference, Computer Society of Iran, CSICC 2025 pp. 559-572
Alzheimer’s disease is a complicated neurodegenerative disorder. It is characterized by the pathological accumulation of amyloid-β peptides and neurofibrillary tangles within the brain, which leads to severe cognitive damage. Studies indicate that retinoid signaling in the brain might have crucial impacts on the pathogenesis of Alzheimer’s disease. All-trans retinoic acid is an active metabolite of vitamin A in the brain and has been argued to have beneficial effects in Alzheimer’s disease. In this chapter, the latest findings on the potential prophylactic and therapeutic effects of retinoid signaling on Alzheimer’s disease will be described. Meanwhile, developing insights into possible mechanisms by which retinoic signaling in the brain modulate aspects of Alzheimer’s disease will be discussed. © 2020 Elsevier Inc. All rights reserved.
Yazdi, A. ,
Doostmohammadi, M. ,
Pourhossein majarshin, F. ,
Beheshti, S. Epilepsy and Behavior (15255050) 105
A seizure may occur because of the imbalance between glutamate and gamma-aminobutyric acid (GABA). Recurrent seizures induce some cognitive problems, such as, depression, learning and memory deficits, and neurodegeneration. Histamine is an appropriate therapeutic target for epilepsy via its effect on regulating neurotransmitter release. Also, evidence indicates the effect of histamine on neuroprotection and alleviating cognitive disorders. An ideal antiepileptic drug is a substance, which has both anticonvulsant effects and decreases the comorbidities that are induced by repeated seizures. Betahistine dihydrochloride (betahistine) is a structural analog of histamine. It acts as histamine H1 receptor agonist and H3 receptor antagonist, which enhances histaminergic neuronal activities. In the present study, we examined the effect of betahistine administration on seizure scores, memory deficits, depression, and neuronal loss induced by pentylenetetrazole (PTZ). Eight- to ten-week-old BALB/c male mice (20–25 g) received betahistine, 1, and 10 mg/kg daily from 7 days before the onset of PTZ-induced kindling until the end of the establishment of the kindling. We found that betahistine prevented generalized tonic–clonic seizures induction and diminished forelimb clonic seizures intensity. Also, it decreased cell death in the hippocampus and cortex, ameliorated the memory deficit and depression induced by PTZ in the kindled animals. Altogether, these results indicate that pretreatment and repetitive administration with betahistine exerts antiepileptogenic and anticonvulsant activity. These findings might be due to the neuroprotective impact of betahistine in the hippocampus and cortex. © 2020 Elsevier Inc.
Physiology and Behavior (1873507X) 223
Antagonism of the functional ghrelin receptors impairs memory formation, but the underlying mechanisms are not well-known. We aimed to evaluate the effect of intracerebral injection of a ghrelin receptor antagonist (D-Lys-3-GHRP-6) on memory consolidation in the inhibitory avoidance task and on the gene expression levels of serotonin HT1A and HT7 receptors, glutamate GluN1 subunit of the NMDA and GluA1 subunit of the AMPA receptors and calcium/calmodulin kinase II-α in the hippocampus of rats. Thirty adult male rats were implanted with cannulas in their lateral ventricles. Three groups of animals (n=5) received D-Lys-3-GHRP-6 (0.5 and 5nM) or saline immediately post-training. Twenty-four hours later, memory retrieval was assessed. Three additional groups of animals (n=5) received D-Lys-3-GHRP-6 (0.5 and 5nM) or saline, but animals in these groups were decapitated, and their hippocampus was removed, 24 hours thereafter. The target gene expression levels were measured using a quantitative real-time PCR method. D-Lys-3-GHRP-6 impaired memory consolidation. Meanwhile, it led to a significant downregulation of the mRNA expression levels of the hippocampal serotonin HT1A and HT7 receptors and glutamate GluA1 subunit of the AMPA receptors, but could not affect that of GluN1 subunit of the NMDA receptors and CaMKII-α. It seems that part of the impairing effect of D-Lys-3-GHRP-6 on inhibitory avoidance memory consolidation might be due to a decrease in the expression of serotonin HT1A and HT7 receptors and glutamate AMPA receptors in the hippocampus of rats. © 2020 Elsevier Inc.
Scientific Reports (20452322) 10(1)
Quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) have an ameliorative effect on diabetes-induced memory impairment. The current study aimed to compare the effect of quercetin (QC) and QCSPIONs on inflammation-related microRNAs and NF-κB signaling pathways in the hippocampus of diabetic rats. The expression levels of miR-146a, miR-9, NF-κB, and NF-κB-related downstream genes, including TNF-α, BACE1, AβPP, Bax, and Bcl-2 were measured using quantitative real-time PCR. To determine the NF-κB activity, immunohistochemical expression of NF-κB/p65 phosphorylation was employed. Computer simulated docking analysis also performed to find the QC target proteins involved in the NF-κB pathway. Results indicate that diabetes significantly upregulated the expression levels of miR-146a, miR-9, TNF-α, NF-κB, and subsequently AβPP, BACE1, and Bax. Expression analysis shows that QCSPIONs are more effective than pure QC in reducing the expression of miR-9. Interestingly, QCSPIONs reduce the pathological activity of NF-κB and subsequently normalize BACE1, AβPP, and the ratio of Bax/Bcl-2 expression better than pure QC. Comparative docking analyses also show the stronger binding affinity of QC to IKK and BACE1 proteins compared to specific inhibitors of each protein. In conclusion, our study suggests the potent efficacy of QCSPIONs as a promising drug delivery system in memory improvement through targeting the NF-κB pathway. © 2020, The Author(s).
Physiology And Pharmacology (24765236) 24(1)pp. 46-53
Introduction: Frankincense expands memory performance in different experimental models of learning. Nevertheless, the causal molecular mechanisms have not been well investigated. The expression levels of some of the synaptic proteins might probably change following the consumption of frankincense. The present study investigated the effect of maternal injection of frankincense during gestation and lactation periods on memory performance and the mRNA expression levels of syntaxin1A and synaptophysin in the hippocampus of the offspring rats. Methods: Adult female Wistar rats weighing 180-220g received two doses (50 or 100mg/kg) of the aqueous extract of frankincense by gavage during gestation and lactation periods for 45 consecutive days, except three days after labor. The control group received water. Spatial memory was assessed in the male offspring rats using the Morris water maze. Quantitative PCR was used to measure mRNAs expression levels of syntaxin1A and synaptophysin. Results: Frankincense improved spatial memory retrieval in the offspring rats. Data analysis by one-way ANOVA demonstrated that frankincense did not change the expression levels of the hippocampal syntaxin1A mRNA in the offspring rats. However, it significantly decreased the expression levels of the hippocampal synaptophysin mRNA. Conclusion: The results indicate that consumption of frankincense during both gestation and lactation periods has a beneficial impact on spatial memory performance, which is accompanied by the down-regulation of the hippocampal synaptophysin mRNA. Nevertheless, this down-regulation did not change the improving effect of frankincense in memory. © 2020, Iranian Society of Physiology and Pharmacology. All rights reserved.
Amanzadeh, E. ,
Esmaeili, A. ,
Abadi, R.E.N. ,
Kazemipour, N. ,
Pahlevanneshan, Z. ,
Beheshti, S. Scientific Reports (20452322) 9(1)
Biomedical application of quercetin (QT) as an effective flavonoid has limitations due to its low bioavailability. Superparamagnetic iron oxide nanoparticle (SPION) is a novel drug delivery system that enhances the bioavailability of quercetin. The effect of short time usage of quercetin on learning and memory function and its signaling pathways in the healthy rat is not well understood. The aim of this study was to investigate the effect of free quercetin and in conjugation with SPION on learning and memory in healthy rats and to find quercetin target proteins involved in learning and memory using Morris water maze (MWM) and computational methods respectively. Results of MWM show an improvement in learning and memory of rats treated with either quercetin or QT-SPION. Better learning and memory functions using QT-SPION reveal increased bioavailability of quercetin. Comparative molecular docking studies show the better binding affinity of quercetin to RSK2, MSK1, CytC, Cdc42, Apaf1, FADD, CRK proteins. Quercetin in comparison to specific inhibitors of each protein also demonstrates a better QT binding affinity. This suggests that quercetin binds to proteins leading to prevent neural cell apoptosis and improves learning and memory. Therefore, SPIONs could increase the bioavailability of quercetin and by this way improve learning and memory. © 2019, The Author(s).
Physiology and Behavior (1873507X) 194pp. 491-496
Methamphetamine (METH) abuse is one the most worldwide problems with wide-ranging effects on the central nervous system (CNS). Chronic METH abuse can associate with cognitive abnormalities and neurodegenerative changes in the brain. Agmatine, a cationic polyamine, has been proposed as a neuromodulator that modulates many effects of abused drugs. The aim of this study was to determine if agmatine can decrease the impairment effect of METH on memory and hippocampal CaMKII-α gene expression, a gene that plays a major role in memory. Male wistar rats (200–220 g) were allocated into 7 groups, including 5 groups of saline, METH (1, 2 mg/kg), Agmatine (5, 10 mg/kg) and 2 groups of agmatine (5, 10 mg/kg) with higher doses of METH (2 mg/kg) for 5 consecutive days (n = 8 in each group). All injections were done intraperitoneally and agmatine was administrated 10 min before METH treatment. Furthermore, Passive avoidance learning (PAL) test was assessed on the 5th day. Retention test was done 24 h after training and the rats were sacrificed immediately. Hippocampi were removed and stored at −80 °C. Finally, hippocampal CaMKII-α gene expression was measured using Quantitative Real-time PCR. Our data showed that chronic METH dose-dependently impaired PAL retrieval, as it decreased step-through latency (STL) and increased time spent in the dark compartment (TDC). While Agmatine with a higher dose (10 mg/kg) significantly decreased impairment effect of METH (2 mg/kg) on PAL and memory. Also, molecular results revealed that METH (2 mg/kg) markedly decreased hippocampal CaMKII-α gene expression while agmatine (10 mg/kg) co-adminstration prevented it. Taken together, the results propose that agmatine may provide a potential therapy for learning and memory deficits induced by METH. © 2018
International Journal Of Nanomedicine (11782013) 13pp. 6311-6324
Background: Diabetes mellitus plays a causative role in cognitive decline. Newly, neuroprotective effects of flavonoids have been widely investigated in neurodegenerative diseases. Quercetin (QC) is a phyto-derived bioactive flavone with numerous beneficial activities. However, its limited permeability to cross the blood–brain barrier, low oral bioavailability, poor aqueous solubility, and rapid gastrointestinal digestion lead to the administration of high dose of QC in clinical application. Materials and methods: In order to overcome these limitations, we conjugated QC with superparamagnetic iron oxide nanoparticles (QCSPIONs) and supplemented streptozotocin-induced diabetic rats with it to improve diabetes-related memory impairment. In this regard, 40 rats were distributed into five groups with eight animals: control, diabetes, and diabetes treated with SPIONs, QC, and QCSPIONs. All treatments (at the dose of 25 mg/kg) were dissolved in deionized water and gavaged for 35 consecutive days. Results: At the end of the study, QCSPIONs possessed significantly better efficacy than free QC on the improvement of memory performance. In the Morris water maze test, QCSPIONs compared to free QC reduced much better the escape latency over training trials (P<0.01) and increased the time spent in the target quadrant in probe trial (P<0.001). In the passive avoidance test, it increased step-through latency (P<0.05) and reduced the time spent in the dark compartment (P<0.01). In addition, both free QC and QCSPIONs were able to prevent the changes in body weight and decrease blood glucose levels in diabetic rats (P<0.05). Conclusion: Overall, according to these results, we conclude that QC in the conjugated state with lower dose offers significantly higher potency in ameliorating diabetes-related memory impairment. Thus, this study offers an effective combined therapy for improving learning and memory. © 2018 Ebrahimpour et al.
Beheshti, S. ,
Ghorbanpour skakakomi, A. ,
Ghaedi, K. ,
Dehestani, H. International Journal of Developmental Neuroscience (07365748) 69pp. 44-48
Background: Frankincense is an oleo gum resin derived from trees of genus Boswellia. It has favorable effects on memory formation. However, the probable underlying molecular mechanisms have not been assessed. Frankincense exerts some of its effects via activation of protein kinases. Calcium/calmodulin kinaseII (CaMKII) and CaMKIV are crucial mediators of learning and memory. We studied the effect of maternal injection of the aqueous extract of frankincense during gestation and lactation periods on spatial memory performance and the mRNA expression levels of the hippocampal CaMKIIand CaMKIV in the offspring rats. Methods: Aqueous extract of Frankincense (50 and 100 mg/kg) or tap water was gavaged to distinct female rats during gestation and lactation periods. Memory performance was assessed in groups of male offspring using Morris water maze. In other groups of the offspring (with no memory test), the hippocampi of the juvenile rats were removed 30 days after labor. A real-time PCR method was used to measure the mRNA levels of CaMKII and CaMKIV. Results: Frankincense improved spatial memory retrieval in the offspring rats in a dose-dependent manner. The mRNA expression of hippocampal CaMKIV was unchanged between groups. However, the mRNA expression of hippocampal CaMKII was dose-dependently upregulated in the rats, whose mothers had received frankincense. Conclusions: Due to the crucial role of the CaMKII in memory formation, the results provide a molecular basis for the effect of administration of frankincense to mother rats on improvement of the memory in the offspring. © 2018 ISDN
Neuropeptides (15322785) 67pp. 20-26
It is well known that the hormone ghrelin affects learning and memory in different experimental models of learning. Though, the effect of antagonism of ghrelin receptor type 1a (GHS-R1a) in various regions of the brain and on different stages of learning has not been examined. In this study the effect of injection of a GHS-R1a selective antagonist (D-Lys-3-GHRP-6) into the basolateral amygdala, dentate gyrus or ventral tegmental area was examined on memory consolidation in the passive avoidance task. Adult male Wistar rats weighing 230–280 g were used. Animals underwent stereotaxic surgery and cannulated in their amygdala, dentate gyrus or ventral tegmental area. One week after surgery, the rats received different doses of D-Lys-3-GHRP-6 (0.08, 0.8, and 8 nM), immediately after training. The control groups received solvent of the drug. Twenty four hours later in the test day, memory retrieval was assessed. In all groups, post-training injection of D-Lys-3-GHRP-6 decreased step-through latency and increased entries into the dark compartment and time spent in the dark compartment, significantly and in a dose-dependent manner. The results indicate that antagonism of the GHS-R1a in the rat amygdala, dentate gyrus or ventral tegmental area impairs memory consolidation and show that the ghrelin signaling has a widespread influence on cognitive performance. © 2017
Journal Of Herbmed Pharmacology (23455004) 7(3)pp. 193-199
Introduction: Medicinal herbs have several components with different pharmacological effects. It has been described that Melissa officinalis is able to improve memory in different models of learning. Nevertheless, its influence has not been studied in animal models of AD. Here, we studied the potential therapeutic effect of M. officinalis in intracerebroventricular (i.c.v) amyloid-β (Aβ) model of Alzheimer's disease (AD). Methods: Male Wistar rats weighing 260-330 g received the hydro-alcoholic extract of M. officinalis (50, 100, 200, 400 mg/kg; P.O), chronically for 30 consecutive days. The control group received solvent of the drug. Memory retrieval was assessed, using the passive avoidance task. Three groups of the rats received Aβ (1-42; 10 μg/rat bilaterally; i.c.v). One group received DMSO 1% (2 μL/rat; i.c.v). Twenty days later memory retrieval was assessed. The Aβ-treated rats, received M. officinalis (50, 100 mg/kg; P.O) or saline (1 mL/kg; P.O), chronically for 30 consecutive days. The DMSO 1%-treated rats received saline (1 mL/kg; P.O). Results: The hydro-alcoholic extract of M. officinalis (50, 100, 200, 400 mg/kg; P.O) did not have a significant effect on step-through latency (STL). Aβ impaired memory retrieval by decreasing STL and increasing the time spent in the dark compartment (TDC). M. officinalis (50, 100 mg/kg; P.O) improved memory retrieval in AD rats by increasing STL and decreasing TDC, significantly. Conclusion: The outcomes of the study show that M. officinalis has a therapeutic effect in the Aβ model of AD. It seems that the extracts of M. officinalis can be suggested as a powerful therapeutic herb for AD patients. © 2018, Nickan Research Institute.
BMC Pharmacology and Toxicology (20506511) 19(1)
Background: Quercetin (QT) as a bioactive flavonoid has a potential therapeutic activity for numerous neuronal injuries and neurodegenerative diseases. However, the low absorption rate of QT, especially through the blood-brain barrier, restricts its bioactivity in the body. The current research took the advantage of superparamagnetic iron oxide nanoparticles (SPIONs) to enhance the bioavailability of quercetin. Methods: Quercetin conjugated with SPIONs was prepared by means of nanoprecipitation method and was characterized by X-ray diffractometer, scanning electron microscope, and Fourier transformed infrared spectrometer analyses. Wistar male rats were orally fed by gavage with QT and QT-SPION at 50 and 100 mg/kg daily doses for 7 days. Using high-performance liquid chromatography (HPLC) method, biodistribution of QT was evaluated in plasma and brain tissue. Results: The outcomes of this research revealed a higher concentration in the plasma and brain of the rats fed with QT-SPION in comparison to free QT. Conclusion: The results of this study confirm that SPION as a targeted drug delivery system enhances the bioavailability of quercetin in the brain about ten folds higher than free quercetin and could be used for the treatment of neurodegenerative disorders. © 2018 The Author(s).
Physiology and Pharmacology (17350581) 21(1)pp. 34-43
Introduction: Retinoid signaling has been argued to have favorable effects on Alzheimer’s disease (AD). We studied the role of chronic intracerebroventricular (ICV) injection of all-trans retinoic acid (ATRA) on the amyloid-beta (Aβ) model of AD. Methods: Adult male rats weighing 260-330 g were divided into 12 groups of 8 each. Six groups of rats received ATRA (3nM, 30nM, 3μM, 0.3mM, 30mM/rat; ICV) or DMSO 1% (2μl/rat; ICV), bilaterally and in a chronic manner (6 times, twice a week). Forty eight hours following the last injection, memory performance was assessed using a passive avoidance paradigm. One group received Aβ (10μg/rat; ICV), bilaterally. The control group received DMSO 1% (2μl/rat; ICV). Twenty days later memory performance was assessed. Three groups of rats received Aβ (10μg/rat; ICV) and then ATRA (3nM or 30nM/rat; ICV) or DMSO 1%, chronically (6 times, twice a week). Another group received DMSO 1% (2μl/rat; ICV) and then, DMSO 1%, chronically (6 times, twice a week). Results: ATRA at doses 0.3mM and 30mM/rat impaired memory retrieval by decreasing step-through latency (STL) and increasing time spent in the dark compartment (TDC), significantly. However, moderate doses (3nM and 30nM/rat) did not change memory performance. ATRA (30nM/rat) increased STL and decreased TDC and NST in the Aβ-treated rats, significantly compared to the group received Aβ- DMSO 1%. Conclusion: The results propose a potential prophylactic effect of ATRA in the ICV Aβ model of AD and indicate the prominence of retinoic acid signaling as a target for AD prevention. © 2017, Iranian Society of Physiology and Pharmacology. All rights reserved.
Behavioural Brain Research (18727549) 320pp. 85-90
Gap junction channels are implicated in learning and memory process. However, their role on each of the particular stages of memory formation has been studied less. In this study, the time profile of the expression levels of hippocampal connexins 36 and 45 (Cx36 and Cx45) mRNAs was measured during memory consolidation, in a passive avoidance paradigm. Totally 30 adult male rats were distributed into 5 groups of each 6. At different times profiles (30 min, 3, 6 and 24 h) following training, rats were decapitated and their hippocampi were immediately removed and frozen in liquid nitrogen. Total RNA was extracted and cDNA was synthesized, using oligo-dt primers. A quantitative real-time PCR was used to measure the levels of each of Cx36 and Cx45 mRNAs. Both connexins showed a rapid upregulation (30 min) at the transcriptional level, which declined in later times and reached to the control level at 24 h. The rapid up-regulation of Cx36 and Cx45 mRNAs might be accompanied with increasing intercellular coupling via gap junction channels and neuronal oscillatory activities required for memory consolidation. The results highlight the role of gap junctional coupling between hippocampal neurons during memory consolidation in the physiological conditions. © 2016 Elsevier B.V.
Journal Of Herbmed Pharmacology (23455004) 5(1)pp. 12-16
Introduction: Frankincense has been shown to possess anti-inflammatory activity. In this study the effect of pretreatment with the hydro-alcoholic extract of frankincense on memory retrieval was assessed in lipopolysaccharide (LPS) treated rats. Methods: Forty-two adult male Wistar rats were distributed into 7 groups of 6 each. One group received LPS (1 mg/kg; i.p) pre-test. The control group received saline (1 ml/kg; i.p). 2 groups of animals received frankincense (50 mg/kg; P.O) or DMSO 5% (1 ml/kg; P.O) and 30 minutes later LPS (1 mg/kg; i.p). Two other groups of animals received frankincense (50 mg/kg; P.O) or DMSO 5% (1 ml/kg; P.O) and 30 minutes later saline (1 ml/kg; i.p). Another group of rats received LPS (1 mg/kg; i.p) and 30 minutes later Ibuprofen (100 mg/kg; P.O). In all the experimental groups, memory retrieval was assessed 4 hours following the last injection, using a passive avoidance task (PAT). Hippocampal TNF-α levels were measured by ELISA as an index of LPS-induced neuroinflammation. Results: LPS impaired memory retrieval by decreasing step-through latency (STL), significantly. LPS also increased levels of TNF-α in the hippocampus as compared to the control group. Administration of frankincense (50 mg/kg; P.O) before LPS (1 mg/kg; i.p) improved memory retrieval as compared to the control group. Frankincense reduced hippocampal TNF-a level in the LPS treated rats, significantly, compared to the control group. Conclusion: The results indicate that the hydro-alcoholic extract of frankincense has the potential to improve memory retrieval in LPS treated rats, possibly via an anti-neuroinflammatory activity.
Neuropeptides (15322785) 52pp. 97-102
Studies have shown that intracerebral administration of ghrelin hormone affects learning and memory in different experimental models of learning. However, the effect of antagonism of ghrelin receptor type 1a (GHS-R1a) on different stages of learning has not been investigated. In this study the effect of intracerebroventricular (i.c.v) injection of a GHS-R1a selective antagonist (d-Lys-3-GHRP-6) was examined on acquisition and consolidation of learning in the passive avoidance task. In total, 72 male Wistar rats weighing 230-280. g were randomly distributed into 9 groups of 8 each. Animals underwent stereotaxic surgery and cannulated in their right ventricle. One week after surgery, the rats received different doses of d-Lys-3-GHRP-6 (0.2, 2, 20 and 80. nM/5. μl; i.c.v) 10. min before, or (2, 20 and 80. nM/5. μl; i.c.v) immediately after training. The control groups received solvent of the drug. Twenty four hours later in the test day, memory retrieval was assessed. Pre-training injection of d-Lys-3-GHRP-6 decreased step-through latency (STL) and increased number of step-throughs into the dark compartment (NST) in a dose-dependent manner, but failed to be statistically significant. It also increased time spent in the dark compartment (TDC), significantly and in a dose-dependent manner. Post-training injection of d-Lys-3-GHRP-6 decreased step-through latency and increased time spent in the dark compartment and number of step-throughs into the dark compartment, significantly and in a dose-dependent manner. The results indicate that antagonism of the GHS-R1a in the rat brain impairs memory encoding on both acquisition and consolidation stages. Further studies are required to elucidate the main brain regions affected by the antagonist. © 2015 Elsevier Ltd.
Physiology and Pharmacology (17350581) 18(4)pp. 477-489
Introduction: Olibanum improves memory in different models of learning. However, the effect of olibanum on models of Alzheimer’s disease has been less studied. In the present study, the effect of olibanum on memory in normal rats and in a rat model of Alzheimer disease induced by intracerebroventricular injections of streptozotocin was evaluated. Methods: Rats received an aqueous extract of olibanum (50, 100 and 300 mg/kg) via gavage, acutely 30 minutes before the test and chronically for 21 consecutive days before assessment of memory racall. In two other groups of animals, two guide cannulas were inserted into the lateral ventricles under stereotaxic surgery. One group received bilateral injections of streptozotocin (1.5 mg/kg/2 μl/side) in the first and third days of surgery. The other group received artificial cerebrospinal fluid. Fourteen days after surgery, learning was evaluated. Two other groups of animals received olibanum (50 mg/kg) or its solvent, for 21 days beginning from one week before injections of streptozotocin. Results: Acute administration of olibanum did not affect learning parameters, but chronic administration of it (50 mg/kg) improved memory retrieval. Streptozotocin increased number of necessary stimulations for induction of short term memory, but decreased step through latency, significantly. In animals which received streptozotocin, olibanum increased step through latency, significantly. Conclusion: Olibanum reduces the risk of Alzheimer’s disease induced by streptozotocin. Further studies with emphasis on active constituents of olibanum may result in development of drugs capable of decreasing probability of Alzheimer’s disease occurrence. © 2014, National Research Council of Canada. All rights reserved.
Forouzanfar, M. ,
Rabiee, F. ,
Ghaedi, K. ,
Beheshti, S. ,
Tanhaei, S. ,
Shoaraye nejati, A. ,
Jodeiri farshbaf, M. ,
Baharvand, H. ,
Nasr-esfahani, M.H. Cell Biology International (10958355) 39(5)pp. 629-637
Fndc5 has been recently recognized as a myokine which could be cleaved and secreted into blood stream. It is termed as irisin with an important role in thermogenesis and energy homeostasis. Increased expression of Fndc5 has been reported upon retinoic acid treatment during neural differentiation and its knockdown decreased neural differentiation and neurite outgrowth. This study tries to evaluate the effect of Fndc5 overexpression on rate of neural differentiation in mouse. (Thus, transduced cell line of mouse embryonic stem cell with ability to express Fndc5 under Doxycycline treatment was established. Subsequently, the effect of overexpression of Fndc5 on different stages of neural differentiation was studied). Our study showed an increase enhancement in neuronal precursor markers and mature neuron markers upon overexpression of Fndc5, concluding that Fndc5 facilitates neural differentiation. This effect might be related to increased expression of BDNF following overexpression of Fndc5. Our findings are consistent with recent studies reporting a similar role for Fndc5 in proliferation of neural cells and increase in the expression of neurotrophins like BDNF. © 2015 International Federation for Cell Biology.
Physiology and Pharmacology (17350581) 19(3)pp. 177-184
Introduction: Gap junctions are specialized cell–cell contacts between eukaryotic cells through which they communicate. This type of communication has the potential to modulate memory process. We evaluated the effects of the gating of the hippocampal CA1 area gap junction channels on memory consolidation, using passive avoidance task. Materials and Methods: 72 adult male Wistar rats were distributed into 9 groups of 8 each. Two guiding cannulas were bilaterally implanted in the hippocampal CA1 area of all rats. One week after surgery, the animals received an electrical shock with the intensity and duration of 0.3 mA and 1s, respectively. Immediately after training 25, 75 or 150 nM doses of carbenoxolone, a non-selective blocker of gap junction channels or 50, 150 and 1500 nM doses of trimethylamine, an opener of gap junction channels were injected. Another group received 50 nM trimethylamine and 10 min later 75 nM carbenoxolone, immediately post-training. 24 hours later, memory retrieval was assessed. Results: Post-training injection of carbenoxolone significantly and dose- dependently decreased step-through latency, whereas post-training injection of trimethylamine showed a tendency toward increasing step-through latency. Post-training injection of trimethylamine (50 nM) increased step-through latency, significantly compared with post-training injection of carbenoxolone (75 nM and 150 nM). Post-training injection of trimethylamine (50 nM) before carbenoxolone (75 nM) reversed the effects of carbenoxolone on inhibition of memory consolidation. Conclusion: These data suggest that the intercellular coupling via gap junction channels in the hippocampal CA1 cells is crucial for memory consolidation in the passive avoidance task. © 2015, Iranian Society of Physiology and Pharmacology. All rights reserved.
European Journal of Pharmacology (00142999) 745pp. 196-200
Morphine produces a state dependent learning. The hippocampus is involved in this kind of learning. Gap junctions (GJs) are involved in some of the effects of morphine and exist in different areas of the hippocampus. We investigated the effects of blocking GJ channels of the hippocampal CA1 area, by means of pre-test bilateral injection of carbenoxolone (CBX), on morphine state dependent learning, using a passive avoidance task. Post-training subcutaneous administrations of morphine (0.5, 2.5, 5 and 7.5 mg/kg) dose-dependently impaired memory retrieval. Pre-test administration of morphine (0.5, 2.5, 5 and 7.5 mg/kg) induced a state-dependent retrieval of the memory acquired under post-training morphine influence. Pre-test injections of CBX (25, 75 and 150 nM) dose dependently prevented memory retrieval by post-training (7.5 mg/kg) and pre-test (0.5, 2.5, 5, 7.5 mg/kg) injections of morphine. The results suggest that intercellular coupling via GJ channels of the hippocampal CA1 area modulates morphine state dependent learning. © 2014 Elsevier B.V. All rights reserved.
Akbarpour, B. ,
Sayyah, M. ,
Babapour, V. ,
Mahdian, R. ,
Beheshti, S. ,
Kamyab, A.R. Neuroscience Bulletin (19958218) 28(6)pp. 729-736
Objective Understanding the molecular and cellular mechanisms underlying epileptogenesis yields new insights into potential therapies that may ultimately prevent epilepsy. Gap junctions (GJs) create direct intercellular conduits between adjacent cells and are formed by hexameric protein subunits called connexins (Cxs). Changes in the expression of Cxs affect GJ communication and thereby could modulate the dissemination of electrical discharges. The hippocampus is one of the main regions involved in epileptogenesis and has a wide network of GJs between different cell types where Cx30 is expressed in astrocytes and Cx32 exists in neurons and oligodendrocytes. In the present study, we evaluated the changes of Cx30 and Cx32 expression in rat hippocampus during kindling epileptogenesis. Methods Rats were stereotaxically implanted with stimulating and recording electrodes in the basolateral amygdala, which was electrically stimulated once daily at afterdischarge threshold. Expression of Cx30 and Cx32, at both the mRNA and protein levels, was measured in the hippocampus at the beginning, in the middle (after acquisition of focal seizures), and at the end (after establishment of generalized seizures) of the kindling process, by real-time PCR and Western blot. Results Cx30 mRNA expression was upregulated at the beginning of kindling and after acquisition of focal seizures. Then it was downregulated when the animals acquired generalized seizures. Overexpression of Cx30 mRNA at the start of kindling was consistent with the respective initial protein increase. Thereafter, no change was found in protein abundance during kindling. Regarding Cx32, mRNA expression decreased after acquisition of generalized seizures and no other significant change was detected in mRNA and protein abundance during kindling. Conclusion We speculate that Cx32 GJ communication in the hippocampus does not contribute to kindling epileptogenesis. The Cx30 astrocytic network localized to perivascular regions in the hippocampus is, however, overexpressed at the initiation of kindling to clear excitotoxic molecules from the milieu. © Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2012.
Beheshti, S. ,
Sayyah, M. ,
Golkar, M. ,
Sepehri, H. ,
Babaie, J. ,
Vaziri, B. Progress in Neuro-Psychopharmacology and Biological Psychiatry (18784216) 34(3)pp. 510-515
Objective: Identification of key molecular changes occurring during epileptogenesis provides better understanding of epilepsy and helps to develop strategies to modify those changes and thus, block the epileptogenic process. Gap junctional communication is thought to be involved in epileptogenesis. This communication can be affected by changes in expression of gap junctional protein subunits called connexins (Cxs). One of the main brain regions involved in epileptogenesis is the hippocampus in which there is a network of gap junctional communication between different cell types. Method: Cx36 and Cx43 expressions at both mRNA and protein level were measured in rat hippocampus during epileptogenesis in the kindling model of epilepsy. Results: Cx36 expression at both mRNA and protein level was upregulated during acquisition of focal seizures but returned to basal level after acquisition of secondarily-generalized seizures. No change in Cx43 gene and protein expression was found during kindling epileptogenesis. Conclusion: These results further point out the significance of Cx36 as a target to modify epileptogenic process and to develop antiepileptogenic treatments. © 2010 Elsevier Inc.
Sayyah, M. ,
Beheshti, S. ,
Shokrgozar m.a., M.A. ,
Eslami-far a., ,
Deljoo z., ,
Khabiri a.r., ,
Haeri rohani a., A. Experimental Neurology (00144886) 191(1)pp. 145-153
Ischaemic, excitotoxic and traumatic brain injuries have been associated with the occurrence of epileptic seizures. Microglia, the principal immune cells in the brain, produce a variety of proinflammatory and cytotoxic factors especially interleukin-1 (IL-1) early after an acute insult. We studied the effect of intracerebroventricularly administered IL-1β on seizure acquisition and on fully kindled seizures in amygdala kindling model of epilepsy. IL-1β (0.01 ng/rat) retarded acquisition of kindled behavioral seizures and growth of afterdischarges (AD). IL-1β (0.01-10 ng/rat) also exhibited significant anticonvulsant effect on established kindled seizures and AD duration. This effect began 0.5 h after administration and was continued up to 72 h. Pretreatment of the kindled animals with nitric oxide synthase inhibitor, N G-nitro-l-arginine methyl ester, or cyclooxygenase inhibitor, piroxicam, reversed the anticonvulsant effect of IL-1β at early time points. Although most of the previous studies indicate a proconvulsant or convulsant property of IL-1, our results support a protective and antiepileptogenic role of IL-1β. © 2004 Elsevier Inc. All rights reserved.
Epilepsy Research (09201211) 57(2-3)pp. 175-180
Seizures are common sequel to brain insults in cases such as stroke, trauma and infection where there is a certain neuroinflammation. Intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) induces an inflammatory state in brain that is used as a model of neuroinflammation. We studied the effect of LPS (0.25 and 2.5μg/rat, i.c.v.) on development of electrical kindling of the amygdala and on fully-kindled seizures. LPS, at the doses used, had no effect on fully-kindled seizures and afterdischarge (AD) duration at 0.5, 2 or 4h after administration. However, daily injection of LPS (2.5μg/rat) retarded acquisition of kindled behavioral seizures. This antiepileptogenic effect could be due to the release of inflammatory mediators from microglia and the related morphological and functional changes in synaptic neurotransmission. © 2003 Elsevier B.V. All rights reserved.
