Rutin via Increase in the CA3 Diameter of the Hippocampus Exerted Antidepressant-Like Effect in Mouse Model of Maternal Separation Stress: Possible Involvement of NMDA Receptors

Background and Aim. Rutin is a flavonol with neuroprotective activity. The aim of the present study is to investigate the role of the glutamatergic system in the antidepressant-like effect of rutin in a mouse model of maternal separation (MS) stress focusing on histological changes in the CA3 area of the hippocampus. Methods. Mouse neonates were exposed to MS paradigm 3 hours daily from postnatal days (PND) 2 to 14. The control and MS mice were divided separately into 16 groups (n=8) (8 groups for each set) including mice that received normal saline, mice that received rutin at doses of 10, 50, and 100 mg/kg, mice that received NMDA at a dose of 150 mg/kg, mice that received ketamine (NMDA antagonist) at a dose of 0.25 mg/kg, mice that received NMDA antagonist plus a subeffective dose of rutin, and mice that received NMDA plus an effective dose of rutin. Forced swimming test (FST) was performed. Afterwards, the hippocampus was evaluated in cases of histopathological changes as well as expression of NR2A and NR2B genes. Results. Rutin significantly reduced immobility time in the FST. The expression of NR2A and NR2B subunits of NMDA receptor in MS mice was significantly higher than that in the control group. Rutin significantly decreased the expression of NR2B and NR2A subunits in the hippocampus. The CA3 diameter and percentage of dark neurons in the hippocampus of MS mice significantly decreased and increased, respectively, which partially reversed following rutin administration. Conclusion. Rutin, partially, through a neuroprotective effect on the hippocampus exerted antidepressant-like effect. We concluded that NMDA receptors, at least in part, mediated the beneficial effect of rutin.

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Adenylyl Cyclase (AC) Mediates the Antidepressant-Like Effects of Tropisetron on a Mouse Model of Maternal Separation Stress

Depression Research and Treatment ◽

10.1155/2021/5586119 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Ali Hosseinzadeh ◽

Shakiba Nasiri Boroujeni ◽

Elham Saghaei ◽

Zahra Loriooini ◽

Saeid Habibian Dehkordi ◽

...

Keyword(s):

Effective Dose ◽

Adenylyl Cyclase ◽

Maternal Separation ◽

Forced Swimming Test ◽

Forced Swimming ◽

Control Group ◽

Immobility Time ◽

Swimming Test ◽

Medicinal Properties

The adenylyl cyclase (AC) pathway is involved in the pathophysiology of depression. Finding new antidepressants with high medicinal properties and low side effects is warranted. Therefore, this study was designed to determine the antidepressant-like effect of tropisetron on a maternal separation (MS) model in mice, considering the possible role of AC. NMRI male mice were divided into eleven groups. The control group was treated with saline and MS groups were treated with saline, tropisetron (a 5-HT3 receptor antagonist) at doses of 1, 3, and 5 mg/kg; forskolin (an activator of AC) at doses of 5, 10, and 25 mg/kg; a subeffective dose of forskolin with a subeffective dose of tropisetron; and an effective dose of tropisetron plus an effective dose of NB001 (3 mg/kg) (an AC inhibitor). After treatment, animals were subjected to behavioral tests including the forced swimming test (FST), splash test, and open field test (OFT). We showed that MS caused depressive-like behaviors determined as an increase in the immobility time in the forced swimming test (FST) and decreased grooming time in the splash test. Our results showed that administration of tropisetron, as well as forskolin, mitigated the depressive-like behaviors in MS mice. We found that coadministration of a subeffective dose of tropisetron plus a subeffective dose of forskolin potentiated the antidepressant-like effect of tropisetron. However, coadministration of an effective dose of NB001 with an effective dose of tropisetron did not significantly affect the antidepressant-like effect of tropisetron. We concluded that the antidepressant-like effects of tropisetron on MS mice are partially mediated through the adenylyl cyclase pathway.

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Limonene through Attenuation of Neuroinflammation and Nitrite Level Exerts Antidepressant-Like Effect on Mouse Model of Maternal Separation Stress

Behavioural Neurology ◽

10.1155/2021/8817309 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Zahra Lorigooini ◽

Shakiba Nasiri Boroujeni ◽

Mohammad Sayyadi-Shahraki ◽

Mohammad Rahimi-Madiseh ◽

Elham Bijad ◽

...

Keyword(s):

Mouse Model ◽

Normal Saline ◽

Maternal Separation ◽

Forced Swimming Test ◽

Open Field Test ◽

Control Group ◽

Nitrite Level ◽

Tnf Α ◽

Immobility Time ◽

Swimming Test

Background and Aim. Depression is a social problem with high economic burden in the society. Finding an effective agent with high efficacy and few side effects is therefore needed. Involvement of neuroimmune response as well as nitric oxide (NO) has been determined in the pathophysiology of depression. Limonene is a terpene with various pharmacological properties. Thus, we aimed to evaluate antidepressant-like effect of limonene on a mouse model of maternal separation (MS) focusing on neuroinflammation and NO level in the hippocampus. Methods. Mice were randomly divided into experimental groups as follows: the control group received normal saline and MS groups received normal saline, limonene (10 and 20 mg/kg), L-NAME (10 mg/kg), L-arginine (L-arg) (75 mg/kg), limonene (10 mg/kg) plus L-NAME, and limonene (20 mg/kg) plus L-arg. Behavioral tests including the forced swimming test (FST), open field test (OFT), and splash test were performed. Finally, serum and hippocampal nitrite levels as well as the expression of inflammatory genes (IL-1β and TNF-α) in the hippocampus were measured. Results. We showed that MS caused depressive-like behavior. Treatment of MS mice with limonene reduced the duration of immobility time in FST and increases the grooming activity time in the splash test. Limonene also reduces serum and brain nitrite levels and reduces the expression of IL-1β and TNF-α in the hippocampus. We found that L-NAME potentiated the effects of a subeffective dose of limonene. Conclusion. We concluded that the antidepressant-like effects of limonene are probably mediated through inhibition of neuroinflammation and attenuation of nitrite levels in the hippocampus.

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Possible Involvement of N-methyl-D-aspartate Receptor (NMDA-R) in the Antidepressant- like Effect of Trigonelline in Male Mice

Current Pharmaceutical Design ◽

10.2174/1381612826666200610181259 ◽

2020 ◽

Vol 26 (39) ◽

pp. 5067-5071 ◽

Cited By ~ 1

Author(s):

Maryam Anjomshoa ◽

Shakiba N. Boroujeni ◽

Esmaeel Bagheri ◽

Zahra Lorigooini ◽

Hossein Amini-Khoei

Keyword(s):

Nmda Receptor ◽

Effective Dose ◽

Receptor Gene ◽

Nmda Antagonist ◽

Hippocampal Volume ◽

Nmda Receptor Antagonist ◽

Neuroprotective Activity ◽

Control Group ◽

Male Mice ◽

Immobility Time

Background and Aim: Depression is a mood disorder with high global prevalence. Depression is associated with a reduction in the hippocampal volume and change in its neurotransmitters function. Trigonelline is an alkaloid with neuroprotective activity. The aim of this study was to investigate the possible role of N-methyl-Daspartate (NMDA) receptor in the antidepressant-like effect of trigonelline, considering histopathological modifications of the hippocampus. Methods: 60 Naval Medical Research Institute (NMRI) male mice were divided into 6 groups including group 1 (normal saline), groups 2, 3 and 4 (trigonelline at doses of 10, 50 and 100 mg/kg), group 5 (effective dose of trigonelline plus NMDA agonist) and group 6 (sub-effective dose of trigonelline plus NMDA antagonist). Forced swimming test (FST) was used to assess depressive-like behavior. Hippocampi were separated under deep anesthesia and used for histopathological evaluation as well as NMDA receptor gene expression assessment. Results: Trigonelline at doses of 10, 50 and 100 significantly reduced the immobility time in the FST in comparison to the control group. The administration of the sub-effective dose of trigonelline plus ketamine (an NMDA receptor antagonist) potentiated the effect of the sub-effective dose of trigonelline. In addition, co-treatment of an effective dose of trigonelline with NMDA mitigated the antidepressant-like effect of trigonelline. Trigonelline at doses of 50 and 100 mg/kg significantly increased the diameter of the CA1 area of the hippocampus. Conclusion: Trigonelline showed an antidepressant-like effect in mice, probably via attenuation of NMDA receptor activity and an increase in the CA1 region of the hippocampus.

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Ferulic acid through mitigation of NMDA receptor pathway exerts anxiolytic-like effect in mouse model of maternal separation stress

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2019-0263 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Zahra Lorigooini ◽

Ali Nouri ◽

Faezeh mottaghinia ◽

Shima Balali-Dehkordi ◽

Elham Bijad ◽

...

Keyword(s):

Nmda Receptor ◽

Mouse Model ◽

Ferulic Acid ◽

Nmda Receptors ◽

Effective Dose ◽

Life Stress ◽

Receptor Agonist ◽

Maternal Separation ◽

Early Life Stress ◽

Central Zone

AbstractBackgroundExperiencing early-life stress plays an important role in the pathophysiology of anxiety disorders. Ferulic acid is a phenolic compound found in some plants which has several pharmacological properties. N-methyl-D-aspartate (NMDA) receptors are involved in the pathophysiology of mood disorders. In this study we aimed to assess the anxiolytic-like effect of ferulic acid in a mouse model of maternal separation (MS) stress by focusing on the possible involvement of NMDA receptors.MethodsMice were treated with ferulic acid (5 and 40 mg/kg) alone and in combination with NMDA receptor agonist/antagonist. Valid behavioral tests were performed, including open field test (OFT) and elevated plus maze test (EPM), while quantitative real time polymerase chain reaction (qRT-PCR) was used to evaluate gene expression of NMDA subunits (GluN2A and GluN2B) in the hippocampus.ResultsFindings showed that treatment of MS mice with ferulic acid increased the time spent in the central zone of the OFT and increased both open arm time and the percent of open arm entries in the EPM. Ferulic acid reduced the expression of NMDA receptor subunit genes. We showed that administration of NMDA receptor agonist (NMDA) and antagonist (ketamine) exerted anxiogenic and anxiolytic-like effects, correspondingly. Results showed that co-administration of a sub-effective dose of ferulic acid plus ketamine potentiated the anxiolytic-like effect of ferulic acid. Furthermore, co-administration of an effective dose of ferulic acid plus NMDA receptor agonist (NMDA) attenuated the anxiolytic-like effect of ferulic acid.ConclusionsIn deduction, our findings showed that NMDA, partially at least, is involved in the anxiolytic-like effect of ferulic acid in the OFT and EPM tests.

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Pathological Alternations of Mediastinal Fat-Associated Lymphoid Cluster and Lung in a Streptozotocin-Induced Diabetic Mouse Model

Microscopy and Microanalysis ◽

10.1017/s1431927620024824 ◽

2020 ◽

pp. 1-14

Author(s):

Yaser H.A. Elewa ◽

Osamu Ichii ◽

Teppei Nakamura ◽

Yasuhiro Kon

Keyword(s):

Endothelial Cells ◽

Lung Injury ◽

Mouse Model ◽

Immune Cells ◽

Inflammatory Markers ◽

Inflammatory Marker ◽

Diabetic Mouse ◽

Control Group ◽

Injury Progression

Diabetes is a devastating global health problem and is considered a predisposing factor for lung injury progression. Furthermore, previous reports of the authors revealed the role of mediastinal fat-associated lymphoid clusters (MFALCs) in advancing respiratory diseases. However, no reports concerning the role of MFALCs on the development of lung injury in diabetes have been published. Therefore, this study aimed to examine the correlations between diabetes and the development of MFALCs and the progression of lung injury in a streptozotocin-induced diabetic mouse model. Furthermore, immunohistochemical analysis for immune cells (CD3+ T-lymphocytes, B220+ B-lymphocytes, Iba1+ macrophages, and Gr1+ granulocytes), vessels markers (CD31+ endothelial cells and LYVE-1+ lymphatic vessels “LVs”), and inflammatory markers (TNF-α and IL-5) was performed. In comparison to the control group, the diabetic group showed lung injury development with a significant increase in MFALC size, immune cells, LVs, and inflammatory marker, and a considerable decrease of CD31+ endothelial cells in both lung and MFALCs was observed. Furthermore, the blood glucose level showed significant positive correlations with MFALCs size, lung injury, immune cells, inflammatory markers, and LYVE-1+ LVs in lungs and MFALCs. Thus, we suggest that the development of MFALCs and LVs could contribute to lung injury progression in diabetic conditions.

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Neuroprotective Activity of the Methanolic Extract of Indigofera aspalathoides against Scopalamine induced Alzheimer's Disease in Experimental Rats

Research Journal of Pharmacy and Technology ◽

10.52711/0974-360x.2021.00898 ◽

2021 ◽

pp. 5163-5168

Author(s):

Rajaram C. ◽

S. Nelson Kumar ◽

S. S. Sheeba Tabassum ◽

Manohar R. ◽

Sumanjali C.

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Traditional Medicine ◽

Methanolic Extract ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Neuroprotective Activity ◽

Control Group ◽

Histological Structure ◽

Anticancer Activities

The plant Indigofera aspalathoides is a traditional medicine with tremendous therapeutic potential which finds it use in treatment of various ailments such as antibacterial, antioxidant, anti-inflammatory, antidiabetic, and anticancer activities. There are no reports that related to the use of this plant in treating patients with Alzheimer’s disease (AD). Hence present study was aimed to scientifically evaluate the neuroprotective effect of the methanolic extract of Indigofera aspalathoides against scopalamine induced Alzheimer’s disease in experimental rats using behavioral tests like elevated plus maze, Y-maze, and rota-rod tests. In addition to this, biochemical evaluation for acetylcholinesterase activity and histopathological evaluation of brain were done. The results suggests that methanolic extract Indigofera aspalathoides (200mg/kg B.wt and 400mg/kg B.wt) used in this study shows significant improvement of various behavioral parameters like locomotion, anxiety, memory, motor integrity and coordination etc when compared to control group. MEIA inhibited brain AChE enzyme, thereby elevating Ach concentration in brain homogenate and ultimately improved memory of rats. Further, more or less normal histological structure of the hippocampus and all amyloid plaques and neurofibrillary tangles that are formed under the influence of scopolamine disappeared in the rats pretreated with MEIA (200mg/kg B.wt and 400mg/kg B.wt). It can be concluded that our results strongly support the anti-Alzheimer’s potential of the methanolic extract of the plant I.aspalathoides and its use in traditional medicine.

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The effect of different partitions of seaweed Sargassum plagyophylum on depression behavior in mice model of despair

Journal of Complementary and Integrative Medicine ◽

10.1515/jcim-2018-0207 ◽

2019 ◽

Vol 16 (4) ◽

Cited By ~ 1

Author(s):

Azadeh Mesripour ◽

Neda Rabian ◽

Afsaneh Yegdaneh

Keyword(s):

Single Dose ◽

Biological Activities ◽

Food Resource ◽

Control Group ◽

Mice Model ◽

Antidepressant Effects ◽

Immobility Time ◽

Term Administration ◽

Swimming Test

Abstract Background Seaweeds are a famous traditional food resource in some countries containing different types of secondary metabolites. These marine organisms have shown different biological activities. The aim of this study was to investigate the effects of hexane and methanol extracts of Sargassum plagyophylum on depression. Methods Sargassum plagyophylum was collected from Persian Gulf. The plant was extracted by maceration with methanol-ethyl acetate solvent. The extract was evaporated and partitioned by hexane and methanol solvents. The two partitions were administered i.p. to male mice either a single dose or for 7 days. Depression was evaluated by the forced swimming test (FST) which higher immobility time indicates depressive-like behavior. Results The immobility time during FST decreased significantly by all the doses of the hexane partitions (notably 40 mg/kg; 10 s ± 2 vs. 114 s ± 12 control group). However, only the lowest dose (20 mg/kg) of the methanol partition reduced immobility time during FST (23 s ± 8, p<0.001). Following the long term administration both of the partitions reduced the immobility time in FST (hexane 27 s ± 11, methanol 70 s ± 14, p<0.05 vs. control 140 s ± 14). Conclusion The hexane partition showed antidepressant effects not only by long-term administration but also by the single dose during FST. The 7 days therapy with methanol partition also induced antidepressant behavior, but only the lowest single dose reduced immobility in FST. The methanol partitions possibly have certain substance that interfered with behavior in the FST. Therefore, S. plagyophylum should be considered for further antidepressant studies.

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Anticonvulsant and Neuroprotective Activities ofPhragmanthera austroarabicaExtract in Pentylenetetrazole-Kindled Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/5148219 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Hibah M. Aldawsari ◽

Basma G. Eid ◽

Thikrayat Neamatallah ◽

Sawsan A. Zaitone ◽

Jihan M. Badr

Keyword(s):

Plant Extract ◽

Hippocampal Neurons ◽

Seizure Activity ◽

Chemical Constituents ◽

Neuroprotective Effect ◽

Intraperitoneal Administration ◽

Neuroprotective Activity ◽

Total Phenolic ◽

Control Group ◽

Phenolic Contents

Anticonvulsant and neuroprotective activity ofPhragmanthera austroarabicaextract were tested in pentylenetetrazole-kindled mice. All the chemical constituents of the plant extract were identified. Additionally, the extract was standardized and proved to contain total phenolic contents equal to379.92±1.32 mg gallic acid equivalents/g dry plant extract. Induction of kindling was achieved by repeated intraperitoneal administration of pentylenetetrazole (35 mg/kg) twice weekly. Male albino mice were givenP.austroarabicaextract (200, 400, or 800 mg/kg). The two higher doses (400 or 800 mg/kg) of the extract significantly caused notable reduction in seizure activity and hippocampal malondialdehyde level compared to pentylenetetrazole control group. The highest dose enhanced cortical GSH level and showed intact DNA in the laddering assay. Upon studying the neuroprotective effect, mice treated with the higher dose of the extract demonstrated an improvement in the percent of surviving neurons in the cortex and hippocampus. We concluded thatP. austroarabicaextract ameliorated seizure activity and protected cortical and hippocampal neurons against pentylenetetrazole-induced kindling in mice.

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Short Therapeutic Window for MK-801 in Transient Focal Cerebral Ischemia in Normotensive Rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199601000-00013 ◽

1996 ◽

Vol 16 (1) ◽

pp. 107-113 ◽

Cited By ~ 64

Author(s):

I. Margaill ◽

S. Parmentier ◽

J. Callebert ◽

M. Allix ◽

R. G. Boulu ◽

...

Keyword(s):

Cerebral Ischemia ◽

Nmda Receptors ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Neuroprotective Activity ◽

Therapeutic Window ◽

Left Middle Cerebral Artery ◽

Mk 801 ◽

Transient Focal Cerebral Ischemia

The present study investigates the role of N-methyl-D-aspartate (NMDA) receptors in a model of transient focal cerebral ischemia in normotensive rats. The left middle cerebral artery and both common carotid arteries were occluded for 60 min. Preliminary studies indicated that this gave reproducible infarctions of the cortex and striatum. These infarctions were the result of severe ischemia followed by complete reperfusion after clamp removal, as showed by striatal tissue Po2 monitoring. Microdialysis indicated that glutamate concentration increased immediately after occlusion and returned to the baseline value 40 min after clamp removal. MK-801 (1 mg kg−1 i.v.), an antagonist of the NMDA glutamatergic receptor, reduced the cortical infarct volume by 29% (p < 0.001) and the striatal infarct volume by 14% (p < 0.05) when given just prior to ischemia, but had no neuroprotective activity when given 30 min after the onset of ischemia. This short therapeutic window for MK-801 suggests that NMDA receptors play only a transient role in reversible focal ischemia in rats.

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Pharmacological Antagonism of Kainate Receptor Rescues Dysfunction and Loss of Dopamine Neurons in a Mouse Model of Human Parkin-induced Toxicity

10.21203/rs.3.rs-36149/v1 ◽

2020 ◽

Author(s):

Maria Regoni ◽

Stefano Cattaneo ◽

Daniela Mercatelli ◽

Salvatore Novello ◽

Alice Passoni ◽

...

Keyword(s):

Mouse Model ◽

Neuroprotective Effect ◽

Chronic Administration ◽

Dopamine Neurons ◽

Kainate Receptors ◽

Substantia Nigra Pars Compacta ◽

Gene Encoding ◽

Neuroprotective Therapy

Abstract BackgroundMutations in the PARK2 gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP), a neurodegenerative disease characterized by dysfunction and death of dopamine (DA) neurons in the substantia nigra pars compacta. Since a neuroprotective therapy for ARJP does not exist, research efforts aimed at discovering potential targets for neuroprotection are critically needed.A previous study demonstrated that loss of parkin function or expression of parkin mutants associated with ARJP causesan accumulation of glutamate kainate receptors (KARs) in human brain tissues and an increase of KAR-mediated currents in neuronsin vitro. MethodsBased on the hypothesisthat such KAR hyper-activation may contribute to the death of nigralDA neurons, we investigated the effect of KAR antagonism on the DA neuron dysfunction and death that occur in the parkinQ311X mouse, a model of human parkin-induced toxicity. ResultsWe found that early accumulation of KARs occurs in the DA neurons of the parkinQ311X mouse model and that chronic administration of the KAR antagonist UBP310 prevents DA neuron loss. This neuroprotective effect was associated with rescue of the abnormal firing rate of nigral DA neurons and downregulation of GluK2, the key KAR subunit. ConclusionsThis study provides novel evidence ofa causal role of glutamate KARs in the DA neuron dysfunction and loss occurring in a mouse model of human parkin-induced toxicity. Our results support KAR as a potential target in the development of a neuroprotective therapy for ARJP.

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