Memory Morris Water Maze Research Articles

Metformin alleviates reactive gliosis and neurodegeneration, improving cognitive deficit in a rat model of temporal lobe epilepsy

Cognitive impairment is a prevalent co-morbidity associated with epilepsy. Emerging studies indicate that neuroinflammation could be a possible link between epilepsy and its comorbidities, including cognitive impairment. In this context, the roles of glial activation, proinflammatory mediators, and neuronal death have been well studied and correlated with epilepsy-associated cognitive impairment in animal studies. While recent reports have demonstrated the anti-epileptogenic and anti-convulsant actions of metformin, its effect on epilepsy associated cognitive deficit remains unknown. Therefore, the current study investigated the effect of metformin treatment on neuroinflammation, neurodegeneration, and cognitive deficits after inducing status epilepticus (SE) with lithium-pilocarpine in rats. Metformin treatment improved the hippocampal-dependent spatial and recognition memory in Morris water maze and Novel object recognition tasks, respectively. Further, metformin treatment attenuated microglial and astroglial activation, accompanied by reduced IL-1β, COX-2 and NF-ĸβ gene expression. Additionally, metformin conferred neuroprotection by inhibiting the neuronal death as assessed by Nissl staining and transmission electron microscopy. These findings suggest that metformin holds promise as a therapeutic intervention for cognitive impairment associated with epilepsy, possibly through its modulation of glial activation and neuronal survival. Further research is needed to elucidate the precise mechanisms and to assess the long-term effect of metformin in epilepsy-associated cognitive impairment.

Repositioning of baricitinib for management of memory impairment in ovariectomized/D-galactose treated rats: A potential role of JAK2/STAT3-PI3K/AKT/mTOR signaling pathway

AimsNeuroinflammation plays a pivotal role in amyloid β (Aβ) plaques formation which is among the hallmarks of Alzheimer's disease (AD). The present study investigated the potential therapeutic effects of baricitinib (BAR), a selective JAK2/ STAT3 inhibitor, in ovariectomized/ D-galactose (OVX/D-gal) treated rats as a model for AD. Main methodsTo induce AD, adult female rats (130–180 g) underwent bilateral ovariectomy and were injected daily with 150 mg/kg, i.p. D-gal for 8 consecutive weeks. BAR (10 and 50 mg/kg/day) was then given orally for 14 days. Key findingsBAR in a dose-dependent effect mitigated OVX/D-gal-induced aberrant activation of JAK2/STAT3 signaling pathway resulting in significant decreases in the expression of p-JAK 2, and p-STAT3 levels, along with deactivating AKT/PI3K/mTOR signaling as evidenced by deceased protein expression of p-AKT, p-PI3K, and p-mTOR. As a result, neuroinflammation was diminished as evidenced by decreased NF-κβ, TNF-α, and IL-6 levels. Moreover, oxidative stress biomarkers levels as iNOS, and MDA were reduced, whereas GSH was increased by BAR. BAR administration also succeeded in reverting histopathological alterations caused by OVX/D-gal, increased the number of intact neurons (detected by Nissl stain), and diminished astrocyte hyperactivity assessed as GFAP immunoreactivity. Finally, treatment with BAR diminished the levels of Aβ. These changes culminated in enhancing spatial learning and memory in Morris water maze, and novel object recognition test. SignificanceBAR could be an effective therapy against neuroinflammation, astrogliosis and cognitive impairment induced by OVX/ D-gal where inhibiting JAK2/STAT3- AKT/PI3K/mTOR seems to play a crucial role in its beneficial effect.

Evaluation of ivermectin and vitamin E based combination with antiseizure rufinamide drug for mitigation of pentylenetetrazole-induced kindling, behavioral challenges and histopathological aberrations.

Pentylenetetrazole- (PTZ)-induced kindling is a broadly used experimental model to evaluate the impact of antiseizure drugs and their novel combination on seizure progression. The current study aimed to evaluate the anti-kindling effects of ivermectin (IVM) and rufinamide (RUFI) alone and their combination with vitamin E. The mice were administered 11 injections of PTZ (40 mg/kg) followed by assessment for anxiety-like behavior and cognitive abilities in a series of behavior tests with subsequent brain isolation for biochemical and histopathological evaluation. The outcomes showed a marked protection by IVM + RUFI (P<0.001) from kindling progression, anxiety-like behavior and cognitive deficit. However, additional supplementation with vitamin E worked superior to duo therapy as these mice were noted to be most fearless to visiting open, illuminated and elevated zones of open field, light/dark and elevated-plus maze (P<0.0001). Further, they showed marked remembrance of the familiar milieu in y-maze (P<0.01) and novel objection recognition (P<0.05) tests. Additionally, their recollection of aversive stimuli in passive avoidance and spatial memory in Morris water maze were evident (P<0.0001), in comparison to kindled mice. The IVM + RUFI duo therapy and its co-administration with vitamin E prevented kindling-triggered oxidative stress in brains and neuronal damage in hippocampus. We conclude that the benefits of the co-administration of vitamin E might be the results of antioxidant and anti-inflammatory effects of vitamin E which might be potentiating the antiseizure effects of RUFI and GABA-A modulating potential by ivermectin.

The effect of intra-nasal co-treatment with insulin and growth factor-rich serum on behavioral defects, hippocampal oxidative-nitrosative stress, and histological changes induced by icv-STZ in a rat model.

Impaired insulin and growth factor functions are thought to drive many alterations in neurodegenerative diseases like dementia and seem to contribute to oxidative stress and inflammatory responses. Recent studies revealed that nasal growth factor therapy could induce neuronal and oligodendroglia protection in rodent brain damage induction models. Impairment of several growth factors signaling was reported in neurodegenerative diseases. So, in the present study, we examined the effects of intranasal co-treatment of insulin and a pool of growth factor-rich serum (GFRS) which separated from activated platelets on memory, and behavioral defects induced by intracerebroventricular streptozotocin (icv-STZ) rat model also investigated changes in the hippocampal oxidative-nitrosative state and histology. We found that icv-STZ injection (3 mg/kg bilaterally) impairs spatial learning and memory in Morris Water Maze, leads to anxiogenic-like behavior in the open field arena, and induces oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia death in the hippocampus. GFRS (1µl/kg, each other day, 9 doses) and regular insulin (4 U/40 µl, daily, 18 doses) treatments improved learning, memory, and anxiogenic behaviors. The present study showed that co-treatment (GFRS + insulin with respective dose) has more robust protection against hippocampal oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia survival in comparison with the single therapy. Memory and behavioral improvements in the co-treatment of insulin and GFRS could be attributed to their effects on neuronal/oligodendroglia survival and reduction of neuroinflammation in the hippocampus.

Empagliflozin alleviates diabetes-induced cognitive impairments by lowering nicotinamide adenine dinucleotide phosphate oxidase-4 expression and potentiating the antioxidant defense system in brain tissue of diabetic rats

BackgroundDiabetes-induced cognitive impairment is a major challenge in patients with uncontrolled diabetes mellitus. It has a complicated pathophysiology, but the role of oxidative stress is central. Therefore, the use of antidiabetic drugs with extra-glycemic effects that reduce oxidative damage may be a promising treatment option. MethodsMale Wistar rats were randomly divided into four groups as normal, normal treated, diabetic and diabetic treated (n = 8 per group). Type 1 diabetes was induced by a single intraperitoneal dose of streptozotocin (STZ) (40 mg/kg). Two treatment groups received empagliflozin for 5 weeks (20 mg/kg/po). Cognitive ability was evaluated using open field, Elevated Plus Maze (EPM) and the Morris Water Maze (MWM) tests at study completion. Blood and brain tissue samples were collected - and analysis for malondialdehyde (MDA) and glutathione (GLT) content and catalase (CAT) and superoxide dismutase (SOD) enzyme activity were performed. Additionally, expression of nicotinamide adenine dinucleotide phosphate oxidase-4 (Nox-4) enzyme in brain tissue was analyzed using RT-PCR. ResultsSTZ increased blood glucose and induced diabetes with oxidative stress by lowering the antioxidant system potency and increasing Nox-4 expression after 5-weeks in brain tissue accompanied by reduction in cognitive performance. Also, diabetes induced anxiety-like behavior and impaired spatial memory in MWM, EPM and open field tests. However, empagliflozin reversed these changes, improving SOD and CAT activity, GLT content and reducing Nox-4 expression and MDA concentration in brain tissue while improving cognitive ability. It reduced anxiety and depression-related activities. It also improved spatial memory in MWM test. ConclusionUncontrolled diabetes negatively impacts mental function and impairs learning and cognitive performance via oxidative stress induction, the Nox-4 enzyme playing a central role. Empagliflozin reverses these effects, improving cognitive ability via promoting the anti-oxidative system and damping Nox-4 free radical generator enzyme expression. Therefore, empagliflozin is a promising treatment, providing both antidiabetic and extra-glycemic benefits for improving brain function in the diabetic milieu.

Deletion of microRNA‐21 exacerbates multiple phenotypes associated with Alzheimer’s disease through the RECK and ADAM10 pathway in a mouse model of Aβ amyloidosis

AbstractBackgroundmicroRNAs have emerged as a new class of therapeutic targets that regulate the expression of target genes by binding their 3’‐untranslated regions. Growing evidence suggests that dysregulation of microRNAs may contribute to the onset and/or progression of various diseases. However, the functional and therapeutic implications of microRNA dysregulation in Alzheimer’s disease (AD) remain largely unclear. To gain insight into the roles of microRNAs in AD pathogenesis, we recently performed unbiased microRNA profiling with entorhinal cortices of AD and age‐matched non‐demented subjects. We found that miRNA‐21 (miR‐21) expression was markedly increased in AD patients. In addition, miR‐21 levels were increased in oligomeric amyloid‐beta (Aβ)‐treated neurons, suggesting that miR‐21 induction is directly associated with Aβ pathology. Therefore, we investigated the pathogenic/therapeutic potential of miR‐21 in AD.MethodTo investigate the role of miR‐21 in amyloid pathology in vivo, we crossed APP/PS1 mice with mir‐21−/− mice to generate APP/PS1;mir‐21+/+, APP/PS1;mir‐21+/− and, APP/PS1;mir‐21−/− mice. We evaluated the changes in the pathological features of AD, such as Aβ levels, amyloid plaques, and gliosis in these mice. Moreover, to investigate the effects of miR‐21 deletion on spatial learning and memory functions, we performed the Morris Water Maze (MWM) and Contextual fear conditioning (CFC) tests.ResultDeletion of miR‐21 increased the levels of insoluble and soluble Aβ40 and Aβ42 levels, as well as increased Aβ‐positive and X‐34‐positive plaque deposition in the cortex and hippocampus. CD45‐positive, IBA1‐positive microgliosis, and GFAP‐positive astrogliosis were also increased in the brain of APP/PS1;mir‐21+/− and APP/PS1;mir‐21−/− mice compared to APP/PS1;mir‐21+/+ mice. Mechanistic studies identified RECK as a potential target gene of miR‐21. miR‐21 deficiency upregulated the RECK protein level, leading to the inhibition of ADAM10 activity. This finding was also corroborated by the decrease in the soluble APPα level. Furthermore, we demonstrated that miR‐21 deficiency decreased spatial learning and contextual memory in MWM and CFC tests, respectively in APP/PS1 mice.ConclusionTaken together, our results demonstrated that miR‐21 may regulate multiple AD‐associated pathologies. Therefore, modulation of miR‐21 may represent a novel potential therapeutic strategy for AD.

The Effect of Zonisamide and Ethanol on Various Types of Memory in Rats.

Background: Antiepileptic drugs might be useful in the treatment of alcohol use disorder. One of these drugs is zonisamide, which has been found to decrease alcohol intake and cravings. An important structure in the pathophysiology of addiction is the hippocampus. Memory deficits, which frequently occur in alcoholics, are associated with ethanol-induced changes in hippocampal plasticity and neurogenesis. The aim of this study was to assess the potential protective effect of zonisamide on memory in rats receiving alcohol and after the discontinuation of its administration. Methods: Wistar rats (n = 43) were tested in four behavioral models, namely: Morris water maze (MWM), passive avoidance (PA), contextual fear conditioning (CFC), and cued fear conditioning (CuFC). Results: Zonisamide co-administered with ethanol impaired spatial memory in MWM, but the drug did not affect memory in PA. However, the beneficial effect of zonisamide was observed after the discontinuation of ethanol administration, which was associated with the improvement of associative memory in CFC and the alleviation of alcohol-induced locomotor disturbances in CuFC. Conclusion: Zonisamide has a differential influence on memory, which depends inter alia on type of the memory, length of ethanol administration, or its absence.

Investigation of the protective effects of lutein on memory and learning using behavioral methods in a male rat model of Alzheimer's disease

• Lutein has neuroprotective and antioxidant properties. • β-amyloid (Aβ) stimulates active oxygen species generation leading to oxidative stress. • Injection of Aβ via oxidative stress decreased the learning and memory. • Lutein decreased the Aβ effects on learning and memory. • Lutein is a potential neuroprotective substance against Alzheimer's disease. Oxidative stress plays an important role in the development of Alzheimer's disease (AD). The purpose of this study was to investigate the protective effects of lutein, a carotenoid with antioxidant functions, on memory and learning using behavioral methods in a rat model of AD. Beta-amyloid (Aβ) reduced passive avoidance learning (PAL), spatial and cognitive memory. On the other hand, lutein improved PAL, spatial memory in Morris water maze and Barnes maze tests, and cognitive memory in novel object recognition test. Levels of malondialdehyde (MDA) and total oxidant status (TOS) increased and total antioxidant capacity (TAC) decreased in the AD group, while in groups receiving lutein, MDA and TOS levels decreased and TAC increased. Lutein improves learning and memory that it is probably due to its antioxidant and neuroprotective properties. These results using an animal model are consistent with lutein as a potential therapeutic agent in the treatment and prevention of AD.

КОГНИТИВНЫЕ НАРУШЕНИЯ И СОСТОЯНИЕ ГЛИАЛЬНЫХ КЛЕТОК МОЗГА В ОТДАЛЕННЫЙ ПЕРИОД ПОСЛЕ ГАММА-ОБЛУЧЕНИЯ ГОЛОВЫ МЫШЕЙ

Purpose: To investigate the effect of fractionated whole-brain γ-irradiation at a cumulative dose of 20 Gy on cognitive functions, the state of brain glial cells and expression of multiple cytokines in mice 2 months after exposure. Material and methods: Male C57Bl/6 mice were exposed to fractionated head γ-irradiation with 5 doses of 4 Gy. Two months after irradiation the behavior and cognitive functions of animals were assessed. After isolation of cells from mice brains the content of resting and activated microglia, microglial cells with M1- and M2-phenotype, astrocytes, proliferating cells were evaluated, and the hippocampal mRNA levels of pro- and anti-inflammatory cytokines (TNFα, IL-1β, IL-6, IL-4, TGFβ) were determined. Results: It was shown that fractionated head γ-irradiation didn’t alter the locomotor activity and associative (context fear) memory, but reduced the episodic memory in novel object recognition test (discrimination index was 0.44 ± 0.08 и 0.02 ± 0.09 in control and irradiated groups, respectively) and spatial memory in Morris water maze (time in target quadrant was 46,8 ± 2,4 % and 37,4 ± 2,8 % in control and irradiated groups, respectively). Exposure of γ-radiation significantly reduced the brain contents of microglial cells (Iba1+) and astrocytes (GFAP+) with concurrent 2.5 times increase in proportion of activated microglia (from 2.0 ± 0.2 % in control to 4.9 ± 0.5 % in irradiated mice), changed the M1- / M2-microglia ratio and significantly decreased the number of proliferating cells (BrdU+) and proliferating microglial cells (BrdU+/Iba1+). An increase in mRNA level of pro-inflammatory cytokine TNFα, a decrease in mRNA level of anti-inflammatory cytokine TGFβ and concurrent increase in mRNA level of IL-4 were detected in hippocampus 2 months after irradiation. Conclusion: We show that fractionated head γ-irradiation at a cumulative dose of 20 Gy reduces the episodic and spatial memory in mice 2 months after exposure. Cognitive dysfunctions detected are associated with neuroinflammation characterized by increasing proportion of activated brain microglia and altered hippocampal pro- and anti-inflammatory cytokine profile.

The differential effect of levetiracetam on memory and anxiety in rats

ObjectiveOne of the newest antiseizure medication is levetiracetam (LEV). It might be effective in various indications, not only related to convulsions. Central nervous system disorders are common during anticonvulsant therapy. The aim of this study was to assess the effect of LEV on various types of memory and anxiety in rats. MethodsAdult male Wistar rats (n = 58) were given LV p.o. as a single (100 mg/kg or 500 mg/kg) or repeated doses (300 mg/kg). The effect of the drug on memory was assessed in the Morris water maze (MWM) (spatial memory), the passive avoidance (PA) (emotional memory) and the novel object recognition (NOR) (recognition memory). The anxiety was evaluated in the elevated plus maze (EPM). ResultsLEV administered as repeated doses disturbed the long-term recognition memory in NOR and locomotor activity in EPM. A single dose affected emotional memory in PA. LEV did not alter spatial memory in MWM. ConclusionsLEV may cause memory and locomotor disturbances, but some of these adverse effects seem to be temporary and limited to the effect of acute dose.

α7nAChR activation protects against oxidative stress, neuroinflammation and central insulin resistance in ICV-STZ induced sporadic Alzheimer's disease

Central insulin resistance is considered as one of the pathological hallmarks of Alzheimer's disease (AD), similar to formation of amyloid plaques and neurofibrillary tangles (NFT). Activation of α7nAChR by GTS-21 has been indicated to reverse peripheral insulin resistance and exert neuroprotection. Therefore, the aim of the present study was to determine the effect of α7nAChR agonist (GTS-21) on intracerebroventricular administration of streptozotocin (ICV-STZ)-induced oxidative stress, neuroinflammation, cholinergic dysfunction, central insulin resistance and cognitive deficits. GTS-21 (1, 4 and 8 mg/kg; i.p.) was administered for 21 days following bilateral ICV-STZ administration (3 mg/kg) in C57BL/6 mice. Neurobehavioral assessments were performed using Morris water maze (MWM) and novel object recognition (NOR). Inflammatory markers (TNF-α, IL-6 and IL-1β) were determined using ELISA. Oxido-nitrosative stress (GSH, MDA and nitrite) and cholinergic activity (acetylcholine esterase and choline acetyltransferase) were estimated in the cortex and hippocampus through biochemical methods. Gene expression of insulin receptor (IR), IRS1, IRS2, BACE1, APP, PI3-K, AKT and GSK3β were determined by q-RT-PCR. ICV-STZ administration induced memory impairment, increased oxidative stress and neuroinflammation, and caused cholinergic dysfunction. Our results demonstrated that activation of α7nAChR by GTS-21 treatment improved memory in MWM and NOR test. Moreover, GTS-21 treatment significantly decreased oxido-nitrosative stress, inflammatory markers and cholinergic dysfunction in cortex and hippocampus. Finally, GTS-21 treatment restored ICV-STZ induced downregulation of IR, IRS1, IRS2, PI3-k, Akt and attenuated GSK3β, APP and BACE-1 indicating improved insulin signalling. Therefore, activation of α7nAChR through GTS-21 might be the potential target for the amelioration of central insulin resistance induced AD.

Neuroprotective Effects of Poria cocos (Agaricomycetes) Essential Oil on Aβ1-40-Induced Learning and Memory Deficit in Rats.

Alzheimer's disease (AD) is a neurodegenerative disease that has become a leading cause of death in recent years. The present study aimed to explore the possible prophylactic effects of Poria cocos essential oil (PCEO) against memory deficits in Aβ rats. Adult male Wistar rats were given Aβ1-42 via ICV injection. The effect of 30 d administration of PCEO by oral gavage was investigated. Novel object recognition (NOR) test, Morris water maze (MWM) test, and passive avoidance memory retention (PAM) task were performed. Aβ decreased the cognitive memory in NOR, spatial memory in MWM, and passive avoidance memory in PAM tests. In contrast, PCEO improved learning and memory in the treated group. The PCEO treatment halts the activity of AChE in the hippocampus and cortex of the AD rats. The central neuronal degeneration in Aβ-injected rats was not only ascertained by the histopathological changes but also confirmed indirectly by the concomitant increase in GFAP immunostaining. The beneficial effects in AD of increasing cellular GPx, GR, CAT, Na+ K+ ATPase and GST through the administration of PCEO may not only result in protection against neurodegeneration but also result in improvement in cognitive function. PCEO may be recommended as a prophylactic and/or adjunct medication for neurodegenerative diseases.

Extremely low intensity magnetic field effectively improves cognitive impairment in intracerebroventricular streptozotocin animal model sparing septo‐hippocampal cholinergic pathway and CAMKII

We have investigated the role of extremely-low-frequency magnetic field (ELF-MF, 17.96µT, 50Hz, 2hr/day for 60 days) exposure on i.c.v. streptozotocin (STZ, 3mg/kg bw, bilaterally, single bolus) induced rat model of AD in a customized chamber. Spatial memory and recognition memory was measured using Morris water maze and one trial object recognition task respectively. Further, acetylcholine, acetylchoniesterase, calcium-calmodulin dependent protein kinase II from frontal cortex and hippocampus and serum Aß1-42 was measured using colorimetric or ELISA technique. Spatial memory in Morris water maze (MWM) showed a significant decrease both in the distance travelled before entering into goal quadrant (p=0.05) as well as in latency to the first entry into goal quadrant (p=0.05) in AD animals, upon ELF-MF exposure. On the other hand, recognition index (p=0.003) and discrimination index (p<0.0001) in the one trial object recognition test (OTORT) on the 60th day after ELF-MF exposure to STZ animals showed a significant increment when compared with AD induced animals. These behavioural results suggests an improvement in cognitive function in i.c.v. STZ animals, upon exposure to ELF-MF. When we looked for serum Aß1-42 of experimental animals, we found a significant reduction (p=0.05) of serum Aß1-42 in AD animals after ELF-MF exposure. Further, concentration of acetylcholine (ACh) was found to be increased (p=0.05) only in hippocampus, whereas AChE level was found to be reduced in both frontal cortex (p=0.05) as well as in hippocampus (p=0.05) after 60 day ELF-MF treatment in i.c.v. STZ animals. Expression of CAMKII increased in frontal cortex (p=0.05) as well as in hippocampus (p0.05) after ELF-MF treatment. These results suggests that memory retention observed in the behavioural results, may be due to the reduction of AChE in hippocampus as well as in frontal cortex, Aß1-42 in serum, and an increase in levels of ACh, CAMKII in hippocampus as well as in the frontal cortex. Therefore, evidences strengthens the notion that, ELF-MF treatment improves cognitive impairment seen in i.c.v. STZ animal model of AD through prevention of synaptic dysfunction, replenishment of ACh as well as CAMKII in hippocampus.

The antiepileptic drug lacosamide and memory – A preclinial study

ObjectiveLacosamide (LC) belongs to a new generation of antiepileptic drugs (AEDs) and demonstrates unique mechanism of action. The drug also shows neuroprotective activity on the hippocampus. In this study, the impact of LC on learning processes was assessed. MethodsAdult male Wistar rats (n = 40) were used. Lacosamide was administered p.o. as a single (25 mg/kg or 75 mg/kg) or repeated doses (75 mg/kg). The effect of the drug was assessed in the Morris water maze (spatial memory) and the passive avoidance (PA) (emotional memory). ResultsLacosamide administered at a single dose or repeatedly did not impair spatial memory in Morris water maze. Higher swimming speed was observed in rats after administration of acute doses of LC. In PA, the disturbance of emotional memory was observed only after the single high dose of LC. ConclusionLacosamide does not impair memory and learning processes. The emotional memory impairment observed after the acute high dose appears to be temporary and did not occur after repeated administration.

Hydrogen Sulfide Ameliorates Lipopolysaccharide-Induced Memory Impairment in Mice by Reducing Apoptosis, Oxidative, and Inflammatory Effects.

Hydrogen sulfide (H2S) is reported to have a neuroprotective activity; however, the role of H2S in neuroinflammation-induced neuronal damage is ambiguous. Here, we aimed to evaluate the underlying mechanisms for the neuroprotective effect of NaHS, a known H2S donor, against lipopolysaccharide (LPS)-induced memory impairment (MI). All the treatments were administered for 28days, and LPS (0.25mg/kg i.p.) was co-administered intermittently for 7days from days 15 to 21. Morris water maze (MWM) and Y-maze tests were performed to evaluate MI. Neurodegeneration was histopathologically examined, and the brain homogenates were characterized for reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor (TNF)-α, interleukin (IL)-6, caspase-3, c-Jun, and acetylcholinesterase (AChE) by biochemical analysis. H2S administration significantly improved spatial and working memory in MWM and Y-maze tasks, respectively. Exogenous H2S significantly reversed LPS-induced oxidative stress as evidenced by improved GSH, MDA, and SOD levels. H2S pretreatment significantly attenuated LPS-induced apoptosis and inflammation by decreasing c-Jun and caspase-3 levels and inhibiting TNF-α and IL-6, respectively. The decrease in these markers was supported by H&E and Nissl staining, which confirmed the anti-necrotic activity of H2S. However, there was no significant improvement in LPS-induced increase in AChE activity. These results indicate that chronic systemic inflammation leads to neurodegeneration and MI and H2S exerts its neuroprotective effect due to its anti-oxidative, anti-inflammatory, and anti-apoptotic potential via modulation of JNK and extrinsic apoptosis pathways.

Effect of chronically electric foot shock stress on spatial memory and hippocampal blood brain barrier permeability

Maintaining blood-brain barrier (BBB) contributes critically to preserving normal brain functions. According to the available evidence, intense or chronic exposure to stress would potentially affect different brain structures, such as the hippocampus, negatively. The purpose of this study was to define the relationship between the BBB permeability of the hippocampus and the performance of spatial learning and memory under chronically electric foot shock stress. Sixteen rats were divided into the control and stress groups equally. Animals in the stress group were exposed to foot shock (1 mA, 1 Hz) for 10-s duration every 60 s (1 h/day) for 10 consecutive days. The anxiety-related behavior, spatial learning, and memory were assessed by an Open Field (OF) and the Morris Water Maze (MWM) respectively. The hippocampal BBB permeability was determined by Evans blue penetration assay. Our results demonstrated that the stress model not only increased locomotor activities in the OF test but reduced spatial learning and memory in MWM. Moreover, these effects coincided with a significant increase in hippocampal BBB permeability. In sum, the stress model can be used in future studies focusing on the relationship between stress and BBB permeability of the hippocampus.

MicroRNA-138-5p Regulates Hippocampal Neuroinflammation and Cognitive Impairment by NLRP3/Caspase-1 Signaling Pathway in Rats.

PurposeNeuroinflammation is an essential causative factor in the pathogenesis and progression of cognitive impairment. The present study aims to evaluate the critical role of microRNA-138-5p (miR-138-5p) in hippocampal neuroinflammation and cognitive impairment through the NLRP3/caspase-1 signaling pathway in rats.Material and MethodsWe established the cognitive impairment rat model and RM (Rat microglia) microglial cellular inflammation model by intracerebroventricular (icv) injection or stimulation of lipopolysaccharide (LPS). Morris water maze (MWM) and Y-maze tests were performed to assess the cognitive behaviors. Quantitative real-time polymerase chain reaction (qRT-PCR), Enzyme-linked immune-sorbent assay (ELISA) and Western blot analysis were utilized to evaluate mRNA or protein expression. Bioinformatic analysis and dual-luciferase reporter gene assay were performed to verify the targeting relationship between NLRP3 and miR-138-5p. Besides, Hematoxylin and eosin (H&E) staining and immunohistochemistry were applied to observe the neuronal morphology and detect the positive cells of the hippocampus, respectively.ResultsCompared to the control groups, LPS-treated rats exhibited significantly impaired learning and memory in MWM and Y-maze tests. The expression of NLRP3, caspase-1 and pro-inflammation cytokines (IL-1β and IL-18) were upregulated, while miR-138-5p was downregulated both in rat hippocampus and RM cells treated with LPS. MiR-138-5p is downregulated in microarray data of cognitive impairment animals and could directly target the 3ʹ-UTR of NLRP3. Furthermore, upregulation of miR-138-5p improved impaired cognitive functions, while inhibited hippocampal neuroinflammation demonstrated by decreased expression of NLRP3/caspase-1 axis, pro-inflammation cytokines and microglial activation. This study demonstrates for the first time that miR-138-5p suppresses the hippocampal NLRP3/caspase-1 signaling pathway activation in cognition impaired rats.ConclusionThe low expression of miR-138-5p after LPS administration may contribute to the activation of the NLRP3/caspase-1 pathway, leading to hippocampal neuroinflammation and cognitive impairment in rat models. These findings indicate a promising therapeutic avenue for cognitive disorders.

Effects of vanillic acid on Aβ1-40-induced oxidative stress and learning and memory deficit in male rats

Alzheimer's disease (AD) is a neurodegenerative disease, in which the accumulation of β-amyloid (Aβ) peptide in the extracellular space causes a progressive reduction in cognitive performance. Aβ stimulates active oxygen species generation leading to oxidative stress and neural cell death. Vanillic Acid (VA) is the oxidant form of vanillin widely found in vanilla beans. VA has many properties, such as suppressing apoptosis and eliminating the harmful effects of oxidative stress in animal models. The VA effects on impaired learning and memory in Aβ rats were assessed. Forty adults male Wistar rats were assigned to the following five groups in random: the control, sham (received saline (vehicle) via intracerebroventricular (ICV) injection), Aβ (received Aβ1–40 via ICV injection), VA (50 mg/kg by oral gavage once a day through four weeks), and Aβ + VA (50 mg/kg) groups. Open field test, novel object recognition (NOR) test, Morris water maze (MWM) test, and passive avoidance learning (PAL) task were performed, and finally, we determined the malondialdehyde (MDA), total antioxidant capacity (TAC) and total oxidant status (TOS) levels. Aβ decreased the cognitive memory in NOR, spatial memory in MWM, and passive avoidance memory in PAL tests. In contrast, VA improved learning and memory in the treated group. Aβ significantly increased MDA and TOS and decreased TAC levels, whereas VA treatment significantly reversed TAC, TOS and MDA levels. In conclusion, VA decreased the Aβ effects on learning and memory by suppressing oxidative stress and can be regarded as a neuroprotective substance in AD.

The Effect of Different Doses of Melatonin on Learning and Memory Deficit in Alzheimer Model of Rats

Background: Alzheimer Disease (AD) is an age-related neurodegenerative disorder with a progressive impairment of cognitive function. The pineal gland hormone melatonin (MEL) has been known as a protection agent against AD. However, the effect of melatonin in various doses is inconsistent. Objectives: In this study, we aimed to investigate two doses of MEL on learning and memory in the amyloid-βeta (Aβ)-induced AD in the rats. Materials &amp; Methods: Forty-eight male Wistar rats were used in the experiment and randomly divided control, sham, vehicle, AD, AD+MEL10 mg/kg, and AD+MEL 20 mg/kg groups. Intracerebroventricular injection of Aβ1–42 was used to develop the animal model of AD. Also, MEL-treated groups received an intraperitoneal injection of MEL for 4 next weeks. The Morris Water Maze (MWM) and Passive Avoidance Learning (PAL) tests were used to examine animals’ learning and memory. The brain of animals was removed for immunohistochemistry for anti- Amyloid Precursor Protein (APP). Results: Intra-peritoneal injection of MEL significantly improve learning and memory in MWM (P=0.000) and PAL test (P=0.000), but there were no significant changes in the two groups that received the melatonin (P&gt;0.05). Histopathological analysis revealed that the clearance of APP deposition in the AD+MEL20 group was considerable compared with the AD+MEL10 group (P=0.000). Conclusion: Our findings indicate that 10 and 20 mg/kg doses of melatonin have similar results on learning and memory in the AD model. But 20 mg/kg of melatonin has significantly more effect on the clearance of APP deposition.

Myricitrinameliorates cognitive deficits in MCAOcerebral strokeratsvia histone acetylation-induced alterations of brain-derived neurotrophic factor.

The present study screened the effect of Myricitrin on cognitive deficits post-cerebral ischemic stroke and the involved mechanism. The rats were submitted to middle cerebral artery occlusion (MCAO) and were treated with sodium butyrate or Myricitrin (15 and 30mg/kg) for 28days. The spatial memory was studied by Morris water maze (MWM). After 4weeks, the rats were euthanized and hippocampus region was utilized for neurochemical and biochemical changes. The extent of histone acetylation was studied by ELISA. Protein levels were analyzed by Western blot analysis. The mRNA levels were analyzed by polymerase chain reaction (PCR). In silico bioinformatics docking studies were done for target confirmation of Myricitrin. The treatment of Myricitrin showed improved memory in MWM compared to rats treated with vehicle, and the effects of Myricitrin were similar to sodium butyrate-treated rats. At a dose of 30mg/kg Myricitrin, the histone deacetylase content was decreased, the expression levels of BDNF were increased, the levels of acetylated H3 and H4 along with Syn-I in the hippocampus region were over-expressed compared to control vehicle-treated rats. However, at low dose, i.e., 15mg/kg Myricitrin failed to show alterations in biochemical as well as neurochemical markers. Docking studies suggested the BDNF and Sun-I as potential target proteins of Myricitrin. The cognitive ameliorating effect of Myricitrin post-cerebral ischemia stroke can be attributed to increased expression of BDNF and Syn-I and modulation of histone acetylation.