Decreased Escape Latency Research Articles

The TSPO-specific Ligand PK11195 Protects Against LPS-Induced Cognitive Dysfunction by Inhibiting Cellular Autophagy.

Perioperative neurocognitive disorders (PND) is a common postoperative neurological complication. Neuroinflammation is a major cause that leads to PND. Autophagy, an intracellular process of lysosomal degradation, plays an important role in the development and maintenance of nervous system. PK11195 is a classic translocator protein (TSPO) ligand, which can improve the cognitive function of rats. In this study, we evaluate the protective effect of PK11195 on the learning and memory of rats. A rat model of lipopolysaccharide (LPS)-induced cognitive dysfunction was established by intraperitoneal injection of LPS. Morris Water Maze (MWM), Western blot, qRT-PCR, confocal microscopy and transmission electron microscopy (TEM) were used to study the role of TSPO-specific ligand PK11195 in LPS-activated mitochondrial autophagy in rat hippocampus. We found that PK11195 ameliorated LPS-induced learning and memory impairment, as indicated by decreased escape latencies, swimming distances and increased target quadrant platform crossing times and swimming times during MWM tests. TSPO, ATG7, ATG5, LC3B and p62 protein and mRNA expression increased in the hippocampus of PND model rats. The hippocampal microglia of PND model rats also have severe mitochondrial damage, and a large number of autophagosomes and phagocytic vesicles can be seen. PK11195 pretreatment significantly decreased the expression of TSPO, ATG7, ATG5, LC3B and p62 protein and mRNA, as well as mitochondrial damage. These findings suggested that PK11195 may alleviate the damage of LPS-induced cognitive dysfunction of rats by inhibiting microglia activation and autophagy.

Reversal of lipopolysaccharide-induced learning and memory deficits by agmatine in mice

Purpose/Aim: Infection and inflammation are important pathological mechanism underlying neurodegenerative disorders and altered behavioral outcomes including learning and memory. The present study was designed to study the curative and preventive effects of agmatine in lipopolysaccharide (LPS)-induced learning and memory impairment in mice. Materials and methods Learning and memory functions in animals were evaluated by using Novel object recognition (NOR) and Morris water maze (MWM) tests. Following 7 days of LPS administration, animals were subjected to NOR test on Day-8 and MWM test on Days-9 to 13 for the assessment of recognition and spatial learning and memory, respectively. Results LPS administration produced significant deficits in recognition and spatial memory in mice after seven days of LPS administration. In LPS pre-treated mice, agmatine treatment on Day-8 resulted in the increased exploration to the novel object. Agmatine treatment (Day 8-12) in mice showed reduction in the escape latency and time spent in the target quadrant (probe trial) in the MWM test. However, co-administration of agmatine with LPS in mice for 7 days showed higher discrimination index in NOR test on Day-8. This co-administration also decreased escape latency and time spent in the target quadrant in MWM test on Days 9-13 as compared to LPS control group. Conclusion Results implies the protective and curative effects of agmatine against LPS-induced loss of memory functions in experimental animals. Highlights Subchronic but not acute lipopolysaccharides induce memory deficits Lipopolysaccharides impairs recognition and spatial memory in mice. Agmatine prevents lipopolysaccharides-induced loss of memory. Agmatine reverses deficits in learning and memory by lipopolysaccharides.

Apocynin ameliorates cognitive deficits in streptozotocin-induced diabetic rats.

The aim was to investigate the improvement properties of apocynin and its potential mechanism on diabetes-associated cognitive decline. In this study, the model of diabetic rat was established by STZ (50 mg/kg) and treated with apocynin (16 mg/kg/d for 12 weeks). The cognitive ability was evaluated by Morris water maze test. The indicators of oxidative stress (SOD and MDA) were analyzed by spectrophotometer. The inflammatory cytokines were measured by real time-PCR and ELISA. The protein expressions of Nrf-2, HO-1, Bcl-2 and Bax were determined by Western blot. Treatment with apocynin ameliorated diabetes-related learning and memory injury, as represented by decreasing escape latency and enhancement of the number of times of crossing platform, in the Morris water maze test. In hippocampus, apocynin markedly augmented SOD activity and inhibited MDA level to alleviate oxidative stress. Moreover, apocynin obviously relieved inflammatory reaction by suppressing TNF-α, IL-1β and IL-6 concentrations. Concomitantly, apocynin also statistically enhanced Nrf-2 and HO-1 protein expression to improve DACD. Lastly, apocynin notably ameliorated Bax/Bcl-2 ratio by regulating Bax and Bcl-2 protein expression to mitigate apoptosis. Our results have shown that apocynin may be a valid therapeutic agent against DACD via modulation of antioxidant, anti-inflammatory, and anti-apoptosis (Tab. 1, Fig. 18, Ref. 35).

Postweaning exposure to lanthanum alters neurological behavior during early adulthood in rats

Lanthanum is a rare-earth element that has been used in various fields including medicine, agriculture and industry. Previously, in utero lanthanum exposure to dams was shown to alter neurobehavior and neurotransmitter levels in rat offspring; however, the effects of postweaning exposure to lanthanum on neurological behavior is still limited. The purpose of this study was to investigate the effects of postweaning exposure to lanthanum on neurological behavior during early adulthood in rats. Rats were orally exposed to 0, 2, 20, 60 mg/kg BW of lanthanum nitrate from postnatal day (PND) 24 to PND60. Our results indicated that lanthanum treatment significantly decreased body weight and food intake. Morris water maze test results showed that lanthanum significantly decreased escape latency and travel distance. Lanthanum treatment also significantly decreased grip strength, hindlimb strength, and running time & distance in motor activity test. Further results showed that lanthanum treatment significantly decreased plasma neurotransmitter levels of acetylcholine and norepinephrine as well as the number of neurons in the CA1 area of the hippocampus. These results suggest that postweaning exposure to lanthanum have adverse effects on neurobehaviors and the central nervous system, with no-observed-adverse-effect level at 2 mg/kg BW and benchmark dose lower confidence limit at 1.7 mg/kg BW.

Sex-Specific Effects of Chronic Creatine Supplementation on Hippocampal-Mediated Spatial Cognition in the 3xTg Mouse Model of Alzheimer's Disease.

The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr (w/w)) diet for 8–9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enhancements with Cr supplementation in both sexes. In females, Cr supplementation increased CREB phosphorylation and levels of IκB (NF-κB suppressor), CaMKII, PSD-95, and high-molecular-weight amyloid β (Aβ) species, whereas Aβ trimers were reduced. These data suggest a beneficial preventative effect of Cr supplementation in females and warrant caution against Cr supplementation in males in the AD-like brain.

Computational and Pharmacological Investigation of (E)-2-(4-Methoxybenzylidene)Cyclopentanone for Therapeutic Potential in Neurological Disorders.

PurposeThis study involved the computational and pharmacological evaluation of (E)-2-(4-methoxybenzylidene)cyclopentan-1-one (A2K10).MethodsIn silico studies were conducted through virtual screening. Morris water and Y-maze tests were conducted to evaluate Alzheimer’s disease. Acute epilepsy haloperidol,and hyperalgesia were used to calculate the epilepsy model, with Parkinson’s disease and mechanical allodynia at a dose of 1–10 mg/kg in the mouse model.ResultsA2K10 exhibited the highest binding affinity against α7 nicotinic acetylcholine receptors (−256.02 kcal/mol). A2K10 decreased escape latency in the Morris water test during different trials. In the Y-maze test, A2K10 dose-dependently increased spontaneous alteration behavior, with maximum effect of 75.5%±0.86%. Furthermore, A2K10 delayed onset of pentylenetetrazole-induced myoclonic jerks and tonic–clonic seizures and decreased duration of tonic–clonic convulsions in mice, with maximum effect of 93.8±5.30, 77.8±2.91, and 12.9±1.99 seconds, respectively. In the haloperidol-induced Parkinson’s disease model, A2K10 significantly prolonged hanging time and reduced tardive dyskinesia. Moreover, A2K10 extended latency in hot-plate hyperalgesia and increased the paw-withdrawal threshold in mechanical allodynia. In toxicity studies, no mortality was observed.ConclusionOverall, the results indicated that A2K10 has potential as an anti-Alzheimer’s, antiepileptic, antiparkinsonian, and analgesic therapeutic compound.

Intranasal injection of recombinant human erythropoietin improves cognitive and visual impairments in chronic cerebral ischemia rats.

The present study aimed to study the protective effect of intranasally delivered recombinant human erythropoietin (rhEPO) on cognitive and visual impairments in a permanent bilateral common carotid artery occlusion (2VO)-induced chronic cerebral ischemia (CCI) rat model. Male Sprague-Dawley rats (age, 6 months) with 2VO-induced CCI were treated with intranasal rhEPO (50 U/100 g) once per week for 8 weeks. A Morris water maze was used to evaluate the spatial learning and memory of the rats. Flash visual evoked potentials were measured to assess retinal function. Hematoxylin and eosin staining was performed to visualize and evaluate histopathological changes in the cerebral cortex, the hippocampus CA1 region and the retina. CCI-induced learning, memory and visual impairments were significantly alleviated in rats treated with rhEPO compared with those treated with a saline vehicle control. This was evidenced by remarkably decreased escape latency, increased frequency of crossing the hidden platform and elevated amplitude of primary wave in the rats treated with rhEPO. In addition, the rats experienced CCI-induced histopathological alterations, demonstrated by thinning of the cerebral cortex and retina, and losses of neurons and retinal ganglion cells. These alterations were significantly reversed in response to rhEPO administration compared with the saline vehicle control group. rhEPO may exert a protective role against cognitive and visual impairments in rats with CCI at least partially through preventing the thinning of the cerebral cortex and retina, as well as by inhibiting the loss of neurons and retinal ganglion cells.

Sodium orthovanadate improves learning and memory in intracerebroventricular-streptozotocin rat model of Alzheimer’s disease through modulation of brain insulin resistance induced tau pathology

Sporadic Alzheimer's disease (sAD) is the most common type of dementia and progressive neurodegenerative disease. To establish the sAD model, intracerebroventricular (ICV) streptozotocin (STZ) at a dose of 3 mg/kg was administered bilaterally in rats on a stereotaxic apparatus. Behavioral tests such as Morris water maze (MWM), novel object recognition (NOR) and open field test were performed to evaluate cognitive and locomotor functions. Two treatment doses (5 mg/kg and 10 mg/kg) of sodium orthovanadate (SOV) and rivastigmine (2 mg/kg) were given orally to ICV-STZ induced rats for 21 days. Cortical and hippocampal tissues were dissected. Estimation of oxidative stress, mitochondrial dysfunction as complex I, II, III, IV activity, cholinergic function as acetylcholinesterase activity, ELISA for phosphorylated tau protein and insulin degrading enzyme (IDE), neuroinflammation as NF-κB gene expression and insulin signaling functioning as Q-RT-PCR for IR, IRS-1, PI3K, AKT, GSK-3β gene expression were performed. Behavioral results with SOV and rivastigmine treatment revealed decreased escape latency and increased discrimination index in MWM and NOR respectively. Treatment results with SOV also demonstrated attenuation of oxidative imbalance, improved mitochondrial activity, and reversed IDE and tau pathology. SOV treatment upregulated gene expression of IR, IRS-1, PI3K, and AKT, and downregulated that of GSK-3β. SOV results were compared with standard drug rivastigmine. Conclusively, the memory enhancement by SOV was mediated through oxidative balance, mitochondrial enzyme complex activation, and improved insulin signaling regulation. However, the primary mechanism of SOV remained attenuation of tau pathology by the upregulation of IRS-1/PI3K/AKT/GSK-3β pathway and reversal of insulin resistance in terms of IDE. Hence, in sAD paradigm, SOV contributed to memory improvement evident with the findings of behavioral studies, which can further potentially have clinical significance in AD.

Cholinergic-enhancing and antioxidant effect of Vigna subterranea (L.) Verdc. (Fabaceae) landrace aqueous extract on scopolamine-induced amnesia in male swiss mice

Background: Currently, no drug effectively curbs down the progression of Alzheimer's disease (AD), and thus early prevention is important. Objectives: The present study was conducted to investigate the protective effects of the aqueous extract of Vigna subterranea seed landrace on amnesia induced by scopolamine in mice. Materials and Methods: V. subterranea aqueous extract (100, 200, and 400 mg/kg BW) was administered by gavage for 9 consecutive days and memory impairment was induced by repeated intraperitoneal injection of scopolamine (1.5 mg/kg). The Y-maze (YM), Morris water maze (MWM), novel object recognition paradigm (NOR), and the T maze™ were used to assess learning, memory, and retention. Superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) levels, and acetyclcholine esterase activity were also evaluated in the mouse hippocampi homogenates. Results: V. subterranea aqueous extract (400 mg/kg) significantly increased the percentage of spontaneous alternation in the YM task and decreased escape latency in the MWM. Moreover, this dose brought about a significant improvement in the time spent in the preferred TM arm and discrimination index in the NOR tasks despite repeated scopolamine injection. Additionally, low acetylcholine esterase levels, reduced lipid peroxidation (MDA), but increased antioxidant enzyme (CAT and SOD) activity were observed in hippocampi homogenate of mice pretreated with the extract. A protective action against hippocampal cell damage was also evident. Conclusion: This finding suggests that the aqueous extract of V. subterranea seed landrace may improve learning and memory.

Ameliorative Effects of the Lyophilized Aqueous Seed Extract of Buchholzia coriacea on Scopolamine-Induced Memory Impairment in Sprague-Dawley Rats

This study investigated the protective effects of lyophilized aqueous seed extract of Buchholzia coriacea (B. coriacea) in enhancing memory and neuroprotection in scopolamine-induced learning and memory impairment using Morris water maze and Y maze. Thirty-five adult male Sprague Dawley were divided into five groups (n=7) according to extract/drug administered. 14 days administration of two different doses (100 and 200 mg/kg) of lyophilized extract of B. coriacea seeds, donepezil (5 mg/kg) concomitantly with scopolamine (1 mg/kg i.p) was carried out. Assessment of Morris water and Y- maze tests, oxidative stress markers and histology demonstration (H and E stain) were carried out during and after administration to evaluate the memory enhancing activity of the lyophilized extract of B. coriacea seeds on scopolamine-induced memory impairment. The two doses of lyophilized extract of B. coriacea seeds, and especially the 200 mg/kg significantly decreased escape latency and increased number of crossing for Morris water maze, while spontaneous alternation was also increased in the Y maze compared to scopolamine only treated group. The extract increased the activity of superoxide dismutase, reduced glutathione and catalase while decreasing malondialdehyde. The extract mitigated the histological evidence of neurodegeneration observed induced by the use of scopolamine. In conclusion, lyophilized aqueous seed extract of B. coriacea poses to be a promising therapeutic agent for the treatment of cognitive dysfunction in addition to its already established medicinal properties.

Hydrogen gas alleviates blood-brain barrier impairment and cognitive dysfunction of septic mice in an Nrf2-dependent pathway

Sepsis-associated encephalopathy (SAE) is a cognitive impairment caused by sepsis and is related to increased morbidity and mortality. Damage to the blood–brain barrier (BBB) has been proved to be one of the important causes of SAE. Molecular hydrogen (H2) is a promising method for the treatment of SAE, yet the underlying mechanism is not clear. This study was designed to demonstrate whether H2 can alleviate SAE by protecting the BBB, and whether it is protected by Nuclear factor erythroid-2-related factor 2 (Nrf2) and its downstream signaling pathways. Either a sham or a cecal ligation and puncture (CLP) procedure was applied to female wild-type (WT) and Nrf2-knock-out (Nrf2-/-) C57BL/6J mice. H2 (2%) was given for 60 min starting at 1 h and 6 h after the sham or CLP procedure. In addition, bEnd.3 cells cultured with medium which contained LPS, Saline, DMSO or ML385 (a Nrf2 inhibitor) were also used in the research. The 7-day survival rates were recorded. The Morris water maze was used to determine cognitive function. Pro-inflammatory and anti-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), HMGB1, and IL-10), antioxidant enzymes, and oxidation products [superoxide dismutase (SOD), chloramphenicol acetyltransferase (CAT), malondialdehyde (MDA), and (8-iso-PGF2α)] were determined by enzyme-linked immunosorbent assay (ELISA). Brain water content, Dextran tracer, and Evans blue extravasation were used to detect the damage of the BBB. Western blot analysis was used to detect β-catenin, phosphorylated β-catenin, adhesion-linked protein VE-cadherin, and associated tight junction protein ZO-1. We found that H2 can improve survival in septic mice, decrease escape latency and platform crossing times, decrease pro-inflammatory cytokines and oxidative product levels in the mouse cortex, and increase the expression of anti-inflammatory factors in WT, but not Nrf2-/-, mice. Moreover, H2 can also decrease brain water content, extravascular dextran, extravascular Evans blue dye, and β-catenin level, and increase ZO-1 and VE-cadherin expressions in WT mice, but not in Nrf2-/- mice. Our result shows that H2 can protect the BBB by decreasing its permeability, thereby reducing SAE and improving cognitive function, which is mediated through Nrf2 and its downstream signaling pathways.

Effects of Delphinidin on Pathophysiological Signs of Nucleus Basalis of Meynert Lesioned Rats as Animal Model of Alzheimer Disease.

Alzheimer's disease (AD) is an advanced neurodegenerative disorder greatly accompanied by cognitive deficits, oxidative stress, inflammation, amyloid plaques deposition, and acetylcholinesterase (AChE) hyper-activation. Growing evidence suggests natural compounds with antioxidant and anti-inflammatory features improve pathophysiological signs of AD. The present study was designed to investigate the effects of Delphinidin (25, 50mg/kg) as an anthocyanidin on spatial memory impairment and AD hallmarks such as hippocampal AChE activity, amyloid plaques deposition, oxidative stress and expression of amyloid precursor protein (APP), AChE, and amyloid beta (Aβ) proteins in nucleus basalis of Meynert (NBM) lesioned rats as the most prevalent animal model of AD. Interestingly, Delphinidin-treated animals showed a significant decrease in escape latency and distance moved. Furthermore, in probe test, NBM lesioned rats treated with both doses of Delphinidin spent more time in the target quadrant zone in Morris water maze task. It could also interact with catalytic site of AChE enzyme and inhibits acetylcholine hydrolysis in in vitro and in vivo conditions. In addition, Delphinidin could scavenge additional produced reactive oxygen molecules dose dependently. Our immunoblotting analysis confirmed high dose of Delphinidin reduced AChE, APP and Aβ contents in AD model. Staining of hippocampus tissue revealed that Delphinidin treatment decreased amyloid plaques formation in NBM lesion rats. It seems that Delphinidin is a plate-like molecule intercalated between β-plated sheets related to Aβ molecules and inhibited amyloid fibril formation. Altogether, Delphinidin and Delphinidin-rich fruits could be suggested as a therapeutic adjuvant in AD and other related cognitive disorders.

A potential role of Zfra in mitigating traumatic brain injury transition to Alzheimer’s disease‐like symptom in mice

Most recently, tumor suppressor WWOX is defined as a risk factor for Alzheimer’s disease(AD). Previously, we determined that accumulation of pS14‐WWOX in the brain hippocampus and cortex correlates with the occurrence of AD and probably other neurodegeneration. Zinc finger‐like protein that regulates apoptosis (Zfra) suppresses pS14‐WWOX accumulation and restores memory loss in triple transgenic mice (3xTg) for AD. During the acute phase traumatic brain injury (TBI), overly expressed WWOX becomes phosphorylated at Tyr33 and is accumulated in the nuclei to cause neuronal death in the impacted areas. We determined that in the novel object recognition tests, mice surviving from TBI (2.8 to 3.3 Newtonian force) significantly spent less exploring time on new objects in both long‐term and short‐term memory tests post TBI for 18 weeks, indicating the occurrence of damage in long‐ and short‐term memory. Further, control and TBI mice were subjected to Morris water maze tests post TBI for 10 weeks to determine the hippocampus‐dependent, spatial memory. Both groups showed a time‐dependent decrease in escape latency, indicating that mild TBI didn’t affect the learning capabilities. BALB/c mice received Zfra4‐10 peptide via tail vein injections prior to TBI (1.7 Newtonian force). Two weeks later, these treated mice significantly spent more time on probing the new object in the short‐term memory task compared to control mice, suggesting that Zfra peptide prevents TBI‐induced memory loss. Interestingly, by immunohistochemistry, significant upregulation of tau phosphorylation at T181 and amyloid beta aggregates was shown rapidly in death‐inducing impact in BALB/c mice (3.5 Newton), and that Zfra significantly prevented the upregulation (~20 to 33%). Together, our observations suggest the transition of TBI to AD‐like symptom in mice are likely to occur, and that Zfra4‐10 peptide prevents the transition.Support or Funding InformationMinistry of Science & Technology, Taiwan, National Health Research Institute, Taiwan, Department of Defense, USA

A Novel One-Day Learning Procedure for Mice.

Current preclinical cognitive assessments are highly time intensive, with lengthy assessment procedures. In this regard, a single-day assay that focuses just on assessing learning behavior in a time-effective and relatable manner would be of value. This article describes the box maze as a short-term behavioral procedure to measure learning in mice. The protocol consists of allowing mice to explore an enclosed space that has eight holes. One of these holes leads to a tunnel that connects to an escape cage, and the latency to enter this escape hole is recorded for each mouse. Mice are tested four times within a single day, and the decrease in escape latency over time is used as a measure of learning. Age is a factor that affects escape latency in the box maze. Hence, the box-maze procedure is proposed as an efficient test to probe aging and aging intervention-related research questions. © 2020 by John Wiley & Sons, Inc.

Cholinergic Enhancing and Antioxidant Effect of Vigna subterranea (L.) Verdc. (Fabaceae) Landrace Aqueous Extract on Scopolamine-Induced Amnesia in Male Swiss Mice

The present study was conducted to investigate protective effects of the aqueous extract of V. subterranea seeds landrace on amnesia induced by scopolamine in mice. V. subterranea aqueous extract (100, 200 and 400 mg/kg BW) was administered by gavage for nine consecutive days and memory impairment was induced by repeated intraperitoneal injection of scopolamine (1.5 mg/kg). The Y-maze (YM), Morris water maze (MWM), novel object recognition paradigm (NOR) and the T maze (TM) were used to assess learning, memory and retention. Superoxide dismutase (SOD), Catalase (CAT), Malondialdehyde (MDA) levels and Acetylcholine esterase activity was also evaluated in the mice hippocampi homogenates. V. subterranea aqueous extract (400 mg/kg) significantly increased the percentage of spontaneous alternation in the YM task and decreased escape latency in the MWM. Moreover, this dose brought about a significantly improvement in the time spent in the preferred TM arm and discrimination index in the NOR tasks despite repeated scopolamine injection. Additionally, low acetylcholine esterase levels, reduced lipid peroxidation (malondialdehyde) but increased antioxidant enzymes (catalase and superoxide dismutase) activity was observed in hippocampi homogenate of mice pre-treated with the extract. A protective action against hippocampal cell damage was also evident. This finding suggests that the aqueous extract of V. subterranea seed landrace may improve learning and memory.

Effect of the King Oyster Culinary-Medicinal Mushroom Pleurotus eryngii (Agaricomycetes) Basidiocarps Powder to Ameliorate Memory and Learning Deficit in Ability in Aβ-Induced Alzheimer's Disease C57BL/6J Mice Model

One of the major causes of Alzheimer's disease (AD) is oxidative stress, which accelerates β-amyloid peptide (AP) plaque and neurofibrillary tangle accumulation in the brain. Pleurotus eryngii is known to be rich in antioxidants, including ergothioneine, adenosine, and polyphenol, which can reduce oxidative stress-related aging. The aim of this study was to investigate the proximate and functional composition of P. eryngii, and evaluate the cognitive effects of low (LPE), medium (MPE), and high (HPE) P. eryngii dosages in an Aβ-induced Alzheimer's disease C57BL/6J mouse model. Mice fed P. eryngii for six weeks showed no adverse effects on body weight gain, food intake efficiency, serum biochemical parameters, and liver and kidney histopathological features. The relative brain weight was significantly lower in Aβ-injected mice (p < 0.05). Further, P. eryngii was shown to delay brain atrophy. Reference memory behavioral tasks showed that LPE, MPE, and HPE significantly decreased escape latency (49-85%) and distance (53-69%, p < 0.05). Probe and T-maze tasks showed that P. eryngii potently ameliorated memory deficit in mice. An AD pathology index analysis showed that P. eryngii significantly decreased levels of brain phosphorylated τ-protein, Aβ plaque deposition, malondialdehyde, and protein carbonyl (p < 0.05). P. eryngii may therefore promote memory and learning capacity in an Aβ-induced AD mouse model.

Protective Effect of Dimethyl Fumarate on Memory Impairment After Cerebral Ischemia-Reperfusion Injury in Rats

BackgroundCerebral ischemia is an important cause of morbidity and mortality worldwide. Dimethyl fumarate (DMF) is indicated for the treatment of patients with relapsing forms of Multiple Sclerosis and psoriasis.ObjectivesIn this study, the effect of DMF on memory and learning impairments and nitrosative stress after cerebral ischemia in rats, was evaluated.MethodsCerebral ischemia was induced via common carotid artery occlusion (CCAO). Rats were randomly divided into three groups (N = 5). Group I included Sham-operated animals who underwent surgery without arterial occlusions, group II (control ischemic) underwent surgery to induce transient global cerebral ischemia for 20 min and received 0.2 - 0.25 mL of distilled water, twice a day by oral gavage, group III included rats which underwent cerebral ischemia and then received DMF (15 mg/kg, twice daily, for 1 week) by oral gavage. Morris water maze test was used to assess spatial memory. Nitric oxide (NO) level in the hippocampus was measured using Griess test.ResultsTreatment of rats with DMF (15 mg/kg, orally, twice daily for 7 days) resulted in a significant decrease in escape latency during training trials. Besides, the time spent in the target quadrant and the number of crossings over the platform area were significantly increased in the DMF-treated rats which were accompanied by a decrease in the proximity to the platform in the probe trial. Furthermore, the results of the Griess assay indicated a significant reduction in the NO levels in the hippocampus of DMF-treated rats.ConclusionsOverall, our findings indicate that DMF improves memory impairment induced by cerebral ischemia/reperfusion injury in rats through the suppression of nitrosative stress in the hippocampus.

Effect of Hydrogen-Rich Water on Radiation-Induced Cognitive Dysfunction in Rats.

The goal of this work was to determine whether hydrogen-rich water (HRW) could attenuate radiation-induced cognitive dysfunction in rats and to explore the underlying mechanisms. Rats received 30 Gy whole-brain irradiation using a 6-MeV electron beam. Either purified water or HRW (0.8-0.9 ppm) was administrated at 10 min prior to irradiation, as well as a daily HRW treatment after irradiation for 30 consecutive days. The Morris water maze was used to test spatial memory in the rats. The concentration of glutathione (GSH), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG) and the super-oxidedismutase (SOD) activity in cerebral cortex, as well as brain-derived neurotrophic factor (BDNF) level in serum, were measured. Immunofluorescence staining was adopted to detect proliferating cells. The expression of BDNF-TrkB pathway-related genes and proteins were detected using qRT-PCR and Western blot. Models of cognitive dysfunction were successfully established using a 30 Gy dose of ionizing radiation. Compared to the radiation treated group, the radiation-HRW treated group showed significantly decreased escape latency (P < 0.05), but increased retention time, swimming distance of original platform quadrant (P < 0.05) and number of platform crossings (P < 0.05). Furthermore, the SOD, GSH (P < 0.05) and BDNF (P < 0.05) levels in the radiation-HRW treated group were higher compared to the radiation treated group. The MDA and 8-OHdG levels (P < 0.05) were decreased in the radiation-HRW treated group when compared to the radiation treated group. Additionally, treatment with HRW increased the number of BrdU+NeuN+ cells in the radiation treated group. The mRNA and protein levels of BDNF and TrkB (P < 0.05) in radiation-HRW treated group was higher than that in the radiation treated group. Collectively, our study indicates that HRW has a protective effect on radiation-induced cognitive dysfunction, and that the possible mechanisms mainly involve anti-oxidative and anti-inflammatory reactions, and its protection of newborn neurons by regulating the BDNF-TrkB signaling pathway.

Treating ultra-low rectal cancer by acupuncture combined with chemotherapy: a case report and literature review

Sepsis-associated encephalopathy (SAE) can cause acute and long-term cognitive impairment and increase the mortality rate in sepsis patients, and we previously reported that 2% hydrogen gas (H2) inhalation has a therapeutic effect on SAE, but the underlying mechanism remains unclear. Dynamic DNA methylation, which catalyzed by DNA methyltransferases (DNMTs), is involved in the formation of synaptic plasticity and cognitive memory in the central nervous system. And brain-derived neurotrophic factor (BDNF), to be a key signaling component in activity-dependent synaptic plasticity, can be induced by neuronal activity accompanied by hypomethylation of its promoter IV. This study was designed to illustrate whether H2 can mediate SAE by alter the BDNF promoter IV methylation mediated by DNMTs. We established an SAE model by cecal ligation and perforation (CLP) in C57BL/6 mice. The Morris water maze test from the 4th to the 10th day after sham or CLP operations were used to evaluate mouse cognitive function. Hippocampal tissues were isolated at the 24 after sham or CLP surgery. Pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6) and High Mobility Group Box 1 (HMGB1) were measured by enzyme-linked immunosorbent assay (ELISA). mRNA or protein levels of DNMTs (DNMT1, DNMT3a and DNMT3b), BDNF promoter IV and total BDNF were detected by RT-PCR and Western blot tests. Immunofluorescence staining were used to determine the expressions of DNMT1 and DNMT3a. The quantitative methylation analysis of the 11 CpG island of the promoter region of BDNF exon IV was determined using the Agena’s MassARRAY EpiTYPER system. We found that 2% H2 inhalation can reduce pro-inflammatory factors, alleviate DNMT1, DNMT3a but not DNMT3b expression, make hypomethylation of BDNF promoter IV at 5 CpG sites, enhance the BDNF levels and then decrease escape latency but increase platform crossing times in septic mice. Our results suggest that 2% H2 inhalation may alleviate SAE through altering the regulation of BDNF promoter IV methylation which mediated by DNMT1 and DNMT3a in the hippocampus of septic mice.

Synthesis, characterization, molecular docking evaluation, antidepressant, and anti-Alzheimer effects of dibenzylidene ketone derivatives.

Novel bioactive compounds as synthetic analogs of the potent herbal medicines can be optimized as potential drug candidates for various neurologic disorders. This study was performed to investigate the newly synthesized dibenzylidene ketone derivatives: (2E,6E)-2,6-dibenzylidene cyclohexanone (A1K1) and (1E,4E)-5-(2,3-dichlorophenyl)-1-(4-methoxyphenyl)-2-methylpenta-1,4-diene-3-one (A2K2) and evaluate its potential anti-Alzheimer's and anti-depressant properties. Both the derivatives are chemically characterized by using HNMR and CNMR techniques. Auto Dock Vina program was used to investigate ligand-protein affinity. Forced swim test, tail suspension test, open field test, Y-maze test, and Morris water maze test (MWM) models were employed to evaluate anti-depressant and anti-Alzheimer's activity of dibenzylidene ketone derivatives in mice. Both A1K1 and A2K2 showed high binding affinities against various proteins involved in depression and Alzheimer's mechanisms like monoamine oxidase B, acetylcholinesterase, norepinephrine transporter 2, serotonin transporter, dopamine receptor, serotonin receptor modulator, and beta-amyloid targets. A1K1 and A2K2 dose-dependently (0.1-1 mg/kg) decreased immobility time, while increased swimming and climbing time of mice in forced swim test (FST). A1K1 and A2K2 decreased animal immobility time in TST. In the open field test, both A1K1 and A2K2 increased the number of ambulations and rearings. A1K1 and A2K2 dose-dependently (0.5-1.0 mg/kg) increased spontaneous alternation behavior (%) and the number of entries of mice in Y-maze test. In the MWM test, A1K1 and A2K2 decreased escape latency time. Overall, both in-silico and in-vivo investigations of A1K1 and A2K2, report their therapeutic potential for antidepressant and anti-Alzheimer properties. Hence, these compounds possess potent neuroprotective properties and may be further evaluated for their therapeutic potential in various neurological disorders.