Impairment In Rats Research Articles

Role of thrombospondin-1 in high-salt-induced mesenteric artery endothelial impairment in rats.

The matrix glycoprotein thrombospondin-1 (THBS1) modulates nitric oxide (NO) signaling in endothelial cells. A high-salt diet induces deficiencies of NO production and bioavailability, therebyleading to endothelial dysfunction. In this study we investigated the changes of THBS1 expression and its pathological role in the dysfunction of mesenteric artery endothelial cells (MAECs) induced by a high-salt diet. Wild-type rats, and wild-type and Thbs1-/- mice were fed chow containing 8% w/w NaCl for 4 weeks. We showed that a high salt diet significantly increased THBS1 expression and secretion in plasma and MAECs, and damaged endothelium-dependent vasodilation of mesenteric resistance arteries in wild-type animals, but not in Thbs1-/- mice. In rat MAECs, we demonstrated that a high salt environment (10-40 mM) dose-dependently increased THBS1 expression accompanied by suppressed endothelial nitric oxide synthase (eNOS) and phospho-eNOS S1177 production as well as NO release. Blockade of transforming growth factor-β1 (TGF-β1) activity by a TGF-β1 inhibitor SB 431542 reversed THBS1 up-regulation, rescued the eNOS decrease, enhanced phospho-eNOS S1177 expression, and inhibited Smad4 translocation to the nucleus. By conducting dual-luciferase reporter experiments in HEK293T cells, we demonstrated that Smad4, a transcription promoter, upregulated Thbs1 transcription. We conclude that THBS1 contributes to endothelial dysfunction in a high-salt environment and may be a potential target for treatment of high-salt-induced endothelium dysfunction.

Neuropeptide cyclo-L-prolylglycine counteracts scopolamine-induced long-term memory impairment in rats in the novel object recognition test

Background. Cyclo-L-prolylglycine (CPG) was designed and synthesized at the V.V. Zakusov as a topological analogue of the classical nootrop piracetam and was further identified as an endogenous compound. Previously, the nootropic effect of CPG was revealed in a model of retrograde amnesia in rats induced by electroconvulsive shock in the passive avoidance test (PAT).Objective. The aim of the present study was to investigate the nootropic effect of CPG under more physiological conditions in the absence of strong stressors.Methods. Amnesia in rats was modeled by intraperitoneal (ip) administration of scopolamine at a dose of 2 mg/kg. CPG was administered ip at doses of 0.1 and 1.0 mg/kg 15 minutes after scopolamine. Short- and long-term memory were recorded in the novel object recognition test.Results. It was found that scopolamine disrupted only the long-term memory of rats. CPG at a dose of 0.1 mg/ kg almost completely counteracted this impairment. CPG by itself had no effect on memory at both doses studied.Conclusion. Thus, CPG exhibits nootropic activity not only in the aversive conditions of the PAT and electroconvulsive shock-induced amnesia, but also in the neutral situation in the novel object recognition test, when the amnesia was caused by the administration of scopolamine.

The neuroprotective potential of turmeric rhizome and bitter melon on aspartame-induced spatial memory impairment in rats

Aspartame is widely used artificial sweetener. However, chronic exposure to aspartame led to spatial memory impairment and elevated oxidative stress in the brain. Extract of turmeric rhizome (Curcuma longa) (TUR) and extract of bitter melon (Momordica charantia) (BM) is known to have antioxidant activity. The present study was aimed to examine the neuroprotective potential of TUR and BM extracts, either as single or as combination, against the effects of aspartame in the brain. Here, Sprague-Dawley rats fed with aspartame (40 mg/kg BW) for 28 days were compared with rats fed with extract and aspartame. To assess neuroprotective potential, rats were given extract 7 days before and during aspartame treatment. Spatial memory was assessed with Morris water maze test followed with H&E staining of hippocampal region. Brain lipid peroxidation and enzymatic activity of malondialdehyde (MDA), glutathione peroxidase (GPx), and Acetylcholinesterase (AChE) were measured to probe status of oxidative stress in the brain. Aspartame-treated rats demonstrated spatial memory impairment and reduced number of hippocampal cells and elevated levels of MDA, downregulated activity of GPx and elevated activity of AChE. In contrast, animals received both aspartame and extract demonstrated better spatial memory function, higher number of hippocampal areas, increased GPX activity, reduced MDA levels, and decreased AChE activity were observed in the brain of extract-treated rats. Taken together, our results suggest that extract of TUR rhizome and BM fruit exhibit antioxidant activity which may contribute to the neuroprotective effects against aspartame-induced memory impairment in rats.

Association of Subclinical Thyroid Dysfunction with Cognitive Impairment in Rats: The Role of Autophagy.

We investigated the effect of subclinical hyperthyroidism and subclinical hypothyroidism on cognitive function in rats and the role of autophagy in this process. Forty Wistar rats were randomized into normal control (NC), hyperthyroidism (Hyper), hypothyroidism (Hypo), subclinical hyperthyroidism (sHyper), and subclinical hypothyroidism (sHypo) groups. Cognitive function (spatial learning and memory) was tested by the Morris water maze test. Hippocampal histopathology was analyzed by H&E staining, and expression levels of caspase-3 in hippocampal CA1 neurons were measured. In addition, immunoblot analysis was performed to detect hippocampal autophagy-related proteins. Escape latency from day 1 to day 4 was significantly longer in the Hypo, Hyper, and sHyper groups than in the NC group (P < 0.01). In addition, the number of rats crossing the virtual platform was significantly lower in the Hypo, Hyper, and sHyper groups than in the NC group (P < 0.01). Compared with the NC group, all four groups had significantly lower residence time in the target quadrant (P < 0.05). Beclin-1 and LC3-II protein expression in hippocampal tissues was significantly higher in the Hyper and sHyper groups than in the NC group (P < 0.01). Beclin-1 and LC3-II protein expression in hippocampal tissues did not significantly differ between the sHypo group and NC group (P > 0.05). Subclinical thyroid dysfunction in rats might lead to cognitive impairment. Subclinical hyperthyroidism might be associated with excessive activation of autophagy and hippocampal neuron damage and necrosis.

A Ketogenic Diet may Improve Cognitive Function in Rats with Temporal Lobe Epilepsy by Regulating Endoplasmic Reticulum Stress and Synaptic Plasticity.

A ketogenic diet (KD) is often used in the treatment of refractory epilepsy. Many studies have found that it also has a positive impact on cognitive comorbidities, but the specific mechanism remains unclear. In many disease models, endoplasmic reticulum stress (ERS) and synaptic plasticity is considered a new therapeutic target for improving cognitive impairment, and it has become a research focus in recent years. Recently, studies have found that a KD has a certain regulatory effect on both ERS and synaptic plasticity, but this result has not been confirmed in epilepsy. To investigate the effect of a KD on ERS and synaptic plasticity. In this study, a rat model of temporal lobe epilepsy (TLE) induced by lithium chloride-pilocarpine was used. After the model was successfully established, the rats in each group were fed a normal diet or a KD for 28 days, and the effect of a KD on the latency and seizure frequency of spontaneous recurrent seizures (SRSs) was observed via video monitoring. Subsequently, a Morris water maze was used to evaluate the spatial learning and memory abilities of the rats in each group; the ultrastructure of the ER and the synapses of the hippocampus were observed by transmission electron microscopy, and the dendritic spine density of the hippocampus was analysed by Golgi staining. Long-term potentiation (LTP) was used to detect the synaptic plasticity of the rats' hippocampi, and the expression of ERS-related proteins and synapse-related proteins was detected by Western blotting. A KD effectively reduced the frequency of SRSs in rats with TLE and improved their learning and memory impairment. Further investigations found that a KD inhibited the up-regulation of glucose-regulated protein 78, phospho-protein kinase-like ER kinase, phosphorylated α subunit of eukaryotic initiation factor 2, activating transcription factor 4 and C/EBP homologous protein expression in the hippocampi of rats with TLE and protected the ultrastructure of the neuronal ER, suggesting that a KD suppressed excessive ERS induced by epilepsy. Concurrently, we also found that a KD not only improved the synaptic ultrastructure and increased the density of dendritic spines in rats with TLE but also reversed the epilepsy-induced LTP deficit to some extent. More importantly, the expression of postsynaptic density protein 95, synaptotagmin-1 and synaptosomal-associated protein 25 in the hippocampi of rats with epilepsy was significantly increased after KD intervention. The study findings indicate that a KD improves learning and memory impairment in rats with epilepsy, possibly by regulating ERS and synaptic plasticity.

Effects of high-frequency transcranial magnetic stimulation on theta-gamma oscillations and coupling in the prefrontal cortex of rats during working memory task.

High-frequency rTMS has been widely used to improve working memory (WM) impairment; however, the underlying neurophysiological mechanisms are unclear. We evaluated the effect of high-frequency rTMS on behaviors relevant to WM as well as coupling between theta and gamma oscillations in the prefrontal cortex (PFC) of rats. Accordingly, Wistar rats received high-frequency rTMS daily for 14days (5Hz, 10Hz, and 15Hz stimulation; 600 pulses; n = 6 per group), whereas the control group received sham stimulation. Electrophysiological signals were recorded simultaneously to obtain the local field potential (LFP) from the PFC, while the rats performed T-maze tasks for the evaluation of WM. Phase-amplitude coupling (PAC) was utilized to determine the effect of high-frequency rTMS on the theta-gamma coupling of LFPs. We observed that rats in the rTMS groups needed a smaller number of training days to complete the WM task as compared to the control group. High-frequency rTMS reinforced the coupling connection strength in the PFC of rats. Notably, the effect of rTMS at 15Hz was the most effective among the three frequencies, i.e., 5Hz, 10Hz, and 15Hz. The results suggested that rTMS can improve WM impairment in rats by modulating the coupling of theta and gamma rhythms. Hence, the current study provides a scientific basis for the optimization of TMS models, which would be relevant for clinical application.

Evaluation of neuroprotective and anti-amnesic effects of the chloroform fraction of Nigella sativa L. on scopolamine-induced memory impairment in rats

The aim of this study was to investigate the neuroprotective and anti-amnesic effects of total extract (NTE) and chloroform fraction of Nigella sativa (NCE) on scopolamine (SCO)-induced memory impairment in the rat. After plant extraction and fractionation, the rats were treated with different doses of NTE (200, 400, and 800 mg/kg) and NCE (50, 100 or 200 mg/kg) before scopolamine administration for 7 successive days compared to donepezil (DON). Learning power and memory capacity of the treated animals were evaluated and the rat brain samples were further assessed for in vivo acetylcholinesterase (AChE) activity, lipid peroxidation, and finally validated by histopathological examination. Pretreatment with NTE and NCE effectively increased antioxidant activity, decreased cholinesterase activity and malondialdehyde (MDA) content in the hippocampal and cortical tissues as well as mitigated scopolamine-induced behavioral, and histological changes in a manner comparable to DON. Based on the pathology results, the most toxicity of NCE was observed at 200 mg/kg. The observed neuroprotective and anti-amnesic effects of NCE indicate that this fraction could be a promising candidate both for further studies to isolate the active components and for use in clinical trials in patients with cognitive impairment.

Silymarin Antioxidant Effect on Ethanol-Induced Anxiety and Learning Impairments in Rats: An Experimental Study

Silymarin Antioxidant Effect on Ethanol-Induced Anxiety and Learning Impairments in Rats: An Experimental Study

Effect of lidocaine on cognitively impaired rats: Anti-inflammatory and antioxidant mechanisms in combination with CRMP2 antiphosphorylation.

Studies have shown that lidocaine has antioxidative stress, anti-inflammatory, and nerve-protective effects. The current study investigated the effects of lidocaine on cognitive function in rats with cognitive dysfunction. A total of 48 rats were randomly assigned to fourgroups of 12 rats each: control group; L (lidocaine) + D (d-galactose) group, d-galactose group (D group); and D + L group. We assessed cognitive function using a Morris water maze (MWM) and pathologic changes of hippocampal sections. An enzyme-linked immunosorbent assay (ELIZA) was used to detect serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels in rats, and protein immunoblotting (western blot) was used to detect brain tissue proteins (collapsing response mediator protein-2 [CRMP2], phosphorylated-collapsing response mediator protein-2 [P-CRMP2], and β-amyloid protein [Aβ]). The MWM showed that the d-gal group (284.09 ± 20.46, 5.20 ± 0.793) performed worse than the L + D (265.37 ± 22.34, 4.170 ± 0.577; p = .000) and D + L groups (254.72 ± 27.87, 3.750; p = .000) in escape latency and number of platform crossings, respectively. The L + D group (44.94 ± 2.92 pg/mL, 6.22 ± 0.50 pg/mL, and 460.02 ± 8.26 nmol/mL) and D + L group (46.88 ± 2.63 pg/mL, 5.90 ± 0.38 pg/mL, and 465.6 ± 16.07 nmol/mL) had significantly lower serum inflammatory levels of interleukin-6, tumor necrosis factor-α, and MDA than the d-gal group (57.79 ± 3.96 pg/mL, 11.25 ± 1.70 pg/mL, and 564.9 ± 15.90 nmol/mL), respectively. The L + D group (3.17 ± 0.41 μg/mL) and D + L group (3.08 ± 0.09 μg/mL) had significantly higher serum inflammatory levels of SOD than the d-gal group (2.20 ± 0.13 μg/mL) (all p = .000). The levels of CRMP2, P-CRMP2, and Aβ in the brain tissue homogenates of the L + D group (0.87 ± 0.04, 0.57 ± 0.0, and 0.16 ± 0.02) and the D + L group (0.82 ± 0.05, 0.58 ± 0.09, and 0.15 ± 0.02) were significantly different than the d-gal group (0.67 ± 0.03, 0.96 ± 0.040, and 0.29 ± 0.05). Lidocaine was shown to reduce cognitive impairment in rats with cognitive dysfunction through anti-inflammatory and antioxidative stress mechanisms in combination with CRMP2 antiphosphorylation.

Different ratios of Schisandra chinensis and Evodia rutaecarpa combination for treating Alzheimer's disease.

Schisandra chinensis and Evodia rutaecarpa are traditional Chinese herbs that have been used for many years to treat neurodegenerative diseases. In Chinese medicine, multiple herbs are often used in combination to enhance their efficacy, and different combination ratios can produce different therapeutic effects, thus flexibly responding to the needs of various patients. This study aimed to investigate the effects of different ratios of Schisandra and Evodia herbs on learning and memory impairment in rats with Alzheimer's disease (AD) and their specific mechanisms of action. Morris water maze and hematoxylin and eosin (HE) staining experiments were performed to evaluate the effects of different ratios of Schisandra-Evodia on learning memory in AD model rats. Immunohistochemical experiments were performed to investigate the effects of Schisandra-Evodia on the Aβ1-42 and P-Tau proteins, and protein immunoblotting (WB) was performed to determine the expression of key proteins in two pathways, BDNF/TrkB/CREB and GSK-3β/Tau. Our experimental results show that all Schisandra-Evodia groups showed significant neuroprotective effects, improved learning memory impairment, and reduced levels of Aβ1-42 and P-Tau proteins in AD model rats. Schisandra-Evodia upregulated BDNF, P-TrkB/TrkB, and P-CREB/CREB protein expression and downregulated GSK-3β and P-Tau/Tau protein expression. Among the different Schisandra-Evodia ratio groups, the 2:1 group showed the strongest therapeutic effect on AD. Our research results indicate that Schisandra-Evodia can reduce Aβ1-42 and P-Tau protein content by modulating the activity of two pathways, BDNF/TrkB/CREB and GSK-3β/Tau, thus improving neuronal cell damage and cognitive deficits caused by AD. In addition, we found that a Schisandra-Evodia ratio of 2:1 had the most profound therapeutic effect on AD.

Comprehensive brain tissue metabolomics and biological network technology to decipher the mechanism of hydrogen-rich water on Radiation-induced cognitive impairment in rats

BackgroundHydrogen-rich water (HRW) has been shown to prevent cognitive impairment caused by ionizing radiation. This study aimed to investigate the pharmacological effects and mechanisms of HRW on ionizing radiation by coupling the brain metabolomics and biological target network methods.Methods and resultsHRW significantly improves the cognitive impairment in rats exposed to ionizing radiation. Based on metabolomics and biological network results, we identified 54 differential metabolites and 93 target genes. The KEGG pathway indicates that glutathione metabolism, ascorbic acid and aldehyde acid metabolism, pentose and glucuronic acid interconversion, and glycerophospholipid metabolism play important roles in ionizing radiation therapy.ConclusionOur study has systematically elucidated the molecular mechanism of HRW against ionizing radiation, which can be mediated by modulating targets, pathways and metabolite levels. This provides a new perspective for identifying the underlying pharmacological mechanism of HRW.

Simulated weightlessness induces hippocampal insulin resistance and cognitive impairment

Growing evidence highlights the potential consequences of long-term spaceflight, including gray matter volume reduction and cognitive dysfunction with subclinical manifestations of diabetes mellitus among astronauts, but the underlying mechanisms remain unknown. In this study, we found that long-term simulated weightlessness induced hippocampal insulin resistance and subsequent neuronal damage and cognitive impairment in rats. Rats subjected to 4-week tail suspension exhibited peripheral insulin resistance, evidenced by increased fasting blood glucose and abnormal glucose tolerance and insulin tolerance, alongside reduced spontaneous activity and impaired recognition memory. In addition, 4 weeks of simulated weightlessness induced neuronal apoptosis and degeneration in the hippocampus, as evidenced by increased TUNEL and Fluoro-Jade B staining-positive neurons. Mechanistically, insulin-stimulated hippocampal Akt phosphorylation was decreased, while PTEN, the negative regulator of insulin signaling, was increased in the hippocampus in tail-suspended rats. Interestingly, treatment with berberine, an insulin sensitizer, partly reversed the above-mentioned effects induced by simulated weightlessness. These data suggest that long-term simulated weightlessness induces cognitive impairment as well as neuronal apoptosis and neural degeneration, partially through hippocampal insulin resistance via PTEN up-regulation. Berberine treatment attenuates hippocampal insulin resistance and improves cognitive function.

Protective effect of a standardized Allium jesdianum extract in an Alzheimer's disease induced rat model

Alzheimer's disease (AD) is a complex disorder with multiple underlying mechanisms. Existing treatment options mostly address symptom management and are associated with numerous side effects. Therefore, exploring alternative therapeutic agents derived from medicinal plants, which contain various bioactive compounds with diverse pharmacological effects, holds promise for AD treatment. This study aims to assess the protective effects of the hydroalcoholic extract of Allium jesdianum on cognitive dysfunction, mitochondrial and cellular parameters, as well as genetic parameters in an intracerebroventricular Streptozotocin (icv-STZ) induced rat model of AD. Male Wistar rats were injected with a single dose of STZ (3 mg/kg, icv) to establish a sporadic AD model. A. jesdianum extract (100, 200, and 400 mg/kg/day) and donepezil (5 mg/kg/day) were orally administered for 14 days following model induction. Cognitive function was evaluated using the radial arm water maze test. Mitochondrial toxicity parameters in various brain regions (whole brain, frontal cortex, hippocampus, and cerebellum) were assessed. Gene expression analysis of miR-330, miR-132, Bax, and Bcl-2 in isolated rat brain neurons was performed using RT-qPCR. A. jesdianum extract significantly attenuated cognitive dysfunction and mitigated mitochondrial toxicity induced by icv-STZ administration. Following STZ injection, there was upregulation of Bax gene expression and downregulation of miR-330, miR-132, and Bcl-2 gene expression. Treatment with A. jesdianum extract resulted in the reversal of the expression of these microRNAs and genes, indicating its potential for improving AD and reducing neuronal apoptosis. This study demonstrates the neuroprotective capabilities of A. jesdianum against STZ-induced oxidative stress and cognitive impairment in rats, highlighting its therapeutic potential in the management of AD.

Nose-to-brain delivery of 18β-Glycyrrhetinic acid using optimized lipid nanocapsules: A novel alternative treatment for Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder and the most relevant form of dementia affecting people worldwide. AD was reported to be associated with increased oxidative stress ending up with neuronal damage. 18β-Glycyrrhetinic acid (GA), triterpenoid aglycone of glycyrrhizin, was reported for its powerful antioxidant activities. However, its high molecular weight and lipophilicity are two major obstacles that limit its use and cause very low brain bioavailability. The aim of the present study was to formulate the GA in lipid nanocapsules (LNCs) for enhanced nose-to-brain delivery, as well as to elucidate its potential neuroprotective effect in AD. The optimized GA-loaded LNCs exhibited nanometric size range, good stability over 6 months, sustained drug release over 24 h and high steady state flux and permeability coefficient across nasal mucosa over 8 h. In-vivo studies were conducted on five groups; control, scopolamine (SCOP)-treated, SCOP + GA-LNCs, SCOP + oral GA suspension, and SCOP + intranasal GA suspension groups. Intranasal administration of GA-LNCs, at a reduced dose of 1 mg/kg, improved scopolamine-induced memory impairment in rats evidenced by behavioral testing, histological examination, and oxidative stress markers; catalase and superoxide dismutase. Collectively, GA-loaded LNCs (with 50 times lower dose) may provide a promising remedy for AD patients worldwide.

Investigating Facilitatory Effects of Lithium on Methamphetamine-induced Spatial Memory Impairments in Rat.

It has long been known that Methamphetamine (MA), as a psychostimulant, leads to long-lasting cognitive deficits. Previous studies have shown that lithium, a mood stabilizer, could facilitate cognitive ability in most of brain diseases. In current study the effects of lithium on spatial memory, hippocampal apoptosis and brain edema in METH-exposed rats are investigated. The present study 32 Wistar rats were used to examine the effects of lithium on spatial memory by the Morris water maze, hippocampal apoptosis using the TUNEL assay, and brain edema following MA administrations. The findings indicated that treatment with lithium significantly ameliorated spatial learning and memory impairment in MA-treated rats. In addition, the findings showed that treatment with lithium significantly reduced brain edema and apoptosis in the CA1 neurons in MA -exposed rats. The results show that treatment with lithium can partially ameliorate the MA-induced neurocognitive deficits in rats, which may be related to its protective effect in the hippocampus.

Croton hirtus attenuating streptozotocin-induced neuroinflammation in rats

ObjectiveThe present study was aimed to investigate the neuroprotective effect of Croton hirtus (CH) extract against streptozotocin (STZ) in rats. Methods(i) The sub-chronic toxicity consisted of 24 adult rats of either sex weighing from 160 to 200 g were divided into four groups with six rats in each group. Rats in group 1 received Dimethyl sulfoxide (DMSO) mixed with saline; rats in groups 2, 3, and 4 received 100, 200, and 400 mg/kg of methanolic extract of CH (MECH) orally by gavage administration for 28 d, respectively. The functional observation battery and locomotor activity were graded as part of their neurobehavioral activity and the brain regions, including cortex and hippocampus, were analyzed for neuropathological abnormalities. (ii) The main research consisted of 30 adult male Wistar rats weighing from 160 to 200 g, which were divided into five groups and six rats in each group, including control (I), STZ (II), Donepezil (III), MECH (100 mg/kg, IV), and MECH (200 mg/kg, V) groups. Rats in group I received citrate buffer orally and DMSO mixed with saline for 14 d. Rats in group II received STZ via intracerebroventricular injection (3 mg/kg, bilateral ICV-STZ) on days 1 and 3 followed by DMSO mixed with saline for 14 d. Rats in groups III, IV, and V received STZ administration on days 1 and 3 followed by Donepezil [3 mg/(kg·d), p.o.] and MECH [100 and 200 mg/(kg·d), p.o.] for 14 d. Rats were tested for learning and memory parameters such as Morris water maze (MWM) and passive avoidance test (PAT). They were sacrificed after completing behavioural experiments; brains were harvested to estimate the acetylcholinesterase (AChE), lipid peroxidation (LPO), glutathione (GSH), and superoxide dismutase (SOD) by using UV-Visible Spectrophotometer; caspase-3 was evaluated by total fluorescence emission spectra; amyloid β (Aβ) levels were detected using enzyme-linked immuosorbent assay (ELISA); and histopathological examination was conducted in the CA1 region of the hippocampus. Results(i) The sub-chronic toxicity results revealed that open field test parameters including line crossing, rearing, entering the middle square, defecating, or urinating did not differ significantly in the MECH rats (P > 0.05). The histopathological observation did not show any lesions in the neuronal cells and inflammation in both the regions in MECH rats compared with control rats. (ii) The main study findings demonstrated that STZ-treated rats showed a significant increase in impairment in learning and memory parameters (P < 0.001), the levels of AChE, caspase-3, Aβ (1-40 and 1-42), and LPO were increased significantly (P < 0.001), and significant decrease was found in the levels of SOD (P < 0.001) and GSH (P < 0.01). Moreover, neuronal damage was found in the hippocampus. In contrast, STZ-induced behavioural and biochemical impairments in rats were considerably decreased by treatment with MECH dose-dependently. ConclusionMECH significantly prevented the memory deficit induced by STZ due to antioxidant action. Restoration of cholinergic functioning may be the cause of behavioural improvement. Therefore, MECH may be able to treat cognitive disorders like Alzheimer's disease (AD).

Neuronal Death Caused by HMGB1-Evoked via Inflammasomes from Thrombin-Activated Microglia Cells.

Microglial cells are a macrophage-like cell type residing within the CNS. These cells evoke pro-inflammatory responses following thrombin-induced brain damage. Inflammasomes, which are large caspase-1-activating protein complexes, play a critical role in mediating the extracellular release of HMGB1 in activated immune cells. The exact role of inflammasomes in microglia activated by thrombin remains unclear, particularly as it relates to the downstream functions of HMGB1. After receiving microinjections of thrombin, Sprague Dawley rats of 200 to 250 gm were studied in terms of behaviors and immunohistochemical staining. Primary culture of microglia cells and BV-2 cells were used for the assessment of signal pathways. In a water maze test and novel object recognition analysis, microinjections of thrombin impaired rats' short-term and long-term memory, and such detrimental effects were alleviated by injecting anti-HMGB-1 antibodies. After thrombin microinjections, the increased oxidative stress of neurons was aggravated by HMGB1 injections but attenuated by anti-HMGB-1 antibodies. Such responses occurred in parallel with the volume of activated microglia cells, as well as their expressions of HMGB-1, IL-1β, IL-18, and caspase-I. In primary microglia cells and BV-2 cell lines, thrombin also induced NO release and mRNA expressions of iNOS, IL-1β, IL-18, and activated caspase-I. HMGB-1 aggravated these responses, which were abolished by anti-HMGB-1 antibodies. In conclusion, thrombin induced microglia activation through triggering inflammasomes to release HMGB1, contributing to neuronal death. Such an action was counteracted by the anti-HMGB-1 antibodies. The refinement of HMGB-1 modulated the neuro-inflammatory response, which was attenuated in thrombin-associated neurodegenerative disorder.

Leukotriene signaling as molecular correlate for cognitive heterogeneity in aging: an exploratory study.

Aging is in general associated with a decline in cognitive functions. Looking more closely, there is a huge heterogeneity in the extent of cognitive (dys-)abilities in the aged population. It ranges from the population of resistant, resilient, cognitively unimpaired individuals to patients with severe forms of dementias. Besides the known genetic, environmental and life style factors that shape the cognitive (dys-)abilities in aging, the underlying molecular mechanisms and signals related to cognitive heterogeneity are completely unknown. One putative mechanism underlying cognitive heterogeneity might be neuroinflammation, exerted through microglia, the brain's innate immune cells, as neuroinflammation is central to brain aging and neurodegenerative diseases. Recently, leukotrienes (LTs), i.e., small lipid mediators of inflammation produced by microglia along aging and neurodegeneration, got in the focus of geroscience as they might determine cognitive dysfunctions in aging. Here, we analyzed the brain's expression of key components of the LT synthesis pathway, i.e., the expression of 5-lipoxygenase (5-Lox), the key enzyme in LT production, and 5-lipoxygenase-activating protein (FLAP) in young and aged rats. More specifically, we used a cohort of rats, which, although grown up and housed under identical conditions, developed into aged cognitively unimpaired and aged cognitively impaired traits. Expression of 5-Lox was increased within the brain of aged rats with the highest levels detected in cognitively impaired animals. The number of microglia cells was higher in the aged compared to the young brains with, again, the highest numbers of 5-Lox expressing microglia in the aged cognitively impaired rats. Remarkably, lower cognitive scores in the aged rats associated with higher numbers of 5-Lox positive microglia in the animals. Similar data were obtained for FLAP, at least in the cortex. Our data indicate elevated levels of the LT system in the brain of cognitively impaired animals. We conclude that 5-Lox expressing microglia potentially contribute to the age-related cognitive decline in the brain, while low levels of the LT system might indicate and foster higher cognitive functions and eventually cognitive reserve and resilience in aging.

Efficacy of electroacupuncture stimulating Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) on spatial learning and memory deficits in rats with insomnia induced by para-chlorophenylalanine: a single acupoint combined acupoints.

To investiage the effect of electroacupuncture (EA) at a single acupoint of Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) and at combined acupoints of Shenmen (HT7) and Baihui (GV20) and Sanyinjiao (SP6) on the PKA/CREB and BDNF/TrkB signaling, as well as neuroapoptosis and neurogenesis in hippocampus and elucidate the underlying mechanism of single and combined acupoints on ameliorating spatial learning and memory deficits in a rat model of primary insomnia. Primary insomnia was modeled by intraperitoneal injection of para-chlorophenylalanine (PCPA) once daily for 2 d. EA was applied at Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6), or Shenmen (HT7) + Baihui (GV20) + Sanyinjiao (SP6) (combined) for 30 min daily for 4 d. Spatial learning and memory function was evaluated by the Morris water maze (MWM) test. Protein expressions of hippocampal cAMP-dependent protein kinase (PKA)-Cβ, phosphorylated cAMP-responsive element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and tyrosine kinase receptor B (TrkB) were evaluated by Western blotting. Neuronal apoptosis in the hippocampus was detected with the transferase-mediated dUTP-X nick end labeling assay. Endogenous neurogenesis was examined with bromodeoxyuridine staining. The MWM test and hippocampal p-CREB, BDNF, and TrkB protein levels in the combined acupoints group were evaluated after the administration of a PKA-selective inhibitor (H89). Spatial learning and memory were significantly impaired in rats with insomnia. The spatial learning deficits were ameliorated in the Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6), and combined groups; this improvement was significantly greater in the combined group than the single acupoint groups. The spatial memory impairment was improved in the combined, Baihui (GV20), and Shenmen (HT7) groups, but not the Sanyinjiao (SP6) group. The expressions of PKA-Cβ, p-CREB, BDNF, and TrkB were decreased in rats with insomnia. All these proteins were significantly upregulated in the combined group. PKA/p-CREB protein levels were elevated in the Baihui (GV20) and Shenmen (HT7) groups, whereas BDNF/TrkB expression was upregulated in the Sanyinjiao (SP6) group. The staining results showed significant attenuation of hippocampal cell apoptosis and increased numbers of proliferating cells in the combined group, whereas the single acupoint groups only showed decreased numbers of apoptotic cells. In the combined group, the PKA inhibitor reversed the improvement of spatial memory and upregulation of p-CREB expression caused by EA, but did not affect its activation of BDNF/TrkB signaling. EA at the single acupoints Baihui (GV20), Shenmen (HT7), or Sanyinjiao (SP6) had an ameliorating effect on the spatial learning and memory deficits induced by insomnia. EA at combined acupoints exerted a synergistic effect on the improvements in spatial learning and memory impairment in rats with insomnia by upregulating the hippocampal PKA/CREB and BDNF/TrkB signaling, facilitating neurogenesis, and inhibiting neuronal apoptosis. These findings indicate that EA at combined acupoints [(Baihui (GV20), Shenmen (HT7), and Sanyinjiao (SP6)] achieves a more pronounced regulation of hippocampal neuroplasticity than EA at single acupoints, which may partly explain the underlying mechanisms by which EA at combined acupoints exerts a better ameliorative effect on the cognitive dysfunction caused by insomnia.

Nicotinamide mononucleotide (NMN) ameliorated Nonylphenol-induced learning and memory impairment in rats via the central 5-HT system and the NAD+/SIRT1/MAO-A pathway.

Nonylphenol (NP) exposure can trigger neurotoxicity and cause learning and memory impairment. Nicotinamide mononucleotide (NMN) has a therapeutic effect on neurodegenerative diseases, but the role of NMN on NP-induced learning and memory impairment is not known. Here, we examined the mitigative effect of NMN on the impaired learning and memory ability of rats exposed to NP. The NP impaired learning and memory in rats, while the low-dose intervention with NMN significantly prolonged the step-through latency of the PAT and improved the NAMPT and NMNAT1 content in brain tissue. At the same time, the NMN intervention also increased the content of 5-HTR1A, 5-HTR4, and 5-HTR6 related to learning and memory in the hippocampus. In line with this, we found that the NMN intervention activated the SIRT1/MAO-A pathway in brain tissue. NMN intervention, especially at 125 mg/kg doses, may improve rats' NP-induced learning and memory impairment via the central 5-HT system and the NAD+/SIRT1/MAO-A pathway in the brain.