Memory Deficits In Mice Research Articles

The Protective Effects of Nicotine and Bucladesine on Impaired Avoidance Memory Caused by Sodium Arsenate Toxicity in Mice

Background: The toxic effect of sodium arsenate on nervous system has been shown; but the protective effects of several compounds against sodium arsenate are not clear. This study aimed to investigate the protective effects of nicotine and bucladesine, two positive modulators of neuronal function, on sodium arsenate toxicity against avoidance memory impairment. Methods: Male mice (N=154) were assigned to 22 groups (12 experimental and 10 control) of seven animals each and were treated as follows: sodium arsenate (2.5, 5, or 10 mg/kg) for 28 days, nicotine (1 mg/kg) for either 1, 2, or 4 days, bucladesine (600 nM/mouse) for either 1, 2, or 4 days, and nicotine (1 mg/kg)+bucladesine (600 nM/mouse)+sodium arsenate (2.5 mg/kg). The last group was treated with 2.5 mg/kg sodium arsenate first, and then received the combination of nicotine and bucladesine for 1, 2, or 4-days. The corresponding control groups did not receive any drug but either saline, deionized water, or combination of deionized water and DMSO, but went through the same procedure as other animals. All mice were trained 24 h in the step-through passive avoidance task. The avoidance memory retention was assessed at 24, 48, 96, and 168 h after the training period by measuring the time they stayed in a dark chamber. Results: All sodium arsenate doses significantly reduced the time stayed in the dark chamber regardless of the treatment duration (24, 48, 96 & 168 h) after training. Both nicotine and bucladesine, whether used singly or combined for 1, 2, and 4 days significantly enhanced the time latency compared to the controls at all of the experimental timepoints following the training. Conclusion: Nicotine and bucladesine showed synergistic effects and reversed the sodium arsenate-induced avoidance memory deficits in mice.

MiR-96 Inhibits SV2C to Promote Depression-Like Behavior and Memory Disorders in Mice.

Accumulating evidence continues to emphasize the role of microRNAs as significant contributors to depression-like behavior and memory disorders. The current study aimed to investigate the mechanism by which miR-96 influences depression-like behavior and memory deficit in mice. A depression-like behavior and memory disorder mouse model was initially established by means of intraperitoneal injection with lipopolysaccharide. Memory deficits in the mice were evaluated using the Novel Object Recognition Test and Morris water maze experiments, whereas the Sucrose Preference Experiment and forced swimming experiments were performed to identify depression-like behavior in mice. The levels of tumor necrosis factor-α, malondialdehyde, superoxide dismutase, glutathione, and the monoamine transmitters 5-hydroxytryptamine and dopamine were subsequently detected in the serum. Reverse transcription-quantitative polymerase chain reaction and Western blot analysis evaluated the expression of miR-96 and SV2C expression in the CA1 hippocampal region of the mice. Finally, the relationship of miR-96 and SV2C was verified by dual-luciferase reporter gene assay. Our data indicated that the expression of miR-96 was increased, whereas that of SV2C was decreased in the CA1 region of mice exhibiting depression-like behavior and memory impairment. When miR-96 was downregulated or SV2C was overexpressed via intra-cerebroventricular injection with a miR-96 antagonist (miR-96 antagomir) or overexpression of SV2C vector, the Novel Object Recognition Test and sucrose preference index were increased, whereas the escape latency, the number of water maze platform crossings, and the immobility time of the mice were decreased. The serum levels of tumor necrosis factor-α, interleukin-1β, and malondialdehyde in the mouse CA1 region of mice were reduced, whereas the levels of superoxide dismutase and glutathione were elevated after the downregulation of miR-96 or overexpression of SV2C. Collectively, our study demonstrates that miR-96 negatively regulates the expression of SV2C, which consequently leads to depression-like behavior and memory impairment in mice. Our findings highlight the potential of miR-96-targeted therapeutics.

Abstract P785: The B Cell Response to Extracellular Glutamate in the Ischemic Brain

Background: Neuronal networks require significant neurotrophic support for functional plasticity after stroke. We showed that B cells exhibit a cell-specific migration pattern in the post-stroke brain. Post-stroke B cell depletion impedes neurogenesis, increases anxiety, and exacerbates memory deficits in mice; deficits generally mediated by brain regions occurring outside the initial infarct. We hypothesize that the post-stroke microenvironment can enhance neurotrophic capacities of B cells to promote plasticity. Methods: Splenic B cells were isolated from 3-5 mo-old male C57Bl/6J mice. B cell N-methyl-D-aspartate receptor (NMDAR) subunits were identified by confocal microscopy. The acute (8 min) Ca 2+ response to 1uM glutamate (glu) +/- NMDAR antagonists (10uM DAPV (competitive NMDAR inhibitor), 30uM ifenprodil (ifen., GluN2B subunit inhibitor), and 10uM TCN201 (GluN2A subunit inhibitor)) was assessed via flow cytometry in B cells (+/- 5ug/mL LPS). B cell viability and neurotrophin (NT)-related genes were assessed by flow cytometry and qPCR, respectively, in B cells (+/- LPS) treated with glu +/- NMDAR antagonists for 24h. Data were analyzed in Graphpad Prism. Results: B cells express functional GluN2A- and GluN2B-containing NMDARs that influx Ca 2+ in response to extracellular glu (*p<0.05). While LPS did not impact NMDAR-dependent Ca 2+ influx in most B cell subsets, Ca 2+ influx was significantly reduced by NMDAR antagonists in LPS-stimulated B cells (Effector B cells (DAPV *p<0.05, ifen **p<0.01), Bregs (DAPV *p<0.05, Ifen *p<0.05), B220 + antibody-secreting cells (ifen *p<0.05, TCN201 *p<0.05)). Furthermore, a 24h glu treatment increased NT (BDNF: 2.28-fold, IL-10: 27.16-fold), NT receptor (TrkB: 1.33-fold) and NMDAR (GluN2A: 2.01-fold, GluN2B: 1.27-fold) expression in LPS-stimulated B cells (vs. untreated controls). Conclusions: Our studies show that B cells respond to glu via NMDARs. Our data suggests that exposure to physiologic levels of glu enhance NMDAR-dependent signaling and upregulate NTs and NT receptors. These results are the first to indicate a glu-induced neurotrophic role for B cells in the ischemic brain. Future studies will determine whether B cell-derived NTs can protect neurons after stroke.

Venlafaxine Attenuated the Cognitive and Memory Deficit in Mice Exposed to Isoflurane Alone.

Post-operative cognitive dysfunction (POCD) is a common complication during the post-operative period. It affects the recovery time of the patient after surgery and the stay time in hospital, which causes a great deal of burden to patients and families emotionally and financially. However, there is no specific and effective treatment available for this disorder. Recent study indicated exposure to general anesthetics contributed to POCD by triggering gamma-amino butyric acid type A (GABAA) receptors hyperactivities that persisted even the anesthetic compounds have been eliminated. Here, we investigated the antidepressant, venlafaxine (VLX), in a mouse model of POCD and studied whether VLX attenuated the cognitive dysfunction of mice exposed to general anesthetic, isoflurane (ISO). We found that ISO significantly induced an increased surface expression of the GABAA receptor subunit, α5, in the hippocampus of the mice. However, VLX treatment reduced the increase in α5 subunit expression. Meanwhile, we found the expression levels of interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), and IL-6 in the brains of mice exposed to ISO were significantly increased. However, VLX could prevent the increase in these cytokines. We also investigated the memory deficit of these mice by using a Y maze behavioral test. Mice with ISO exposure showed decreased alternation performance that could be prevented by the VLX treatment. Collectively, our results here are in line with the previous findings that α5 subunit plays an important role of the formation of POCD, but VLX may be a promising candidate compound for the treatment of POCD.

The flavonoids of okra insulates against oxidative stress, neuroinflammation and restores BDNF levels in Aβ1–42 induced mouse model of Alzheimer's disease

Okra (Abelmoschus esculentus [L.] Moench.) has been used as a natural drug in East or West Africa for many centuries, as well as consumed in most areas of the world as a tropical vegetable. The study aimed to evaluate whether the flavonoids of okra fruit (FOF) administration influence Aβ1-42-induced learning and memory impairment, and explore the underlying mechanisms. The Y-maze task and the Morris water maze test were used for evaluating cognition processes. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and glutathione peroxidase (GSH-Px) were detected by ELISA kits. The expressions of nuclear factor kappa-light chain-enhancer of activated B (NF-κB), brain-derived neurotrophic factor (BDNF), cAMP-response element-binding protein (CREB), extracellular signal-regulated kinase (ERK), phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), glycogen synthase kinase-3β (GSK-3β) were studied by western blot. Histopathological changes were observed by H.E. straining. The results showed that intracerebroventricular injection of Aβ1-42 was effective in producing memory deficits in mice. Besides, Aβ1-42 exposure could significantly increase the levels of NF-κB, TNF-α, IL-1β, and decreased T-AOC, the activities of SOD and GSH-Px in the hippocampus and cortex. Furthermore, the level of BDNF was also reduced, accompanied by down-regulated CREB/ERK and PI3K/AKT/GSK-3β signaling pathways in the hippocampus and cortex. Nevertheless, chronic administration of FOF (100 or 300mg/kg, i.g.) significantly prevented Aβ1-42-induced behavioral and biochemical alterations. It also suggested that FOF could improve the cognitive deficits in AD-like model mice, which might be mediated by regulation of BDNF levels in cortex and hippocampus and up-regulating of CREB/ERK and PI3K/AKT/GSK3β pathways, as well as alleviation of oxidative stress and neuroinflammation.

Antipsychotic-like effect of ethyl acetate fraction of Terminalia macroptera leaf in mice.

Psychosis is a chronic neuropsychiatric disorder that affects millions of individuals worldwide and impairs the quality of life and productivity of the patients. Terminalia macroptera Guill & Perr. (Combrataceae) is a plant that is used in the management of anxiety related disorders. The present study investigates the antipsychotic effects of ethyl acetate fraction of T. macroptera (EFTM) leaf in ketamine-induced psychosis in mice. Acute toxicity of EFTM was determine using Lorke’s method. Ketamine (25 mg/kg) was injected once daily for 7 consecutive days in Swiss albino mice to induce psychosis. The effect of the extracts (100, 200 and 400 mg/kg) was evaluated against psychotic-like behaviors induced by ketamine including locomotor activity and stereotypy in the open field test, immobility duration in the forced swim test, and memory impairment using the Y- maze test. The acute antipsychotic effect of EFTM was evaluated on apomorphine climbing test, while woodblock test was performed to assess its extrapyramidal side effects. The LD50 was found to be 3807 mg/kg p.o. which is considered safe. EFTM (100, 200 and 400 mg/kg) exhibited significant antipsychotic effect by reducing ketamine-induced hyperactivity, immobility, and memory deficit in mice, EFTM also suppressed stereotypic climbing behavior due to apomorphine. Accordingly, the antipsychotic activity of EFTM was not associated with extrapyramidal side effects as evidenced by lack of catalepsy. The study revealed that EFTM ameliorated psychotic-like symptoms and is devoid of extrapyramidal side effects in mice, underscoring its antipsychotic-like effect.

The Anti-Inflammatory Drug Aspirin Does Not Protect Against Chemotherapy-Induced Memory Impairment by Paclitaxel in Mice.

Inflammation has been proposed to play a causal role in chemobrain which—if true—would represent an opportunity to repurpose existing anti-inflammatory drugs for the prevention and treatment of chemobrain. Here, we show that the chemoagent paclitaxel induces memory impairment and anhedonia in mice within 24 h of treatment cessation, but inflammation is not present until 2 weeks after treatment. We find no evidence of brain inflammation as measured by cytokine analysis at any time point. Furthermore, treating with aspirin to block inflammation did not affect paclitaxel-induced memory impairment. These findings suggest that inflammation may not be responsible for memory impairment induced by paclitaxel. These results contrast with recent findings of a causal role for inflammation in cancer-induced memory deficits in mice that were prevented by treatment with oral aspirin, suggesting that cognitive impairment in cancer patients undergoing treatment may arise from multiple convergent mechanisms.

Biofabricated zinc oxide nanoparticles impair cognitive function via modulating oxidative stress and acetylcholinesterase level in mice

Current work was designed to explore the effect of ZnO nanoparticles (ZnONP) biofabricated by using Trianthema portulacastrum (TP) leaves extract on mice brain hippocampus. ZnO nanoparticles of TP leaves (ZnOTP) were synthesized by co-precipitation method and further characterized by using various techniques such as UV-Vis spectrophotometer, Field Emission Scanning Electron Microscopy (FESEM), Fourier Transform Infrared (FTIR), and Energy Dispersive X-ray (EDX). ZnOTP were evaluated for in vitro antioxidant activity, in vivo behavior models (for assessment of cognitive ability), acetylcholinesterase (AChE) activity along with other neurotransmitters content determination, estimation of various oxidative stress parameters and analysis of zinc content in the brain as well as plasma. Histopathological evaluation of the brain hippocampus of each group was performed to corroborate the statistical results. Spherical ZnOTP of 10 to 20 nm size embedded with different phytoconstituents of TP was confirmed. Results of our study revealed a significant memory deficit in mice treated with ZnOTP. Neuronal degeneration was also observed via a significant increase in AChE activity and oxidative stress levels in the brain of mice administered with ZnOTP. Exposure of ZnOTP was also found responsible for modulation of neurotransmission in hippocampus area. Further, ZnOTP disturbed the zinc homeostasis in hippocampus via elevation of zinc content in brain as well as plasma. Histopathology of hippocampus supported the damaging impact of ZnOTP by an increase in vacuolated cytoplasm and focal gliosis in groups treated with ZnOTP. Results demonstrated the neurotoxic effect of ZnOTP on brain hippocampus via cognitive impairment by alteration of neurotransmitter level, zinc content and oxidative stress.

Anti-inflammatory IL-10 administration rescues depression-associated learning and memory deficits in mice

BackgroundMajor depressive disorder is a widespread mood disorder. One of the most debilitating symptoms patients often experience is cognitive impairment. Recent findings suggest that inflammation is associated with depression and impaired cognition. Pro-inflammatory cytokines are elevated in the blood of depressed patients and impair learning and memory processes, suggesting that an anti-inflammatory approach might be beneficial for both depression and cognition.MethodsWe subjected mice to the learned helplessness paradigm and evaluated novel object recognition and spatial memory. Mice were treated with IL-10 intranasally or/and microglia cells were depleted using PLX5622. Statistical differences were tested using ANOVA or t tests.ResultsWe first established a mouse model of depression in which learning and memory are impaired. We found that learned helplessness (LH) impairs novel object recognition (NOR) and spatial working memory. LH mice also exhibit reduced hippocampal dendritic spine density and increased microglial activation compared to non-shocked (NS) mice or mice that were subjected to the learned helpless paradigm but did not exhibit learned helplessness (non-learned helpless or NLH). These effects are mediated by microglia, as treatment with PLX5622, which depletes microglia, restores learning and memory and hippocampal dendritic spine density in LH mice. However, PLX5622 also impairs learning and memory and reduces hippocampal dendritic spine density in NLH mice, suggesting that microglia in NLH mice produce molecules that promote learning and memory. We found that microglial interleukin (IL)-10 levels are reduced in LH mice, and IL-10 administration is sufficient to restore NOR, spatial working memory, and hippocampal dendritic spine density in LH mice, and in NLH mice treated with PLX5622 consistent with a pro-cognitive role for IL-10.ConclusionsAltogether these data demonstrate the critical role of IL-10 in promoting learning and memory after learned helplessness.

Protective effect of ginsenoside Rh2 on scopolamine-induced memory deficits through regulation of cholinergic transmission, oxidative stress and the ERK-CREB-BDNF signaling pathway.

Rh2 is a rare ginsenoside and there are few reports of its effect on cognition compared with other similar molecules. This study aimed to establish the impact of Rh2 treatment on improving scopolamine (Scop)-induced memory deficits in mice and illuminate the underlying mechanisms. First, memory-related behavior was evaluated using two approaches: object location recognition (OLR), based on spontaneous activity, and a Morris water maze (MWM) task, based on an aversive stimulus. Our results suggested that Rh2 treatment effectively increased the discrimination index of the mice in the OLR test. In addition, Rh2 elevated the crossing numbers and decreased the escape latency during the MWM task. Moreover, Rh2 markedly upregulated the phosphorylation of the extracellular signal-regulated kinase (ERK)-cAMP response element binding (CREB)-brain derived neurotrophic factor (BDNF) pathway in the hippocampus. Meanwhile, the administration of Rh2 significantly promoted the cholinergic system and dramatically suppressed oxidative stress in the hippocampus. Taken together, Rh2 exhibited neuroprotective effects against Scop-induced memory dysfunction in mice. Rh2 activity might be ascribed to several underlying mechanisms, including its effects on modulating the cholinergic transmission, inhibiting oxidative stress and activating the ERK-CREB-BDNF signaling pathway. Consequently, the ginsenoside Rh2 might serve as a promising candidate compound for Alzheimer's disease.

Neonatal Isoflurane Anesthesia or Disruption of Postsynaptic Density-95 Protein Interactions Change Dendritic Spine Densities and Cognitive Function in Juvenile Mice.

Experimental evidence shows postnatal exposure to anesthesia negatively affects brain development. The PDZ2 domain, mediating protein-protein interactions of the postsynaptic density-95 protein, serves as a molecular target for several inhaled anesthetics. The authors hypothesized that early postnatal disruption of postsynaptic density-95 PDZ2 domain interactions has persistent effects on dendritic spines and cognitive function. One-week-old mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active postsynaptic density-95 wild-type PDZ2 peptide along with their respective controls. A subset of these mice also received 4 mg/kg of the nitric oxide donor molsidomine. Hippocampal spine density, long-term potentiation, novel object recognition memory, and fear learning and memory were evaluated in mice. Exposure of 7-day-old mice to isoflurane or postsynaptic density-95 wild-type PDZ2 peptide relative to controls causes: (1) a long-term decrease in mushroom spines at 7 weeks (mean ± SD [spines per micrometer]): control (0.8 ± 0.2) versus isoflurane (0.4 ± 0.2), P < 0.0001, and PDZ2MUT (0.7 ± 0.2) versus PDZ2WT (0.4 ± 0.2), P < 0.001; (2) deficits in object recognition at 6 weeks (mean ± SD [recognition index]): naïve (70 ± 8) versus isoflurane (55 ± 14), P = 0.010, and control (65 ± 13) versus isoflurane (55 ± 14), P = 0.045, and PDZ2MUT (64 ±11) versus PDZ2WT (53 ± 18), P = 0.045; and (3) deficits in fear learning at 7 weeks and memory at 8 weeks (mean ± SD [% freezing duration]): Learning, control (69 ± 12) versus isoflurane (52 ± 13), P < 0.0001, and PDZ2MUT (65 ± 14) versus PDZ2WT (55 ± 14) P = 0.011, and Memory, control (80 ± 17) versus isoflurane (56 ± 23), P < 0.0001 and PDZ2MUT (73 ± 18) versus PDZ2WT (44 ± 19) P < 0.0001. Impairment in long-term potentiation has fully recovered here at 7 weeks (mean ± SD [% baseline]): control (140 ± 3) versus isoflurane (137 ± 8), P = 0.560, and PDZ2MUT (136 ± 17) versus PDZ2WT (128 ± 11), P = 0.512. The isoflurane induced decrease in mushroom spines was preventable by introduction of a nitric oxide donor. Early disruption of PDZ2 domain-mediated protein-protein interactions mimics isoflurane in decreasing mushroom spine density and causing learning and memory deficits in mice. Prevention of the decrease in mushroom spine density with a nitric oxide donor supports a role for neuronal nitric oxide synthase pathway in mediating this cellular change associated with cognitive impairment.

Accumulation of PSA-NCAM marks nascent neurodegeneration in the dorsal hippocampus after neonatal hypoxic-ischemic brain injury in mice

Neonatal hypoxia-ischemia (nHI) disrupts hippocampal GABAergic development leading to memory deficits in mice. Polysialic-acid neural-cell adhesion molecule (PSA-NCAM) developmentally declines to trigger GABAergic maturation. We hypothesized that nHI changes PSA-NCAM abundance and cellular distribution, impairing GABAergic development, and marking nascent neurodegeneration. Cell degeneration, atrophy, and PSA-NCAM immunoreactivity (IR) were measured in CA1 of nHI-injured C57BL6 mice related to: (i) cellular subtype markers; (ii) GAD65/67 and synatophysin (SYP), pre-synaptic markers; (iii) phospho-Ser396Tau, cytoskeletal marker; and (iv) GAP43, axonalregeneration marker. PSA-NCAM IR was minimal in CA1 of shams at P11. After nHI, PSA-NCAM IR was increased in injured pyramidal cells (PCs), minimal in parvalbumin (PV)+INs, and absent in glia. PSA-NCAM IR correlated with injury severity and became prominent in perikaryal cytoplasm at P18. GAD65/67 and SYP IRs only weakly related to PSA-NCAM after nHI. Injured phospho-Ser396Tau+ PCs and PV+INs variably co-expressed PSA-NCAM at P40. While PCs with cytoplasmic marginalized PSA-NCAM had increased perisomatic GAP43, those with perikaryal cytoplasmic PSA-NCAM had minimal GAP43. PSA-NCAM increased in serum of nHI-injured mice. Increased PSA-NCAM is likely a generic acute response to nHI brain injury. PSA-NCAM aberrant cellular localization may aggravate neuronal degeneration. The significance of PSA-NCAM as a biomarker of recovery from nHI and nascent neurodegeneration needs further study.

Involvement of Oxidative Stress and Nerve Growth Factor in Behavioral and Biochemical Deficits of Experimentally Induced Musculoskeletal Pain in Mice: Ameliorative Effects of Heraclin.

Musculoskeletal pain is a widespread complex regional pain syndrome associated with altered emotional and cognitive functioning along with heightened physical disability that has become a global health concern. Effective management of this disorder and associated disabilities includes accurate diagnosis of its biomarkers and institutingmechanism-based therapeutic interventions. Herein, we explored the role of heraclin, a plant-derived molecule, in musculoskeletal pain and its underlying mechanistic approaches in an experimental mouse model. Reserpine (0.5mg/kg) for 3 consecutive days evoked hyperalgesia, motor incoordination, lack of exploratory behavior, anxiety, and cognition lapse in mice. Reserpine-challenged mice displayed higher serum cytokine level, alteredbrain neurotransmitter content, elevated brain and muscle oxidative stress, and upregulated brain nerve growth factor receptor expression. Treatment with heraclin (10mg/kg for 5 consecutive days) exerted analgesic effect and improved motor coordination and memory deficits in mice. Heraclin arrested serum cytokine rise, normalized brain neurotransmitter content, reduced tissue oxidative stress, and downregulated the nerve growth factor receptor expression. Therefore, it may be suggested that heraclin exerts beneficial effects against reserpine-induced musculoskeletal pain disorder possibly through the attenuation of NGFR-mediated pain and inflammatory signaling. Graphical Abstract.

Inhibition of mTORC1 improves STZ-induced AD-like impairments in mice

Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) share some pathological features, including tau hyperphosphorylation and deficits in insulin signaling, but the underlying mechanism and effective drugs for treating AD are unknown. The AD-like brain impairments are almost same in both of mouse type 2 DM models induced by the multiple low-dose intraperitoneal (i.p.) streptozotocin (STZ) injection and twice intracerebroventricular (i.c.v.) STZ injection. We found that memory disorders, impairment of insulin signaling, and AD-like tauopathies were exhibited in two different STZ-induced mouse models and that the level of Advanced Glycation End Products (AGEs) was increased in two STZ mouse models. Inhibition of mTORC1 with rapamycin reversed the deficits of insulin signaling associated kinases activity, decreased levels of AGEs and AD-like tau phosphorylation, and also improved memory deficit in both STZ mice. Rapamycin attenuated HG-induced tau hyperphosphorylation via the AKT/AMPK/GSK-3β pathways and p70S6K in SH-SY5Y cells. Taken together, these data demonstrated that rapamycin improved STZ-induced AD-like tauopathies and memory deficit in mice via improving p70S6K and AKT/AMPK/GSK-3β signaling and decreasing AGEs. Therefore, regulating insulin signaling via mTORC1 is a new strategy for preventing T2DM-associated AD, and mTORC1 is a potential drug target.

Agmatine reverses memory deficits induced by Aβ1–42 peptide in mice: A key role of imidazoline receptors

Agmatine is a biogenic amine synthesized following decarboxylation of L-arginine by the enzyme arginine decarboxylase and exhibits favourable outcome in neurodegenerative disorders. Present study was designed to examine the relationship between agmatine and the imidazoline receptors in memory deficits induced by Aβ1-42 peptide in mice. Mice were treated with single intracerebroventricular (i.c.v.) injection of Aβ1-42 peptide (3μg) and evaluated for learning and memory in Morris water maze (MWM) and subjected to Aβ1-42, TNF-α and IL-6 and BDNF immunocontent analysis within the hippocampus. While the learning and memory impairment was evident in the mice subjected to MWM test following Aβ1-42 peptide administration, there was a significant increase in Aβ1-42, TNF-α and IL-6 and reduction in BDNF immunocontent within the hippocampus. Daily intraperitoneal (i.p.) treatment with agmatine (10 and 20mg/kg); imidazoline I1 receptor agonist, moxonidine and imidazoline I2 receptor agonist, 2-BFI starting from day 8 to 27 post-Aβ1-42 injection, significantly prevented the cognitive deficits and normalized the Aβ1-42 peptide, IL-6, TNF-α and BDNF immunocontent in hippocampus. On the other hand, pre-treatment with imidazoline I1 receptor antagonist, efaroxan and imidazoline I2 receptor antagonist, BU 224 attenuated the effects of agmatine on learning and memory in MWM, IL-6, TNF-α and BDNF content. In conclusion, the present study provides functional evidence for the involvement of the imidazoline receptors in agmatine induced reversal of Aβ1-42 induced memory deficits in mice. The data projects agmatine and imidazoline receptor agonists as a potential therapeutic target for the treatment of AD.

Propane-2-sulfonic acid octadec-9-enyl-amide alleviates scopolamine-induced spatial learning and memory deficits in mice

Our previous reports demonstrated that the novel peroxisome proliferator-activated receptors α and γ (PPARα/γ) dual agonist propane-2-sulfonic acid octadec-9-enyl-amide (N15) alleviates cognitive ability in the chronic phase of ischemic stroke. However, the potential effects of N15 on Alzheimer’s disease (AD) animal models have not been elucidated. In the present study, we investigated the effects of N15 on scopolamine-induced cognitive dysfunction and cholinergic system ability. N15 (50, 100 or 200 mg/kg) was administered to mice via oral gavage for 21 days, and spatial cognitive dysfunction was induced via an intraperitoneal injection of scopolamine (4 mg/kg) for 6 days. We found that N15 pretreatment markedly ameliorated scopolamine-induced spatial cognitive impairment and enhanced cholinergic system reactivity in the hippocampus. N15 pretreatment also significantly increased the expression levels of growth-associated protein-43, synaptophysin, brain-derived neurotrophic factor and neurotrophin-3 in the hippocampus. Our data demonstrate that N15 has an anti-amnesic effect, which may be mediated by enhancing cholinergic activity and synaptic plasticity. These findings support N15 as a potent neuropharmacological drug against AD.

Neuroprotective Effects of Euonymus alatus Extract on Scopolamine-Induced Memory Deficits in Mice

Euonymus alatus is considered to elicit various beneficial effects against cancer, hyperglycemia, menstrual discomfort, diabetic complications, and detoxification. The young leaves of this plant are exploited as food and also utilized for traditional medicine in East Asian countries, including Korea and China. Our preliminary study demonstrated that ethanolic extract from the Euonymus alatus leaf (EAE) exhibited the strongest antioxidant enzyme-inducing activity among more than 100 kinds of edible tree leaf extracts. This study investigated whether EAE could attenuate the cognitive deficits caused by oxidative stress in mice. Oral intubation of EAE at 100 mg/kg bw or higher resulted in significant improvements to the memory and behavioral impairment induced via i.p. injection of scopolamine. Furthermore, EAE enhanced the expression levels of hippocampal neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor in mice, activated the Nrf2, and the downstream heme oxygenase-1 (HO-1) a quintessential antioxidant enzyme. As rutin (quercetin-3-O-rutinose) was abundantly present in EAE and free quercetin was able to induce defensive antioxidant enzymes in an Nrf2-dependent manner, our findings suggested that quercetin derived from rutin via the intestinal microflora played a significant role in the protection of the mouse hippocampus from scopolamine-induced damage through BDNF-mediated Nrf2 activation, thereby dampening cognitive decline.

Anti-HIV drugs promote β-amyloid deposition and impair learning and memory in BALB/c mice.

Growing evidence suggested that antiretroviral (ARV) drugs may promote amyloid beta (Aβ) accumulation in HIV-1-infected brain and the persistence of HIV-associated neurocognitive disorders (HANDs). It has also been shown that lipid peroxidation upregulates β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) expression and subsequently promotes Aβ peptide production. In the present study, we examined whether chronic exposure to the anti-HIV drugs tenofovir disoproxil fumarate (TDF) and nevirapine induces lipid peroxidation thereby promoting BACE1 and Aβ generation and consequently impair cognitive function in mice. TDF or nevirapine was orally administered to female BALB/c mice once a day for 8 weeks. On the 7th week of treatment, spatial learning and memory were assessed using the Morris water maze test. The levels of lipid peroxidation, BACE1, amyloid β 1-42 (Aβ1-42) and Aβ deposits were measured in the hippocampal tissue upon completion of treatment. Chronic administration of nevirapine induced spatial learning and memory impairment in the Morris water maze test, whereas TDF did not have an effect. TDF and nevirapine administration increased hippocampal lipid peroxidation and Aβ1-42 concentration. Nevirapine further upregulated BACE1 expression and Aβ deposits. Our results suggest that chronic exposure to TDF and nevirapine contributes to hippocampal lipid peroxidation and Aβ accumulation, respectively, as well as spatial learning and memory deficits in mice even in the absence of HIV infection. These findings further support a possible link between ARV drug toxicity, Aβ accumulation and the persistence of HANDs.

Multitarget Activities of Kleeb Bua Daeng, a Thai Traditional Herbal Formula, Against Alzheimer's Disease.

The Kleeb Bua Daeng formula (KBD) is a Thai traditional medicine for brain health promotion. On the basis of the activities of its individual components, the KBD could have good potential for the treatment of Alzheimer’s disease (AD). Herein, we investigated the KBD as an AD treatment. The ethanol extracts of KBD and its components, i.e., Nelumbo nucifera (NN), Piper nigrum fruits (BP), and the aerial part of Centella asiatica (CA) exhibited antioxidant activity, as determined by both ABTS and DPPH assays. The Ellman’s assay revealed that the KBD, NN, and BP showed an ability to inhibit acetylcholinesterase. The thioflavin T assay indicated that the KBD, NN, BP, and CA inhibited beta-amyloid aggregation. The neuroprotection and Western blot analysis revealed that the KBD reduced H2O2-induced neuronal cell death by inhibiting the expression of pro-apoptotic factors, i.e., cleaved caspase-9 and -3, p-P65, p-JNK, and p-GSK-3β, as well as by inducing expression of anti-apoptotic factors, i.e., MCl1, BClxl, and survivin. Furthermore, the KBD could improve scopolamine induced memory deficit in mice. Our results illustrate that the KBD with multimode action has the potential to be employed in AD treatment. Thus, the KBD could be used as an alternative novel choice for the prevention and treatment of patients with AD.

Neuroprotective effect of red quinoa seeds extract on scopolamine-induced declarative memory deficits in mice: The role of acetylcholinesterase and oxidative stress

Abstract The effect of red quinoa seed extract obtained by soxhlet (RQ-S) on scopolamine (SCP)-induced memory deficits in the object recognition task in mice was evaluated, as well as the involvement of oxidative stress and AChE activity. Four quinoa extracts were obtained: two from white quinoa and two from red quinoa, extracted by soxhlet or shaking. The content of total phenolic compounds (TPC), total flavonoids (TF) and antioxidant activity was determined in the four extracts. The RQ-S showed the highest TPC and TF content and antioxidant activity compared with the others quinoa extracts. The administration of RQ-S prevented memory deficit, changes of AChE activity and oxidative stress indicators (SOD, catalase, TBARS and ROS) induced by SCP, in the hippocampus and partially in the cerebral cortex. These results provide evidence that RQ-S is an alternative to protect SCP-induced memory deficits in mice, and suggest the involvement of oxidative stress and AChE activity.