Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice.

Early pathological upregulation of adenosine A2A receptors (A2ARs), one of the caffeine targets, by neurons is thought to be involved in the development of synaptic and memory deficits in Alzheimer's disease (AD) but mechanisms remain ill-defined. To tackle this question, we promoted a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice developing AD-like amyloidogenesis. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioural changes were not linked to major change in the development of amyloid pathology but rather associated with increased phosphorylated tau at neuritic plaques. Moreover, proteomic and transcriptomic analyses coupled with quantitative immunofluorescence studies indicated that neuronal upregulation of the receptor promoted both neuronal and non-neuronal autonomous alterations, i.e. enhanced neuroinflammatory response but also loss of excitatory synapses and impaired neuronal mitochondrial function, presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction, as seen in the brain of patients, contributes to amyloid-related pathogenesis and underscores the potential of A2AR as a relevant therapeutic target for mitigating cognitive impairments in this neurodegenerative disorder.

Choline chloride shows gender-dependent positive effects on social deficits, learning/memory impairments, neuronal loss and neuroinflammation in the lipopolysaccharide-induced rat model of autism.

The neuroprotective effects of choline chloride, an essential nutrient, a precursor for the acetylcholine and synthesis of membrane phospholipids, have been associated with neurological and neurodegenerative diseases. Its contribution to autism spectrum disorder, a neurodevelopmental disorder, remains unknown. Thus, we aimed to evaluate the effects of choline chloride on social behaviours, and histopathological and biochemical changes in a rat autism model. The autism model was induced by administration of 100 µg/kg lipopolysaccharide (LPS) on the 10th day of gestation. Choline chloride treatment (100 mg/kg/day) was commenced on PN5 and maintained until PN50. Social deficits were assessed by three-chamber sociability, open field, and passive avoidance learning tests. Tumour necrosis factor alpha (TNF-α), interleukin-2 (IL) and IL-17, nerve growth factor (NGF), and glutamate decarboxylase 67 (GAD67) levels were measured to assess neuroinflammatory responses. In addition, the number of hippocampal and cerebellar neurons and glial fibrillary acidic protein (GFAP) expression were evaluated. Social novelty and passive avoidance learning tests revealed significant differences in choline chloride-treated male rats compared with saline-treated groups. TNF-α, IL-2, and IL-17 were significantly decreased after choline chloride treatment in both males and females. NGF and GAD67 levels were unchanged in females, while there were significant differences in males. Histologically, significant changes in terms of gliosis were detected in hippocampal CA1 and CA3 regions and cerebellum in choline chloride-treated groups. The presence of ameliorative effects of choline chloride treatment on social behaviour and neuroinflammation through neuroinflammatory, neurotrophic, and neurotransmission pathways in a sex-dependent rat model of LPS-induced autism was demonstrated.

Microglial gp91phox-mediated neuroinflammation and ferroptosis contributes to learning and memory deficits in rotenone-treated mice.

Apart from dopaminergic neurotoxicity, exposure to rotenone, a commonly used insecticide in agriculture, also adversely affects hippocampal and cortical neurons, resulting in cognitive impairments in mice. We recently established a role of microglia-mediated neuroinflammation in rotenone-elicited deficits of cognition, yet the mechanisms remain elusive. Here, we investigated the involvement of NADPH oxidase 2 (NOX2) catalytic subunit gp91phox in rotenone-induced cognitive deficits and the associated mechanisms. Our study demonstrated that rotenone exposure elevated expression of gp91phox and phosphorylation of the NOX2 cytosolic subunit p47phox, along with NADPH depletion in the hippocampus and cortex of mice, indicating NOX2 activation. Specific knockdown of gp91phox in microglia via adeno-associated virus delivery resulted in reduced microglial activation, proinflammatory gene expression and improved learning and memory capacity in rotenone-intoxicated mice. Genetic deletion of gp91phox also reversed rotenone-elicited cognitive dysfunction in mice. Furthermore, microglial gp91phox knockdown attenuated neuronal damage and synaptic loss in mice. This intervention also suppressed iron accumulation, disruption of iron-metabolism proteins and iron-dependent lipid peroxidation and restored the balance of ferroptosis-related parameters, including GPX4, SLC711, PTGS2, and ACSL4 in rotenone-lesioned mice. Intriguingly, pharmacological inhibition of ferroptosis with liproxstatin-1 conferred protection against rotenone-induced neurodegeneration and cognitive dysfunction in mice. In summary, our findings underscored the contribution of microglial gp91phox-dependent neuroinflammation and ferroptosis to learning and memory dysfunction in rotenone-lesioned mice. These results provided valuable insights into the pathogenesis of cognitive deficits associated with pesticide-induced Parkinsonism, suggesting potential therapeutic avenues for intervention.

Perinatal choline supplementation prevents learning and memory deficits and reduces brain amyloid Aß42 deposition in AppNL-G-F Alzheimer's disease model mice.

Alzheimer's disease (AD) is characterized by cognitive and memory impairments and neuropathological abnormalities. AD has no cure, inadequate treatment options, and a limited understanding of possible prevention measures. Previous studies have demonstrated that AD model mice that received a diet high in the essential nutrient choline had reduced amyloidosis, cholinergic deficits, and gliosis, and increased neurogenesis. In this study, we investigated the lifelong effects of perinatal choline supplementation on behavior, cognitive function, and amyloidosis in AppNL-G-F AD model mice. Pregnant and lactating mice were given a diet containing either 1.1 g/kg (control) or 5 g/kg (supplemented) of choline chloride until weaning and subsequently, all offspring received the control diet throughout their life. At 3, 6, 9, and 12 months of age, animals were behaviorally tested in the Open Field Test, Elevated Plus Maze, Barnes Maze, and in a contextual fear conditioning paradigm. Immunohistochemical analysis of Aß42 was also conducted on the brains of these mice. AppNL-G-F mice displayed hippocampal-dependent spatial learning deficits starting at 3-months-old that persisted until 12-months-old. These spatial learning deficits were fully prevented by perinatal choline supplementation at young ages (3 and 6 months) but not in older mice (12 months). AppNL-G-F mice also had impaired fearful learning and memory at 9- and 12-months-old that were diminished by choline supplementation. Perinatal choline supplementation reduced Aß42 deposition in the amygdala, cortex, and hippocampus of AppNL-G-F mice. Together, these results demonstrate that perinatal choline supplementation is capable of preventing cognitive deficits and dampening amyloidosis in AppNL-G-F mice and suggest that ensuring adequate choline consumption during early life may be a valuable method to prevent or reduce AD dementia and neuropathology.

Wnt3a/GSK3ß/ß-catenin Signalling Modulates Doxorubicin-associated Memory Deficits in Breast Cancer.

BACKGROUND: Chemobrain is widespread in breast cancer patients receiving chemotherapy. However, the exact mechanism, especially the associated signalling pathway, is not currently clear. This study was to evaluate the behavioural changes in breast cancer mice after chemotherapy and to further explore the role of Wnt3a/glycogen synthase kinase (GSK3ß)/ß-catenin signalling in chemobrain. METHODS: MMTV-PyMT(+) breast cancer mice were injected intraperitoneally with doxorubicin (4 mg/kg) once a week for three weeks to establish a chemobrain model. The Morris water maze (MWM) and novel object recognition (NOR) tests were performed to assess the learning and memory ability. Electron microscopy was used to observe the structural changes in the hippocampal CA1 region. The brain tissue of breast cancer mice after chemotherapy was taken out for mRNA-seq detection. Then, the expression levels and phosphorylation of key proteins in the Wnt3a/GSK3 ß/ß-catenin signalling pathway were evaluated through Western blotting (WB) and immunofluorescence. RESULTS: Doxorubicin-induced spatial and short-term memory impairment was observed in breast cancer mice, and obvious neuronal damage could be seen in the hippocampal CA1 region. Immunofluorescence staining for GSK3ß was increased. Wnt signalling pathway is highly enriched from mRNA-seq analysis, with GSK3ß genes at important nodes. The relative protein levels of p-PI3K, p-AKT, p-GSK3 ß, Wnt3a and TCF-1 were decreased significantly, while the p-ß-catenin level was increased. After injection of the GSK3ß inhibitor sb216763 (1 ng/0.5 µl/side), hippocampal neuronal injury was alleviated to some extent, and the changes in the expression of proteins upstream and downstream of this signalling pathway were reversed. CONCLUSION: Wnt3a/GSK3 ß/ß-catenin signalling is likely involved in doxorubicin-induced memory impairment. This result provides basic evidence for the further study of chemobrain in breast cancer.

Infliximab alleviates memory impairment in rats with chronic pain by suppressing neuroinflammation and restoring hippocampal neurogenesis.

Patients with chronic pain commonly report impaired memory. Increasing evidence has demonstrated that inhibition of neurogenesis by neuroinflammation plays a crucial role in chronic pain-associated memory impairments. There is currently a lack of treatment strategies for this condition. An increasing number of clinical trials have reported the therapeutic potential of anti-inflammatory therapies targeting tumour necrosis factor-α (TNF-α) for inflammatory diseases. The present study investigated whether infliximab alleviates chronic pain-associated memory impairments in rats with chronic constriction injury (CCI). We demonstrated that infliximab alleviated spatial memory impairment and hyperalgesia induced by CCI. Furthermore, infliximab inhibited the activation of hippocampal astrocytes and microglia and decreased the release of proinflammatory cytokines in CCI rats. Furthermore, infliximab reversed the decrease in the numbers of newborn neurons and mature neurons in the dentate gyrus (DG) caused by chronic pain. Our data provide evidence that infliximab alleviates chronic pain-associated memory impairments, suppresses neuroinflammation and restores hippocampal neurogenesis in a CCI model. These facts indicate that infliximab may be a potential therapeutic agent for the treatment of chronic pain and associated memory impairments.

Bilateral ictal EEG is associated with better memory outcome after hippocampal sclerosis surgery.

OBJECTIVE: To compare memory outcomes after surgery for unilateral hippocampal sclerosis (HS)-associated epilepsy in patients with unilateral and bilateral ictal electrographic involvement. METHODS: We prospectively evaluated HS patients, aged 18-55 years and IQ ≥70. Left (L) and right (R) surgical groups underwent noninvasive video-EEG monitoring and Wada test. We classified patients as Ipsilateral if ictal EEG was restricted to the HS side, or Bilateral, if at least one seizure onset occurred contralaterally to the HS, or if ictal discharge evolved to the opposite temporal region. Patients who declined surgery served as controls. Memory was evaluated on two occasions with Rey Auditory-Verbal Learning Test and Rey Visual-Design Learning Test. Baseline neuropsychological test scores were compared between groups. Pre- and postoperative scores were compared within each group. Reliable change index Z-scores (RCI) were obtained using controls as references, and compared between surgical groups. RESULTS: We evaluated 64 patients. Patients were classified as: L-Ipsilateral (9), L-Bilateral (15), L-Control (9), R-Ipsilateral (10), R-Bilateral (9), and R-Control (12). On preoperative evaluation, memory performance did not differ among surgical groups. Right HS patients did not present postoperative memory decline. L-Ipsilateral group presented postoperative decline on immediate (P = 0.036) and delayed verbal recall (P = 0.011), while L-Bilateral did not decline. L-Ipsilateral had lower RCI Z-scores, indicating delayed verbal memory decline compared to L-Bilateral (P = 0.012). SIGNIFICANCE: Dominant HS patients with bilateral ictal involvement presented less pronounced postoperative verbal memory decline compared to patients with exclusive ipsilateral ictal activity. Surgery was indicated in these patients regardless of memory impairment on neuropsychological testing, since resection of the left sclerotic hippocampus could result in cessation of contralateral epileptiform activity, and, therefore, improved memory function.

Postoperative seizure and memory outcome of temporal lobe epilepsy with hippocampal sclerosis: A systematic review.

We conducted a systematic review and meta-analysis to evaluate postoperative seizure and memory outcomes of temporal lobe epilepsy with different hippocampal sclerosis (HS) subtypes classified by International League Against Epilepsy (ILAE) Consensus Guidelines in 2013. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and MOOSE (Meta-Analysis of Observational Studies in Epidemiology) guidelines, we searched PubMed, Embase, Web of Science, and Cochrane Library from January 1, 2013 to August 6, 2023. Observational studies reporting seizure and memory outcomes among different HS subtypes were included. We used the Newcastle-Ottawa scale to assess the risk of bias and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to grade the quality of evidence. Seizure freedom and improved outcome (Engel 1 or ILAE class 1-2) ≥1 year after surgery were defined as the primary and secondary seizure outcome. A random-effects meta-analysis by DerSimonian and Laird method was performed to obtain pooled risk ratio (RRs) with 95% confidence interval (CIs). The memory impairment was narratively reviewed because of various evaluation tools. Fifteen cohort studies with 2485 patients were eligible for the meta-analysis of seizure outcome. Six cohorts with detailed information on postoperative memory outcome were included. The pooled RRs of seizure freedom, with moderate to substantial heterogeneity, were .98 (95% CI = .84-1.15) between HS type 2 and type 1, 1.11 (95% CI = .82-1.52) between type 3 and type 1, and .80 (95% CI = .62-1.03) between the no-HS and HS groups. No significant difference of improved outcome was found between different subtypes (p > .05). The quality of evidence was deemed to be low to very low according to GRADE. The long-term seizure outcome (≥5 years after surgery) and memory impairment remained controversial.

Associations of neuroinflammatory IL-6 and IL-8 with brain atrophy, memory decline, and core AD biomarkers - in cognitively unimpaired older adults.

Concentrations of pro-inflammatory cytokines -interleukin-6 (IL-6) and interleukin-8 (IL-8) - are increased with age and in Alzheimer's disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62-91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time - up to 9 years - with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-ß (Aß-42) concentrations (for a subsample). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aß-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology.

Carprofen alleviates Alzheimer-like phenotypes of 5XFAD transgenic mice by targeting the pathological hallmarks induced by amyloid-ß aggregation.

Alzheimer's disease (AD) is characterized by misfolding, oligomerization, and accumulation of amyloid-ß (Aß) peptides in the brain. Aß monomers transform into Aß oligomers, which are toxic species, inducing tau hyperphosphorylation and the downstream effects on microglia and astrocytes, triggering synaptic and cognitive dysfunctions. The oligomers then deposit into Aß plaques, primarily composed of ß-stranded fibrils, required for definitive AD diagnosis. As amyloid burden plays the pivotal role in AD pathogenesis, many efforts are devoted in preventing amyloidosis as a therapeutic approach to impede the disease progression. Here, we discovered carprofen, a non-steroidal anti-inflammatory drug, accelerates Aß aggregating into fibrils and increases Aß plaques when intraperitoneally injected to 5XFAD transgenic mouse model. However, the drug seems to alleviate the key Alzheimer-like phenotypes induced by Aß aggregation as we found attenuated neuroinflammation, improved post-synaptic density expression, associated with synaptic plasticity, and decreased phosphorylated tau levels. Carprofen also rescued impaired working memory as we discovered improved spontaneous alternation performance through Y-maze test assessed with Aß(1-42)-infused mouse model. Collectively, while carprofen accelerates the conversion of Aß monomers into fibrils in vitro, the drug ameliorates the major pathological hallmarks of AD in vivo.

Natural antioxidant formula ameliorates lipopolysaccharide-induced impairment of hippocampal neurogenesis and contextual fear memory through suppression of neuroinflammation in rats.

This study investigated the ameliorating effects of a natural antioxidant formula (NAF) consisting of Ginkgo biloba leaf extract, docosahexaenoic acid/eicosapentaenoic acid, ferulic acid, flaxseed oil, vitamin E, and vitamin B12 on a lipopolysaccharide (LPS)-induced cognitive dysfunction model in rats. Six-week-old rats received a diet containing 0.5% (w/w) NAF for 38 days from Day 1, and LPS (1 mg/kg body weight) was administered intraperitoneally once daily on Days 8 and 10. On Day 11, LPS alone increased interleukin-1ß and tumor necrosis factor-α in the hippocampus and cerebral cortex and the numbers of M1-type microglia/macrophages and GFAP+ reactive astrocytes in the hilus of the hippocampal dentate gyrus. NAF treatment decreased brain proinflammatory cytokine levels and increased the number of M2-type microglia/macrophages. During Days 34-38, LPS alone impaired fear memory acquisition and the extinction learning process, and NAF facilitated fear extinction learning. On Day 38, LPS alone decreased the number of type-3 neural progenitor cells in the hippocampal neurogenic niche, and NAF restored the number of type-3 neural progenitor cells and increased the numbers of both immature granule cells in the neurogenic niche and reelin+ hilar interneurons. Thus, NAF exhibited anti-inflammatory effects and ameliorated LPS-induced adverse effects on hippocampal neurogenesis and fear memory learning, possibly through amplification of reelin signaling by hilar interneurons. These results suggest that neuroinflammation is a key factor in the development of LPS-induced impairment of fear memory learning, and supplementation with NAF in the present study helped to prevent hippocampal neurogenesis and disruptive neurobehaviors caused by neuroinflammation.

Neural atrophy produced by AAV tau injections into hippocampus and anterior cortex of middle-aged mice.

Animal models of tauopathy help in understanding the role of mutations in tau pathobiology. Here, we used adeno-associated viral (AAV) vectors to administer three tau genetic variants (tauwild-type, tauP301L, and tauR406W) intracranially into 12-month-old C57BL/6Nia mice and collected tissue at 16 months. Vectors designed to express green fluorescent protein controlled for surgical procedures and exogenous protein expression by AAV. The tau genetic variants produced considerably different phenotypes. Tauwild-type and tauP301L caused memory impairments. The tauP301L caused increased amounts of aggregated tau, measured both neurochemically and histologically. Tauwild-type produced elevated levels of soluble tau and phosphorylated tau by ELISA and increased staining for phosphorylated forms of tau histologically. However, only the tauwild-type caused localized atrophy of brain tissue at the sites near the injection. The tauR406W had low protein expression and produced no atrophy or memory impairments. This supports the potential use of AAV expressing tauwild-type in aged mice to examine events leading to neurodegeneration in Alzheimer's disease pathology.

Deficiency of Autism-Related Gene Dock4 Leads to Impaired Spatial Memory and Hippocampal Function in Mice at Late Middle Age.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lasts lifelong and causes noticeably higher premature mortality. Although the core symptoms and other behavioral deficits of ASD can persist or be deteriorated from early development to old age, how aging affects the behaviors and brain anatomy in ASD is largely unknown. DOCK4 is an ASD risk gene highly expressed in the hippocampus, and Dock4 knockout (KO) mice display ASD-like behaviors in adulthood (4- to 6-month-old). In this study, we evaluated the behavioral and hippocampal pathological changes of late-middle-aged (15- to 17-month-old) Dock4 male KO mice. Aged Dock4 KO mice continuously showed similar social deficit, elevated anxiety, and disrupted object location memory as observed in the adulthood, when compared to their wild-type (WT) littermates. Notably, Dock4 KO mice displayed an age-related decline of hippocampal dependent spatial memory, showing decreased spatial memory in Barnes maze than their WT littermates at late middle age. Morphological analysis from WT and Dock4 KO littermates revealed that Dock4 deficiency led to decreased mature neurons and oligodendrocytes but increased astrocytes in the hippocampus of late-middle-aged mice. Together, we report that ASD-like behaviors mostly persist into late-middle age in Dock4 KO mice, with specific alterations of spatial memory and hippocampal anatomy by age, thus providing new evidence for understanding age differences in behavioral deficits of ASD.

Sweroside Ameliorated Memory Deficits in Scopolamine-Induced Zebrafish (Danio rerio) Model: Involvement of Cholinergic System and Brain Oxidative Stress.

Sweroside is a secoiridoid glycoside and belongs to a large group of naturally occurring monoterpenes with glucose sugar attached to C-1 in the pyran ring. Sweroside can promote different biological activities such as antifungal, antibacterial, hepatoprotective, gastroprotective, sedative and antitumor, antioxidant, and neuroprotective activities. Zebrafish were given sweroside (12.79, 8.35, and 13.95 nM) by immersion once daily for 8 days, along with scopolamine (Sco, 100 µM) 30 min before the initiation of the behavioral testing to cause anxiety and memory loss. Employing the novel tank diving test (NTT), the Y-maze, and the novel object recognition test (NOR), anxiety-like reactions and memory-related behaviors were assessed. The following seven groups (n = 10 animals per group) were used: control, Sco (100 µM), sweroside treatment (2.79, 8.35, and 13.95 nM), galantamine (GAL, 2.71 µM as the positive control in Y-maze and NOR tests), and imipramine (IMP, 63.11 µM as the positive control in NTT test). Acetylcholinesterase activity (AChE) and the antioxidant condition of the brains were also evaluated. The structure of sweroside isolated from Schenkia spicata was identified. Treatment with sweroside significantly improved the Sco-induced decrease of the cholinergic system activity and brain oxidative stress. These results suggest that sweroside exerts a significant effect on anxiety and cognitive impairment, driven in part by the modulation of the cholinergic system activity and brain antioxidant action.

Heptafluoroisobutyronitrile (C4F7N), a gas used for insulating and arc quenching in electrical switchgear, is neurotoxic in the mouse brain.

Fluoronitrile gas (C4F7N, CAS number 42532-60-5) is one of the most promising candidates as insulating and/or breaking medium in high and medium voltage electrical equipment. Besides its promising properties, C4F7N gas is however not devoid of acute toxicity when used pure or in gas mixtures. The toxicity was not extensively analyzed and reported. The aim of the present study was to analyze in mice the consequences of a single exposure to C4F7N gas, at different concentrations and different timepoints after exposure. Male and female Swiss mice were exposed to breathable air or C4F7N gas, at 800 ppmv or 1500 ppmv, for 4 h on day 0. Behavioral tests (spontaneous alternation in the Y-maze and object recognition) were performed on days 1, 7 and 14 to assess memory alterations. The animals were then sacrificed and their brains dissected for biochemical analyses or fixed with paraformaldehyde for histology and immunohistochemistry. Results showed behavioral impairments and memory deficits, with impairments of alternation at days 1 and 7 and object recognition at day 14. Histological alterations of pyramidal neuronal layer in the hippocampus, neuroinflammatory astroglial reaction, and microglial alterations were observed, more marked in female than male mice. Moreover, the biochemical analyses done in the brain of 1500 ppmv exposed female mice showed a reductive stress with decreased lipid peroxidation and release of cytochrome c, leading to apoptosis with increases in caspase-9 cleavage and γ-H2AX/H2AX ratio. Finally, electrophysiological analyses using a multi-electrode array allowed the measure of the extracellular activity of pyramidal neurons in the CA2 area and revealed that exposure to the gas not only prevented the induction of long-term potentiation but even provoked an epileptoid-like activity in some neurons suggesting major alterations of synaptic plasticity. This study therefore showed that an acute exposure of mice to C4F7N gas provoked, particularly in female animals, memory alterations and brain toxicity characterized by a reductive stress, microglial toxicity, loss of synaptic plasticity and apoptosis. Its use in industrial installations must be done with extreme caution.

Anoectochilus roxburghii flavonoids extract ameliorated the memory decline and reduced neuron apoptosis via modulating SIRT1 signaling pathway in senescent mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Anoectochilus roxburghii (A. roxburghii) is a precious herb and folk medicine in many Asian countries. It has been used traditionally to treat diabetes, etc., and also used as a dietary therapy to delay senescence. AIM OF THE STUDY: This study was to evaluate the neuroprotective effects of A. roxburghii flavonoids extract (ARF) and whether its effects were due to the regulation of SIRT1 signaling pathway in senescent mice and in D-galactose (D-gal) induced aging in SH-SY5Y cells. MATERIALS AND METHODS: 18-month-old mice were randomly divided into senescent model, low-dose ARF, high-dose ARF and vitamin E group. 2-Month-old mice were as a control group. After 8 weeks treatment, Morris water maze (MWM) was performed. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), monoamine oxidase (MAO) and acetylcholinesterase (ACh-E) in the cortex were determined. Hippocampus morphologic changes were observed with haematoxylin and eosin (H&E), Nissl, senescence-associated-galactosidase (SA-ß-gal) and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) staining. Apoptosis-related molecular expressions in the hippocampus were performed by western blotting. Furthermore, after stimulated by EX527 (a SIRT1 inhibitor), the SIRT1-dependent neuroprotective effects of ARF were determined by measuring SRIT1 and p53 expression in SH-SY5Y aging cells induced by D-gal. RESULTS: ARF could significantly ameliorate memory decline in senescent mice and reduce the generations of ROS, MDA and the activities of MAO and ACh-E, while increasing SOD activities in the cortex of aging mice. ARF obviously improved hippocampus pathological alterations, increased the number of Nissl bodies, while reducing senescent and apoptotic cells in senescent mice hippocampus. Further, ARF positively regulated SIRT1 expression, and reduced apoptosis-related molecules p53, p21 and Caspase-3 expression, while increasing the ratio of Bcl-2/Bax. In D-gal-induced SH-SY5Y cells, the effects of ARF on SIRT1 and p53, and the ability of scavenging ROS were mostly abolished after incubation with the EX527. CONCLUSIONS: ARF, in a SIRT1-dependent manner, exerted neuroprotection via modulating SIRT1/p53 signaling pathway against memory decline and apoptosis due to age-induced oxidative stress damage in senescent mice.

Sesamin: Insights into its protective effects against lead-induced learning and memory deficits in rats.

BACKGROUND: Lead (Pb) is one of the most hazardous pollutants that induce a wide spectrum of neurological changes such as learning and memory deficits. Sesamin, a phytonutrient of the lignan class, exhibits anti-inflammatory, anti-apoptotic, and neuroprotective properties. The present study was designed to investigate the effects of sesamin against Pb-induced learning and memory deficits, disruption of hippocampal theta and gamma rhythms, inflammatory response, inhibition of blood δ-aminolevulinic acid dehydratase (δ-ALA-D) activity, Pb accumulation, and neuronal loss in rats. METHODS: Sesamin treatment (30 mg/kg/day; P.O.) was started simultaneously with Pb acetate exposure (500 ppm in standard drinking water) in rats, and they continued for eight consecutive weeks. RESULTS: The results showed that chronic exposure to Pb disrupted the learning and memory functions in both passive-avoidance and water-maze tests, which was accompanied by increase in spectral theta power and theta/gamma ratio, and a decrease in spectral gamma power in the hippocampus. Additionally, Pb exposure resulted in an enhanced tumor necrosis factor-alpha (TNF-α) content, decreased interleukin-10 (IL-10) production, inhibited blood δ-ALA-D activity, increased Pb accumulation, and neuronal loss of rats. In contrast, sesamin treatment improved all the above-mentioned Pb-induced pathological changes. CONCLUSION: This data suggests that sesamin could improve Pb-induced learning and memory deficits, possibly through amelioration of hippocampal theta and gamma rhythms, modulation of inflammatory status, restoration of the blood δ-ALA-D activity, reduction of Pb accumulation in the blood and the brain tissues, and prevention of neuronal loss.

Meprin ß knockout reduces brain Aß levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease.

ß-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the major described ß-secretase to generate Aß peptides in Alzheimer's disease (AD). However, all therapeutic attempts to block BACE1 activity and to improve AD symptoms have so far failed. A potential candidate for alternative Aß peptides generation is the metalloproteinase meprin ß, which cleaves APP predominantly at alanine in p2 and in this study we can detect an increased meprin ß expression in AD brain. Here, we report the generation of the transgenic APP/lon mouse model of AD lacking the functional Mep1b gene (APP/lon × Mep1b-/-). We examined levels of canonical and truncated Aß species using urea-SDS-PAGE, ELISA and immunohistochemistry in brains of APP/lon mouse × Mep1b-/-. Additionally, we investigated the cognitive abilities of these mice during the Morris water maze task. Aß1-40 and 1-42 levels are reduced in APP/lon mice when meprin ß is absent. Immunohistochemical staining of mouse brain sections revealed that N-terminally truncated Aß2-x peptide deposition is decreased in APP/lon × Mep1b-/- mice. Importantly, loss of meprin ß improved cognitive abilities and rescued learning behavior impairments in APP/lon mice. These observations indicate an important role of meprin ß within the amyloidogenic pathway and Aß production in vivo.

Mechanistic Insights into Ameliorating Effect of Geraniol on D-Galactose Induced Memory Impairment in Rats.

Geraniol (GE), an important ingredient in several essential oils, displayed pleiotropic biological activities through targeting multiple signaling cascades. In the current study, we aimed to examine the protective effect of GE on D-galactose (D-gal) induced cognitive impairment and explore the underlying mechanisms. Forty male Wistar rats (8 weeks old) were randomly categorized into 4 groups; Group I (saline + vehicle [edible oil]), group II (saline + geraniol) (100 mg/kg/day orally), group III (D-galactose) (100 mg/kg/day subcutaneously injected), and group IV (D-galactose + geraniol). Behavioral impairments were evaluated. Brain levels of malondialdehyde (MDA) and reduced glutathione (GSH) as well as superoxide dismutase (SOD) and acetylcholinesterase (AchE) activities were estimated. The levels of inflammatory markers [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, IL-6, and nuclear factor kappa beta (NF-kß)], endoplasmic reticulum stress sensors [inositol requiring protein 1(IRE1) and protein kinase RNA-like endoplasmic reticulum kinase (PERK)], brain-derived neurotrophic factor (BDNF), and mitogen-activated protein kinases (MAPK) pathway were measured by ELISA. Also, hippocampal histopathological assessment and immunohistochemical analysis of glial fibrillary acidic protein (GFAP) and caspase-3 were performed. Glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) mRNA expression and protein levels were assessed. GE effectively ameliorated aging-related memory impairment through increasing GSH, BDNF, Ach levels, and SOD activity. Additionally, GE treatment caused a decrease in the levels of MDA, inflammatory mediators, and ER stress sensors as well as the AchE activity together with concomitant down-regulation of GRP78 and CHOP mRNA expression. Moreover, GE improved neuronal architecture and rat's spatial memory; this is evidenced by the shortened escape latency and increased platform crossing number. Therefore, GE offers a unique pharmacological approach for aging-associated neurodegenerative disorders.

Nesfatin-1 ameliorates oxidative brain damage and memory impairment in rats induced with a single acute epileptic seizure.

AIMS: We aimed to investigate putative neuroprotective effects of nesfatin-1 on oxidative brain injury and memory dysfunction induced by a single epileptic seizure and to compare these effects with those of antiepileptic phenytoin. MAIN METHODS: Wistar albino rats were randomly divided into a control group and pentylenetetrazole (PTZ)-seizure groups pretreated intraperitoneally (ip) with saline or nesfatin-1 (NES-1; 0.3, 1 or 3 µg/kg/day) or phenytoin (PHE; 40 mg/kg/day) or PHE + NES-1 (0.3 µg/kg/day) at 30 min before the single-dose PTZ injection (45 mg/kg; ip). All treatments were repeated at the 24th and 48th h of the provoked epileptic seizure. Passive-avoidance test was performed to assess memory function. The rats were decapitated at the 72nd hour of seizures and brain tissues were analyzed for histopathological changes and for measuring levels of malondialdehyde, glutathione, myeloperoxidase activity and reactive oxygen/nitrogen species. KEY FINDINGS: In parallel to the effects of phenytoin, NES-1 reduced seizure score, elevated antioxidant glutathione content, depressed generation of nitric oxide and protected against seizure-induced neuronal damage. Additionally, increased malondialdehyde levels and elevated glial fibrillary acidic protein immunoreactivity in the cortex and hippocampus were decreased and memory dysfunction was improved by NES-1. However, NES-1 had no impact on myeloperoxidase activity or production of reactive oxygen species in the brain. SIGNIFICANCE: The findings of the present study demonstrate that nesfatin-1 treatment provides neuroprotection against seizure-induced oxidative damage and memory dysfunction by inhibiting reactive nitrogen species and upregulating antioxidant capacity, indicating its potential in alleviating memory deficits and increasing the effectiveness of conventional anti-convulsant therapies.