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.

Postoperative Learning and Memory Dysfunction Is More Severe in Males But Is Not Persistent and Transmittable to Next Generation in Young Adult Rats.

BACKGROUND: Postoperative cognitive dysfunction (POCD) affects numerous patients each year and is associated with poor outcomes. Currently, the duration of POCD is not known. This preclinical study determined whether POCD was persistent, different between sexes and transmittable to the next generation. METHODS: Two-month-old Sprague-Dawley rats had left carotid artery exposure under isoflurane anesthesia and their learning and memory were assessed from 5 days, 2 months, and 4 months after surgery. Rats with or without surgery were mated when they were 4 or 6 months old, and the learning and memory of the offspring were tested at 2 months of age. RESULTS: Males exposed to surgery took a longer time to identify the target box after training sessions in a Barnes maze and had less freezing behavior in context-related fear conditioning than control rats when the tests were started 5 days after surgery. Similarly, female rats had a poorer performance than control rats in the Barnes maze test from 5 days after surgery. However, these poorer performances were not observed when the tests were administered 2 or 4 months after surgery. The offspring of rats with surgery had a performance similar to that of the offspring of control rats. CONCLUSIONS: Our results suggest that both male and female rats develop POCD but that the learning and memory dysfunction appears to be more severe in male rats. POCD may not be persistent and does not transmit to the next generation.

Learning and memory impairment and transcriptomic profile in hippocampus of offspring after maternal fructose exposure during gestation and lactation.

Increased fructose intake is a global issue, especially in mothers. Maternal fructose exposure during gestation and lactation can affect learning and memory in offspring; however, the detailed mechanism is still unknown. The hippocampus is a mind locale liable for learning and memory. Here, we established a maternal high-fructose diet model by administering 13% and 40% fructose water, applied the Morris Water Maze test on postnatal day 60 offspring, and performed full-length RNA sequencing using the Oxford Nanopore Technologies platform to explore the changes in gene expression in the hippocampus. The results showed that learning and memory in offspring were negatively affected. Compared with the control group, 369 differentially expressed transcripts (DETs) were identified in the 13% fructose group, and 501 DETs were identified in the 40% fructose group. Gene Ontology enriched term and Kyoto Encyclopedia of Genes and Genomes enriched pathway analyses identified several terms and pathways related to brain development and cognitive function. Furthermore, we confirmed that the Wnt/ß-catenin signaling pathway was down-regulated and neuron degeneration was enhanced. In summary, our results indicate that maternal fructose exposure during gestation and lactation can impair learning and memory in offspring and affect brain function at the transcriptome level.

Comparative study on detectability of learning and memory disorder between two water maze tests commonly used in juvenile rat toxicity studies using isoflurane inhaled rat model.

Evaluation of learning and memory is crucial in juvenile animal toxicity studies (JAS) during the development of CNS active drugs, but there are no currently recommended test methods. We compared the ability of the Morris water maze (MWM) and the Biel water maze (BWM) to detect learning and memory disorder (LMD) using rats inhaled isoflurane (IFN). Rats were treated with 1% IFN using inhalation on postnatal day (PND) 7 for 6 h. All rats were subjected to the MWM on PND 33 and the BWM on PND 55/57 (Experiment 1), or the BWM on PND 32/33 and the MWM on PND 54/55 (Experiment 2). On PND 70, the brain was weighed and then neurohistopathology was conducted. There were no IFN-related changes in clinical signs and body weight. In the tests beginning on PND 32/33, the MWM clearly detected IFN-related LMD in both sexes whereas the BWM detected LMD only in males. With an additional benefit of a simpler procedure, the MWM was considered superior to the BMW for JAS. LMD was not detected in both mazes tested from PND 54/55/57, which was considered due to weak effect and/or recovery of brain function with growth. Single IFN inhalation on PND 7 was considered useful as positive control to induce LMD caused by postnatal exposure in rats, but stronger treatment regimens was recommended.

Amelioration of scopolamine-induced learning and memory impairment by the TRPV4 inhibitor HC067047 in ICR mice.

Alzheimer's disease (AD) is one of the most common causes of neurodegenerative diseases in the elderly. Cholinergic dysfunction is one of the pathological hallmarks of AD and leads to learning and memory impairment. Transient receptor potential vanilloid 4 (TRPV4), a nonselective cation channel, is involved in learning and memory functions. HC067047, a TRPV4 specific inhibitor, has been reported to protect neurons against cerebral ischemic injury and amyloid-ß-(Aß) 40-induced hippocampal cell death. However, whether HC067047 could improve scopolamine (SCP)-induced cognitive dysfunction in mice is still unknown. The aims of this study were to verify whether HC067047 could ameliorate the SCP-induced learning and memory impairments in mice and to elucidate its underlying mechanisms of action. In this study, we examined the neuroprotective effect of the HC067047 against cognitive dysfunction induced by SCP (5 mg/kg, i.p.), a muscarinic receptor antagonist. The results showed that administration of HC067047 (10 mg/kg, i.p.) significantly ameliorated SCP-induced cognitive dysfunction as assessed by the novel place recognition test (NPRT) and novel object recognition test (NORT). In the Y-maze test, HC067047 significantly enhanced the time spent in the novel arm in SCP mice. To further investigate the molecular mechanisms underlying the neuroprotective effect of HC067047, expression of several proteins involved in apoptosis was examined. The results demonstrated that HC067047 treatment decreased the protein levels of proapoptotic proteins such as Bax and caspase-3 in the hippocampus of SCP mice. In addition, HC067047 enhanced expression of the neurogenesis marker DCX and improved levels of the mature neuronal marker NeuN in SCP mice. These findings suggest the neuroprotective potential of the TRPV4 inhibitor HC067047 for the management of dementia with learning and memory loss.

Persistent exercise fatigue and associative learning deficits in combination with transient glucose dyshomeostasis in a mouse model of Gulf War Illness.

AIMS: To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1]. MAIN METHODS: Adult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S). KEY FINDINGS: Relative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair. SIGNIFICANCE: Our findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans.

Prenatal fluoxetine impairs non-hippocampal but not hippocampal memory in adult male rat offspring.

Fluoxetine is often prescribed to treat depression during pregnancy. Rodent studies have shown that fluoxetine exposure during early development can induce persistent changes in the emotional behavior of the offspring. However, the effects of prenatal fluoxetine on memory have not been elucidated. This study evaluates the memory of adult male offspring from rat dams orally administered with a clinically relevant dose of 0.7 mg/kg fluoxetine from 9 weeks before pregnancy to 1 week before delivery. Hippocampal-dependent (Morris Water Maze, MWM) and non-hippocampal-dependent (Novel Object Recognition, NOR) memory paradigms were assessed. Anxiety- and depressive-like symptoms were also evaluated using the Open Field Test, Tail Suspension Test and Sucrose Preference Test. Male rats exposed to fluoxetine during gestation displayed NOR memory impairments during adulthood, as well as increased anxiety- and depressive-like symptoms. In the MWM, the offspring of fluoxetine-treated dams did not show learning deficits. However, a retention impairment was found on remote memory, 15 days after the end of training. Molecular analyses showed increased expression of NMDA subunit NR2B, and a decrease in NR2A-to- NR2B ratio in the temporal cortex, but not in the hippocampus, suggesting changes in NMDA receptor composition. These results suggest that in utero exposure to fluoxetine induces detrimental effects on non-hippocampal memory and in remote retention of hippocampal-dependent memory, which is believed to be stored in the temporal cortex, possibly due to changes in cortical NMDA receptor subunit stoichiometry. The present results warrant the need for studies on potential remote memory deficits in human offspring exposed to fluoxetine in utero.

Manganese exposure during early larval stages of C. elegans causes learning disability in the adult stage.

Manganese (Mn), even though an essential trace element, causes neurotoxicity in excess. In adults, over-exposure to Mn causes clinical manifestations, including dystonia, progressive bradykinesia, disturbance of gait, slurring, and stuttering of speech. These symptoms are mainly because of Mn-associated oxidative stress and degeneration of dopamine neurons in the central nervous system. Children with excessive Mn exposure often show learning disabilities but rarely show symptoms associated with dopaminergic neuron dysfunction. It is unclear why Mn exposure shows distinctive clinical outcomes in developing brains versus adult brains. Studies on nematode C. elegans have demonstrated that it is an excellent model to elucidate Mn-associated toxicity in the nervous system. In this study, we chronically exposed Mn to L1 larval stage of the worms to understand the effects on dopamine neurons and cognitive development. The worms showed modified behavior to exogenous dopamine compared to the control. The dopamine neurons showed resistance to neurodegeneration on repeated Mn exposure during the adult stage. As observed in mammalian systems, these worms showed significantly low olfactory adaptive learning and memory. This study shows that C. elegans alters adaptive developmental plasticity during Mn overexposure, modifying its sensitivity towards the metal ion and leads to remodeling in its innate learning behavior.

Melatonin protects against methamphetamine-induced Alzheimer's disease-like pathological changes in rat hippocampus.

Methamphetamine (METH) is a psychostimulant drug of abuse. METH use is associated with cognitive impairments and neurochemical abnormalities comparable to pathological changes observed in Alzheimer's disease (AD). These observations have stimulated the idea that METH abusers might be prone to develop AD-like signs and symptoms. Melatonin, the pineal hormone, is considered as a potential therapeutic intervention against AD. We thus conducted the present study to explore potential protective roles of melatonin against METH-induced deficits in learning and memory as well as in the appearance of AD-like pathological changes in METH-treated male Wistar rats. We found that melatonin ameliorated METH-induced cognitive impairments in those rats. Melatonin prevented METH-induced decrease in dopamine transporter (DAT) expression in rat hippocampus. Melatonin reversed METH-induced activation of ß-arrestin2, reduction of phosphorylation of protein kinase B (Akt) and METH-induced excessive activity of glycogen synthase kinase-3ß (GSK3ß). Importantly, melatonin inhibited METH-induced changes in the expression of ß-site APP cleaving enzyme (BACE1), disintegrin and metalloproteinase 10 (ADAM10), and presenilin 1 (PS1), as well as the reduction of amyloid beta (Aß)42 production. Immunofluorescence double-labeling demonstrated that melatonin not only prevented the METH-induced loss of DAT but also prevented METH-induced Aß42 overexpression in the dentate gyrus, CA1, and CA3. Furthermore, melatonin also suppressed METH-induced increase in phosphorylated tau. Significantly, melatonin attenuated METH-induced increase in N-methyl-D-aspartate receptor subtype 2 B (NR2B) protein expression and restored METH-induced reduction of Ca2+/calmodulin-dependent protein kinase II (CaMKII). This suggested that melatonin attenuated the toxic effect of METH on the hippocampus involving the amyloidogenic pathway. Taken together, our data suggest that METH abuse may be a predisposing risk factor for AD and that melatonin could serve as a potential therapeutic agent to prevent METH-induced AD like pathology.

Pseudoginsenoside-F11 ameliorates okadiac acid-induced learning and memory impairment in rats via modulating protein phosphatase 2A.

We have reported that pseudoginsenoside-F11 (PF11) can significantly improve the cognitive impairments in several Alzheimer's disease (AD) models, but the mechanism has not been fully elucidated. In the present study, the effects of PF11 on AD, in particular the underlying mechanisms related with protein phosphatase 2A (PP2A), were investigated in a rat model induced by okadaic acid (OA), a selective inhibitor of PP2A. The results showed that PF11 treatment dose-dependently improved the learning and memory impairments in OA-induced AD rats. PF11 could significantly inhibit OA-induced tau hyperphosphorylation, suppress the activation of glial cells, alleviate neuroinflammation, thus rescue the neuronal and synaptic damage. Further investigation revealed that PF11 could regulate the protein expression of methyl modifying enzymes (leucine carboxyl methyltransferase-1 and protein phosphatase methylesterase-1) in the brain, thus increase methyl-PP2A protein expression and indirectly increase the activity of PP2A. Molecular docking analysis, structural alignment and in vitro results showed that PF11 was similar in the shape and electrostatic field feature to a known activator of PP2A, and could directly bind and activate PP2A. In conclusion, the present data indicate that PF11 can ameliorate OA-induced learning and memory impairment in rats via modulating PP2A.

Administration of Selenium Nanoparticles Reverses Streptozotocin-Induced Neurotoxicity in the male rats.

Alzheimer's disease is the most common neurodegenerative disease associated with deposition of amyloid-beta and the increased oxidative stress. High free radical scavenging ability of selenium nanoparticles (SeNPs) has been acknowledged, so in the present study, the effects of treatment with SeNPs on Streptozotocin (STZ)-induced neurotoxicity were evaluated in the male rats. Learning and memory impairment was induced by intraventricular injection of STZ. Following induction of memory impairment, the rats received 0.4 mg/kg of SeNPs daily for one month. Memory function, antioxidant capacity, and deposition of Amyloid ß (Aß) were assessed using the shuttle box task, biochemical methods, and Congo red staining. Injection of STZ caused memory impairment, a decrease in the level of total thiol group (TTG), and an increase in the malondialdehyde (MDA) content and deposition of Aß. Administration of SeNPs reversed the neurotoxicity induced by STZ. It seems that SeNPs likely had neuroprotective effects on the animal model of Alzheimer's disease through increasing antioxidants҆ capacity.

Continuous artificial light at night exacerbates diisononyl phthalate-induced learning and memory impairment in mice: Toxicological evidence.

Previously, we reported that exposure to diisononyl phthalate (DINP) resulted in cognitive deficits and anxiety in mice (https://doi.org/10.1038/srep14676). Artificial light at night (ALAN) is now recognized as being a potential threat to human health. However, toxicological evidence concerning exposure to a combination of ALAN and DINP in vivo is limited. To this end, mice were orally exposed to different concentrations of DINP for 28 consecutive days, and ALAN (intensity 150 lux, every night for 12 h). The results showed that oxidative stress levels increased with increasing DINP exposure concentrations, which triggered apoptosis (Bcl-2 levels decreased, Bax levels increased), resulting in nerve cell damage and a decline in the learning and memory abilities of mice. The combined effects of ALAN and DINP exposure on the learning ability and memory of mice are more serious than for DINP exposure alone. The antioxidant vitamin E was shown to have a certain antagonistic effect on the oxidative damage caused by ALAN and DINP exposure. These results highlight a previously unknown relationship between exposure to ALAN and DINP-induced learning and memory impairment, and provide evidence that ALAN may be exacerbating the effects of DINP.

A longitudinal study of the impact of marijuana on adult memory function: Prenatal, adolescent, and young adult exposures.

More Americans are using marijuana than in previous decades but there are concerns over its long-term impact on cognitive functioning, especially memory. The literature on marijuana use and cognitive functioning is mixed, with some studies showing recovery of functioning upon abstinence from the drug and others showing long-term effects that persist. The latter seems especially true for individuals who initiate marijuana at a younger age and engage in more chronic patterns of use. The goal of the current study is to use prospectively collected data on young adults from a prenatal cohort to determine if there is an effect of early and/or current marijuana use on young adult memory, controlling for prenatal exposure to marijuana use, childhood memory deficits, and other significant covariates of memory functioning. At the 22-year follow-up phase of the Maternal Health Practices and Child Development (MHPCD) study, 524 young adults (58% Black, 42% White, 52% female) completed the Wechsler Memory Scale-III. Multiple regression analyses and structural equation modeling were used to determine the effect of marijuana exposure during gestation, early adolescence, and young adulthood on young adult memory function. Results indicated that initiating marijuana use before age 15 placed young adults at greater risk of memory deficits, even after controlling for childhood memory and current marijuana use. First trimester marijuana exposure also indirectly predicted young adult memory function via childhood memory deficits and early initiation of marijuana. These findings highlight the risk of prenatal marijuana exposure and early initiation of marijuana for long-term memory function in adulthood.

Neuroprotective effect of Betalain against AlCl3-induced Alzheimer's disease in Sprague Dawley Rats via putative modulation of oxidative stress and nuclear factor kappa B (NF-κB) signaling pathway.

Alzheimer's disease (AD) is the most progressive form of neurodegenerative disease, which severely impairs cognitive function. Oxidative stress is identified to contribute to the mechanisms responsible for the pathogenesis of such neurodegenerative diseases. Aluminum is a potent neurotoxin for inducing oxidative stress associated with neurodegenerative diseases. The treatment for AD is limited; hence more treatment options are the need of the day. Betalain is known for its multitude of medicinal assets, including anti-inflammatory activity. Hence, this study was intended to investigate the possible protective effect of betalain against aluminum chloride (AlCl3) induced AD on Sprague Dawley (SD) rats. AlCl3 (100 mg/kg) was administrated orally to induce the AD in SD rats. The rats were supplemented with low and high betalain doses (10 mg/kg and 20 mg/kg) for four weeks. At the end of the experiment, the rats were subjected to behavioral examination and sacrificed to study the biochemical and histological parameters. The results showed attenuation of memory and learning capacity, suppression of lipid oxidation (MDA) through regulation of antioxidant content (SOD, CAT, and GSH) and inhibition of lactate dehydrogenase (LDH), nitric oxide (NO), acetylcholinesterase (AChE), and transmembrane protein (Na+K+ATPase) activity. In addition, the NF-ƙB associated mRNA expression (TNF-α IL-6, Il-1ß, iNOS, COX-2) was decreased, as evidenced in histopathological results. The present investigation established that the betalain treatment ameliorated the AlCl3 induced AD by modulating NF-κB pathway activation.

Imidazopyridine-Based 5-HT6 Receptor Neutral Antagonists: Impact of N1-Benzyl and N1-Phenylsulfonyl Fragments on Different Receptor Conformational States.

G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound 7e, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT6R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT6R (7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT6R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT6R.

Association Between Behavioral and Learning Outcomes and Single Exposures to Procedures Requiring General Anesthesia Before Age 3: Secondary Analysis of Data From Olmsted County, MN.

BACKGROUND: Two prior population-based (children born in Olmsted County, MN), retrospective cohort studies both found that multiple exposures to anesthesia before age 3 were associated with a significant increase in the frequency of attention-deficit hyperactivity disorder (ADHD) and learning disabilities (LD) later in life. The primary purpose of this secondary analysis of these data was to test the hypothesis that a single exposure to anesthesia before age 3 was associated with an increased risk of ADHD. We also examined the association of single exposures with LD and the need for individualized educational plans as secondary outcomes. METHODS: This analysis includes 5339 children who were unexposed to general anesthesia before age 3 (4876 born from 1976 to 1982 and 463 born from 1996 to 2000), and 1054 children who had a single exposure to anesthesia before age 3 (481 born from 1976 to 1982 and 573 born from 1996 to 2000). The primary outcome of interest was ADHD. Secondary outcomes included LD (reading, mathematics, and written language) and the need for individualized educational programs (speech/language and emotion/behavior). To compare the incidence of each outcome between those who were unexposed and singly exposed to anesthesia before the age of 3 years, an inverse probability of treatment weighted proportional hazards model was used. RESULTS: For children not exposed to anesthesia, the estimated cumulative frequency (95% confidence interval [CI]) of ADHD at age 18 was 7.3% (95% CI, 6.5-8.1) and 13.0% (95% CI, 10.1-16.8) for the 1976-1982 and 1996-2000 cohorts, respectively. For children exposed to a single anesthetic before age 3, the cumulative frequency of ADHD was 8.1% (95% CI, 5.3-12.4) and 17.6% (95% CI, 14.0-21.9) for the 1976-1982 and 1996-2000 cohorts, respectively. In weighted analyses, single exposures were not significantly associated with an increased frequency of ADHD (hazard ratio [HR], 1.21; 95% CI, 0.91-1.60; P = .184). Single exposures were also not associated with an increased frequency of any LD (HR, 0.98; 95% CI, 0.78-1.23), or the need for individualized education plans. CONCLUSIONS: This analysis did not find evidence that single exposures to procedures requiring general anesthesia, before age 3, are associated with an increased risk of developing ADHD, LD, or the need for individualized educational plans in later life.

Flavonoids ameliorate aluminum chloride-induced learning and memory impairments via suppression of apoptosis and oxidative stress in rats.

The study was to investigate the effects of flavonoids (rutin, puerarin, and silymarin) on learning and memory function in rats exposed to aluminum chloride (AlCl3). Wistar rats were administered flavonoids at a dose of 100 mg/(kg·bw)/day or 200 mg/(kg·bw)/day after exposed to 281.40 mg/(kg·bw)/day AlCl3·6H2O. The results of Morris water maze suggested that rutin and puerarin increased the frequency of crossing the platform and swimming time spent in the target quadrant of AlCl3-induced rats significantly. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay indicated that three flavonoids could alleviate apoptosis of hippocampal neurons induced by AlCl3. Real time-PCR and western blot suggested that rutin, puerarin and 100 mg/(kg·bw)/day silymarin could decrease the AlCl3-induced high expression of Bcl-2 associated X protein (Bax) mRNA and protein in hippocampus, but the expression of B cell lymphoma/leukemia-2 (Bcl-2) mRNA and protein was not significantly different among groups. Flavonoids could up regulate the low expression of autophagy related proteins (Beclin 1 (Bcl-2-interacting protein with a coiled-coil domain 1) and LC3 (microtubule-associated protein 1 light chain 3)) caused by AlCl3 exposure. Flavonoids could also adjust the change in adenosine triphosphatase, superoxide dismutase, glutathione peroxidase and malondialdehyde induced by intake of AlCl3. The results of inductively coupled plasma atomic emission spectroscopy (ICP-AES) suggested that flavonoids could effectively reduce the high Al level in brain and serum of AlCl3 exposed rats. In conclusion, three flavonoids may improve learning and memory function by inhibiting excessive apoptosis and oxidative stress in AlCl3 exposed rats.

Perinatal Exposure to Triclosan Results in Abnormal Brain Development and Behavior in Mice.

Triclosan (TCS) is one of the most common endocrine-disrupting chemicals (EDCs) present in household and personal wash products. Recently, concerns have been raised about the association between abnormal behavior in children and exposure to EDC during gestation. We hypothesized that exposure to TCS during gestation could affect brain development. Cortical neurons of mice were exposed in vitro to TCS. In addition, we examined in vivo whether maternal TCS administration can affect neurobehavioral development in the offspring generation. We determined that TCS can impair dendrite and axon growth by reducing average length and numbers of axons and dendrites. Additionally, TCS inhibited the proliferation of and promoted apoptosis in neuronal progenitor cells. Detailed behavioral analyses showed impaired acquisition of spatial learning and reference memory in offspring derived from dams exposed to TCS. The TCS-treated groups also showed cognition dysfunction and impairments in sociability and social novelty preference. Furthermore, TCS-treated groups exhibited increased anxiety-like behavior, but there was no significant change in depression-like behaviors. In addition, TCS-treated groups exhibited deficits in nesting behavior. Taken together, our results indicate that perinatal exposure to TCS induces neurodevelopment disorder, resulting in abnormal social behaviors, cognitive impairment, and deficits in spatial learning and memory in offspring.

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

OBJECTIVES: Growing evidence suggested that antiretroviral (ARV) drugs may promote amyloid beta (Aß) accumulation in HIV-1-infected brain and the persistence of HIV-associated neurocognitive disorders (HANDs). It has also been shown that lipid peroxidation upregulates ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) expression and subsequently promotes Aß 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 Aß generation and consequently impair cognitive function in mice. METHODS: 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 ß 1-42 (Aß1-42) and Aß deposits were measured in the hippocampal tissue upon completion of treatment. RESULTS: 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 Aß1-42 concentration. Nevirapine further upregulated BACE1 expression and Aß deposits. CONCLUSION: Our results suggest that chronic exposure to TDF and nevirapine contributes to hippocampal lipid peroxidation and Aß 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, Aß accumulation and the persistence of HANDs.

Sirtuin 2 Inhibition Attenuates Sevoflurane-Induced Learning and Memory Deficits in Developing Rats via Modulating Microglial Activation.

Sevoflurane is a widely used inhalational anesthetic in pediatric medicine that has been reported to have deleterious effects on the developing brain. Strategies to mitigate these detrimental effects are lacking. Sirtuin 2 (SIRT2) is a member of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases involved in a wide range of pathophysiological processes. SIRT2 inhibition has emerged as a promising treatment for an array of neurological disorders. However, the direct effects of SIRT2 on anesthesia-induced damage to the immature brain are unclear. Neonatal rats were exposed to 3% sevoflurane or 30% oxygen for 2 h daily with or without SIRT2 inhibitor AK7 pretreatment from postnatal day 7 (P7) to P9. One cohort of rats were euthanized 6, 12, and/or 24 h after the last gas exposure, and brain tissues were harvested for biochemical analysis and/or immunohistochemical examination. Cognitive functions were evaluated using the open field and Morris water maze tests on P25 and P28-32, respectively. SIRT2 was significantly up-regulated in neonatal rat hippocampus at 6 and 12 h post-anesthesia. Pretreatment with SIRT2 inhibitor AK7 reversed sevoflurane-induced hippocampus-dependent cognitive impairments. Furthermore, AK7 administration mitigated sevoflurane-induced neuroinflammation and microglial activation. Concomitantly, AK7 inhibited pro-inflammatory/M1-related markers and increased anti-inflammatory/M2-related markers in microglia. AK7 might prevent sevoflurane-induced neuroinflammation by switching microglia from the M1 to M2 phenotype. Downregulation of SIRT2 may be a novel therapeutic target for alleviating anesthesia-induced developmental neurotoxicity.