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Background: Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides., Methods: We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate., Results: Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients., Conclusions: In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.)., (Copyright © 2023 Massachusetts Medical Society.)

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid-beta peptides (Aβ) resulting in senile plaques and intracellular hyperphosphorylated tau protein resulting in neurofibrillary tangles (NFTs). Mucuna beans (Mucuna pruriences (L.) DC. var. utilis) are unique plants containing 3-9% L-3,4-dihydroxyphenylalanine (L-DOPA). Here we investigated the effect of the administration of Mucuna beans on AD prevention by feeding triple-transgenic mice (3 × Tg-AD mice) with a diet containing Mucuna beans for 13 months. The levels of Aβ oligomers and detergent-insoluble phosphorylated tau decreased in the brain of mice fed with Mucuna beans (Mucuna group) compared to those of the Control group. Aβ accumulation and phosphorylated tau accumulation in the brain in the Mucuna group were also reduced. In addition, administration of Mucuna beans improved cognitive function. These results suggest that administration of Mucuna beans may have a preventive effect on AD development in 3 × Tg-AD mice., (© 2022. The Author(s).)

Lead (Pb) is a well-known neurotoxicant and environmental hazard. Recent experimental evidence has linked Pb exposure with neurological deterioration leading to neurodegenerative diseases, such as Alzheimer's disease. To understand brain regional distribution of Pb and its interaction with other metal ions, we used synchrotron micro-x-ray fluorescence technique (μ-XRF) to map the metal distribution pattern and to quantify metal concentrations in mouse brains. Lead-exposed mice received oral gavage of Pb acetate once daily for 4 weeks; the control mice received sodium acetate. Brain tissues were cut into slices and subjected for analysis. Synchrotron μ-XRF scans were run on the PETRA III P06 beamline (DESY). Coarse scans of the entire brain were performed to locate the cortex and hippocampus, after which scans with higher resolution were run in these areas. The results showed that: a) the total Pb intensity in Pb-exposed brain slices was significantly higher than in control brain; b) Pb typically deposited in localized particles of <10 um 2 in both the Pb-exposed and control brain slices, with more of these particles in Pb-exposed samples; c) selenium (Se) was significantly correlated with Pb in these particles in the cortex and hippocampus/corpus callosum regions in the Pb-exposed samples, and the molar ratio of the Se and Pb in these particles is close to 1:1. These results indicated that Se may play a crucial role in Pb-induced neurotoxicity. Our findings call for further studies to investigate the relationship between Pb exposure and possible Se detoxification responses, and the implication in the etiology of Alzheimer's disease., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alcohol-related brain injury is characterized by cognitive deficits and brain atrophy with the prefrontal cortex particularly susceptible. White matter in the human brain is lipid rich and a major target of damage from chronic alcohol abuse; yet, there is sparse information on how these lipids are affected. Here, we used untargeted lipidomics as a discovery tool to describe these changes in the prefrontal, middle temporal, and visual cortices of human subjects with alcohol use disorder and controls. Significant changes to the lipidome, predominantly in the prefrontal and visual cortices, and differences between the white and grey matter of each brain region were identified. These effects include broad decreases to phospholipids and ceramide, decreased polyunsaturated fatty acids, decreased sphingadiene backbones, and selective decreases in cholesteryl ester fatty acid chains. Our findings show that chronic alcohol abuse results in selective changes to the neurolipidome, which likely reflects both the directs effects on the brain and concurrent effects on the liver., (© 2021 International Society for Neurochemistry.)

Synthetic cathinones are used as stimulants of abuse. Many abused drugs, including stimulants, activate nuclear factor-κB (NF-κB) transcription leading to increases in NF-κB-regulated pro-inflammatory cytokines, and the level of inflammation appears to correlate with length of abuse. The purpose of this study was to measure the profile of IL-1α, IL-1β, IL-6, CCL2 and TNF-α in brain and plasma to examine if drug exposure alters inflammatory markers. Male and female Sprague-Dawley rats were trained to self-administer α-pyrrolidinopentiophenone (α-PVP) (0.1 mg/kg/infusion), 4-methylmethcathinone (4MMC) (0.5 mg/kg/infusion), or saline through autoshaping, and then self-administered for 21 days during 1 h (short access; ShA) or 6 h (long access; LgA) sessions. Separate rats were assigned to a naïve control group. Cytokine levels were examined in amygdala, hippocampus, hypothalamus, prefrontal cortex, striatum, thalamus, and plasma. Rats acquired synthetic cathinone self-administration, and there were no sex differences in drug intake. Synthetic cathinone self-administration produced sex differences in IL-1α, IL-1β, IL-6, CCL2 and TNF-α levels. There were widespread increases in inflammatory cytokines in the brains of male rats compared to females, particularly for 4MMC, whereas females were more likely to show increased inflammatory cytokines in plasma compared to saline groups than males. Furthermore, these sex differences in cytokine levels were more common after LgA access to synthetic cathinones than ShA. These results suggest that synthetic cathinone use likely produces sex-selective patterns of neuroinflammation during the transition from use to abuse. Consequently, treatment need may differ depending on the progression of synthetic cathinone abuse and based on sex., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Oxidative stress, an adverse consequence of brain ischemia-reperfusion injury (IRI), activates matrix metalloproteinase enzymes which cause to destruction of extracellular matrix and tight junction proteins. Oxidative stress during stroke increases serum endothelin-1 and endothelin B receptor (ETBR) expression. Apelin-13, an endogenous peptide, is expressed in numerous tissues that regulate diverse physiological and pathological processes. This study aimed to investigate the effect of intravenous (IV) injection of apelin-13 on cerebral vasogenic edema due to brain IRI. Animals were divided into sham, ischemia, and treat groups. IRI model was induced by middle cerebral artery occlusion (MCAO) for 60 min followed by 23 h reperfusion. Apelin-13 was injected into the tail vein 5 min before reperfusion. Neurological defects were evaluated with longa test. Brain water content and BBB permeability were assessed according to cerebral dry-wet weight and brain Evans blue extraction. Malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were measured using the colorimetric method. Expression of occludin and claudin-5, matrix metalloproteinase- 2 and 9 (MMP-2 & 9) and, ETBR were evaluated using Western blot. Brain IRI was associated with BBB breakdowns and vasogenic edema. Apelin-13 significantly reduced BBB permeability and vasogenic edema. Apelin-13 significantly attenuated IRI-related oxidative stress. Apelin-13 decreased expression of mmp-2, 9 and ETBR, prevented from decrement of occludin and claudin-5 expersion, which protected BBB integrity and reduced vasogenic edema. In conclusion, our results have suggested that an IV injection of apelin-13 could somehow reduce vasogenic edema via targeting oxidative stress and ETBR expression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Obesity drives an imbalanced signature of specialized pro-resolving mediators (SPM). Herein, we investigated if high fat diet-induced obesity dysregulates the concentration of SPM intermediates in the brains of C57BL/6 J mice. Furthermore, given the benefits of EPA for cardiometabolic diseases, major depression, and cognition, we probed the effect of an EPA supplemented high fat diet on brain SPM intermediates. Mass spectrometry revealed no effect of the high fat diet on PUFA-derived brain metabolites. EPA also did not have an effect on most brain PUFA-derived metabolites except an increase of 12-hydroxyeicosapentaenoic acid (12-HEPE). In contrast, EPA dramatically increased serum HEPEs and lowered several PUFA-derived metabolites. Finally, untargeted mass spectrometry showed no effects of the high fat diet, with or without EPA, on the brain metabolome. Collectively, these results show the murine brain resists a deficiency in SPM pathway markers in response to a high fat diet and that EPA supplementation increases 12-HEPE levels., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Excessive fluoride is capable of inducing cognitive deficits, but the mechanisms remain elusive. This study aimed to investigate the effects and underlying mechanisms of fluoride on mitochondrial dysfunction and neurobiological alterations, as well as cognitive impairment. C57BL/6 mice were orally administered 25, 50, and 100 mg/L NaF for 90 days. Cultured human neuroblastoma SH-SY5Y cells were exposed to NaF (110 mg/L) for 24 h in the presence or absence of Sirt3 overexpression. The results demonstrated that chronic exposure to high fluoride induced cognitive deficits and neural/synaptic injury in mice. Fluoride reduced mitochondrial antioxidant enzyme activities and elevated SOD2 acetylation by downregulating Sirt3 expression in the brains of mice and NaF-treated SH-SY5Y cells. Moreover, fluoride lowered mtDNA transcription and induced mitochondrial dysfunction along with increased FoxO3A acetylation in the brains of mice and NaF-treated SH-SY5Y cells. Subsequent experiments revealed that overexpression of Sirt3 significantly attenuated the adverse effects of fluoride on radical scavenging capabilities and mtDNA transcription, as well as mitochondrial function in SH-SY5Y cells. These results suggest that chronic long-term fluoride exposure evokes neural/synaptic injury and cognitive impairment through mitochondrial dysfunction and its associated oxidative stress, which is, at least partly, mediated by Sirt3 inhibition in the mouse brain., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: The contribution of neuroinflammation in cognitive impairment is increasingly recognized. Non-steroidal anti-inflammatory drugs had been proven that it could improve cognitive impairment in large dose but with more side effect, which limited the application. The main objective of this study was to investigate whether the combined use of nicotine and celecoxib could obtain synergistic neuroprotective effect in ischemic rats., Methods: Twenty adult Sprague-Dawley (SD) rats underwent ischemic model surgery by injecting endothelin-1 into the left thalamus, which were classified into four groups with different interventions: nicotine (1.5 mg/kg/d), celecoxib (15 mg/kg/d), nicotine (1.5 mg/kg/d) +celecoxib (15 mg/kg/d), or saline after surgery. The other five SD rats also underwent same surgery by injecting saline instead of endothelin-1, as the control group. Morris water maze (MWM) test was adopted to assess the cognition. Micro PET/CT with 2-[ 18 F]-A-85380 were performed for α 4 β 2 -nAChRs detection in vivo. Western blot, real-time PCR and immunohistochemical staining were adopted to detect the expression of α 4 β 2 -nAChRs and inflammatory factors which included TNF-α, IL-1β, IL-6 in brain tissue. Microglial activation in the brain was monitored by immunofluorescence with IBA1 staining., Results: The MWM test showed rats given with nicotine or celecoxib alone showed much better memory than rats with saline, no difference was observed between nicotine and celecoxib. The rat memory was recovered most significant when the nicotine and celecoxib were combined (p < 0.05). Micro-PET/CT showed much more tracer uptake in the left thalamus and whole brain in rats given with nicotine, or nicotine + celecoxib (nico + cele group) than saline treated rats, whereas the rats given celecoxib did not. Compared with saline treated rats, we found the proteins of α 4 nAChR and β 2 nAChR in rats given nicotine or nico + cele increased significantly, and mRNA/proteins of TNF-α, IL-1β and IL-6 decreased at the same time. The α  4 nAChR and β  2 nAChR proteins in rats given celecoxib is the same as saline treated rats, whereas the inflammatory factors decreased obviously compared with saline treated rats. Microglial activation was confirmed in saline treated rats, which was inhibited in rats give nicotine, celecoxib or both., Conclusions: The study revealed the combined use of nicotine and celecoxib may improve the cognitive function in ischemic rats, with a better effect than either alone. Both nicotine and celecoxib can inhibit inflammation, but through different mechanisms: nicotine can activate α 4 β 2 -nAChRs while celecoxib is cyclooxygenase-2 inhibitor. Our findings suggest the combined application of two drugs with different anti-inflammation mechanism could attenuate cognitive impairment more effectively in ischemic rats, which may hold therapeutic potential in the clinical practice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Alcohol is the most commonly used psychoactive drug, often taken in conjunction with opioid drugs. Since both alcohol and opioids can induce CNS depression, it is often assumed that alcohol potentiates the known hypoxic effects of opioid drugs. To address this supposition, we used oxygen sensors to examine the effects of alcohol on brain oxygenation and hypoxic responses induced by intravenous heroin in awake, freely moving rats. To eliminate robust sensory effects of alcohol following its oral or intraperitoneal delivery, alcohol was administered directly into the stomach via chronically implanted intragastric catheters at human relevant doses. Alcohol delivered at a 0.5 g/kg dose did not affect brain oxygen levels, except for a weak transient increase during drug delivery. This phasic oxygen increase was stronger at a 2.0 g/kg alcohol dose and followed by a weaker tonic increase. Since alcohol absorption from intragastric delivery is much slower and more prolonged than with intraperitoneal or intravenous injections, the rapid rise of brain oxygen levels suggests that alcohol has a direct action on sensory afferents in the stomach well before the drug physically reaches brain tissue via circulation. Despite slow tonic increases in brain oxygen, alcohol at the 2.0 g/kg dose strongly potentiates heroin-induced oxygen responses, increasing both the magnitude and duration of oxygen decrease. Therefore, under the influence of alcohol, the use of opioid drugs becomes much more dangerous, increasing brain hypoxia and enhancing the probability of serious health complications, including coma and death., (Published by Elsevier Ltd.)

Puberty includes a highly stress-sensitive period with significant sex differences in the neurophysiological and behavioural outcomes of a peripheral immune challenge. Sex differences in the pubertal neuroimmune network's responses to systemic LPS may explain some of these enduring sex-specific outcomes of a pubertal immune challenge. However, the functional implications of these sex-specific neuroimmune responses on the local microenvironment are unclear. Western blots were used to examine treatment- and sex-related changes in expression of regulatory proteins in inflammation (NFκB), cell death (AIF), oxidative stress (SOD-1), and synaptic plasticity (PSD-95) following symptomatic recovery (i.e., one week post-treatment) from pubertal immune challenge. Across the four examined brain regions (i.e., hippocampus, PFC, hypothalamus, and cerebellum), only PSD-95 levels were altered one week post-treatment by the pubertal LPS treatment. Unlike their female counterparts, seven-week-old males showed increased PSD-95 expression in the hippocampus (p < .05). AIF, SOD-1, and NFκB levels in both sexes were unaffected by treatment (all p > .05), which suggests appropriate resolution of NFκB-mediated immune responses to pubertal LPS without stimulating AIF-mediated apoptosis and oxidative stress. We also report a significant male-biased sex difference in PSD-95 levels in the PFC and in cerebellar expression of SOD-1 during puberty (all p < .05). These findings highlight the sex-specific vulnerability of the pubertal hippocampus to systemic LPS and suggest that a pubertal immune challenge may expedite neurodevelopment in the hippocampus in a sex-specific manner., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Dexmedetomidine (Dex) has been suggested to exert a protective function in ischemic brain injury. In this study, we aimed to elucidate the intrinsic mechanisms of Dex in regulating microglia pyroptosis in ischemic brain injury via the purinergic 2X7 receptor (P2X7R)/NLRP3/Caspase-1 signaling pathway. First, permanent middle cerebral artery occlusion (p-MCAO) rat model was established, followed by the measurement of behavioral deficit, neuronal injury, the volume of brain edema and the infarct size. Dex treatment was suggested to alleviate the neurological deficits in p-MCAO rats and reduce the brain water content and infarct size. Additionally, rat microglia were cultured in vitro and a model of oxygen and glucose (OGD) was established. Microglia cell activity and ultrastructure were detected. Dex could increase cell activity and reduce LDH activity, partially reversing the changes in cell morphology. Furthermore, the activation of P2X7R/NLRP3/Caspase-1 pathway was tested. The obtained findings indicated Dex suppressed microglial pyroptosis by inhibiting the P2X7R/NLRP3/Caspase-1 pathway. Inhibition of P2X7R or NLRP3 could inhibit Caspase-1 p10 expression, improve cell activity, and reduce LDH activity. The same result was verified in vivo experiments. This study indicated that Dex inhibited microglia pyroptosis by blocking the P2X7R/NLRP3/Caspase-1 pathway, thus playing a protective role against ischemic brain injury., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Increased microglial NADPH oxidase (NOX 2 ) production may make an important contribution to the increased incidence and severity of ischemic stroke associated with diabetes. Imidazoline receptors are closely associated with neuroprotection, but the neuroprotective effects of the selective I 2 -imidazoline receptor ligand 2-(2-benzofuranyl)-2-imidazoline (2BFI) in diabetes has not been established. The effect of 2BFI on microglial NOX 2 production was investigated using a co-culture of neurons and microglia, and the effect on cerebral ischemia-reperfusion (IR) injury was determined in diabetic rats. Garcia neurological scores, brain infarct volumes, brain water content, TUNEL staining, blood-brain barrier, and immunofluorescent labeling for microglia were evaluated. Western blots were used to determine gp91 phox and Tyr1472 expression. Anti-inflammatory cytokine (IL-10) and inflammatory cytokine secretion was determined using ELISA kits. The brain infarct volumes, TUNEL-positive neurons, expression of microglia, brain water content, blood-brain barrier structure damage, and gp91 phox and Tyr1472 expression were increased, the Garcia neurological scores were significantly decreased in the IR group, and 2BFI relieved these alterations. The IL-10 concentration was increased in the IR group; 2BFI significantly improved this increase. The neuron apoptosis and necrosis rates, and production of reactive oxygen species (ROS) and inflammatory cytokines, including IL-6, IL-8, TNF-α, and 8-iso-PGF2α, were significantly increased by high glucose stimulation combined with oxygen-glucose deprivation treatment, which were inhibited by 2BFI. The 2BFI ameliorated cerebral ischemia-reperfusion injury in diabetes and decreased neuron death in an in vitro model. The mechanism underlying these findings may be related to the decreased production of inflammatory factors and reactive oxygen species from microglia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rationale: 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a potent serotonin 5-HT 2A/2C receptor agonist with hallucinogenic activity. There is no data on the 25I-NBOMe effect on brain neurotransmission and animal performance after chronic administration., Objectives: We examined the effect of a 7-day treatment with 25I-NBOMe (0.3 mg/kg/day) on neurotransmitters' release and rats' behavior in comparison to acute dose., Methods: Changes in dopamine (DA), serotonin (5-HT), acetylcholine (ACh), and glutamate release were studied using microdialysis in freely moving rats. The hallucinogenic activity was measured in the wet dog shake (WDS) test. The animal locomotion was examined in the open field (OF) test, short-term memory in the novel object recognition (NOR) test. The anxiogenic/anxiolytic properties of the drug were tested using the light/dark box (LDB) test., Results: Repeated administration of 25I-NBOMe decreased the response to a challenge dose of DA, 5-HT, and glutamatergic neurons in the frontal cortex as well as weakened the hallucinogenic activity in comparison to acute dose. In contrast, striatal and accumbal DA and 5-HT release and accumbal but not striatal glutamate release in response to the challenge dose of 25I-NBOMe was increased in comparison to acute treatment. The ACh release was increased in all brain regions. Behavioral tests showed a motor activity reduction and memory deficiency in comparison to a single dose and induction of anxiety after the drug's chronic and acute administration., Conclusions: Our findings suggest that multiple injections of 25I-NBOMe induce tolerance to hallucinogenic activity and produce alterations in neurotransmission. 25I-NBOMe effect on short-term memory, locomotor function, and anxiety seems to be the result of complex interactions between neurotransmitter pathways., (© 2021. The Author(s).)

It has been suggested that cannabis consumption during adolescence may be an initial step to cocaine use in adulthood. Indeed, previous preclinical data show that adolescent exposure to cannabinoids (both natural and synthetic) potentiates cocaine self-administration in rats. Here we aimed at gaining a deeper understanding of the cellular activation patterns induced by cocaine as revealed by Fos imaging and how these patterns may change due to adolescent exposure to THC. Male and female Wistar rats were administered every other day THC (3 mg/kg i.p.) or vehicle from postnatal day 28-44. At adulthood (PND90) they were given an injection of cocaine (20 mg/kg i.p.) or saline and sacrificed 90 min later. Cocaine-induced Fos activation was measured by immunohistochemistry as an index of cellular activation. We found that cocaine-induced activation in the motor cortex was stronger in THC-exposed rats. Moreover, there was significant sex-dependent interaction between cocaine and adolescent THC exposure in the dorsal hypothalamus, suggesting that cocaine induced a more robust cellular activation in THC-exposed females but not in THC-treated males. Other THC- and cocaine-induced effects were also evident. These results add to the previous literature suggesting that the behavioral, cellular, molecular, and brain-activating actions of cocaine are modulated by early experience with cannabinoids and provide additional knowledge that may explain the enhanced actions of cocaine in rats exposed to cannabinoids during their adolescence., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Post-traumatic stress disorder (PTSD) is characterized by depression/anxiety and memory failure, primarily fear memory. According to the reports, neuroinflammation and synaptic plasticity can play a role in the neurophysiological mechanisms underlying PTSD. Bromodomain-containing protein 4 (Brd4) intriguingly affects regulating of inflammatory responses and learning and memory. This study aimed to explore the effect of inhibiting Brd4 on depression/anxiety-like behaviors, spatial and fear memory, and underlying mechanisms in a model of PTSD. Inescapable foot shocks (IFS) with a sound reminder in 6 days were used to induce PTSD-like behaviors which were tested using contextual and cue fear tests, sucrose preference test, open-field test, elevated plus maze test, and Y-maze test. Meanwhile, the Brd4 inhibitor JQ1 was used as an intervention. The results found that IFS induced PTSD-like behaviors and indicated obvious Brd4 expression in microglia of the prefrontal cortex (PFC), hippocampus, and amygdala, pro-inflammatory cytokines over-expression, microglial activation, and nuclear factor-kappa B over-expression in PFC and hippocampus but not in amygdala. Meanwhile, the alterations of immediate early genes (IEGs) were found in PFC, hippocampus, and amygdala. Besides, dendritic spine density was reduced in PFC and hippocampus but was elevated in amygdala of rats with IFS. In addition, treatment with JQ1 significantly reduced freezing time in the contextual and cue fear test, reversed the behavioral impairment, decreased the elevated neuroinflammation, and normalized the alteration in IEGs and dendritic spine densities. The results suggested that Brd4 was involved in IFS-induced PTSD-like behaviors through regulating neuroinflammation, dynamics of IEGs, and synaptic plasticity., (© 2021 International Society for Neurochemistry.)

Ethnopharmacological Relevance: Cymbopogon citratus (DC.) Stapf (C. citratus) is consumed as an infusion in folk medicine due to its pharmacological properties and action in the central nervous system. Epilepsy is a neurological disorder that affects millions of people. Since the currently available antiepileptic drugs often cause undesirable side effects, new alternative therapeutic strategies based on medicinal plants have been proposed., Aim of the Study: This study aimed to investigate the anticonvulsant and neuroprotective effects of C. citratus essential oil (EO) and hydroalcoholic extract (E1) from its leaves, as well as of its related compounds citral (CIT) and geraniol (GER) against the effects of pentylenetetrazole (PTZ) induced seizures in zebrafish (Danio rerio)., Materials and Methods: To evaluate the anticonvulsant properties of the samples, adult animals were pre-treated (by immersion) and subsequently exposed to PTZ solution. The involvement of GABA A receptors in the antiepileptic effects was investigated by the coadministration of flumazenil (FMZ), a known GABA A receptor antagonist. Oxidative stress markers malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and nitric oxide (NO) were assessed in zebrafish brain homogenates after PTZ exposure., Results: All samples increased the latency time for the first seizure, which was reduced when animals were pretreated with FMZ, suggesting the involvement of GABA A receptors in the observed properties. The association between CIT and GER at the lowest concentration studied showed a synergistic effect on the anticonvulsant activity. Decreases in MDA and NO levels and increases in GSH and CAT levels in the brain of treated animals suggested the neuroprotective effect of the compounds investigated., Conclusions: Our results proved that C. citratus EO, E1, CIT and GER have anticonvulsant effects in zebrafish and could be used as a promising adjuvant therapeutic strategy for epilepsy treatment. Furthermore, zebrafish demonstrated to be an alternative animal model of epilepsy to evaluate the anticonvulsant and neuroprotective effects of C. citratus., (Copyright © 2021. Published by Elsevier B.V.)

Despite reports that quinoline antimalarials including chloroquine (Chq) exhibit idiosyncratic neuropsychiatric effects even at low doses, the drug continues to be in widespread use during pregnancy. Surprisingly, very few studies have examined the potential neurotoxic action of Chq exposure at different points of gestation or how this phenomenon may affect neurophysiological well-being in later life. We therefore studied behavior, and the expression of specific genes and neurochemicals modulating crucial neural processes in offspring of rats exposed to prophylactic dose of Chq during different stages of gestation. Pregnant rats were injected 5 mg/kg/day (3 times) of Chq either during early- (first week), mid- (second week), late- (third week), or throughout- (all weeks) gestation, while controls received PBS injection. Behavioral characterization of offspring between postnatal days 15-20 in the open field, Y-maze, elevated plus and elevated zero mazes revealed that Chq evoked anxiogenic responses and perturbed spatial memory in rats, although locomotor activity was generally unaltered. In the prefrontal cortex (PFC), hippocampus and cerebellum of rats prenatally exposed to Chq, RT-qPCR analysis revealed decreased mRNA expression of presynaptic marker synaptophysin, which was accompanied by downregulation of postsynaptic marker PSD95. Synaptic marker PICK1 expression was also downregulated in the hippocampus but was unperturbed in the PFC and cerebellum. In addition to recorded SOD downregulation in cortical and hippocampal lysates, induction of oxidative stress in rats prenatally exposed to Chq was corroborated by lipid peroxidation as evinced by increased MDA levels. Offspring of rats infused with Chq at mid-gestation and weekly treatment throughout gestation were particularly susceptible to neurotoxic changes, especially in the hippocampus. Interestingly, Chq did not cause histopathological changes in any of the brain areas. Taken together, our findings causally link intrauterine exposure to Chq with postnatal behavioral impairment and neurotoxic changes in rats., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: To use proton magnetic resonance spectroscopy (1HMRS) and diffusion weighted imaging (DWI) to identify ethanol in the brain directly after consumption, and examine changes in brain metabolite levels and brain microstructure relative to the duration of time following exposure to alcohol., Methods: The study involved 44 male volunteers (18-55 years). All brain changes were assessed in the frontal lobes, occipital lobes, basal ganglia and cerebellum, however the detailed analyses focused on the frontal lobes. All participants were examined four times, i.e. before and 0.5-hour, 1 hour and 2 hours after consumption of 150 mL pure vodka (60 g of ethanol)., Results: The highest ethanol levels were identified between 0.5 and 1 hour following alcohol intake. There were significant increases in the concentrations of lipids and lactates approximately one hour after alcohol consumption, and the concentration levels were found to normalise during the following two hours. Some statistically insignificant trends of changes were found for tCr, tCho, mI, GABA, Glc, Glx and tNAA. For the DWI and ADC (Apparent Diffusion Coefficient of water) values, the findings showed statistically insignificant decrease and increase, followed by a tendency towards normalisation. Similar associations in changes of metabolite concentrations and DWI and ADC values were found in the other locations investigated in the study., Conclusion: A single dose of alcohol as used in this experiment produces increases in lipids and lactates in brain tissues that appear reversible., (© The Author(s) 2020. Medical Council on Alcohol and Oxford University Press.)

Despite the increasing prevalence of autism spectrum disorder (ASD), there is still a deficiency in understanding its exact pathophysiology and treatment, therefore validation of translational ASD animal model is warranted. Although strong evidences support the valproic acid (VPA) model of autism, yet a controversy exists regarding the best timing of exposure whether prenatal or postnatal. Accordingly, this study was designed to compare the time dependent effects of VPA exposure as regard its ability to induce autistic like changes in male Wistar rats. In this study, two different protocols of VPA exposure (prenatal and postnatal) were compared at different levels (behavioral, neurochemical and histopathological). Results of this study revealed that both prenatal and postnatal VPA exposures induced autistic-like behaviors manifested by reduced social interaction, increased repetitive stereotyped behavior and anxiety, cognitive dysfunction, lowered sensitivity to pain, and neurodevelopmental delay. Furthermore, inflammatory cytokines and oxidative/nitrosative stress markers were elevated in prefrontal cortex and hippocampal homogenates. Likewise, histopathological and immunohistochemical assessment confirmed the neurodegenerative and the apoptotic changes in prefrontal cortex, hippocampus and cerebellum exhibited by decreased viable cells number and Nissl's granules optical density, and increased caspase-3 immunoreactivity respectively. Interestingly, ASD core symptoms and histopathological changes were significantly (P < 0.05) altered in prenatal VPA model compared to postnatal VPA model. Additionally, postnatal mortality in prenatal model (4.3%) was much lower compared to the postnatal model (22.7%). In conclusion, our study overweighs the ability of prenatal VPA model over postnatal VPA model to induce behavioral and neuropathological alterations that simulate those observed in autistic individuals with a lower postnatal animal mortality, highlighting the privilege of prenatal over postnatal VPA exposure as a translational model for understanding pathophysiology and developing novel targets for management of ASD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mercury is a neurotoxic chemical that represents one of the greatest pollution threats to Arctic ecosystem health. Evaluating the direct neurotoxic effects of mercury in free ranging wildlife is challenging, necessitating the use of neurochemical biomarkers to assess potential sub-clinical neurological changes. The objective of this study was to characterize the distribution and speciation of mercury, as well as exposure-associated changes in neurochemistry, across multiple brain regions (n = 10) and marine mammal species (n = 5) that each occupy a trophic niche in the Arctic ecosystem. We found consistent species differences in mean brain and brain region-specific concentrations of total mercury (THg) and methyl mercury (MeHg), with higher concentrations in toothed whales (narwhal, pilot whales and harbour porpoise) compared to fur-bearing mammals (polar bear and ringed seal). Mean THg (μg/g dw) in decreasing rank order was: pilot whale (11.9) > narwhal (7.7) > harbour porpoise (3.6) > polar bear (0.6) > ringed seal (0.2). The higher THg concentrations in toothed whales was associated with a marked reduction in the percentage of MeHg (<40 %) compared to polar bears (>70 %) that had lower brain THg concentrations. This pattern in mercury concentration and speciation corresponded broadly to an overall higher number of mercury-associated neurochemical biomarker correlations in toothed whales. Of the 226 correlations between mercury and neurochemical biomarkers across brain regions, we found 60 (27 %) meaningful relationships (r>0.60 or p < 0.10). We add to the growing weight of evidence that wildlife accumulate mercury in their brains and demonstrate that there is variance in accumulation across species as well as across distinct brain regions, and that some of these exposures may be associated with sub-clinical changes in neurochemistry., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Perillyl alcohol (POH) is a monocyclic terpene that has strong antitumor activity. Brain tumors are particularly difficult to treat with therapeutic agents, and clinical trials have shown their low tolerance through oral administration. We proposed the entrapment of POH into an oil-in-water chitosan nanoemulsion aiming its intranasal administration for brain targeting. An ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitation of total metabolite perillic acid (PA) in plasma and brain of rats. The rat samples containing the metabolite were treated by liquid-liquid extraction with acetonitrile. The mobile phase was 0.1% formic acid in water (solvent A) and 0.1% formic acid in methanol (solvent B), at a flow rate of 0.3 mL min -1 in gradient elution. The chromatography was run for 10 min, and analytical curves were built in acetonitrile, plasma, and brain. The PA was detected in positive ion mode with multiple reaction monitoring. The method has shown high selectivity, sensitivity, and throughput. The low quantification limits of 162, 178, and 121 ng mL -1 for acetonitrile, brain, and plasma, respectively, indicate a good detectability of the method. The repeatability and precision observed were within the limits recommended in the literature. The accuracy of the method was verified through high recovery rates (106-118%). The validated method was successfully applied to the pharmacokinetic study of the metabolite PA after the intranasal administration of free or POH-loaded nanoemulsion in rats. The results showed that chitosan nanoemulsion improved the plasma and brain bioavailability of POH, representing a promising alternative to free POH treatment., (© 2020 John Wiley & Sons, Ltd.)

Functional magnetic resonance imaging (fMRI) is an extensively used method for the investigation of normal and pathological brain function. In particular, fMRI has been used to characterize spatiotemporal hemodynamic response to pharmacological challenges as a non-invasive readout of neuronal activity. However, the mechanisms underlying regional signal changes are yet unclear. In this study, we use a meta-analytic approach to converge data from microdialysis experiments with relative cerebral blood volume (rCBV) changes following acute administration of neuropsychiatric drugs in adult male rats. At whole-brain level, the functional response patterns show very weak correlation with neurochemical alterations, while for numerous brain areas a strong positive correlation with noradrenaline release exists. At a local scale of individual brain regions, the rCBV response to neurotransmitters is anatomically heterogeneous and, importantly, based on a complex interplay of different neurotransmitters that often exert opposing effects, thus providing a mechanism for regulating and fine tuning hemodynamic responses in specific regions.

4-Bromo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25B-NBOMe) is a hallucinogen exhibiting high binding affinity for 5-HT 2A/C serotonin receptors. In the present work, we investigated its effect on dopamine (DA), serotonin (5-HT), acetylcholine (ACh), and glutamate release in the rat frontal cortex, striatum, and nucleus accumbens. Hallucinogenic activity, impact on cognitive and motor functions, and anxiogenic/anxiolytic properties of this compound were also tested. The release of DA, 5-HT, ACh, and glutamate was studied using microdialysis in freely moving animals. Hallucinogenic activity was investigated using head and body twitch response (WDS), cognitive functions were examined with the novel object recognition test (NOR), locomotor activity was studied in the open field (OF), while anxiogenic/anxiolytic effect was tested using the light/dark box (LDB). Neurotoxicity was evaluated with the comet assay. 25B-NBOMe increased DA, 5-HT, and glutamate release in all studied brain regions, induced hallucinogenic activity, and lowered the recognition index (Ri) vs. control in the NOR test. It also decreased locomotor activity of rats in the OF test. The effect of 25B-NBOMe in the NOR test was inhibited by scopolamine. In the LDB test, the time spent in the dark zone was longer in comparison to control and was dose-dependent. In contrast to MDMA, 25B-NBOMe showed subtle genotoxic effect observed in the comet assay.Our findings indicate that 25B-NBOMe shows hallucinogenic activity in the wide range of doses. The changes in neurotransmitter levels may be related to 25B-NBOMe affinity for 5-HT 2A receptor. Alterations in the NOR, OF, and LDB indicate that 25B-NBOMe impacts short-term memory, locomotion, and may be anxiogenic.

Selective serotonin reuptake inhibitors (SSRI) are commonly used to treat depression during pregnancy. SSRIs cross the placenta and may influence the maturation of the foetal brain. Clinical and preclinical findings suggest long-term consequences of SSRI perinatal exposure for the offspring. The mechanisms of SSRI effects on developing brain remain largely unknown and there are no directional approaches for prevention of the consequences of maternal SSRI treatment during pregnancy. The heptapeptide Semax (MEHFPGP) is a synthetic analogue of ACTH(4-10) which exerts marked nootropic and neuroprotective activities. The aim of the present study was to investigate the long-term effects of neonatal exposure to the SSRI fluvoxamine (FA) in white rats. Additionally, the study examined the potential for Semax to prevent the negative consequences of neonatal FA exposure. Rat pups received FA or vehicle injections on postnatal days 1-14, a time period equivalent to 27-40 weeks of human foetal age. After FA treatment, rats were administered with Semax or vehicle on postnatal days 15-28. During the 2nd month of life, the rats underwent behavioural testing, and monoamine levels in brain structures were measured. It was shown that neonatal FA exposure leads to the impaired emotional response to stress and novelty and delayed acquisition of food-motivated maze task in adolescent and young adult rats. Furthermore, FA exposure induced alterations in the monoamine levels in brains of 1- and 2- month-old rats. Semax administration reduced the anxiety-like behaviour, improved learning abilities and normalized the levels of brain biogenic amines impaired by the FA exposure. The results demonstrate that early-life FA exposure in rat pups produces long-term disturbances in their anxiety-related behaviour, learning abilities, and brain monoamines content. Semax exerts a favourable effect on behaviour and biogenic amine system of rats exposed to the antidepressant. Thus, peptide Semax can prevent behavioural deficits caused by altered 5-HT levels during development., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Renin Angiotensin System plays significant role in the memory acquisition and consolidation apart from its hemodynamic function in the pathophysiology of Alzheimer's disease (AD). It has been reported that Ang (1-7) ameliorates the cognitive impairment in experimental animals. However, the effect of Ang (1-7)/Mas receptor signaling is yet to be explored in Aβ42-induced memory impairment. Aβ42 was intracerebroventricularly injected into the male rats on day-1 (D-1) of the experimental schedule of 14 days. All the drugs were administered from D-1 to D-14 in the study design. Aβ42 significantly increased the escape latency during Morris water maze (MWM) test on D-10 to13 in the animals. Further, Aβ42 significantly decreased the time spent and percentage of total distance travelled in the target quadrant of the rats on D-14 in the MWM test. Aβ42 also significantly decreased the spontaneous alteration behavior on D-14 during Y-maze test. Moreover, there was a significant increase in the level of Aβ42, decrease in the cholinergic function (in terms of decreased acetylcholine and activity of cholinesterase, and increased activity of acetylcholinesterase), mitochondrial function, integrity and bioenergetics, and apoptosis in all the rat brain regions. Further, Aβ42 significantly decreased the level of expression of heme oxygenase-1 in all the rat brain regions. Ang (1-7) attenuated Aβ42-induced changes in the behavioral, biochemical and molecular observations in all the selected rat brain regions. However, A779, Mas receptor blocker, significantly abolished the beneficial effects of Ang (1-7) in Aβ42-induced cognitive deficit animals. These observations clearly indicate that the Ang (1-7)/Mas receptor activation could be a potential alternative option in the management of AD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aggression is a complex social behaviour that allows individuals to compete for access to limited resources (eg, mates, food and territories). Excessive or inappropriate aggression, however, has become problematic in modern societies, and current treatments are largely ineffective. Although previous work in mammals suggests that aggressive behaviour varies seasonally, seasonality is largely overlooked when developing clinical treatments for inappropriate aggression. Here, we investigated how the hormone melatonin regulates seasonal changes in neurosteroid levels and aggressive behaviour in Siberian hamsters, a rodent model of seasonal aggression. Specifically, we housed males in long-day (LD) or short-day (SD) photoperiods, administered timed s.c. melatonin injections (which mimic a SD-like signal) or control injections, and measured aggression using a resident-intruder paradigm after 9 weeks of treatment. Moreover, we quantified five steroid hormones in circulation and in brain regions associated with aggressive behaviour (lateral septum, anterior hypothalamus, medial amygdala and periaqueductal gray) using liquid chromatography-tandem mass spectrometry. SD hamsters and LD hamsters administered timed melatonin injections (LD-M) displayed increased aggression and exhibited region-specific decreases in neural dehydroepiandrosterone, testosterone and oestradiol, but showed no changes in progesterone or cortisol. Male hamsters also showed distinct associations between neurosteroids and aggressive behaviour, in which neural progesterone and dehydroepiandrosterone were positively correlated with aggression in all treatment groups, whereas neural testosterone, oestradiol and cortisol were negatively correlated with aggression only in LD-M and SD hamsters. Collectively, these results provide insight into a novel neuroendocrine mechanism of mammalian aggression, in which melatonin reduces neurosteroid levels and elevates aggressive behaviour., (© 2021 British Society for Neuroendocrinology.)

Objectives: Water contaminated with arsenic affected millions of people worldwide and arsenic exposure is related to various neurological disorders. Hence, the current study was planned to investigate the neuroprotective activity of diosmin (DSN) against arsenic induced neurotoxicity as an attempt to identify therapeutic intervention to combat arsenicism., Materials and Methods: Sodium arsenite an inducer of neurotoxicity was administered orally (13 mg/kg) and DSN treatment at two selected doses (50 and 100 mg/kg) was done for 21 days. Behavioral and biochemical variations were examined by various parameters. Furthermore, histopathological and immunohistochemistry studies were done with the brain sections., Results: The behavioral studies evidenced that arsenic has suppressed the exploratory behavior and motor coordination in rats and DSN treatment has recovered the behavioral changes to normal. Arsenic administration has also found to induce oxidative stress and DSN co-treatment has ameliorated the oxidative stress markers. Interestingly, depleted levels of neurotransmitters were observed with the arsenic and it was restored back by the DSN treatment. Histopathological alterations like pyknosis of the neuronal cells were identified with arsenic exposure and subsided upon DSN co administration. Immunohistochemical studies have revealed the expression of NOX4 and its gp91 phox and P47 phox subunits and its suppression by DSN treatment may be the key therapeutic factor of it., Conclusions: Treatment with DSN showed a beneficial effect in protecting against arsenic-induced neurotoxicity by suppressing the toxicity changes and the antioxidant effect of DSN might be attributed to its ability of suppressing NOX4 and its subunits., Competing Interests: None

Synaptic impairment may be the main cause of cognitive dysfunction in brain aging that is probably due to a reduction in synaptic contact between the axonal buttons and dendritic spines. Rho proteins including the small GTPase Rac1 have become key regulators of neuronal morphogenesis that supports synaptic plasticity. Small Rho- and Ras-GTPases are post-translationally modified by the isoprenoids geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP), respectively. For all GTPases, anchoring in the plasma membrane is essential for their activation by guanine nucleotide exchange factors (GEFs). Rac1-specific GEFs include the protein T lymphoma invasion and metastasis 1 (Tiam1). Tiam1 interacts with the TrkB receptor to mediate the brain-derived neurotrophic factor (BDNF)-induced activation of Rac1, resulting in cytoskeletal rearrangement and changes in cellular morphology. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) acts as a highly affine-selective TrkB receptor agonist and causes the dimerization and autophosphorylation of the TrkB receptor and thus the activation of downstream signaling pathways. In the current study, we investigated the effects of 7,8-DHF on cerebral lipid isoprenoid and Rho protein levels in male C57BL/6 mice aged 3 and 23 months. Aged mice were daily treated with 100 mg/kg b.w. 7,8-DHF by oral gavage for 21 days. FPP, GGPP, and cholesterol levels were determined in brain tissue. In the same tissue, the protein content of Tiam1 and TrkB in was measured. The cellular localization of the small Rho-GTPase Rac1 and small Rab-GTPase Rab3A was studied in total brain homogenates and membrane preparations. We report the novel finding that 7,8-DHF restored levels of the Rho proteins Rac1 and Rab3A in membrane preparations isolated from brains of treated aged mice. The selective TrkB agonist 7,8-DHF did not affect BDNF and TrkB levels, but restored Tiam1 levels that were found to be reduced in brains of aged mice. FPP, GGPP, and cholesterol levels were significantly elevated in brains of aged mice but not changed by 7,8-DHF treatment. Hence, 7,8-DHF may be useful as pharmacological tool to treat age-related cognitive dysfunction although the underlying mechanisms need to be elucidated in detail.

Hepatic encephalopathy depicts the cluster of neurological alterations that occur during acute or chronic hepatic injury. Hyperammonemia, inflammatory injury, and oxidative stress are the main predisposing factors for the direct and indirect changes in cerebral metabolism causing encephalopathy. The aim of this study was to evaluate the possible synergistic effect between aminoguanidine (AG; 100 mg/kg, p.o.) and l-carnosine (CAR; 200 mg/kg, p.o.) on hepatic encephalopathy that was induced by thioacetamide (TAA; 100 mg/kg, i.p.) administered three times weekly for six weeks. Behavioral changes, biochemical parameters, histopathological analysis, and immunohistochemical and ultrastructural studies were conducted 24 h after the last treatment. Combining AG with CAR improved TAA-induced locomotor impairment and motor incoordination evidenced by reduced locomotor activity and decline in motor skill performance, as well as ameliorated cognitive deficits. Moreover, both drugs restored the levels of serum hepatic enzymes and serum and brain levels of ammonia. In addition, the combination significantly modulated hepatic and brain oxidative stress biomarkers, inflammatory cytokines, and cleaved caspase-3 expression. Furthermore, they succeeded in activating nuclear erythroid 2-related factor 2 (Nrf2) expression and heme oxygenase-1 (HO-1) activity and ameliorating markers of hepatic encephalopathy, including hepatic necrosis and brain astrocyte swelling. This study shows that combining AG with CAR exerted a new intervention for hepatic and brain damage in hepatic encephalopathy due to their complementary antioxidant, anti-inflammatory effects and hypoammonemic effects via Nrf2/HO-1 activation and NO inhibition.

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 instituting mechanism-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 (0.5 mg/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, altered brain neurotransmitter content, elevated brain and muscle oxidative stress, and upregulated brain nerve growth factor receptor expression. Treatment with heraclin (10 mg/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.

Purpose: The study evaluated the neuroprotective effect and pharmacokinetic profile of turmeric extract and their metabolites in the blood and brain in an aluminum-induced neurotoxic animal model., Methods: Swiss albino mice received turmeric extract (TE), TE-essential oil combination (TE+EO) at doses of 25 and 50 mg/kg/day orally, vehicle (control), and a positive control group. Neurotoxicity was induced by injecting aluminum chloride (40 mg/kg/day, i.p.), and the effect of the intervention was studied for 45 days. The pharmacokinetic and behavioral biochemical markers of brain function and brain histopathological changes were evaluated., Results: The AUC 0- t showed a 30.1 and 54.2 times higher free curcumin concentration in plasma with 25 mg/kg and 50 mg/kg of TE+EO vs. TE, respectively. The concentration of free curcumin in the brain was 11.01 and 13.71-fold higher for 25 mg/kg and 50 mg/kg of TE+EO vs. TE, respectively. Aluminum impairs spatial learning and memory, which was significantly reversed with TE+EO by 28.6% (25 mg/kg) and 39.4% (50 mg/kg). In the elevated plus maze test, 44.8% (25 mg/kg) and 67.1% (50 mg/kg) improvements were observed. A significant reduction in aluminum-induced lipid peroxidation was observed. Also, the levels of glutathione, acetylcholinesterase, and catalase were improved with TE+EO. Damage to the hippocampal pyramidal cells was averted with TE+EO., Conclusion: The neuroprotective and antioxidant response confirms the benefits of TE+EO against aluminum-induced neurotoxicity. The presence of free curcumin and its metabolites in the brain and plasma establishes its improved bioavailability and tissue distribution. Therefore, the benefits of TE+EO could be harnessed in neurodegenerative diseases., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 David Banji et al.)

Rationale: Alzheimer's disease (AD) is a chronic, severe, progressive neurodegenerative disorder associated with cognitive and memory impairment that ultimately causes death. Most approved drugs can only alleviate some of the symptoms of AD, but no interventions have been found that reverse the underlying disease mechanisms. Rhodiola crenulata extract (RCE) has been reported to alleviate AD symptoms in rats. However, its underlying mechanism of action is still unclear., Methods: A brain lipidomics study was conducted to investigate the protective effects of RCE against AD in rats to identify potential biomarkers of AD using Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS) coupled with high-performance reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC). Differences in lipid metabolism profiles were evaluated using multivariate statistical analysis. Finally, the possible mechanism of action of RCE on AD was investigated by analysing metabolic pathways., Results: The RPLCHILIC/FT-ICR MS results showed 20 lipid components with significant differences between the control and model groups. After administration of RCE, the levels of 10 lipids in AD rats tended to shift toward reference levels. The pathway analysis revealed that the protective effect of RCE against AD might be related to regulation of glycerophospholipid metabolism., Conclusions: This study provides a novel perspective on the potential intervention mechanism of RCE in the treatment of AD., (© 2020 John Wiley & Sons, Ltd.)

Consumption of a high-fat diet has adverse impacts on metabolism, neurobehavioral, and neurochemical homeostasis in both humans and experimental animals. Here, we examined the effects of two different cultivars of Corylus avellana L. in a mouse model of metabolic syndrome. Corylus avellana L. reduced weight gain in mice that were treated with a high-fat diet, improved their behavioral parameters as exemplified by locomotion and rearing, working-memory, and reduced grooming and anxiety indices. Both Corylus avellana L. varieties reduced blood glucose levels and lipid peroxidation, improved lipid profile, and antioxidant status in mice placed on a high fat diet. Finally, brain acetylcholinesterase activity was also reduced, dopamine level was increased, while caspase-3 level in the brain was reduced. Thus, the Corylus avellana L. cultivars improve metabolic, behavioral, and neurochemical homeostasis in a diet with a high-fat content.

The health effects of mercury vapor exposure on the brain in volcanic areas have not been previously addressed in the literature. However, 10% of the worldwide population inhabits in the vicinity of an active volcano, which are natural sources of elemental mercury emission. To evaluate the presence of mercury compounds in the brain after chronic exposure to volcanogenic mercury vapor, a histochemical study, using autometallographic silver, was carried out to compare the brain of mice chronically exposed to an active volcanic environment (Furnas village, Azores, Portugal) with those not exposed (Rabo de Peixe village, Azores, Portugal). Results demonstrated several mercury deposits in blood vessels, white matter and some cells of the hippocampus in the brain of chronically exposed mice. Our results highlight that chronic exposure to an active volcanic environment results in brain mercury accumulation, raising an alert regarding potential human health risks. These findings support the hypothesis that mercury exposure can be a risk factor in causing neurodegenerative diseases in the inhabitants of volcanically active areas.

The impact of immunization with Anisakis simplex larval antigen on the occurrence and progression of experimental autoimmune encephalomyelitis (EAE) induced in mice was studied. C57BL/6J mice were immunized with the MOG 35-55 peptide and one batch was treated with A. simplex total larval antigen on days 1, 8, 10 and 12 after EAE induction. Significantly higher values were obtained in the EAE clinical parameters of the antigen-treated group. Likewise, there was a significant decrease in the weights of the animals. Anisakis-treatment produced a significant decrease in anti-MOG 35-55 specific IgG1 on day 21. On day 14 there was an increase in serum IL-2, IL-6, IL-10, IL-17A, and TGF-β in the treated group. On day 21, a decrease in IL-4, IL-6, TNF-α, TGF-β was observed. All brain determinations were made on day 21. The treatment decreased values of IL-6, IL-10, IL-17A and TNF-α. A. simplex antigen caused a significantly higher incidence of EAE and an advance in the appearance of the disease manifestations. However, treatment with the antigen was able to cause a decrease in proinflammatory cytokines (IL-6, IL-17A, and TNF-α) in nervous tissue that could establish a future preventive scenario for myelin damage., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Childhood lead (Pb 2+ ) intoxication is a global public health problem best known for producing deficits in learning and poor school performance. Human and preclinical studies have suggested an association between childhood Pb 2+ intoxication and proclivity to substance abuse and delinquent behavior. While environmental factors have been implicated in opioid addiction, less is known about the role of exposure to environmental pollutants on the brain opioid system. Opioid receptors are involved in the biological effects of opioids and other drugs of abuse. In this study, we examine the effect of chronic developmental Pb 2+ exposure (1500 ppm in the diet) on μ-opioid receptor (MOR) levels in the rat brain using [ 3 H]-d-Ala2-MePhe4-Gly-ol5 enkephalin ([ 3 H]-DAMGO) quantitative receptor autoradiography at different developmental stages (juvenile, early-adolescent, late adolescent and adult) in male and female rats. Our results indicate that chronic developmental Pb 2+ exposure increases the levels of [ 3 H]-DAMGO specific binding to MOR in juvenile and early adolescent Pb 2+ -exposed male and female rat brain with no changes in late-adolescent (PN50) and minor changes in Pb 2+ -exposed adult male rats (PN120). Specifically, at PN14, Pb 2+ -exposed males had an increase in MOR binding in the lateral posthalamic nuclei (LPTN), and Pb 2+ -exposed females had increased MOR binding in LPTN, medial thalamus, and hypothalamus. At PN28, Pb 2+ -exposed males had increased MOR levels in the striatum, stria medullaris of the thalamus, LPTN, medial thalamus, and basolateral amygdala, while Pb 2+ -exposed females showed an increase in nucleus accumbens core, LPTN, and medial thalamus. No changes were detected in any brain region of male and female rats at PN50, and at PN120 there was a decrease in MOR binding of Pb 2+ -exposed males in the medial thalamus. Our findings demonstrate age and gender specific effects of MOR levels in the rat brain as a result of chronic developmental Pb 2+ exposure. These results indicate that the major changes in brain MOR levels were during pre-adolescence and early adolescence, a developmental period in which there is higher engagement in reward and drug-seeking behaviors in humans. In summary, we show that chronic exposure to Pb 2+ , an ubiquitous and well-known environmental contaminant and neurotoxicant, alters MOR levels in brain regions associated with addiction circuits in the adolescent period, these findings have important implications for opioid drug use and abuse., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Dietary recommendations are frequently developed based on nutrient deficiency or prevention of disease, but less attention has been paid to the dietary guidelines to promote brain health. Active and healthy aging is a prerequisite for improving quality of life as people age, and evidence is establishing a relationship between diet and brain health. This work studied the effect of a diet based on foods rich in antioxidants, especially polyphenols, in rats, three days a week for 20 months starting at 14 months. Behavioral analysis testing working memory, spatial and episodic memory, as well as brain monoaminergic neurotransmitters involved in these processes but also in general brain health were analyzed. In addition, hippocampal SIRT1 protein which has an important role in regulating normal brain function was evaluated. The results show that long-term intake of polyphenol-enriched diet improves memory and learning, correlating with restoration of brain monoaminergic neurotransmitters and hippocampal SIRT1 levels in aged rats. These results agree with reports revealing a neuroprotective effect of different polyphenolic compounds on age-related brain decline, based on its antioxidant and anti-inflammatory properties; and demonstrate that consumption of antioxidant-rich foods, a few days a week, gives good long-term results in terms of brain health.

Although several recent studies have suggested that neuroinflammation plays a role in depression, both medication and neuroinflammatory preventive strategies have been poorly investigated. Recent studies have indicated that preconditioning with lipopolysaccharide (LPS) reduces the damage that occurs following ischemic stroke and brain trauma. However, to date, the effects of LPS preconditioning on psychiatric symptoms have not been reported. Thus, we assessed gene expression and behavioral changes affected by preconditioning with low-dose (LD) LPS in male mice with systemic inflammation induced by administration of high-dose (HD) LPS. mRNA expression analyses of cytokine-, glial-, and oxidative stress-associated genes revealed that majority of these genes responded to HD LPS. Differential gene expression in the presence and absence of LD LPS preconditioning, identified a subset of genes that may contribute to the mechanism of LPS preconditioning in the brain. Notably, LPS preconditioning attenuated an increase in expression of the astrocyte marker Gfap caused by systemic inflammation, suggesting that astrocytes have a key role in endotoxin tolerance in the brain induced by LPS preconditioning. As increased astrocyte in the brain of patients with depression is suggested to contribute to the pathophysiology of major depression, LPS preconditioning might be applicable to the prevention and treatment of depression. Unfortunately, in this study, LPS preconditioning did not show a reversal effect on behavior decline due to high-dose LPS-induced systemic inflammation. Alternative aspects of behavioral changes should be assessed to identify behavioral components that are affected by LPS preconditioning. Nonetheless, the findings in the present study indicate the possibility of the mechanism of endotoxin tolerance induction in the brain via astrocyte regulation by LPS preconditioning. Since there has been reported pharmacological significance of astrocytes in psychiatric disorders, regulation of endotoxin tolerance might be a key method to control psychiatric symptoms., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Lead (Pb) is a neurotoxic heavy metal pollutant. Despite the efforts to reduce Pb environmental exposure and to prevent Pb poisoning, exposure in human populations persists. Studies of adults with history of childhood lead exposure have consistently demonstrated cognitive impairments that have been associated with sustained glutamate signaling. Additionally, some clinical studies have also found correlations between Pb exposure and increased proclivity to drug addiction. Thus, here we sought to investigate if developmental Pb exposure can increase propensity to alcohol consumption and relapse using an alcohol self-administration paradigm. Because Pb exposure is associated with increased glutamatergic tone, we also studied the effects on the expression of synaptic and non-synaptic glutamate transporters in brain regions associated with drug addiction such as the nucleus accumbens (NAc), dorsomedial striatum (DMS), dorsolateral striatum (DLS), and medial prefrontal cortex (mPFC). We found that while developmental Pb exposure did not increase risk for alcohol self-administration, it did play a role in relapsing to alcohol. The effects were associated with differential expression of the glutamate transporter 1 (GLT1) and the glutamate/cystine antiporter (xCT). In the NAc and DLS the expression of GLT1 was found to be significantly reduced, while no changes were found in DMS or mPFC. Contrastingly, xCT was found to be upregulated in NAc but downregulated in DLS, with no changes in DMS or mPFC. Our data suggest that lead exposure is involved in relapse to alcohol seeking, an effect that could be associated with downregulation of GLT1 and xCT in the DLS., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Several biochemical parameters within the brain are altered by antidepressants. However, it is still uncertain which parameters are important for the evaluation of the effectiveness of these drugs. What seems certain is that the response of the nervous system is dynamic. The dynamic nature of the nervous system is still poorly understood, although it has implications in clinical management. Criteria for evaluating treatment resistant depression are based on this temporal variability. The present study was designed to evaluate dynamic alterations in catecholaminergic receptors and calcyon (associated with monoaminergic theory of depression) in the rat brain as well as brain-derived neurotrophic factor (BDNF) and tyrosine kinase beta (TRKB; related to neurotrophin theory) induced by three antidepressant drugs (ADs) with various pharmacological profiles (imipramine, desipramine, and citalopram) administered for 21 days or acutely, followed by various drug-free periods. Receptor autoradiography and in situ hybridization studies allowed us to identify changes in various brain regions simultaneously in each rat. Repeated treatment with ADs induced biochemical alterations, which were in agreement with the results of previous studies. These alterations include the downregulation of β1, β2, and α1 adrenergic receptors, upregulation of α2-adrenergic receptors and dopamine D2 receptors, and increased expression of BDNF in the hippocampus. Additionally, we observed dynamic alterations in the measured parameters after acute drug administration, particularly at the level of dopamine receptors, which were extremely sensitive to a single dose of ADs followed by various drug-free periods. All three ADs induced the upregulation of dopamine D2 receptor mRNA levels in the nucleus accumbens. The same effect was induced by single doses of ADs followed by various drug-free periods. The obtained results indicate that alterations in the availability of neurotransmitters at synapses induced by ADs are strong enough to induce immediate and long-lasting adaptive changes in the neuronal network., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Leigh syndrome is a fatal neurometabolic disorder caused by defects in mitochondrial function. Mechanistic target of rapamycin (mTOR) inhibition with rapamycin attenuates disease progression in a mouse model of Leigh syndrome (Ndufs4 knock-out (KO) mouse); however, the mechanism of rescue is unknown. Here we identify protein kinase C (PKC) downregulation as a key event mediating the beneficial effects of rapamycin treatment of Ndufs4 KO mice. Assessing the impact of rapamycin on the brain proteome and phosphoproteome of Ndufs4 KO mice, we find that rapamycin restores mitochondrial protein levels, inhibits signalling through both mTOR complexes and reduces the abundance and activity of multiple PKC isoforms. Administration of PKC inhibitors increases survival, delays neurological deficits, prevents hair loss and decreases inflammation in Ndufs4 KO mice. Thus, PKC may be a viable therapeutic target for treating severe mitochondrial disease.

While neuropsychiatric drugs influence neural activity across multiple brain regions, the current understanding of their mechanism of action derives from studies that investigate an influence of a given drug onto a pre-selected and small number of brain regions. To understand how neuropsychiatric drugs affect coordinated activity across brain regions and to detect the brain regions most relevant to pharmacological action in an unbiased way, studies that assess brain-wide neuronal activity are paramount. Here, we used whole-brain immunostaining of the neuronal activity marker cFOS, and graph theory to generate brain-wide maps of neuronal activity upon pharmacological challenges. We generated brain-wide maps 2.5 h after treatment of the atypical dopamine transporter inhibitor modafinil (10, 30, and 100 mg/kg) or the vesicular monoamine transporter 2 inhibitor tetrabenazine (0.25, 0.5 and 1 mg/kg). Modafinil increased the number of cFOS positive neurons in a dose-dependent manner. Moreover, modafinil significantly reduced functional connectivity across the entire brain. Graph theory analysis revealed that modafinil decreased the node degree of cortical and subcortical regions at the three doses tested, followed by a reduction in global efficiency. Simultaneously, we identified highly interconnected hub regions that emerge exclusively upon modafinil treatment. These regions were the mediodorsal thalamus, periaqueductal gray, subiculum, and rhomboid nucleus. On the other hand, while tetrabenazine had mild effects on cFOS counts, it reduced functional connectivity across the entire brain, cortical node degree, and global efficiency. As hub regions, we identified the substantia innominata and ventral pallidum. Our results uncovered novel mechanisms of action at a brain-wide scale for modafinil and tetrabenazine. Our analytical approach offers a tool to characterize signatures of whole-brain functional connectivity for drug candidates and to identify potential undesired effects at a mesoscopic scale. Additionally, it offers a guide towards targeted experiments on newly identified hub regions., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: A number of recent studies have reported an association between intraoperative burst suppression and postoperative delirium. These studies suggest that anesthesia-induced burst suppression may be an indicator of underlying brain vulnerability. A prominent feature of electroencephalogram (EEG) under propofol and sevoflurane anesthesia is the frontal alpha oscillation. This frontal alpha oscillation is known to decline significantly during aging and is generated by prefrontal brain regions that are particularly prone to age-related neurodegeneration. Given that burst suppression and frontal alpha oscillations are both associated with brain vulnerability, we hypothesized that anesthesia-induced frontal alpha power could also be associated with burst suppression., Methods: We analyzed EEG data from a previously reported cohort in which 155 patients received propofol (n = 60) or sevoflurane (n = 95) as the primary anesthetic. We computed the EEG spectrum during stable anesthetic maintenance and identified whether or not burst suppression occurred during the anesthetic. We characterized the relationship between burst suppression and alpha power using logistic regression. We proposed 5 different models consisting of different combinations of potential contributing factors associated with burst suppression: (1) a Base Model consisting of alpha power; (2) an Extended Mechanistic Model consisting of alpha power, age, and drug dosing information; (3) a Clinical Confounding Factors Model consisting of alpha power, hypotension, and other confounds; (4) a Simplified Model consisting only of alpha power and propofol bolus administration; and (5) a Full Model consisting of all of these variables to control for as much confounding as possible., Results: All models show a consistent significant association between alpha power and burst suppression while adjusting for different sets of covariates, all with consistent effect size estimates. Using the Simplified Model, we found that for each decibel decrease in alpha power, the odds of experiencing burst suppression increased by 1.33-fold., Conclusions: In this study, we show how a decrease in anesthesia-induced frontal alpha power is associated with an increased propensity for burst suppression, in a manner that captures individualized information above and beyond a patient's chronological age. Lower frontal alpha band power is strongly associated with higher propensity for burst suppression and, therefore, potentially higher risk of postoperative neurocognitive disorders. We hypothesize that low frontal alpha power and increased propensity for burst suppression together characterize a "vulnerable brain" phenotype under anesthesia that could be mechanistically linked to brain metabolism, cognition, and brain aging.

Epidemiological studies have pointed at diabetes as a risk factor for Alzheimer's disease (AD) and this has been supported by several studies in animal models of both type 1 and type 2 diabetes. However, side-by-side comparison of the two types of diabetes is limited. We investigated the role of insulin deficiency and insulin resistance in the development of memory impairments and the effect of Exendin-4 (Ex4) treatment in a mouse model of AD. Three-4-month-old female wild type (WT) mice and mice overexpressing human tau and amyloid precursor protein (TAPP) were injected with streptozotocin (STZ) or fed a high-fat diet (HFD). A second study was performed in TAPP-STZ mice treated with Ex4, a long-lasting analog of GLP-1. Plasma and brain were collected at study termination for ELISA, Western blot, and immunohistochemistry analysis. Learning and memory deficits were impaired in TAPP transgenic mice compared with WT mice at the end of the study. Deficits were exaggerated by insulin deficiency in TAPP mice but 12 weeks of insulin resistance did not affect memory performances in either WT or TAPP mice. Levels of phosphorylated tau were increased in the brain of WT-STZ and TAPP-STZ mice but not in the brain of WT or TAPP mice on HFD. In the TAPP-STZ mice, treatment with Ex4 initiated after established cognitive deficits ameliorated learning, but not memory, impairments. This was accompanied by the reduction of amyloid β and phosphorylated tau expression. Theses studies support the role of Ex4 in AD, independently from its actions on diabetes., (© 2020 Wiley Periodicals LLC.)

Background: Anesthesia in pregnant rodents causes neurotoxicity in fetal and offspring rodents. However, the underlying mechanisms and targeted treatments remain largely to be determined. Isoflurane and propofol are among commonly used anesthetics. Thus, we set out to investigate whether propofol can mitigate the isoflurane-induced neurotoxicity in mice., Methods: Pregnant C57BL/6 mice at gestational day 15 (G15) were randomly assigned to 4 groups: control, isoflurane, propofol, and isoflurane plus propofol. Levels of interleukin (IL)-6 and poly-ADP ribose polymerase (PARP) fragment were measured in the brains of G15 embryos, and levels of postsynaptic density (PSD)-95 and synaptophysin were determined in the hippocampal tissues of postnatal day 31 (P31) offspring using Western blotting and immunohistochemical staining. Learning and memory functions in P31 offspring were determined using a Morris water maze test., Results: Isoflurane anesthesia in pregnant mice at G15 significantly increased brain IL-6 (222.6% ± 36.45% vs 100.5% ± 3.43%, P < .0001) and PARP fragment (384.2% ± 50.87% vs 99.59% ± 3.25%, P < .0001) levels in fetal mice and reduced brain PSD-95 (30.76% ± 2.03% vs 100.8% ± 2.25%, P < .0001) and synaptophysin levels in cornu ammonis (CA) 1 region (57.08% ± 4.90% vs 100.6% ± 2.20%, P < .0001) and dentate gyrus (DG; 56.47% ± 3.76% vs 99.76% ± 1.09%, P < .0001) in P31 offspring. Isoflurane anesthesia also impaired cognitive function in offspring at P31. Propofol significantly mitigated isoflurane-induced increases in brain IL-6 (117.5% ± 10.37% vs 222.6% ± 36.45%, P < .0001) and PARP fragment (205.1% ± 35.99% vs 384.2% ± 50.87%, P < .0001) levels in fetal mice, as well as reductions in PSD-95 (49.79% ± 3.43% vs 30.76% ± 2.03%, P < .0001) and synaptophysin levels in CA1 region (85.57% ± 2.97% vs 57.08% ± 4.90%, P < .0001) and DG (85.05% ± 1.87% vs 56.47% ± 3.76%, P < .0001) in hippocampus of P31 offspring. Finally, propofol attenuated isoflurane-induced cognitive impairment in offspring., Conclusions: These findings suggest that gestational isoflurane exposure in mice induces neuroinflammation and apoptosis in embryos and causes cognitive impairment in offspring. Propofol can attenuate these isoflurane-induced detrimental effects.

A versatile method was developed and validated for simultaneous determination of the monoamine neurotransmitters (MNT) dopamine (DA), 3-4-dyhydroxyphenilacetic acid (DOPAC), homovanilic acid (HVA), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) in rat brain microdialysate samples using high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). The method allowed for small sample volume, using positive and negative ionization mode in a single run analysis without any derivatization or cleanup steps. Analytes were quantified at concentrations ranging from 100 ng/mL to 0.05, 10, 0.5, 0.1 or 1 ng/mL (lower limit of quantification, LLOQ) of DA, DOPAC, HVA, 5-HT and 5-HIAA, respectively, showing linearity (r > 0.98), accuracy, and precision (R.S.D ± 15%) according to validation limits accepted by international guidelines. The method was successfully applied for monitoring the concentration changes of MNT in microdialysate samples from medium prefrontal cortex of Wistar rats in a neurodevelopmental model of schizophrenia before and after quetiapine 5 mg/kg i.v. bolus dose administration. No alterations in MNTs were observed in schizophrenia phenotyped rats (SPR) in comparison to the baseline shading a light on the limited response rate to antipsychotic drugs observed in chronic schizophrenic patients., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the leading cause of late-onset dementia, and there exists an unmet medical need for effective treatments for AD. The accumulation of neurotoxic amyloid-β (Aβ) plaques contributes to the pathophysiology of AD. EPHX2 encoding soluble epoxide hydrolase (sEH)-a key enzyme for epoxyeicosatrienoic acid (EET) signaling that is mainly expressed in lysosomes of astrocytes in the adult brain-is cosited at a locus associated with AD, but it is unclear whether and how it contributes to the pathophysiology of AD. In this report, we show that the pharmacologic inhibition of sEH with 1-trifluoromethoxyphenyl- 3-(1-propionylpiperidin-4-yl) urea (TPPU) or the genetic deletion of Ephx2 reduces Aβ deposition in the brains of both male and female familial Alzheimer's disease (5×FAD) model mice. The inhibition of sEH with TPPU or the genetic deletion of Ephx2 alleviated cognitive deficits and prevented astrocyte reactivation in the brains of 6-month-old male 5×FAD mice. 14,15-EET levels in the brains of these mice were also increased by sEH inhibition. In cultured adult astrocytes treated with TPPU or 14,15-EET, astrocyte Aβ clearance was increased through enhanced lysosomal biogenesis. Infusion of 14,15-EET into the hippocampus of 5×FAD mice prevented the aggregation of Aβ. Notably, a higher concentration of 14,15-EET (200 ng/ml) infusion into the hippocampus reversed Aβ deposition in the brains of 6-month-old male 5×FAD mice. These results indicate that EET signaling, especially 14,15-EET, plays a key role in the pathophysiology of AD, and that targeting this pathway is a potential therapeutic strategy for the treatment of AD. SIGNIFICANCE STATEMENT There are limited treatment options for Alzheimer's disease (AD). EPHX2 encoding soluble epoxide hydrolase (sEH) is located at a locus that is linked to late-onset AD, but its contribution to the pathophysiology of AD is unclear. Here, we demonstrate that sEH inhibition or Ephx2 deletion alleviates pathology in familial Alzheimer's disease (5×FAD) mice. Inhibiting sEH or increasing 14,15-epoxyeicosatrienoic acid (EET) enhanced lysosomal biogenesis and amyloid-β (Aβ) clearance in cultured adult astrocytes. Moreover, the infusion of 14,15-EET into the hippocampus of 5×FAD mice not only prevented the aggregation of Aβ, but also reversed the deposition of Aβ. Thus, 14,15-EET plays a key role in the pathophysiology of AD and therapeutic strategies that target this pathway may be an effective treatment., (Copyright © 2020 the authors.)

Background: Previous studies have shown that seizures can cause cognitive disorders. On the other hand, the Curcuma zedoaria (CZ) has beneficial effects on the nervous system. However, there is little information on the possible effects of the CZ extract on seizures. The aim of this study was to investigate the possible effects of CZ extract on cognitive impairment and oxidative stress induced by epilepsy in rats., Methods: Rats were randomly divided into different groups. In all rats (except the sham group), kindling was performed by intraperitoneal injection of pentylenetetrazol (PTZ) at a dose of 35 mg/kg every 48 h for 14 days. Positive group received 2 mg/kg diazepam + PTZ; treatment groups received 100, 200 or 400 mg/kg CZ extract + PTZ; and one group received 0.5 mg/kg flumazenil and CZ extract + PTZ. Shuttle box and Morris Water Maze tests were used to measure memory and learning. On the last day of treatments PTZ injection was at dose of 60 mg/kg, tonic seizure threshold and mortality rate were recorded in each group. After deep anesthesia, blood was drawn from the rats' hearts and the hippocampus of all rats was removed., Results: Statistical analysis of the data showed that the CZ extract significantly increased the tonic seizure threshold and reduced the pentylenetetrazol-induced mortality and the extract dose of 400 mg/kg was selected as the most effective dose compared to the other doses. It was also found that flumazenil (a GABA A receptor antagonist) reduced the tonic seizure threshold compared to the effective dose of the extract. The results of shuttle box and Morris water maze behavioral tests showed that memory and learning decreased in the negative control group and the CZ extract treatment improved memory and learning in rats. The CZ extract also increased antioxidant capacity, decreased MDA and NO in the brain and serum of pre-treated groups in compared to the negative control group., Conclusion: It is concluded that the CZ extract has beneficial effects on learning and memory impairment in PTZ-induced epilepsy model, which has been associated with antioxidant effects in the brain or possibly exerts its effects through the GABAergic system.

The low dose of radiation (LDR) has received growing attention for its beneficial neuroprotective effect. This study was designed to investigate the enhancing effect of LDR on the antidepressant potential of resveratrol against diazepam-induced depression in mice. Female mice divided into five groups; control, diazepam (2 mg/kg), LDR (0.5Gy) + diazepam, resveratrol (20 mg/kg) + diazepam, LDR + resveratrol+diazepam. Mice received diazepam showed depressive symptoms as evidenced by decreased locomotor activity in the open field and increased immobility time in the forced swimming and tail suspension tests integrated with a marked decline in biogenic amines (serotonin, norepinephrine, and dopamine) in brain tissues. These effects were ameliorated by LDR or resveratrol administration demonstrating an antidepressant activity. Interestingly, LDR triggered the antidepressant effect of resveratrol as it restored the changes in behavioral tests, neurotransmitters, and neuro-histoarchitecture. In conclusion, these findings suggested that LDR could be considered as a novel adjuvant that augmented the resveratrol antidepressant effect and might serve as a potential therapeutic approach for depression., (© 2020 Wiley Periodicals LLC.)