Ketamine administration causes cognitive impairment by destroying the circulation function of the glymphatic system.

BACKGROUND: Ketamine, as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was originally used in general anesthesia. Epidemiological data show that ketamine has become one of the most commonly abused drugs in China. Ketamine administration might cause cognitive impairment; however, its molecular mechanism remains unclear. The glymphatic system is a lymphoid system that plays a key role in metabolic waste removal and cognitive regulation in the central nervous system. METHODS: Focusing on the glymphatic system, this study evaluated the behavioral performance and circulatory function of the glymphatic system by building a short-term ketamine administration model in mice, and detected the expression levels of the 5-HT2c receptor, ΔFosb, Pten, Akt, and Aqp4 in the hippocampus. Primary astrocytes were cultured to verify the regulatory relationships among related indexes using a 5-HT2c receptor antagonist, a 5-HT2c receptor short interfering RNA (siRNA), and a ΔFosb siRNA. RESULTS: Ketamine administration induced ΔFosb accumulation by increasing 5-HT2c receptor expression in mouse hippocampal astrocytes and primary astrocytes. ΔFosb acted as a transcription factor to recognize the AATGATTAAT bases in the 5' regulatory region of the Aqp4 gene (-1096 bp to -1087 bp), which inhibited Aqp4 expression, thus causing the circulatory dysfunction of the glymphatic system, leading to cognitive impairment. CONCLUSIONS: Although this regulatory mechanism does not involve the Pten/Akt pathway, this study revealed a new mechanism of ketamine-induced cognitive impairment in non-neuronal systems, and provided a theoretical basis for the safety of clinical treatment and the effectiveness of withdrawal.

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

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

Sevoflurane causes neurotoxicity and cognitive impairment by regulating Hippo signaling pathway-mediated ferroptosis via upregulating PRKCD.

BACKGROUND: Sevoflurane (SEV) has been found to induce neurotoxicity and cognitive impairment, leading to the development of degenerative diseases. Protein kinase C delta (PRKCD) is upregulated in the hippocampus of SEV-treated mice and may be related to SEV-related neurotoxicity. However, the underlying molecular mechanisms by which SEV mediates neurotoxicity via PRKCD remain unclear. METHODS: Normal mice and PRKCD knockout (KO) mice were exposed to SEV. Hippocampal neurons were isolated from mice hippocampal tissues. H&E staining was used for pathological morphology of hippocampal tissues, and NISSL staining was used to analyze the number of hippocampal neurons. The mRNA and protein levels were determined using quantitative real-time PCR, western blot, immunofluorescence staining and immunohistochemical staining. The mitochondrial microstructure was observed by transmission electron microscopy. Cell viability was detected by cell counting kit 8 assay, and ferroptosis was assessed by detecting related marker levels. The cognitive ability of mice was assessed by morris water maze test. And the protein levels of PRKCD, ferroptosis-related markers and Hippo pathway-related markers were examined by western bolt. RESULTS: SEV increased PRKCD expression and ferroptosis in hippocampal tissues of mice. Also, SEV promoted mouse hippocampal neuron injury by inducing ferroptosis via upregulating PRKCD expression. Knockout of PRKCD alleviated SEV-induced neurotoxicity and cognitive impairment in mice, and relieved SEV-induced ferroptosis in hippocampal neurons. PRKCD could inhibit the activity of Hippo pathway, and its knockdown also overturned SEV-mediated ferroptosis by activating Hippo pathway. CONCLUSION: SEV could induce neurotoxicity and cognitive impairment by promoting ferroptosis via inactivating Hippo pathway through increasing PRKCD expression.

Integrated ribosome and proteome analyses reveal insights into sevoflurane-induced long-term social behavior and cognitive dysfunctions through ADNP inhibition in neonatal mice.

A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment. Davunetide, an active fragment of the activity-dependent neuroprotective protein (ADNP), has been implicated in social and cognitive protection. However, the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood. In this study, ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice. The neuropathological basis was also explored using Golgi staining, morphological analysis, western blotting, electrophysiological analysis, and behavioral analysis. Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane. In adulthood, anterior cingulate cortex (ACC) neurons exposed to sevoflurane exhibited a decrease in dendrite number, total dendrite length, and spine density. Furthermore, the expression levels of Homer, PSD95, synaptophysin, and vglut2 were significantly reduced in the sevoflurane group. Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). Notably, davunetide significantly ameliorated the synaptic defects, social behavior deficits, and cognitive impairments induced by sevoflurane. Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca 2+ activity via the Wnt/ß-catenin signaling, resulting in decreased expression of synaptic proteins. Suppression of Wnt signaling was restored in the davunetide-treated group. Thus, ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.

The role of chitosan in mitigating tert-butylhydroquinone induced cognitive impairment and neurotoxicity in a rat model.

OBJECTIVE: This study aimed to investigate the impact of tert-butylhydroquinone (TBHQ), chitosan, and their combination on memory and neurobiochemical parameters in a rat model. The primary objectives were to assess the cognitive effects of TBHQ, explore the cognitive-enhancing properties of chitosan, and evaluate the combined effects of these substances. MATERIALS AND METHODS: A rat model was employed for behavioral tests, biochemical analyses, and histological examinations. Rats were exposed to TBHQ, chitosan, or a combination of both, and cognitive function was assessed through behavioral tests. Biochemical analyses focused on neurobiochemical parameters associated with memory and oxidative stress. Histological examinations were conducted to observe any structural changes in the brain. RESULTS: TBHQ exposure was associated with memory impairments and increased oxidative stress, indicating potential neurotoxic effects. Chitosan supplementation demonstrated cognitive-enhancing effects and showed promise in mitigating the memory impairments and oxidative stress induced by TBHQ. The combination of chitosan and TBHQ presented a potential protective effect on neurological health. CONCLUSIONS: Chitosan supplementation alongside TBHQ may mitigate memory impairments and oxidative stress associated with TBHQ exposure in a rat model. The study provides valuable insights into the cognitive effects of TBHQ and the neuroprotective potential of chitosan, highlighting the need for further research to elucidate molecular pathways and clinical implications. These findings contribute to understanding chitosan's role in safeguarding neurological health in conditions where TBHQ exposure is a concern, warranting further investigations for translational applications in human health.

CCR5 antagonist maraviroc alleviates doxorubicin-induced neuroinflammation and neurobehavioral deficiency by regulating NF-κB/NLRP3 signaling in a breast cancer mouse model.

The chemotherapeutic agent Doxorubicin (DOX) is known to cause chemotherapy-induced cognitive impairment (CICI). Maraviroc, a potent C-C chemokine receptor 5 (CCR5) antagonist, shows neuroprotective properties, while its role in CICI remains unclear. This study determined the therapeutic potential of maraviroc on CICI. Adult C57BL/6J mice with implanted breast cancer cells received four weekly intraperitoneal injections of saline (Control group), 5 mg/kg DOX (DOX group), 10 mg/kg maraviroc (MVC group), or 5 mg/kg DOX with 10 mg/kg maraviroc (DOX + MVC group). The Morris Water Maze (MWM) was used for neurobehavioural test. Western blot analysis and immunofluorescence were used to evaluate the expressions of inflammatory markers, apoptosis-related proteins, and synaptic-related proteins. The volume and weight of tumor were also evaluated after treatments. DOX treatment significantly increased chemokines (CCL3, CCL4) and inflammatory cytokines (IL-1ß, TNF-α) in tumor-bearing mice hippocampus. While maraviroc administration reduced hippocampal proinflammatory factors compared to the DOX group. Furthermore, it also lowered apoptosis markers, restored synaptic proteins levels, and inhibited the NF-κB/NLRP3 pathway. Accordingly, maraviroc treatment significantly improved DOX-induced neurobehavioural impairments as evidenced by an increased number of platform crossings and percentage of target quadrant time in the MWM test. Additionally, when combined with DOX, maraviroc had additional inhibitory effects on tumor growth. These findings suggest that maraviroc can mitigate DOX-induced CICI by suppressing elevated proinflammatory chemokines and cytokines through the NF-κB/NLRP3 pathway, potentially offering an anti-tumor benefit. This research presents a promising therapeutic approach for DOX-induced CICI, enhancing the safety and efficacy of cancer treatments.

Fer-1 Protects against Isoflurane-Induced Ferroptosis in Astrocytes and Cognitive Impairment in Neonatal Mice.

Early and prolonged exposure to anesthetic agents could cause neurodevelopmental disorders in children. Astrocytes, heavily outnumber neurons in the brain, are crucial regulators of synaptic formation and function during development. However, how general anesthetics act on astrocytes and the impact on cognition are still unclear. In this study, we investigated the role of ferroptosis and GPX4, a major hydroperoxide scavenger playing a pivotal role in suppressing the process of ferroptosis, and their underlying mechanism in isoflurane-induced cytotoxicity in astrocytes and cognitive impairment. Our results showed that early 6 h isoflurane anesthesia induced cognitive impairment in mice. Ferroptosis-relative genes and metabolic changes were involved in the pathological process of isoflurane-induced cytotoxicity in astrocytes. The level of GPX4 was decreased while the expression of 4-HNE and generation of ROS were elevated after isoflurane exposure. Selectively blocking ferroptosis with Fer-1 attenuated the abovementioned cytotoxicity in astrocytes, paralleling with the reverse of the changes in GPX4, ROS and 4-HNE secondary to isoflurane anesthesia. Fer-1 attenuated the cognitive impairment induced by prolonged isoflurane exposure. Thus, ferroptosis conduced towards isoflurane-induced cytotoxicity in astrocytes via suppressing GPX4 and promoting lipid peroxidation. Fer-1 was expected to be an underlying intervention for the neurotoxicity induced by isoflurane in the developing brain, and to alleviate cognitive impairment in neonates.

The duration-dependent and sex-specific effects of neonatal sevoflurane exposure on cognitive function in rats.

Clinical studies have found that neonatal sevoflurane exposure can increase the risk of cognitive dysfunction. However, recent studies have found that it can exhibit neuroprotective effects in some situations. In this study, we aimed to explore the effects of sevoflurane neonatal exposure in rats. A total of 144 rat pups (72 males and 72 females) were assigned to six groups and separately according to sevoflurane exposure of different times on the seventh day after birth. Blood gas analysis and western blot detection in the hippocampus were conducted after exposure. The Morris water maze test was conducted on the 32nd to 38th days after birth. The expression of PSD95 and synaptophysin in the hippocampus was detected after the Morris water maze test. We found that neonatal exposure to sevoflurane promoted apoptosis in the hippocampus, and Bax and caspase-3 were increased in a dose-dependent manner. The 2-h exposure had the greatest effects on cognitive dysfunction. However, with the extension of exposure time to 6 h, the effects on cognitive function were partly compensated. In addition, sevoflurane exposure decreased synaptogenesis in the hippocampus. However, as the exposure time was extended, the suppression of synaptogenesis was attenuated. In conclusion, neonatal sevoflurane exposure exhibited duration-dependent effects on cognitive function via Bax-caspase-3-dependent apoptosis and bidirectional effects on synaptogenesis in rats.

Cornuside ameliorates cognitive impairments via RAGE/TXNIP/NF-κB signaling in Aß1-42 induced Alzheimer's disease mice.

Cornuside has been discovered to improve learning and memory in AD mice, however, its underlying mechanism was not fully understood. In the present study, we established an AD mice model by intracerebroventricular injection of Aß1-42, which were treated with cornuside (3, 10, 30 mg/kg) for 2 weeks. Cornuside significantly ameliorated cognitive function of AD mice in series of behavioral tests, including Morris water maze test, nest building test, novel object recognition test and step-down test. Additionally, cornuside could attenuate neuronal injury, and promote cholinergic synaptic transmission by restoring the level of acetylcholine (ACh) via inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as facilitating choline acetyltransferase (ChAT). Furthermore, cornuside inhibited oxidative stress levels amplified as decreased malondialdehyde (MDA), by inhibiting TXNIP expression, improving total anti-oxidative capacity (TAOC), raising activities of superoxide dismutase (SOD) and catalase (CAT). Cornuside also reduced the activation of microglia and astrocytes, decreased the level of proinflammatory factors TNF-α, IL-6, IL-1ß, iNOS and COX2 via interfering RAGE-mediated IKK-IκB-NF-κB phosphorylation. Similar anti-oxidative and anti-inflammatory effects were also found in LPS-stimulated BV2 cells via hampering RAGE-mediated TXNIP activation and NF-κB nuclear translocation. Virtual docking revealed that cornuside could interact with the active pocket of RAGE V domain directly. In conclusion, cornuside could bind to the RAGE directly impeding the interaction of Aß and RAGE, and cut down the expression of TXNIP inhibiting ROS production and oxidative stress, as well as hamper NF-κB p65 mediated the inflammation.

Proteomic Landscape Associated with Cognitive Impairment in Individuals with Long-term Methamphetamine Dependence.

BACKGROUND: Methamphetamine (METH) is a highly addictive drug that directly affects the central nervous system. METH use not only harms the user's health but also poses risks and costs to society. Prolonged METH dependence has been shown to impair cognition, which may be the primary factor in impulsive drug-seeking behaviors and high relapse rates. However, the molecular mechanisms underlying METH addiction and METH-induced cognitive decline remain poorly understood. METHODS: To illuminate the potential molecular mechanisms underpinning METH addiction, we compared serum protein expression levels between 12 long-term METH users and 12 healthy controls using label-free quantitative proteomics. Bioinformatic analyses were conducted to determine functional networks and protein-protein interactions. RESULTS: In total, 23 differentially expressed proteins were identified between the two groups. The differentially expressed proteins were related to cognitive dysfunction, neuroinflammation, immune impairment, metabolic disturbances, and calcium binding and regulation. CONCLUSIONS: These 23 proteins may underpin the multi-system damage induced by chronic METH exposure. Our findings provide novel insights into the molecular basis of METH addiction and inform potential prevention and treatment strategies for individuals with METH dependence.

Melatonin mitigates cisplatin-induced cognitive impairment in rats and improves hippocampal dendritic spine density.

Cisplatin-induced cognitive impairment (chemobrain) affects a considerable percentage of cancer patients and has no established pharmacological treatment. Chemobrain can be associated with neuroinflammation and oxidative stress. Melatonin, a pineal hormone, is known to have antioxidant, anti-inflammatory and neuroprotective potential. In this study, we investigated cisplatin-induced cognitive impairment in rats and whether melatonin can improve or reverse this impairment. Behavioral testing involved measuring working memory using the novel location recognition test (NLRT) under conditions of cisplatin or cisplatin + melatonin treatment, followed by the collection of rats' brains. The brains were subsequently stained with Golgi-Cox stain and then the hippocampus area CA3 of each one was examined, and dendritic spine density was calculated. Treatment with cisplatin resulted in deficits in the rats' performance in the NLRT (P < 0.05). These deficits were prevented by the coadministration of melatonin (P < 0.05). Cisplatin also reduced the density of dendritic spines in the hippocampus (P < 0.0001), specifically CA3 area, while the coadministration of melatonin significantly reversed this reduction (P < 0.001). This study showed that melatonin can ameliorate cisplatin-induced spatial memory deficits and dendritic spines density abnormalities in rats. Given that melatonin is a safe and wildly used supplement, it is feasible to explore its use as a palliative intervention in cancer treatment.

[Drug-induced cognitive impairment and dementia]. / Lekarstvenno-indutsirovannye kognitivnye narusheniya i dementsiya.

One of the reasons for the development or worsening of cognitive impairment (CI) may be the use of a number of drugs: non-steroidal anti-inflammatory drugs, antiarrhythmics, antidepressants, glucocorticosteroids, antitumor drugs and a number of others. The negative effect of drugs on cognitive functions is realized due to many pathophysiological mechanisms: disruption of hormonal regulation, decreased neuronal excitability, increased activity of gamma-aminobutyric acid receptors, decreased cerebral circulation, atrophic changes in the brain; many mechanisms have not been fully established. Risk factors for the development of drug-induced CIs are: old age or childhood, brain damage, chronic diseases, genetic factors, the patient's initial CI, polypharmacy, dose and duration of drug use, acute infectious diseases, metabolic disorders, dehydration, acute urinary retention, etc. To diagnose and differentially diagnose drug-induced CI, it is necessary to establish a connection between the start of taking a suspected drug-inducer and a decrease in cognitive functions. The first step in the treatment of drug-induced CI is the abolition of an inducer drug or a reduction in its dose, in cases where it is impossible to discontinue the drug and there is no replacement, special slow-release dosage forms can be considered. The main measures to prevent drug-induced CI include the use of drugs with the lowest risk of their development, assessment of drug interactions, and the use of modern scales to assess the risk of developing this side-effect (anticholinergic burden scale, etc.).

Protective effects of paeonol against cognitive impairment in lung diseases.

Pulmonary inflammation may lead to neuroinflammation resulting in neurological dysfunction, and it is associated with a variety of acute and chronic lung diseases. Paeonol is a herbal phenolic compound with anti-inflammatory and anti-oxidative properties. The aim of this study is to understand the beneficial effects of paeonol on cognitive impairment, pulmonary inflammation and its underlying mechanisms. Pulmonary inflammation-associated cognitive deficit was observed in TNFα-stimulated mice, and paeonol mitigated the cognitive impairment by reducing the expressions of interleukin (IL)-1ß, IL-6, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) in hippocampus. Moreover, elevated plasma miR-34c-5p in lung-inflamed mice was also reduced by paeonol. Pulmonary inflammation induced by intratracheal instillation of TNFα in mice resulted in immune cells infiltration in bronchoalveolar lavage fluid, pulmonary edema, and acute fibrosis, and these inflammatory responses were alleviated by paeonol orally. In MH-S alveolar macrophages, tumor necrosis factor (TNF) α- and phorbol myristate acetate (PMA)-induced inflammasome activation was ameliorated by paeonol. In addition, the expressions of antioxidants were elevated by paeonol, and reactive oxygen species production was reduced. In this study, paeonol demonstrates protective effects against cognitive deficits and pulmonary inflammation by exerting anti-inflammatory and anti-oxidative properties, suggesting a powerful benefit as a potential therapeutic agent.

Cadmium exposure induced neuronal ferroptosis and cognitive deficits via the mtROS-ferritinophagy pathway.

Exposure to environmental cadmium (Cd) is known to cause neuronal death and cognitive decline in humans. Ferroptosis, a novel iron-dependent type of regulated cell death, is involved in various neurological disorders. In the present study, Cd exposure triggered ferroptosis in the mouse hippocampus and in the HT22 murine hippocampal neuronal cell line, as indicated by significant increases in ferroptotic marker expression, intracellular iron levels, and lipid peroxidation. Interestingly, ferroptosis of hippocampal neurons in response to Cd exposure relied on the induction of autophagy since the suppression of autophagy by 3-methyladenine (3-MA) and chloroquine (CQ) substantially ameliorated Cd-induced ferroptosis. Furthermore, nuclear receptor coactivator 4 (NCOA4)-mediated degradation of ferritin was required for the Cd-induced ferroptosis of hippocampal neurons, demonstrating that NCOA4 knockdown decreased intracellular iron levels and lipid peroxidation and increased cell survival, following Cd exposure. Moreover, Cd-induced mitochondrial reactive oxygen species (mtROS) generation was essential for the ferritinophagy-mediated ferroptosis of hippocampal neurons. Importantly, pretreatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively attenuated Cd-induced hippocampal neuronal death and cognitive impairment in mice. Taken together, these findings indicate that ferroptosis is a novel mechanism underlying Cd-induced neurotoxicity and cognitive impairment and that the mtROS-ferritinophagy axis modulates Cd-induced neuronal ferroptosis.

GPX4 degradation contributes to fluoride-induced neuronal ferroptosis and cognitive impairment via mtROS-chaperone-mediated autophagy.

Ferroptosis is a newly recognized type of programmed cell death that is implicated in the pathophysiological process of neurological disorders. Our previous studies have revealed that exposure to high concentrations of fluoride for long periods of time induces hippocampal neural injury and cognitive deficits. However, whether ferroptosis is involved in fluoride-induced neuronal death and the underlying mechanism remain unknown. In this study, the results indicated that exposure to high fluoride triggered ferroptosis in SH-SY5Y cells and in the hippocampus of mice. Fluoride exposure accelerated the lysosomal degradation of GPX4 and led to neuronal ferroptosis, while GPX4 overexpression protected SH-SY5Y cells against fluoride-induced neurotoxicity. Intriguingly, the enhanced chaperone-mediated autophagy (CMA) induced by fluoride stimulation was responsible for GPX4 degradation because the inhibition of CMA activity by LAMP2A knockdown effectively prevented fluoride-induced GPX4 loss. Furthermore, mitochondrial ROS (mtROS) accumulation caused by fluoride contributed to CMA activation-mediated GPX4 degradation and subsequent neuronal ferroptosis. Notably, the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or the ROS scavenger N-acetyl-L-cysteine (NAC) alleviated fluoride-evoked hippocampal neuronal death and synaptic injury as well as cognitive deficits in mice. The present studies indicates that ferroptosis is a novel mechanism of fluoride-induced neurotoxicity and that chronic fluoride exposure facilitates GPX4 degradation via mtROS chaperone-mediated autophagy, leading to neuronal ferroptosis and cognitive impairment.

The NRF2 activator RTA-408 ameliorates chronic alcohol exposure-induced cognitive impairment and NLRP3 inflammasome activation by modulating impaired mitophagy initiation.

BACKGROUND: Chronic alcohol exposure induces cognitive impairment and NLRP3 inflammasome activation in the mPFC (medial prefrontal cortex). Mitophagy plays a crucial role in neuroinflammation, and dysregulated mitophagy is associated with behavioral deficits. However, the potential relationships among mitophagy, inflammation, and cognitive impairment in the context of alcohol exposure have not yet been studied. NRF2 promotes the process of mitophagy, while alcohol inhibits NRF2 expression. Whether NRF2 activation can ameliorate defective mitophagy and neuroinflammation in the presence of alcohol remains unknown. METHODS: BV2 cells and primary microglia were treated with alcohol. C57BL/6J mice were repeatedly administered alcohol intragastrically. BNIP3-siRNA, PINK1-siRNA, CCCP and bafilomycin A1 were used to regulate mitophagy in BV2 cells. RTA-408 acted as an NRF2 activator. Mitochondrial dysfunction, mitophagy and NLRP3 inflammasome activation were assayed. Behavioral tests were used to assess cognition. RESULTS: Chronic alcohol exposure impaired the initiation of both receptor-mediated mitophagy and PINK1-mediated mitophagy in the mPFC and in vitro microglial cells. Silencing BNIP3 or PINK1 induced mitochondrial dysfunction and aggravated alcohol-induced NLRP3 inflammasome activation in BV2 cells. In addition, alcohol exposure inhibited the NRF2 expression both in vivo and in vitro. NRF2 activation by RTA-408 ameliorated NLRP3 inflammasome activation and mitophagy downregulation in microglia, ultimately improving cognitive impairment in the presence of alcohol. CONCLUSION: Chronic alcohol exposure-induced impaired mitophagy initiation contributed to NLRP3 inflammasome activation and cognitive deficits, which could be alleviated by NRF2 activation via RTA-408.

Cognitive impairment following sedative overdose.

INTRODUCTION: Patients with sedative overdose may have residual cognitive impairment at the time they are deemed medically cleared for discharge. Impairment could affect the performance of high-risk activities, including driving. The Trail Making Test is an alpha-numeric assessment that can be performed at the bedside to assess cognitive function. We examined whether there were differences in cognitive function when medically cleared between patients that overdosed on sedative and non-sedative drugs. METHODS: A prospective, observational study assessed cognitive function using the Trail Making Test between 2018 and 2021. Patients (16 years and greater) completed testing upon medical clearance if they spoke English and had no previous neurological injury. Continuous covariates were compared using t-tests or Mann-Whitney U tests and multiple linear regression; binary variables were modelled using logistic regression. RESULTS: Of 171 patients enrolled, 111 (65 per cent) had sedative overdose; they were older (median 32.1 versus 22.2 years) and more likely to be male (58.6 per cent versus 36.7 per cent). Benzodiazepines and paracetamol were the commonest drug overdoses. Patients with sedative overdose performed worse on Trail Making Test part A (37.0 versus 33.1 seconds, P = 0.017) and Trail Making Test part B (112.4 versus 81.5 seconds, P = 0.004). Multiple linear regression analysis indicated that patient age (P < 0.001, 1.7 seconds slower per year, 95 per cent confidence interval: 0.9-2.6 seconds) and perception of recovery (P = 0.006, 36.4 seconds slower if perceived not recovered, 95 per cent confidence interval: 10.8-62.0 seconds) were also associated with Trail Making Test part B times. Patients with sedative overdose were more likely to be admitted to the intensive care unit (Odds Ratio: 4.9, 95 percent confidence interval: 1.1-22.0; P = 0.04). DISCUSSION: Our results are broadly in keeping with previously published work, but include a wider range of drug overdose scenarios (polypharmacy and recreational drugs). While patients demonstrated some perception of their cognitive impairment, our model could not reliably be used to provide individual discharge advice. The study design did not allow us to prove causation of cognitive impairment, or to make comparison between the strength of an overdose to the trail making test time. CONCLUSIONS: Trail Making Test results suggested that patients who had sedative drug overdoses may have significant cognitive deficits even when medically cleared. Risk of harm may be minimised with advice to avoid high-risk activities such as driving. More profound impacts seen on the Trail Making Test part B than A may mean higher-order thinking is more affected than simple cognitive function.

Kai-xin-san improves cognitive impairment in D-gal and Aß25-35 induced ad rats by regulating gut microbiota and reducing neuronal damage.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai-Xin-San (KXS) is a classic herbal formula for the treatment and prevention of AD (Alzheimer's disease) with definite curative effect, but its mechanism, which involves multiple components, pathways, and targets, is not yet fully understood. AIM OF THE STUDY: To verify the effect of KXS on gut microbiota and explore its anti-AD mechanism related with gut microbiota. MATERIALS AND METHODS: AD rat model was established and evaluated by intraperitoneal injection of D-gal and bilateral hippocampal CA1 injections of Aß25-35. The pharmacodynamics of KXS in vivo includes general behavior, Morris water maze test, ELISA, Nissl & HE staining and immunofluorescence. Systematic analysis of gut microbiota was conducted using 16S rRNA gene sequencing technology. The potential role of gut microbiota in the anti-AD effect of KXS was validated with fecal microbiota transplantation (FMT) experiments. RESULTS: KXS could significantly improve cognitive impairment, reduce neuronal damage and attenuate neuroinflammation and colonic inflammation in vivo in AD model rats. Nine differential intestinal bacteria associated with AD were screened, in which four bacteria (Lactobacillus murinus, Ligilactobacillus, Alloprevotella, Prevotellaceae_NK3B31_group) were very significant. CONCLUSION: KXS can maintain the ecological balance of intestinal microbiota and exert its anti-AD effect by regulating the composition and proportion of gut microbiota in AD rats through the microbiota-gut-brain axis.

Molecular crosstalk and putative mechanisms underlying mitochondrial quality control: The hidden link with methylmercury-induced cognitive impairment.

Methylmercury (MeHg) is a neurotoxin associated with foetal neurodevelopmental and adult cognitive deficits. Neurons are highly dependent on the tricarboxylic acid cycle and oxidative phosphorylation to produce ATP and meet their high energy demands. Therefore, mitochondrial quality control (MQC) is critical for neuronal homeostasis. While existing studies have generated a wealth of data on the toxicity of MeHg, the complex cascades and molecular pathways governing the mitochondrial network remain to be elucidated. Here, 0.6, 1.2 and 2.4 mg/kg body weight of MeHg were administered intragastrically to pregnant Sprague Dawley rats to model maternal MeHg exposure. The results of the in vivo study revealed that MeHg-treated rats tended to perform more directionless repetitive strategies in the Morris Water Maze and fewer target-orientation strategies than control offspring. Moreover, pathological injury and synaptic toxicity were observed in the hippocampus. Transmission electron microscopy (TEM) demonstrated that the autophagosomes encapsulated damaged mitochondria, while showing a typical mitochondrial fission phenotype, which was supported by the activation of PINK1-dependent key regulators of mitophagy. Moreover, there was upregulation of DRP1 and FIS1. Additionally, MeHg compensation promoted mitochondrial biogenesis, as evidenced by the activation of the mitochondrial PGC1-α-NRF1-TFAM signalling pathway. Notably, SIRT3/AMPK was activated by MeHg, and the expression and activity of p-AMPK, p-LKB1 and SIRT3 were consistently coordinated. Collectively, these findings provide new insights into the potential molecular mechanisms regulating MeHg-induced cognitive deficits through SIRT3/AMPK MQC network coordination.

Precise timing of audiovisual stimulation conquers chemobrain.

In a recent study, Kim et al. utilized gamma entrainment using sensory stimuli (GENUS) to rescue cognitive impairment and glial dysregulation associated with cisplatin and methotrexate chemotherapy, specifically when applied both throughout and after chemotherapy administration. GENUS provides a time-dependent, non-invasive method for treating chemobrain, with broader implications for resolving neurodegenerative neuroinflammation.