Neurochemistry International[JOURNAL]
Sun
200 papers
RNA sequencing analysis identifies sex differences in transcriptional signatures in the dorsal striatum of female and male rats after withdrawal from methamphetamine self-administration.
Gujar VV, Daiwile AP, Palande V … +1 more , Cadet JL
Neurochem Int · 2025 Jul · PMID 40280491 · Full text
Significant methamphetamine (METH)-induced behavioral differences exist between the two sexes of humans and other animals. These dissimilarities may be related to sexual dimorphism in baseline molecular and biochemical m...
Significant methamphetamine (METH)-induced behavioral differences exist between the two sexes of humans and other animals. These dissimilarities may be related to sexual dimorphism in baseline molecular and biochemical mechanisms in brain reward neuroanatomical pathways. As a first step towards identifying sex-based differences in methamphetamine-induced transcriptional signatures, we used RNA sequencing analysis to measure genome-wide changes in gene expression in the dorsal striatum of rats that had self-administered METH. We trained rats to self-administer METH (0.1 mg/kg/infusion, i.v.) using two 3-hr daily sessions (with 30 min time out between sessions) for 20 days. Control rats self-administered saline under similar conditions. This was followed by drug seeking tests on withdrawal days 3 (WD3) and 30 (WD30). Behavioral results show that male rats took more METH than female rats. In both male and female rats, some animals escalated (high-takers) whereas others did not escalate (low-takers) their METH intake during the behavioral experiment. Rats were euthanized 24 h after the second drug seeking test. RNA was extracted from the dorsal striatum (dSTR) and used in RNA sequencing analysis. The data identified substantial baseline differences in gene expression between female and male control rats. In addition, METH use and withdrawal were associated with significant sex-related differences in changes in striatal gene expression, with minimal overlaps of altered mRNAs. Thus, the present results provide further supporting evidence for sexually dimorphic responses to METH exposure. These observations support the notion of sex-specific approaches to the treatment of patients who suffer from METH use disorder.
Non-canonical STAT3 pathway induces alterations of mitochondrial dynamic proteins in the hippocampus of an LPS-induced murine neuroinflammation model.
Millot P, Duquesne L, San C … +6 more , Porte B, Pujol C, Hosten B, Hugon J, Paquet C, Mouton-Liger F
Neurochem Int · 2025 Jun · PMID 40209854 · Publisher ↗
The activation of STAT3 is a crossroads of cellular regulation, induced in its canonical pathway by phosphorylation on a critical tyrosine residue (Y705). The existence of a STAT3 non-canonical signaling mechanisms, indu...
The activation of STAT3 is a crossroads of cellular regulation, induced in its canonical pathway by phosphorylation on a critical tyrosine residue (Y705). The existence of a STAT3 non-canonical signaling mechanisms, induced by phosphorylation at serine 727 (S727), has been recently identified in vitro. After cytoplasmic activation, non-canonical STAT3 could move to the level of mitochondria-endoplasmic reticulum contacts (MERCs). We have previously shown that LPS injections in mouse model induce STAT3 canonical pathway, leading to its nuclear translocation and to neuroinflammation. However, the effects of LPS on activation of the non-canonical pathway and its consequences on protein complexes of MERCs remain to be determined. In an in vivo LPS mouse model, we found that systemic inflammation induces in hippocampus the non-canonical STAT3 pathway. LPS-induced STAT3 affects specifically MERC protein BAP31, and that of a mitochondrial membrane protein known to interact with it, TOM40. These findings shed light on the role of STAT3 on mitochondrial - endoplasmic reticulum interaction under inflammatory conditions, offering new perspectives for targeting mitochondrial function and STAT3 activation in disease contexts.
Illustrating the distribution and metabolic regulatory effects of nuciferine by mass spectrometry imaging and spatial metabolomics.
Liu G, Wu Y, Pan L … +6 more , Wang Q, Zhang Y, Yan J, Zhang P, Zhang W, Kong D
Neurochem Int · 2025 Jun · PMID 40204158 · Publisher ↗
Nuciferine has been widely used in traditional Chinese medicine compound preparations and natural edible resources. Most current studies have concentrated on its lipid-lowering and weight-loss effects, while relatively f...
Nuciferine has been widely used in traditional Chinese medicine compound preparations and natural edible resources. Most current studies have concentrated on its lipid-lowering and weight-loss effects, while relatively few have explored its impact on central nervous system disorders. To investigate the effects of nuciferine on the nervous system and its potential pharmacological mechanisms, we mapped the distribution of nuciferine and its key metabolites in brain microregions and major organs of mice using air-flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI). Nuciferine was found to be distributed throughout the brain, particularly in the prefrontal cortex and hippocampus. Additionally, nuciferine was detected in several peripheral organs, including the heart, liver, kidneys, and spleen. We also identified the distribution of a major demethylated metabolite (M1), which correlated with the localization of the CYP1A2 enzyme. Metabolomic analysis revealed that nuciferine significantly alters purine metabolism, specifically increasing adenosine levels while decreasing xanthine and hypoxanthine. This metabolic shift suggests a potential enhancement of neuroinhibitory effects, contributing to nuciferine's sedative, hypnotic, and analgesic properties. These findings provide novel insights into the neuropharmacological mechanisms of nuciferine.
Mechanism of Tau protein incorporation into exosomes via cooperative recognition of KFERQ-like motifs by LAMP2A and HSP70.
Xu S, Liu K, Qian S … +4 more , Wu J, Hu J, Zhou D, Zheng T
Neurochem Int · 2025 Jun · PMID 40187566 · Publisher ↗
Aggregates of the tau protein is a well-known hallmark of Alzheimer's disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD). Tau can be propagated between nerve cells or brain areas, similar as 'seed'...
Aggregates of the tau protein is a well-known hallmark of Alzheimer's disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD). Tau can be propagated between nerve cells or brain areas, similar as 'seed'. As a member of small extracellular vesicles, exosomes may act as one of the most important 'seeding machines', disseminating toxic tau and phosphorylated tau proteins between cells and thereby amplifying their neurotoxic effects. Therefore, exploring the underlying mechanisms of Tau loading into exosomes is of great importance. In this study, human P301L tau transfections were established in SH-SY5Y cells (SY5Y-EGFP-TauP301L cells). The content of membrane protein LAMP2A and HSP70 proteins was significantly increased in the SY5Y-EGFP-Tau P301L cells compared to control group. Tau containing KFERQ-like motifs pentapeptide interact with LAMP2A and HSP70, forming a multi-protein complex, which can be loaded into a subpopulation of exosomes. Moreover, knockout of LAMP2A significantly reduced the content of Tau protein in exosomes obtained from SY5Y-EGFP-Tau P301L cells. Thus, exosome-mediated secretion of tau protein may depend on the formation of multi-protein (KFERQ-like motif pentapeptide in tau,LAMP2A and HSP70) complex. These findings revealed the presence of a novel mechanism by which release of tau through exosome secretion pathway and that LAMP2A may play an important role in the regulation of exosome-mediated secretion of tau, which may become a potential therapeutic target for AD or other Tauopathies.
Sp4/HD11 and Sp1/HAT-p300 complexes induce apoptotic cell death in CuCl-treated neurons by modulating histone acetylation on BCL-W and BAX promoters.
Ruggiero S, Guida N, Mascolo L … +11 more , Serani A, Ferrante A, Galasso F, Sanguigno L, Piemonte E, De Rosa E, Montuori P, Triassi M, Di Renzo G, Galgani M, Formisano L
Neurochem Int · 2025 Jun · PMID 40185277 · Publisher ↗
Copper is a metal physiologically present in the brain that becomes neurotoxic at high concentrations; on the other hand, pharmacological inhibition of Histone Deacetylases (HDs) or of Histone Acetyltransferases (HATs) r...
Copper is a metal physiologically present in the brain that becomes neurotoxic at high concentrations; on the other hand, pharmacological inhibition of Histone Deacetylases (HDs) or of Histone Acetyltransferases (HATs) reduce neuronal death caused by several neurotoxicants. Herein, we found that CuCl (300 μM in SH-SY5Y cells or 100 μM in cortical neurons) determined apoptotic cell death, that was counteracted by the class IV HDs inhibitor Mocetinostat (MOCE) and by the HAT-p300 inhibitor C646, but not by the class I and II HDs inhibitors. Interestingly, HD11 and HAT-p300 protein levels increased after both 12 and 24 h of CuCl exposure and their silencing partially limited CuCl-neurodetrimental effect. Furthermore, in CuCl-treated cells the transcriptional factor Sp4 co-localized with HD11 on the promoter of anti-apoptotic gene BCL-W, determining histone H3 hypo-acetylation, a marker of gene repression. Contrarily, Sp1 co-localized with HAT-p300 on the pro-apoptotic gene BAX, determining histone H4 hyper-acetylation, a hallmark of transcriptional activation. In addition, siRNA against Sp4 prevented HD11 binding on BCL-W promoter and its consequent down-regulation, whereas Sp1 knocking-down, by reducing HAT-p300 interaction on BAX gene promoter counteracted its up-regulation. Importantly, while the single knocking-down of Sp1, Sp4, HD11 and HAT-p300 partially mitigated CuCl-induced cell death, the double-transfection of siRNAs for Sp1 and Sp4, or for HD11 and HAT-p300, completely reverted the neurotoxic effect of CuCl. Collectively, we found that CuCl-induced neuronal apoptosis is determined by the binding of Sp1/HAT-p300 and of Sp4/HD11 transcriptional complexes on the BAX and BCL-W gene, respectively, unraveling a new pathway involved in Copper-induced neurotoxicity.
Chronic inflammatory pain suppresses alcohol intake and accumbal dopamine response.
Cuitavi J, Riera-Calabuig A, Campos-Jurado Y … +4 more , Lorente JD, de Jorge M, Polache A, Hipólito L
Neurochem Int · 2025 Jun · PMID 40180247 · Publisher ↗
Alcohol use disorders (AUDs) are influenced by factors that initiate, maintain, and/or induce relapse. Chronic pain is both a risk factor for and consequence of AUD, sharing neurological pathways that affect the mesolimb...
Alcohol use disorders (AUDs) are influenced by factors that initiate, maintain, and/or induce relapse. Chronic pain is both a risk factor for and consequence of AUD, sharing neurological pathways that affect the mesolimbic dopaminergic system. This study examines how inflammatory pain impacts long-term alcohol intake and mesolimbic dopamine transmission in alcohol-naïve rats. Inflammatory pain was induced in eight-week-old Sprague Dawley rats using complete Freund adjuvant (CFA), while controls received saline. Two protocols were followed: one group had continuous access to 20 % ethanol for one month (n = 10/sex), and the second group for three months (n = 8/sex) in a two-bottle choice paradigm. Mechanical nociception was assessed weekly using the Von Frey test. Dopamine levels in the nucleus accumbens core were measured through microdialysis during the final 1.5 months of ethanol exposure in the second cohort. Due to experimental limitations animals underwent microdialysis at different time points after alcohol was firstly introduced, this was done in a balanced manner by alternating sex and group. After a month of alcohol exposure, rats showed no differences in alcohol consumption. However, from the second month until the end, rats exhibited a non-sex-dependent decrease in alcohol intake, significantly lower in CFA-animals. This reduction was accompanied by a blunted ethanol-evoked dopamine release in the nucleus accumbens. Moreover, low mechanical nociception was maintained until the end of the experiment in CFA-animal. These findings provide insights into the effect of pain on alcohol-elicited neurochemical responses and drinking behaviour, showing how pain alters dopamine response to alcohol, affecting drinking patterns and prolonging nociception from CFA.
Suppression of KDM5C mitigates the symptoms of Alzheimer's disease by up-regulating BDNF expression.
Han J, Hong R, Cao C … +7 more , Zhang L, Sun A, Li Y, Chi Y, Zhang L, Yang Y, Qu X
Neurochem Int · 2025 Jun · PMID 40180246 · Publisher ↗
Histone methylation, a common form of chromatin remodeling, has been found to be associated with various neurological and cognitive disorders. However, little is known about how this mechanism contributes to the onset an...
Histone methylation, a common form of chromatin remodeling, has been found to be associated with various neurological and cognitive disorders. However, little is known about how this mechanism contributes to the onset and progression of Alzheimer's disease (AD). Here, we found that lysine demethylase 5C (KDM5C), a histone H3 lysine 4 di- and tri-methyl (H3K4me2/3)-specific demethylase encoded by an X-linked mental retardation-related gene, displayed a progressive increase in the hippocampus with age in 3 × Tg-AD mice. Suppression of KDM5C partially mitigated the cognitive decline according to water maze, Y maze, and novel object recognition tests. In addition, significantly decreased amyloid plaques, enhanced long-term potentiation (LTP), and up-regulated expression of synaptic proteins were observed in KDM5C knockdown 3 × Tg-AD mice. Mechanistically, suppression of KDM5C could promote the expression of brain-derived neurotrophic factor (BDNF) to partially protect hippocampal neurons from beta-amyloid damage. In the promoter region of Bdnf, KDM5C was bound to the repressor element-1 (RE-1) motif to reduce the nearby H3K4me3 level and inhibit gene transcription. Mutations in the RE-1 motif reversed the inhibitory effect of KDM5C. Our results emphasize that KDM5C excess is one of the reasons for the onset and progression of AD and that suppression of KDM5C in the hippocampus should be considered a potential therapeutic target to ameliorate cognitive impairment and pathological symptoms in AD.
Potential roles of inhalation aromatherapy on stress-induced depression by inhibiting inflammation in the peripheral olfactory system.
Song H, Yang A, Wang Y … +2 more , Xu R, Hu W
Neurochem Int · 2025 Jun · PMID 40158533 · Publisher ↗
According to principles of Traditional Chinese Medicine, the nose is the passage for exogenous evil to invade the body, while essential or volatile oils extracted from herbs have the effects of dispelling melancholy, rep...
According to principles of Traditional Chinese Medicine, the nose is the passage for exogenous evil to invade the body, while essential or volatile oils extracted from herbs have the effects of dispelling melancholy, repelling foulness, and resuscitation with aromatics. Inhalation aromatherapy can target the brain and has a potential therapeutic effect on mood disorders. However, in particular, the mechanism of the effect of inhalation aromatherapy on the olfactory mucosa (OM) of the nasal cavity at the peripheral level, the first step in olfactory detection, where olfactory sensory neurons (OSNs) relay information to brain for signal processing, remains unclear. Here, we examined the roles of inhalation aromatherapy with compound essential oils derived from Bergamot, Peppermint and Rosa rugose on chronic unpredictable mild stress (CUMS)-induced depression and explored potential therapeutic targets in the peripheral OM. We found that inhalation aromatherapy effectively ameliorated CUMS-induced depression and olfactory dysfunction in rats. Strikingly, inhalation aromatherapy improved pathological changes, significantly reduced apoptosis levels, and promoted olfactory neurogenesis in the OM, which may contribute to the beneficial effects on the olfactory function of depressed rats. Further, inhalation aromatherapy significantly may reverse inflammation levels in the OM through Sirt1/FKBP5/GR/NF-κB signaling pathway, and prevented neuroinflammation in other parts of the olfactory system such as the hippocampus and prefrontal cortex, which may play a role in the olfactory impairments in rats with depression. Collectively, we have demonstrated that inhalation aromatherapy could efficiently prevent the local inflammatory responses in the OM of CUMS depression model rats. These findings provide new insights into the treatment of depression with aromatherapy, as well as new concept for the identification of novel antidepressant strategies.
The C. elegans glutamate transporters GLT-4 and GLT-5 regulate protein expression, behavior, and lifespan.
Bronstone GJ, Harton M, Muldowney M … +5 more , Reigle J, Funk AJ, O'Donovan SM, McCullumsmith RE, Bauer DE
Neurochem Int · 2025 Jun · PMID 40147734 · Full text
Glutamate transporters are important for regulating extracellular glutamate levels, impacting neural function and metabolic homeostasis. This study explores the behavioral, lifespan, and proteomic profiles in Caenorhabdi...
Glutamate transporters are important for regulating extracellular glutamate levels, impacting neural function and metabolic homeostasis. This study explores the behavioral, lifespan, and proteomic profiles in Caenorhabditis elegans strains with either glt-4 or glt-5 null mutations, highlighting contrasting phenotypes. Δglt-4 mutants displayed impaired mechanosensory and chemotactic responses, reduced lifespans, and decreased expression levels of ribosomal proteins and chaperonins involved in protein synthesis and folding. In contrast, Δglt-5 mutants displayed heightened chemorepulsion, extended lifespans, and upregulation of mitochondrial pyruvate carriers and cytoskeletal proteins. Proteomic profiling via mass spectrometry identified 53 differentially expressed proteins in Δglt-4 mutants and 45 in Δglt-5 mutants. Δglt-4 mutants showed disruptions in ribonucleoprotein complex organization and translational processes, including downregulation of glycogen phosphorylase and V-type ATPase subunits, while Δglt-5 mutants revealed altered metabolic protein expression, such as increased levels of mitochondrial pyruvate carriers and decreased levels of fibrillarin and ribosomal proteins. Gene ontology enrichment analysis highlighted differential regulation of protein biosynthesis and metabolic pathways between the strains. Overall, these findings underscore the distinct, tissue-specific roles of GLT-4 and GLT-5 in C. elegans, with broader implications for glutamate regulation and systemic physiology. The results also reinforce the utility of C. elegans as a model for studying glutamate transporters' impact on behavior, longevity, and proteostasis.
Morphine self-administration decreases intrinsic excitability of accumbal medium spiny neurons and suppresses the innate immune system in male Wistar rats.
Adermark L, Cadeddu D, Lucente E … +3 more , Danielsson K, Söderpalm B, Ericson M
Neurochem Int · 2025 Jun · PMID 40127781 · Publisher ↗
INTRODUCTION: Morphine alleviates severe pain but is addictive and associated with weakened immune system. Interestingly, the immunosuppressive effects have been linked to central circuits including the nucleus accumbens...
INTRODUCTION: Morphine alleviates severe pain but is addictive and associated with weakened immune system. Interestingly, the immunosuppressive effects have been linked to central circuits including the nucleus accumbens shell (NAc), suggesting that there might be a direct link between reward processing in the NAc and weakened immune system. The overall aim with this study was to assess the impact displayed by morphine self-administration on neuroplasticity in the NAc shell and circulating white blood cells. METHODS: Wistar rats received morphine injections over ten days, and locomotor activity was monitored. Next, morphine self-administration, and relapse drinking after forced abstinence, were assessed. Lastly, electrophysiological recordings were conducted in the NAc ex vivo to define neurophysiological adaptations, and hematological analysis were conducted in parallel. RESULTS: While ten days of morphine injections were not sufficient to affect morphine self-administration, behavioral sensitization to the locomotor stimulatory properties of morphine was observed and further correlated with the amount of morphine consumed following forced abstinence. Electrophysiological slice recordings demonstrated no effect on excitatory neurotransmission, but the intrinsic excitability of NAc neurons was significantly depressed compared to water drinking controls. In addition, hematological analysis demonstrated a significant decline in the number of white blood cells, especially monocytes and neutrophils, while erythrocytes were not affected. The amount of circulating white blood cells further correlated with morphine intake, but not with neurophysiological parameters. CONCLUSION: The data presented here demonstrates that morphine self-administration produces accumbal neuroplasticity and biological transformations that could contribute to the addictive and immunosuppressive properties of morphine.
METTL3/IGF2BP2/IκBα axis participates in neuroinflammation in Alzheimer's disease by regulating M1/M2 polarization of microglia.
Zhu L, Liu C, Wang Y … +5 more , Zhu X, Wu L, Chen L, Zhou J, Wang F
Neurochem Int · 2025 Jun · PMID 40107503 · Publisher ↗
BACKGROUND: Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD. METHOD: Microgli...
BACKGROUND: Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD. METHOD: Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N-methyladenosine (mA) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF. RESULTS: Stimulation with Aβ led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα mA modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα. CONCLUSION: Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.
Nicotine enhances object recognition memory through activation of the medial prefrontal cortex to the perirhinal cortex pathway.
Esaki H, Imai K, Nishikawa K … +3 more , Nishitani N, Deyama S, Kaneda K
Neurochem Int · 2025 May · PMID 40073977 · Publisher ↗
Nicotine enhances recognition memory across species; however, the underlying neuronal mechanisms remain incompletely understood. Our previous study using a novel object recognition (NOR) test and electrophysiological rec...
Nicotine enhances recognition memory across species; however, the underlying neuronal mechanisms remain incompletely understood. Our previous study using a novel object recognition (NOR) test and electrophysiological recordings of mouse brain slices demonstrated that nicotine enhanced object recognition memory by stimulating nicotinic acetylcholine receptors in the medial prefrontal cortex (mPFC). To elucidate this further, we conducted the NOR test combined with pharmacology, chemogenetics, optogenetics, and ex vivo electrophysiology in male C57BL/6J mice. Chemogenetic inhibition of mPFC excitatory neurons suppressed nicotine-induced enhancement of object recognition memory, whereas their activation alone was sufficient to enhance memory. Anatomical studies indicate that the mPFC sends projections to the perirhinal cortex (PRH), a brain region involved in object recognition memory. Therefore, we focused on mPFC-PRH projections. Whole-cell patch-clamp recordings with optogenetic stimulation revealed that PRH pyramidal neurons received monosynaptic and glutamatergic inputs from the mPFC. Chemogenetic suppression of mPFC neurons projecting to the PRH blocked the nicotine-induced enhancement of object recognition memory, whereas activation of these neurons alone was sufficient to enhance memory. To achieve precise temporal control, optogenetic inhibition of the mPFC-PRH pathway during the training session blocked the effects of nicotine, and its activation alone enhanced memory. Furthermore, unilateral intra-mPFC nicotine infusion enhanced object recognition memory, and this effect was suppressed by ipsilateral intra-PRH infusion of an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist. These findings indicate that nicotine enhances object recognition memory by activating glutamatergic projections from the mPFC to PRH.
Biochemical and medical aspects of vitamin B research.
Makarchikov AF, Wins P, Bettendorff L
Neurochem Int · 2025 May · PMID 40058602 · Publisher ↗
Vitamin B is an indispensable food factor for the human and animal body. In animals, vitamin B is found in the form of thiamine and its phosphate esters - thiamine mono-, di- and triphosphate, as well as an adenylated de...
Vitamin B is an indispensable food factor for the human and animal body. In animals, vitamin B is found in the form of thiamine and its phosphate esters - thiamine mono-, di- and triphosphate, as well as an adenylated derivative - adenosine thiamine triphosphate. At present, the only vitamin B form with biochemical functions being elucidated is thiamine diphosphate, which serves as a coenzyme for several important enzymes involved in carbohydrate, amino acid, fatty acid and energy metabolism. Here we review the latest developments in the field of vitamin B research in animals. Transport, metabolism and biological role of thiamine and its derivatives are considered as well as the involvement of vitamin B-dependent processes in human diseases and its therapeutic issues, a field that has gained momentum with several important recent developments.
Repeated administration of esketamine ameliorates mechanical allodynia in mice with chemotherapy-induced peripheral neuropathy: A role of gut microbiota and metabolites.
Luan WW, Gu HW, Qiu D … +5 more , Ding X, Liu PM, Hashimoto K, Yang JJ, Wang XM
Neurochem Int · 2025 May · PMID 40054499 · Publisher ↗
Chemotherapy-induced peripheral neuropathy (CIPN) severely diminishes the quality of life for cancer survivors, yet effective treatments remain scarce. Esketamine, a commonly used anesthetic, has demonstrated neuroprotec...
Chemotherapy-induced peripheral neuropathy (CIPN) severely diminishes the quality of life for cancer survivors, yet effective treatments remain scarce. Esketamine, a commonly used anesthetic, has demonstrated neuroprotective effects by restoring gut microbiome dysbiosis. In this study, we investigated the impact of esketamine on nociceptive sensitivity in a mouse model of CIPN and explored the potential involvement of the gut microbiome. In mice treated with oxaliplatin, repeated esketamine doses (in contrast to a single dose) significantly improved the paw withdrawal threshold (PWT). Western blot and qPCR analyses further revealed that repeated esketamine administration markedly reduced microglial activation and neuroinflammation in the dorsal root ganglion (DRG), underscoring its potent anti-inflammatory properties. Moreover, fecal 16S rRNA analysis indicated that esketamine partially restored the abnormal gut microbiota composition (β-diversity). Plasma metabolome analysis showed that repeated esketamine treatment significantly lowered the elevated levels of 6H-indolo[2,3-b]quinoline and restored the reduced levels of (3-exo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octane observed in oxaliplatin-treated mice. In addition, fecal microbiota transplantation from esketamine-treated CIPN mice notably improved both the diminished PWT and DRG neuroinflammation in oxaliplatin-treated mice. Collectively, these findings suggest that repeated esketamine administration may alleviate mechanical allodynia in CIPN mice by modulating neuroinflammation, gut microbiota, and associated metabolites.
Age-related memory decline is accelerated by pinealectomy in young adult and middle-aged rats via BDNF / ERK / CREB signalling.
Tchekalarova J, Atanasova D, Krushovlieva D … +6 more , Barbutska D, Atanasova M, Rashev P, Nenchovska Z, Mourdjeva M, Koeva Y
Neurochem Int · 2025 May · PMID 40043851 · Publisher ↗
Memory decline is considered a normal part of aging, while the relationship between melatonin deficiency and cognitive function is complex and not fully understood. The present study investigated the role of melatonin de...
Memory decline is considered a normal part of aging, while the relationship between melatonin deficiency and cognitive function is complex and not fully understood. The present study investigated the role of melatonin deficiency at different ages on working and short-term recognition and spatial memory in rats. An age-related decline in memory function was tested using the Y-maze, the object recognition test, and the radial arm maze. The brain-derived neurotrophic factor (BDNF), TrkB receptor, the extracellular signal-regulated kinase (ERK)1/2 and pERK1/2 expression in the hippocampus was assessed by immunohistochemistry. The pCREB/CREB ratio in the frontal cortex (FC) and hippocampus was evaluated by ELISA. Young adult and middle-aged rats with pinealectomy had memory impairment whereas old melatonin-deficient rats were unaffected. Aging was associated with reduced expression of BDNF and its receptor throughout the hippocampus and reduced ratio of pCREB/CREB in the FC and hippocampus, whereas pinealectomy exacerbated this process in 3- and 14-month-old rats. The region-specific reduced expression of the ERK1/2 and pERK1/2 was observed in young adult rats with pinealectomy. However, in middle-aged rats, the expression of these signaling molecules was either downregulated or upregulated in different regions of the hippocampus. Our study provides insights into the molecular pathways involved in age-related memory changes associated with melatonin deficiency, highlighting the importance of the BDNF/ERK1/2/CREB pathway in the hippocampus and suggesting a critical period for intervention.
Research progress on the mechanisms of microglial extracellular vesicles affecting the prognosis of ischemic stroke.
An Y, Su G, Chen W … +4 more , Song J, Chai M, Zhu L, Zhang Z
Neurochem Int · 2025 May · PMID 40015338 · Publisher ↗
Ischemic stroke is the major type of stroke and one of the main causes of morbidity, mortality, and long-term disability worldwide. Microglia play a complex and crucial role in stroke. They are the primary immune cells i...
Ischemic stroke is the major type of stroke and one of the main causes of morbidity, mortality, and long-term disability worldwide. Microglia play a complex and crucial role in stroke. They are the primary immune cells in the brain and can rapidly respond to the pathological changes caused by stroke. They promote neuroprotection and repair after ischemic stroke through various mechanisms, such as activation and polarization, dynamic interactions with other cells (neurons, astrocytes, oligodendrocytes, vascular endothelial cells, etc.), and phagocytosis to clear dead cell debris. Among the multiple pathways through which microglia exert their neuroprotective effects, the secretion of extracellular vesicles is one of the most important. The focus of this review is to analyze the latest progress in research on ischemic stroke related to microglia-derived extracellular vesicles, discuss their mechanisms of action, and provide new strategies for improving stroke prognosis. To obtain relevant articles, we conducted a comprehensive search in Pubmed and Web of Science, with keywords related to ischemic stroke and microglia-derived extracellular vesicles or exosomes. A total of 59 articles were included in the review. Existing studies have shown that after a stroke occurs, microglia release extracellular vesicles containing proteins, nucleic acids, metabolites, etc. These vesicles target corresponding receptor cells and can slow down the development of stroke and improve stroke outcomes through various means, such as reducing neuronal apoptosis, inhibiting neuronal autophagy, suppressing neuronal ferroptosis, preventing neuronal pyroptosis, alleviating inflammatory responses, reducing glial scar formation, promoting myelin regeneration and repair, and facilitating blood-brain barrier repair.
DOT1L in neural development and neurological and psychotic disorders.
Shen F, Zeng L, Gao Y
Neurochem Int · 2025 May · PMID 39993657 · Publisher ↗
Disruptor of Telomeric Silencing 1-Like (DOT1L) is the sole methyltransferase in mammals responsible for catalyzing the mono-, di-, and trimethylation of histone H3 at lysine 79 (H3K79), a modification crucial for variou...
Disruptor of Telomeric Silencing 1-Like (DOT1L) is the sole methyltransferase in mammals responsible for catalyzing the mono-, di-, and trimethylation of histone H3 at lysine 79 (H3K79), a modification crucial for various cellular processes, including gene transcription, cell cycle regulation, DNA repair, and development. Recent studies have increasingly linked DOT1L to the nervous system, where it plays a vital role in neurodevelopment and neuronal function. It has been shown to regulate the proliferation and differentiation of neural progenitor cells, promote neuronal maturation, and influence synaptic function, all of which are essential for proper neural circuit formation and brain function. Moreover, dysregulation of DOT1L has been associated with several neurological disorders, highlighting its potential role in disease pathology. Abnormal expression or activity of DOT1L has been implicated in cognitive deficits and neurodegenerative diseases, underscoring the enzyme's significance in both the development and maintenance of the nervous system. This review synthesizes recent findings on DOT1L's role in the nervous system, emphasizing its importance in neurodevelopment and exploring its potential as a therapeutic target for treating neurological disorders.
Kaempferol promotes angiogenesis through HIF-1α/VEGF-A/Notch1 pathway in ischemic stroke rats.
Zhang S, Liu C, Li W … +10 more , Zhang Y, Yang Y, Yang H, Zhao Z, Xu F, Cao W, Li X, Wang J, Kong L, Du G
Neurochem Int · 2025 May · PMID 39988285 · Publisher ↗
Stroke is a severe disease characterized by the obstruction of blood vessels in the central nervous system. An essential therapeutic strategy for ischemic stroke is strengthening angiogenesis, which effectively promotes...
Stroke is a severe disease characterized by the obstruction of blood vessels in the central nervous system. An essential therapeutic strategy for ischemic stroke is strengthening angiogenesis, which effectively promotes the long-term recovery of neurological function. Therefore, it is critical to explore and develop new drugs that promote angiogenesis after ischemic stroke. Kaempferol has been employed to treat ischemic diseases; However, its proangiogenic effects in ischemic stroke remain unclear. In the study, we explored the long-term therapeutic effects and mechanisms of kaempferol on ischemic stroke in vivo and in vitro. A rat model of autologous thrombus stroke and oxygen-glucose deprivation (OGD)-induced human brain microvascular endothelial cells (HBMECs) model was established to assess the effects of kaempferol in vivo (50 mg/kg/d, ig, 14 d) and in vitro (0.1, 0.3, 1 μmol L). The results showed that long-term administration of kaempferol ameliorated neurological deficits and infarct volume in ischemic stroke rats. In addition, kaempferol relieved vascular embolization; enhanced microvascular endothelial cell survival, proliferation, migration, and lumen formation; increased the density of microvessels in the peri-infarct cortex; and promoted neovascular structure remodeling by increasing the coverage of astrocyte end-feet and expression of tight-junction proteins (TJPs). Further analysis revealed that the HIF-1α/VEGF-A/Notch1 signaling pathway was activated by kaempferol, and that inhibition of Notch1 blocked kaempferol-induced angiogenesis. Taken together, our results indicate that kaempferol exerts neuroprotective effects by stimulating endogenous angiogenesis and neovascular structural remodeling via the HIF-1α/VEGF-A/Notch1 signaling pathway, suggesting the therapeutic potential of kaempferol in ischemic stroke.
Astrocyte-neuron metabolic crosstalk in ischaemic stroke.
Ren ZL, Lan X, Cheng JL … +9 more , Zheng YX, Chen CA, Liu Y, He YH, Han JH, Wang QG, Cheng FF, Li CX, Wang XQ
Neurochem Int · 2025 May · PMID 39988284 · Publisher ↗
Ischemic stroke (IS) is caused by temporary or permanent obstruction of the brain's blood supply. The disruption in glucose and oxygen delivery that results from the drop in blood flow impairs energy metabolism. A signif...
Ischemic stroke (IS) is caused by temporary or permanent obstruction of the brain's blood supply. The disruption in glucose and oxygen delivery that results from the drop in blood flow impairs energy metabolism. A significant pathological feature of IS impaired energy metabolism. Astrocytes, as the most prevalent glial cells in the brain, sit in between neurons and the microvasculature. By taking advantage of their special anatomical location, they play a crucial part in regulating cerebral blood flow (CBF) and metabolism. Astrocytes can withstand hypoxic and ischemic conditions better than neurons do. Additionally, astrocytes are essential for maintaining the metabolism and function of neurons. Therefore, the "neurocentric" perspective on neuroenergetics is gradually giving way to a more comprehensive perspective that takes into account metabolic interaction between astrocytes and neurons. Since neurons in the core region of the infarct are unable to undergo oxidative metabolism, the focus of attention in this review is on neurons in the peri-infarct region. We'll go over the metabolic crosstalk of astrocytes and neurons during the acute phase of IS using three different types of metabolites: lactate, fatty acids (FAs), and amino acids, as well as the mitochondria. After IS, astrocytes in the peri-infarct zone can produce lactate, ketone bodies (KBs), glutamine (Gln), and l-serine, shuttling these metabolites, along with mitochondria, to neurons. This process helps maintain the energy requirements of neurons, preserves their redox state, and regulates neurotransmitter receptor activity.
Dysregulation of immune system markers, gut microbiota and short-chain fatty acid production following prenatal alcohol exposure: A developmental perspective.
Vella VR, Ainsworth-Cruickshank G, Luft C … +6 more , Wong KE, Parfrey LW, Vogl AW, Holman PJ, Bodnar TS, Raineki C
Neurochem Int · 2025 May · PMID 39988283 · Full text
Prenatal alcohol exposure (PAE) can severely impact fetal development, including alterations to the developing immune system. Immune perturbations, in tandem with gut dysbiosis, have been linked to brain and behavioral d...
Prenatal alcohol exposure (PAE) can severely impact fetal development, including alterations to the developing immune system. Immune perturbations, in tandem with gut dysbiosis, have been linked to brain and behavioral dysfunction, but this relationship is poorly understood in the context of PAE. This study takes an ontogenetic approach to evaluate PAE-induced alterations to brain and serum cytokine levels and both the composition and metabolic output of the gut microbiota. Using a well-established rat model of PAE, cytokine levels in the serum, prefrontal cortex, amygdala, and hypothalamus as well as gut microbiota composition and short-chain fatty acid (SCFA) levels were assessed at three postnatal (P) timepoints: P8 (infancy), P22 (weaning), and P38 (adolescence). Male PAE rats had increased cytokine levels in the amygdala and hypothalamus, but not prefrontal cortex, at P8. This altered neuroimmune function was not seen in the PAE females. The effect of PAE on central cytokine levels was reduced at P22/38, the same age at which PAE-induced alterations in serum cytokine levels emerge in both sexes. PAE reduced bacterial diversity in both sexes at P8, but only in females at P38, where a PAE-induced unique community composition emerged. Both sexes had alterations to specific bacterial taxa (e.g., Firmicutes), some of which are important in producing the SCFA butyric acid, which was decreased in PAE animals at P22. These results demonstrate that PAE leads to sex- and age-specific alterations in immune function, gut microbiota and SCFA production, highlighting the need to consider both age and sex in future work.
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