Neurochemistry International[JOURNAL]
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200 papers
Circulating metabolomic changes in Lennox-Gastaut syndrome: correlation with clinico-radiological severity.
Kalita J, Pandey A, Nizami FM … +2 more , Dubey AK, Baishya B
Neurochem Int · 2025 Oct · PMID 40812733 · Publisher ↗
Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy characterized by multiple types of seizures typically occurring between 1 and 7 years of age, cognitive impairment and characteristic electroencephalographic a...
Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy characterized by multiple types of seizures typically occurring between 1 and 7 years of age, cognitive impairment and characteristic electroencephalographic abnormalities. Circulating metabolomic profile may give insight into the ongoing metabolic pathway abnormalities in these patients, but there is no such study. We report NMR based metabolomic profile in LGS and its association with clinical severity, MRI changes and EEG findings. LGS children between 2 and 18 years were included based on clinical and EEG diagnostic criteria. Detailed neurological examinations, frequency and type of seizures, EEG changes, cranial MRI and NMR based serum metabolomic profile were measured. The Clinical Global Impairment Severity Scale (CGI-S) was used to rate severity of LGS. Twenty-six LGS patients and 11 healthy matched controls were included. The median age of the patients was 6 (range 2-17) years, and 19 were males. Their median CGI-S score was 6, and all had more than one type of seizures. Seven metabolites namely lactate, glucose, glutamate, pyruvate, glutamine, glycine, citrate and creatinine were crucial for discrimination of LGS from the controls, among which glutamate was upregulated and citrate, pyruvate, and glutamine were down regulated in LGS. Glutamate associated with developmental quotient (r = -0.48) and pyruvate with focal seizures (r = 0.47) and cystic encephalomalacia on cranial MRI (p = 0.02). NMR metabolomic profile including glutamate, glutamine, glycine, glucose, pyruvate, lactate, citrate and creatinine can discriminate LGS from the controls. Role of antiglutamatergic drugs may be beneficial in controlling seizures, and needs future study.
Epigenetic dysregulation and the etiology of spina bifida.
Lumour-Mensah T, Korrick S, Lemos B … +1 more , Mazumdar M
Neurochem Int · 2025 Oct · PMID 40803372 · Full text
Spina bifida is a complex and multifactorial congenital defect driven by both genetic and environmental factors. As such, epigenetic studies of spina bifida present an opportunity to study the joint contribution of both...
Spina bifida is a complex and multifactorial congenital defect driven by both genetic and environmental factors. As such, epigenetic studies of spina bifida present an opportunity to study the joint contribution of both genes and the environment in the development of this disorder. This review focuses specifically on epigenetic research that may help us to understand the ways in which dysregulation of the epigenome and downstream cellular processes can confer increased risk of spina bifida. To do so, we discuss the epigenetic regulation of genes linked to spina bifida risk among children born with the disorder and their parents as well as evidence from experimental studies. We also discuss pathways necessary for normal neural tube development and specific documented dysregulation of these pathways in individuals with spina bifida. We conclude that the epigenome plays an important role in spina bifida etiology and should be further studied in additional populations, and tissue types, as well as cellular and animal models.
TRPM8 modulation alters uptake of Transferrin-mediated Fe, mitochondrial Fe and intracellular Ca-levels in microglia.
Sing R, Shikha D, Goswami C
Neurochem Int · 2025 Oct · PMID 40784409 · Publisher ↗
Microglia play an important role in the immunity of the central nervous system, crucial in maintaining homeostasis. However, under diseased conditions, this cell accumulates Fe, triggering inflammatory and neurotoxic eff...
Microglia play an important role in the immunity of the central nervous system, crucial in maintaining homeostasis. However, under diseased conditions, this cell accumulates Fe, triggering inflammatory and neurotoxic effects that contribute to neurodegenerative disorders such as Alzheimer's and Parkinson's. Hence, the study of dysregulated microglial activation and overload of Fe is crucial in the context of neurodegenerative conditions. Emerging research has identified cold-sensitive ion channels, i.e., TRPM8 in microglia, which can regulate key subcellular functions. This study explores the regulatory function of the TRPM8 in Fe metabolism and its implications for potential ferroptosis in BV2 microglial cells. We used highly specific fluorescence probes, pharmacological modulators of TRPM8 and performed life cell imaging to understand the uptake of Transferrin-488, mitochondrial Fe-level, cellular Ca-levels in live BV2 cells under different experimental conditions. Our findings reveal that TRPM8 activation leads to enhanced Transferrin-488-mediated cytosolic Fe-uptake, disrupts mitochondrial superoxide levels, and promotes cell death. Interestingly, under inflammatory conditions induced by LPS treatment, TRPM8 exhibits a distinct functional role. These results position TRPM8 as an important regulator of microglial Fe metabolism. This study indicates the involvement of TRPM8 in overload of Fe leading to ferroptosis and potential for M1-M2 polarization in microglia. These findings impose TRPM8 as a potential therapeutic target for neurodegenerative diseases, and aging.
Increased spinal adenosine after subacute cervical injury correlates with sustained upregulation of CD39 and CD73 in microglia.
Berschel MR, Nikodemova M, Oberto JR … +3 more , Marciante AB, Michaelson A, Mitchell GS
Neurochem Int · 2025 Oct · PMID 40759307 · Full text
Cervical spinal cord injuries (cSCI) are associated with decreased breathing ability. Although no treatment options are currently available, moderate acute intermittent hypoxia (mAIH) is a promising therapeutic modality...
Cervical spinal cord injuries (cSCI) are associated with decreased breathing ability. Although no treatment options are currently available, moderate acute intermittent hypoxia (mAIH) is a promising therapeutic modality to improve breathing function after cSCI. Moderate AIH elicits phrenic motor plasticity via distinct, competing serotonin- or adenosine-driven mechanisms that interact via powerful crosstalk inhibition that constrains or even abolishes plasticity. The dominant mechanism driving plasticity depends on the spinal serotonin/adenosine balance. Shortly after cSCI, repeated AIH exposure elicits plasticity via an adenosine-dependent mechanism but reverts to serotonin-dominance with chronic cSCI. In healthy CNS, microglia regulate AIH-induced phrenic motor plasticity via enzymatic activities of ectonucleotidases (CD39, CD73) by converting extracellular ATP to adenosine. We hypothesized that cSCI increases microglial ectonucleotidase expression, elevating adenosine levels that may alter therapeutic responses to mAIH post-cSCI. We assessed microglial CD39 and CD73 expression at the subacute (1 & 2 weeks) and chronic (8 weeks) stages post C2-hemisection, both at the injury site (C1-C3) and in spinal segments containing phrenic motor neurons below the injury (C3-C6). Both enzymes were upregulated (mRNA & protein) 1- and 2-weeks post injury but returned to baseline by 8 weeks. In association, spinal adenosine increased significantly at 2, but not 8 weeks post-injury. Further, microglial CD39 and CD73 expression strongly correlate with P2Y12 receptor expression. Thus, shifting adenosine levels between subacute and early chronic cSCI may impact mechanism regulating mAIH-induced respiratory motor plasticity and breathing recovery at different times post-cSCI.
DUSP1-mediated suppression of p38 MAPK signaling pathway reduces ferroptosis in cerebral ischemia-reperfusion injury.
Ma S, Zhang X, Fan J … +12 more , Chen M, Yao Q, Zhang N, Shi K, Duan M, Yang H, Gao T, Ma X, Wang J, Li W, Zhou C, Zhan S
Neurochem Int · 2025 Oct · PMID 40752646 · Publisher ↗
Ferroptosis constitutes a critical pathological mechanism in cerebral ischemia-reperfusion injury (CI/RI), significantly influencing neurological outcomes. While dual specificity phosphatase 1 (DUSP1) demonstrates neurop...
Ferroptosis constitutes a critical pathological mechanism in cerebral ischemia-reperfusion injury (CI/RI), significantly influencing neurological outcomes. While dual specificity phosphatase 1 (DUSP1) demonstrates neuroprotective effects against CI/RI, its regulatory role in ferroptosis remains to be elucidated. This study systematically investigated the therapeutic potential of DUSP1 through ferroptosis modulation in both in vitro and in vivo models. Using oxygen-glucose deprivation/reoxygenation (OGD/R)-treated PC12 cells with either DUSP1 overexpression or knockdown, we comprehensively assessed ferroptosis parameters including cell viability, malondialdehyde content, glutathione levels, intracellular iron concentration, reactive oxygen species accumulation, and expression of key ferroptosis-related proteins. In middle cerebral artery occlusion/reperfusion (MCAO/R) rat models, pharmacological inhibition of DUSP1 was employed to evaluate its impact on cerebral infarction volume, neurological deficits, histopathological changes, and ferroptosis biomarkers. Mechanistic studies incorporated the p38 mitogen-activated protein kinase pathway inhibitor adezmapimod. Our results demonstrated that (1) ferroptosis was significantly induced in both the OGD/R and MCAO/R models, accompanied by upregulated DUSP1 expression; (2) DUSP1 overexpression attenuated ferroptosis and ameliorated CI/RI, whereas genetic knockdown exacerbated these pathological processes; (3) pharmacological inhibition of DUSP1 aggravated cerebral injury and ferroptosis markers in MCAO/R rats; and (4) adezmapimod treatment effectively rescued ferroptosis progression in DUSP1-deficient cells by restoring glutathione peroxidase 4 and ferroportin expression while downregulating transferrin receptor and Ferritin Heavy Chain levels. These findings establish that DUSP1 confers neuroprotection against CI/RI through p38-mediated ferroptosis regulation, suggesting its promise as a novel therapeutic target for ischemic stroke.
Casticin inhibits the release of synaptic vesicular glutamate from rat hippocampal nerve terminals.
Lu CW, Lin TY, Pan WJ … +4 more , Chang YY, Chiu KM, Lee MY, Wang SJ
Neurochem Int · 2025 Oct · PMID 40752645 · Publisher ↗
The effect of casticin, major polymethoxyflavone extracted from Vitex rotundifolia, on glutamate release and its underlying mechanisms was investigated in rat hippocampal synaptosomes. Casticin inhibited 4-aminopyridine...
The effect of casticin, major polymethoxyflavone extracted from Vitex rotundifolia, on glutamate release and its underlying mechanisms was investigated in rat hippocampal synaptosomes. Casticin inhibited 4-aminopyridine (4-AP)-evoked glutamate release, with an IC of approximately 7.2 μM. It reduced the 4-AP-evoked increase in intrasynaptosomal Ca concentration without affecting the synaptosomal membrane potential. The inhibitory effect of casticin on glutamate release was markedly prevented by ω-conotoxin GVIA, an N-type Ca channel blocker, but not by ω-agatoxin VIA, a P/Q-type Ca channel blocker. Further analysis of FM1-43 dye release showed that casticin suppressed glutamate release by decreasing synaptic vesicle exocytosis. Consistently, casticin also reduced 4-AP-induced phosphorylation of synapsin I, a presynaptic protein that regulates synaptic vesicle mobilization. Transmission electron microscopy (TEM) revealed that casticin decreased the proportion of release-competent synaptic vesicles in 4-AP-stimulated hippocampal synaptosomes. Taken together, these findings suggest that casticin inhibits glutamate release from rat hippocampal nerve terminals, potentially by suppression of N-type Ca channel and reducing the availability of synaptic vesicles for exocytosis.
Aerobic exercise rescues synaptic plasticity in early-stage Alzheimer's disease by suppressing miR-3473e to activate EphB2-dependent NMDA/AMPA receptor signaling.
Tong X, Tong Z, Wu W … +9 more , Yang J, Wang J, Wang Y, Chen D, Wang Y, Zeng F, Du Q, Chen Y, Liu W
Neurochem Int · 2025 Oct · PMID 40716190 · Publisher ↗
Cognitive dysfunction in early-stage Alzheimer's disease (AD) involves significant impairments in synaptic plasticity and dendritic spines integrity. Intriguingly, exercise interventions have demonstrated efficacy in enh...
Cognitive dysfunction in early-stage Alzheimer's disease (AD) involves significant impairments in synaptic plasticity and dendritic spines integrity. Intriguingly, exercise interventions have demonstrated efficacy in enhancing cognitive function. However, the precise molecular mechanisms, particularly the upstream endogenous regulators (such as miRNAs) through which exercise mediates this synaptic improvement, remain unclear. Our findings indicated that 12 weeks of aerobic exercise effectively increased learning and memory, promoted amyloid beta (Aβ) and cerebral amyloid angiopathy (CAA) clearance in early-stage AD. Furthermore, aerobic exercise markedly enhanced dendritic spines density of pyramidal neurons in cortical layers II/III and the hippocampal CA1 region, as well as the expression of synapse-associated proteins such as cAMP response element-binding protein (CREB), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95). Whole genome RNA sequencing (RNA-Seq) and bioinformatics analysis was performed to identify miR-3473e, a target closely related to AD and also a response factor that serves as a key mediator of aerobic exercise benefits. Subsequent findings revealed that miR-3473e was overexpressed in the brains of APP/PS1 mice, whereas aerobic exercise led to a decrease in its expression. Moreover, aerobic exercise enhanced its downstream targets, EPH receptor B2 (EphB2) and solute carrier family 1 member 1 gene (Slc1a1) as well as increased downstream GluN1, GRIA1 and p-GluN2B/GluN2B protein expression levels. In summary, we demonstrate that aerobic exercise can improve synaptic plasticity, and these effects are mediated via suppression of miR-3473e and regulation EphB2-NMDA/AMPA receptor signaling pathway, underscoring the potential of aerobic exercise to enhance cognitive function in early-stage of AD.
Probing impact of sleep deprivation on hippocampal neurochemistry in rats using CEST imaging and H-MRS at 7.0T MRI.
Zhao Z, Wang L, Zhang X … +3 more , Chen Y, Zheng X, Wu R
Neurochem Int · 2025 Oct · PMID 40675254 · Publisher ↗
PURPOSE: Sleep is a physiological process that plays a crucial role in maintaining cognitive functions. The hippocampus, a key brain region implicated in cognition, is particularly sensitive to sleep deprivation. we aim...
PURPOSE: Sleep is a physiological process that plays a crucial role in maintaining cognitive functions. The hippocampus, a key brain region implicated in cognition, is particularly sensitive to sleep deprivation. we aim to investigate impact of sleep deprivation on hippocampal neurochemistry in rats using CEST imaging and H-MRS. METHODS: Twelve female Sprague-Dawley rats were randomly divided into sleep deprivation and control groups. All rats experienced Morris water maze training and testing from Day 1 to Day 6 and underwent MRI scans including CEST imaging and H-MRS on Days 1 and Day 3. Lastly, rats were euthanized for Nissl staining. RESULTS: Sleep deprivation led to a significant decrease in CEST signals across various frequency offsets (0.5-3.5 ppm) in the hippocampus (P < 0.05). Meanwhile, sleep deprivation caused an increase in glutamate (P < 0.0001) with no alterations in other metabolites (P > 0.05). Behaviorally, sleep deprivation impaired learning-memory abilities, evidenced by reduced target quadrant distance (P < 0.001) and time (P < 0.01) in the Morris water maze. Histologically, sleep deprivation caused a decline of surviving neurons in the hippocampal CA1 and CA3 regions (P < 0.001). These indicators correlated negatively with the concentrations of glutamate (P < 0.05) and positively with most of the CEST signals (P < 0.05) in the hippocampus. CONCLUSION: The integration of CEST imaging and H-MRS offers a promising approach for identifying imaging biomarkers that aid in the assessment and management of sleep deprivation's impact on hippocampal neurochemistry.
Combined administration of cocaine and alcohol alters the expression of brain peptide/protein profiles in rats: a MALDI imaging mass spectrometry approach.
Marcos A, Alberdi P, Castillo-Sarmiento CA … +2 more , Ambrosio E, Ballesteros-Yáñez I
Neurochem Int · 2025 Sep · PMID 40651505 · Publisher ↗
While the concurrent use of alcohol and cocaine is common in patterns of polysubstance use, little is known about the combined effects of these substances on the brain. Proteomics approaches enable the identification of...
While the concurrent use of alcohol and cocaine is common in patterns of polysubstance use, little is known about the combined effects of these substances on the brain. Proteomics approaches enable the identification of potential biomarkers and new pharmacological targets for the diagnosis and treatment of addiction and related psychiatric disorders. The main goal of this study was to explore how the combination of cocaine and alcohol affects brain peptide/protein signatures in the mesolimbic dopaminergic pathway. To this end, we used a chronic and simultaneous intravenous administration of these substances in a Wistar rat animal model. Peptide/protein profiles in five brain regions (ventral hippocampus, dorsal hippocampus, amygdala, nucleus accumbens and prefrontal cortex) from individual animals were characterised by means of matrix-assisted laser desorption/ionisation imaging mass spectrometry (MALDI-IMS). Our results showed that, compared to exposure to cocaine or alcohol separately, the combination of cocaine and alcohol has a synergistic effect on the number of differentially expressed peptides/proteins (DEPs) detected in all regions, particularly the amygdala. ANOVA reveals 13 DEPs, corresponding to 12 peptides/proteins, that vary significantly between all groups. Gene ontology (GO) analysis indicated that most of the DEPs found for the combined treatment are enriched in neuropeptide receptor binding, neuropeptide signalling and regulation of circadian sleep/wake process pathways. Our findings demonstrate that the combination of cocaine and alcohol significantly exacerbates the effects of each substance separately on the expression of peptides and proteins with multiple physiological functions, including the opioid- and GABA-ergic neurotransmission systems. This study therefore provides the basis for future research on biomarkers and substance recovery therapies. These insights underscore the importance of examining the interactions between cocaine and alcohol in terms of their effects on neurotransmitter systems in the context of polysubstance use, particularly when addressing issues related to cocaine and alcohol co-use.
Refinement of TSLP expression mediates chronic allodynia associated with IL22/STAT3 axis.
Lu CC, Lu YY, Tsai HP … +1 more , Wu CH
Neurochem Int · 2025 Sep · PMID 40651504 · Publisher ↗
Chronic allodynia is a painful response to an innocuous stimulus because of maladaptive neuroplasticity within the central nervous system. IL22 is a pleiotropic mediator owing to its proinflammatory and immunosuppressive...
Chronic allodynia is a painful response to an innocuous stimulus because of maladaptive neuroplasticity within the central nervous system. IL22 is a pleiotropic mediator owing to its proinflammatory and immunosuppressive effects. In this study, we aimed to investigate the potential of modulating TSLP expressions to treat chronic allodynia and elucidate the underlying mechanisms associated with IL22. TSLP mice were generated, and four mouse groups were created as follows: wild-type (WT) + PBS, TSLP knockout (KO) + PBS, WT + bleomycin, and TSLP KO + bleomycin. Repeated bleomycin administration reduced the IL22/STAT3 pathway to trigger chronic allodynia in C57BL/6 mice. The degree of gliosis and neuron loss were significantly greater in the somatosensory cortex and spinal cord dorsal horn of the bleomycin-treated mice compared with those in the PBS-treated mice. Compared with those in WT mice treated with bleomycin, in TSLP-deficient mice, the degree of gliosis and neuron loss were significantly lower in the somatosensory cortex and spinal cord dorsal horn and the mechanical withdrawal threshold was altered. Differentiated human SH-SY5Y cells were created to investigate the neuroprotective effects of TSLP refinement against hydrogen peroxide (HO)-induced neurotoxicity. The deficiency of TSLP protected differentiated SH-SY5Y cells against HO-induced neurotoxicity. IL22 stimulator not only rescued the HO-induced neurotoxicity but augmented the protective effect of si-TSLP on differentiated SH-SY5Y cells. Our data confirmed that a lack of TSLP decreased the expression of TSLPR/STAT5, the bleomycin-induced chronic allodynia and the HO-induced neurotoxicity. In addition, inhibiting TSLP rescued the IL22/STAT3-mediated effect, which regulated neuroglial interactions to relieve chronic allodynia. Targeting TSLP/TSLPR is a potential therapeutic approach for relieving chronic allodynia by regulating gliosis, neuron loss, and the IL22/STAT3 axis.
Repetitive transcranial magnetic stimulation as a universal modulator of synaptic plasticity: Bridging the gap between functional and structural plasticity.
Popovic D, Dragic M
Neurochem Int · 2025 Sep · PMID 40639590 · Publisher ↗
Repetitive transcranial magnetic stimulation (rTMS) is a painless and non-invasive technique for neuromodulation that has shown great potential in therapy of several neurodegenerative and neuropsychiatric disorders both...
Repetitive transcranial magnetic stimulation (rTMS) is a painless and non-invasive technique for neuromodulation that has shown great potential in therapy of several neurodegenerative and neuropsychiatric disorders both in patients and animal models. In addition to its non-invasiveness, the main rationale for using it for these disorders is that the positive effects extend beyond the stimulation period and can last up to several minutes, hours or even days after the last application. While the mechanisms underlying these long-lasting positive effects have not yet been fully deciphered, current literature supports hypothesis of modulation of both functional and structural plasticity. Dendritic spines are structures on dendritic branches that regulate synaptic transmission at the level of postsynapse and represent one of the structural and functional carriers of synaptic plasticity. Since rTMS has been proposed to induce long-term potentiation/long-term depression-like effects, based on the existing literature in animal studies, we suggest several molecular mechanisms which could underpin rTMS-induced structural plasticity manifested at the level of dendritic spines that include processes starting from spinogenesis to gradual spine maturation and eventual spine shrinkage and loss. The results gathered in this review postulate rTMS as a universal modulator of synaptic plasticity, which could guide future research and help in optimizing appropriate protocols of transcranial magnetic stimulation for adequate disorders and pathologies.
Circular RNAs from the MAPT and TARDBP genes: Novel players in neurodegeneration?
Bagheri N, Margvelani G, Chiang TW … +3 more , Nelson PT, Chuang TJ, Stamm S
Neurochem Int · 2025 Oct · PMID 40633584 · Publisher ↗
The microtubule associated protein tau (MAPT) and TAR DNA binding protein (TARDBP) genes play crucial roles in neurodegeneration. The tau protein encoded by MAPT is the main component of tau tangles, a pathologic hallmar...
The microtubule associated protein tau (MAPT) and TAR DNA binding protein (TARDBP) genes play crucial roles in neurodegeneration. The tau protein encoded by MAPT is the main component of tau tangles, a pathologic hallmark of "tauopathies" such as Alzheimer's disease (AD). Cytosolic accumulations of TDP-43, encoded by TARDBP are characteristic for LATE (Limbic-predominant age-related TDP-43 encephalopathy) and other TDPopathies. In addition to the well-characterized mRNA splicing isoforms, both genes generate a multitude of circular RNAs (circRNAs). Both MAPT and TARDBP express circular RNA-specific exons characterized by suboptimal splice sites and lengths and are frequently derived from Alu-elements. Most circTau and to date all circTARDBP RNAs expressed in brain are human-specific, suggesting a possible unique contribution to human brain disease. TARDBP and MAPT circRNAs harbor open reading frames and circTau RNAs were shown to be translated into polypeptides in cells. Thus, circRNAs from the MAPT and TARDBP genes should be considered in molecular analysis of AD, LATE and other neurological diseases.
The potentiating activity of benzodiazepine site of the GABA(A) receptor is inhibited by competitive antagonists of orthosteric site.
Solntseva EI, Bukanova JV, Kondratenko RV
Neurochem Int · 2025 Sep · PMID 40623449 · Publisher ↗
Benzodiazepines (BDZs) are widely-prescribed drugs that act as positive allosteric modulators of GABA receptor, enhancing the GABA-elicited chloride current (I). In this work, we studied the influence of competitive anta...
Benzodiazepines (BDZs) are widely-prescribed drugs that act as positive allosteric modulators of GABA receptor, enhancing the GABA-elicited chloride current (I). In this work, we studied the influence of competitive antagonists of the GABA receptor gabazine (GBZ), bicuculline (Bic), and amiloride (Ami) on the potentiating effect of the agonist of BDZ site zolpidem (Zolp). These antagonists bind to their own sites, which partially overlap with the orthosteric site. The experiments were carried out on native GABA receptors in isolated Purkinje cells of the rat cerebellum. The I was measured using the patch-clamp technique and a system of fast application. The effects of the drugs on I were assessed by the change in the EC value for GABA dose-effect curve constructed in the ranges of 0.5-100 μM GABA. Changes in EC values as a percentage relative to the control were calculated. 0.5 μM Zolp shifted the GABA curve to the left and decreased the EC by 54 % (from 4.8 μM to 2.2 μM). Competitive antagonists shifted the GABA curve to the right and increased the EC to 72.6 μM (0.5 μM GBZ), 25.5 μM (500 μM Ami) and 28.8 μM (5 μM Bic). With the addition of Zolp, these EC values decreased by 21-25 % and were 56.8 μM (GBZ), 19.2 μM (Ami), and 22.7 μM (Bic), respectively. The results show that the potentiating effect of Zolp is reduced by half in the presence of competitive GABA receptor antagonists (p < 0. 001).
N-acetyltransferase 10 in the nucleus accumbens participates in methamphetamine-induced conditioned place preference and hyperlocomotion in mice.
Zeng ZH, Zhang LX, Li MQ … +6 more , Wang XQ, Zou GJ, Yao JY, Li CQ, Cui YH, Li F
Neurochem Int · 2025 Sep · PMID 40614933 · Publisher ↗
Drug addiction is characterized by compulsive drug use despite significant negative consequences. N-acetyltransferase 10 (NAT10), a member of the Gcn5-related N-acetyltransferases (GNAT) family, has been associated with...
Drug addiction is characterized by compulsive drug use despite significant negative consequences. N-acetyltransferase 10 (NAT10), a member of the Gcn5-related N-acetyltransferases (GNAT) family, has been associated with depression, anxiety-like behaviors, and cognitive dysfunction. However, its role in addiction remains largely unknown. In the present study, we observed increased expression of NAT10 in the nucleus accumbens (NAc) of mice treated either singly or repeatedly with 2 mg/kg methamphetamine (METH). To assess the role of NAT10 in addiction-related behaviors, we established mouse models of conditioned place preference (CPP) and hyperlocomotion. Using intraperitoneal administration of 0.1 mg/kg SCH23390, a dopamine D1 receptor (D1R) antagonist, we found that D1R antagonism significantly suppressed the METH-induced upregulation of NAT10 in the NAc and inhibited hyperlocomotion. Furthermore, stereotaxic delivery of a short hairpin RNA (shRNA)-based adeno-associated virus (AAV-shNAT10) into the NAc reduced both METH-induced hyperlocomotion and CPP. AAV-shNAT10 also inhibited METH-induced upregulation of PSD95 and preserved dendritic morphology in the NAc. These findings suggest that NAT10 contributes to the development of METH-induced reward-related behaviors by modulating dendritic plasticity in the NAc.
Acute ketamine enhances social behavior and dendritic plasticity in the amygdala by increasing BDNF, GAP43, and TRKB presence following excitotoxic neonatal ibotenic acid lesion.
Martínez-Torres NI, Cárdenas-Bedoya J, Torres-Mendoza BM
Neurochem Int · 2025 Sep · PMID 40609956 · Publisher ↗
Schizophrenia is a highly disabling psychopathology that is a significant burden on public health systems and is characterized by both positive and negative symptoms. One of these negative symptoms is social isolation, w...
Schizophrenia is a highly disabling psychopathology that is a significant burden on public health systems and is characterized by both positive and negative symptoms. One of these negative symptoms is social isolation, which responds poorly to available treatments. Ketamine (KET) has been shown to enhance social behavior in various preclinical models, accompanied by neurobiological changes. In this study, we used a preclinical model of schizophrenia involving neonatal ventral hippocampal (NVHL) bilateral lesions induced by excitotoxicity with ibotenic acid (IA) at postnatal day 7 (PD). Thirty male Sprague-Dawley rats, aged 7 PD, were assigned to one of the following groups: Intact, Sham, Intact + KET, IA + Saline, and IA + KET, with n = 6 per group. Rats in the Sham, IA + Saline, and IA + KET groups underwent stereotaxic surgery and were administered with either 0.3 % saline or IA at 7 PD. At 35 PD, the rats received either saline or ketamine (15 mg/kg) and were assessed using the three-chamber social test. A Golgi-modified technique was then employed to evaluate neuronal changes in the amygdala with Sholl analysis. Also, immunohistochemistry was conducted to measure brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TRKB), and growth-associated protein 43 (GAP43). Acute KET treatment rescued social behavior, increased dendritic tree complexity, and elevated BDNF, TRKB, and GAP43 protein presence. Our results suggest that acute sub-anesthetic administration of KET may help alleviate social isolation symptoms. This dose could provide a window of opportunity to encourage individuals with schizophrenia to initiate and continue their treatment.
Thiamet-G ameliorates Parkinson's disease-associated cognitive impairment via increasing O-GlcNAcylation of STING in the microglia.
Zhu S, Wang N, Chen S … +2 more , Zou J, Tan S
Neurochem Int · 2025 Sep · PMID 40578440 · Publisher ↗
Microglia activation contributed to the development of Parkinson's disease (PD)-associated cognitive impairment and targeting microglia may be a promising strategy for improving the cognitive function in PD. O-GlcNAclyti...
Microglia activation contributed to the development of Parkinson's disease (PD)-associated cognitive impairment and targeting microglia may be a promising strategy for improving the cognitive function in PD. O-GlcNAclytion is a novel protein post-translational modification with cognitive enhancing effects. This study aimed to investigate the effects of Thiamet-G (TMG), an O-GlcNAcase inhibitor that can increase the intracellular O-GlcNAclytion levels, on PD-associated cognitive impairment and the mechanism related to microglia activation. A PD mouse model was established using rotenone (ROT) and the cognitive functions of these mice were investigated by behavioral tests. The anti-inflammatory effects of TMG were tested in the BV2 microglia cells. TMG treatment significantly improved the cognitive function in the ROT-induced PD mouse model as evidenced by the Y-maze test and objective recognition test. Histological studies showed that TMG decreased the reactive microglia via increasing the total protein O-GlcNAclytion levels in the hippocampus of the PD mice. In the in vitro studies, TMG inhibited ROT-induced inflammation via decreasing the pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 in BV2 microglia cells. Bioinformatic analysis revealed that STING, a core protein in the innate immunity regulation, might be a novel target of O-GlcNAclytion. The immunoprecipitation experiments further confirmed that TMG inhibited STING phosphorylation via increasing O-GlcNAcylation. Taken together, TMG might ameliorate PD-associated cognitive impairment via increasing O-GlcNAcylation of STING in microglia, which provided evidence supporting that inhibiting the inflammatory response of microglia by elevating the O-GlcNAclytion levels might be an effective strategy for improving the cognitive function in PD.
Differential synaptic inhibition and serotonin 5-HT receptor-mediated modulation in identified dorsal horn neurons.
Salio C, Ferrini F, Bighinati A … +3 more , Lacivita E, Leopoldo M, Bardoni R
Neurochem Int · 2025 Sep · PMID 40553827 · Publisher ↗
Serotonergic modulation of pain transmission in the spinal cord involves the activation of multiple receptor types, including 5-HT receptors. Activation of spinal 5-HT receptors appears to have a predominant antinocicept...
Serotonergic modulation of pain transmission in the spinal cord involves the activation of multiple receptor types, including 5-HT receptors. Activation of spinal 5-HT receptors appears to have a predominant antinociceptive effect in various animal models. Although the serotonergic modulation of dorsal horn circuits has been extensively investigated, information about the specific effects of serotonergic receptors on identified neuron types remains limited. To address this, we have employed transgenic mice expressing channelrhodopsin-2 (ChR2) in inhibitory neurons, under the control of the vesicular GABA transporter (VGAT) promoter. Postsynaptic inhibitory responses (oIPSCs) induced by optogenetic stimulation of spinal cord slices displayed distinct properties in superficial dorsal horn VGAT+ and VGAT- neurons (inhibitory and putative excitatory neurons, respectively). While oIPSCs recorded from VGAT + neurons showed GABA- and glycine-mediated components of similar amplitudes, oIPSCs from VGAT- neurons were predominantly mediated by glycine. Consistently, immunofluorescence staining for the glycine transporter GlyT2 in mice expressing dTomato in GAD2 neurons revealed that GlyT2+ boutons primarily contact putative excitatory interneurons, which are negative for GAD2. Activation of 5-HT receptors by the agonist LP-211 significantly enhanced both the frequency of spontaneous inhibitory currents and the amplitude of oIPSCs in VGAT- neurons. In minimal optical stimulation experiments, application of LP-211 reduced the number of synaptic failures and increased the quantal content of oIPSCs, indicating presynaptic modulation mediated by 5-HT receptors. Our results suggest that enhanced synaptic inhibition of dorsal horn excitatory interneurons may contribute to the role of 5-HT receptors in suppressing pain transmission at the spinal cord level.
Antinociceptive and anti-inflammatory effects of dihydroaustrasulfone alcohol in alleviating peripheral neuropathy via Nrf2/HO-1 pathway in rats.
Sung CS, Cheng HJ, Yang SN … +6 more , Li PJ, Huang SY, Chen WF, Chen NF, Tsai JK, Wen ZH
Neurochem Int · 2025 Sep · PMID 40553826 · Publisher ↗
Peripheral neuropathic pain is closely associated with neuroinflammation and oxidative stress accumulation in the spinal cord dorsal horn (SCDH), but effective treatments remain limited. Dihydroaustrasulfone alcohol (WA2...
Peripheral neuropathic pain is closely associated with neuroinflammation and oxidative stress accumulation in the spinal cord dorsal horn (SCDH), but effective treatments remain limited. Dihydroaustrasulfone alcohol (WA25), a synthetic precursor of austrasulfone obtained from a Formosan soft coral, has anti-inflammatory and antioxidant properties. However, its potential therapeutic effect on neuropathic pain is yet to be established. This study aimed to elucidate the cellular mechanisms responsible for therapeutic potential of WA25 in rats with neuropathic pain. Neuropathic pain was induced in rats via chronic constriction injury (CCI), and WA25 was intrathecally administered in these rats. To evaluate the analgesic effects of WA25 and the underlying cellular mechanisms, nociceptive behavior assessment and immunofluorescence staining, respectively, were employed. WA25 significantly alleviated CCI-induced nociceptive behavior, neuroinflammation, and oxidative stress accumulation. Further, WA25 enhanced the expression of astrocytic nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the ipsilateral SCDH, suggesting its role in mitigating inflammation and oxidative stress. The co-administration of the HO-1 inhibitor ZnPP abolished the analgesic, anti-inflammatory, and antioxidant effects of WA25. The findings of the study suggest that WA25 effectively attenuates nociceptive sensitization, neuroinflammation, and oxidative stress accumulation in rats via the activation of the Nrf2/HO-1 signaling pathway, highlighting its potential as a therapeutic agent for neuropathic pain management.
Anti-inflammatory and analgesic effects of marine-derived antimicrobial peptide tilapia piscidin 3(TP3) in alleviating chronic constriction injury-induced neuropathic pain in rats.
Tsai JK, Wu ZS, Yang SN … +7 more , Huang SY, Chen HL, Teng WN, Su FW, Chen WF, Wen ZH, Sung CS
Neurochem Int · 2025 Sep · PMID 40544868 · Publisher ↗
Neuropathic pain has multiple etiologies, and many patients remain inadequately treated. The cyclic adenosine monophosphate (cAMP) signaling pathway plays a critical role in inflammatory responses, particularly through t...
Neuropathic pain has multiple etiologies, and many patients remain inadequately treated. The cyclic adenosine monophosphate (cAMP) signaling pathway plays a critical role in inflammatory responses, particularly through the upregulation of proinflammatory cytokines. This study aimed to investigate the anti-inflammatory and analgesic properties of the marine-derived antimicrobial peptide Tilapia Piscidin 3 (TP3), using a chronic constriction injury (CCI) model to simulate neuropathic pain. In vitro assays showed that TP3 exerted a dose-dependent inhibitory effect on lipopolysaccharide-induced proinflammatory cytokine expression in mouse BV-2 microglia and RAW 264.7 macrophages. Nociceptive behavioral tests revealed that intrathecal (IT) administration of TP3 alleviated CCI-induced mechanical allodynia and thermal hyperalgesia. Immunofluorescence analysis showed that IT TP3 significantly increased phosphodiesterase 4D (PDE4D) levels and decreased the expression of cAMP, brain-derived neurotrophic factor (BDNF), and tumor necrosis factor-α in astrocytes within the dorsal horn of the spinal cord in CCI rats. The antinociceptive effects of TP3 were abolished by the PDE4D inhibitor rolipram, highlighting the role of PDE4D-mediated modulation of the cAMP pathway in producing these effects. These findings suggest that TP3 may be a promising therapeutic agent for treating neuropathic pain by exerting anti-inflammatory and analgesic effects through regulation of the cAMP pathway.
Pathway-specific regulation of amphetamine-induced conditioned place preference by chemogenetic modulation of basolateral amygdala projections to prelimbic cortex and nucleus accumbens subregions.
Han J, Rim H, Jang H … +3 more , Cai WT, Kim WY, Kim JH
Neurochem Int · 2025 Sep · PMID 40541740 · Publisher ↗
Individuals with substance use disorders develop maladaptive associative memories, linking environmental contexts with drug experiences. The basolateral amygdala (BLA), prelimbic cortex (PrL), and nucleus accumbens (NAc)...
Individuals with substance use disorders develop maladaptive associative memories, linking environmental contexts with drug experiences. The basolateral amygdala (BLA), prelimbic cortex (PrL), and nucleus accumbens (NAc) are central components of the neural circuitry underlying these associations. However, it remains unclear how specific BLA outputs differentially regulate the expression of contextual drug memories. Using designer receptors exclusively activated by designer drugs, we selectively modulated neuronal activity with deschloroclozapine as the activating agent during the expression of amphetamine-induced conditioned place preference (CPP) in the BLA pathways to the PrL, NAc core, and NAc shell. Our findings revealed a dissociation between these pathways: the BLA-to-PrL circuit exerted bidirectional control over CPP expression, with inhibition significantly enhancing and activation attenuating drug-context associations. In contrast, BLA-to-NAc core manipulations selectively modulated locomotor aspects of conditioned responses without affecting place preference, while BLA-to-NAc shell manipulations produced no significant effects on CPP expression. These results demonstrate that the BLA has a distinctive pathway-specific roles in the expression of contextual drug memory.
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