Neurochemistry International[JOURNAL]
Sun
200 papers
Paeonol ameliorates scopolamine- and β-amyloid 1-42 oligomer-induced cognitive impairments through modulation of the TGR5-PKA-cAMP response element-binding-brain-derived neurotrophic factor pathway and inhibition of acetylcholinesterase.
Lee YW, Cho YE, Kim SY … +8 more , Cho SY, Lee SJ, Do YJ, Lee NH, Kim DH, Ryu JH, Bae HJ, Park SJ
Neurochem Int · 2026 · PMID 42167685 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and cholinergic signaling deficits. Paeonol (2-hydroxy-4-methoxyacetophenone), a phenolic compound d...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and cholinergic signaling deficits. Paeonol (2-hydroxy-4-methoxyacetophenone), a phenolic compound derived from Paeonia suffruticosa, has well-documented neuroprotective activity, but potential cognitive benefits and the underlying mechanisms have not been widely examined. Here, we investigated the potential of paeonol to improve cognitive function in scopolamine- and Aβ oligomer-induced mouse models of AD. Paeonol significantly improved the performance of both models in the Y-maze, novel object recognition, and passive avoidance tests, particularly at 10 mg/kg. Western blotting of excised brain tissue revealed that paeonol treatment reversed scopolamine- and Aβ oligomer-induced suppression of hippocampal PKA and cAMP response element-binding (CREB) phosphorylation and concomitantly enhanced brain-derived neurotrophic factor (BDNF) expression. Notably, paeonol also reversed scopolamine- and Aβ-induced downregulation of Takeda G-protein-coupled receptor 5 (TGR5), an upstream regulator of the PKA-CREB-BDNF pathway, and molecular docking simulations predicted a possible paeonol-TGR5 interaction. Moreover, paeonol suppressed scopolamine-induced elevation of acetylcholinesterase activity with efficacy comparable to the clinical inhibitor donepezil. These findings support the potential of paeonol as a naturally sourced multitarget therapeutic agent for AD.
Epigenetic mechanisms of (electro)acupuncture in acute neuroprotection and rehabilitation of stroke.
Wang JY, Wu T, Lin L … +2 more , Xu YM, Lau ATY
Neurochem Int · 2026 May · PMID 42162672 · Publisher ↗
(Electro)acupuncture is a simple, convenient, effective, and affordable therapeutic modality in traditional Chinese medicine (TCM). Guided by the principles of Inspection, Auscultation and olfaction, Inquiry, and Palpati...
(Electro)acupuncture is a simple, convenient, effective, and affordable therapeutic modality in traditional Chinese medicine (TCM). Guided by the principles of Inspection, Auscultation and olfaction, Inquiry, and Palpation (the four diagnostic methods), holistic concept, and treatment based on pattern identification, it regulates the functions of zang-fu organs, qi, blood, and body fluids, thereby enhancing organ vitality. Epigenetics refers to the alteration of gene expression through DNA/RNA/histone epigenetics modification. Stroke is a vascular injury caused by multiple etiologies, leading to pathologies in the central nervous system (CNS). This review first outlines the epidemiological characteristics and pathophysiological features of stroke in China. Subsequently, it focuses on the epigenetic regulatory mechanisms of acupuncture and electroacupuncture (EA) in post-stroke rehabilitation, while briefly summarizing relevant research on their neuroprotective effects in the acute phase. It focuses on exploring how acupuncture and EA regulate the molecular mechanisms underlying acute phase neuroprotection and convalescent phase neural repair after stroke through epigenetic pathways such as histone modification and non-coding RNA, while also addressing the current research gaps in the recovery phase, particularly for hemorrhagic stroke. Finally, we prospect the challenges and future directions of acupuncture and EA in epigenetics research, aiming to help researchers gaining a deeper understanding of the principles of acupuncture and EA therapy and provide a more sufficient molecular theoretical basis for these treatments.
Lrp10 insufficiency upregulates mRNA and protein of neurotoxic α-synuclein and causes degeneration of substantia nigra dopaminergic neurons in heterozygous or homozygous Lrp10 knockout mice.
Wang HL, Liu SY, Chiu CC … +5 more , Yeh TH, Chiu TJ, Yeh YC, Wu PR, Weng YH
Neurochem Int · 2026 · PMID 42142532 · Publisher ↗
Heterozygous intronic mutations of LRP10 (low density lipoprotein receptor-related protein 10) gene, which produce LRP10 haploinsufficiency by impairing splicing of LRP10 mRNA and generating loss-of-function truncated LR...
Heterozygous intronic mutations of LRP10 (low density lipoprotein receptor-related protein 10) gene, which produce LRP10 haploinsufficiency by impairing splicing of LRP10 mRNA and generating loss-of-function truncated LRP10, cause autosomal dominant Parkinson's disease (PD). Heterozygous Lrp10 knockout mice, which replicate heterozygous intronic mutation of LRP10-induced LRP10 haploinsufficiency, and homozygous Lrp10 knockout mice were utilized to elucidate molecular pathomechanisms underlying Lrp10 insufficiency-triggered demise of substantia nigra pars compacta (SNpc) dopaminergic neurons. Lrp10 and Lrp10 knockout mice displayed PD motor impairment, neurodegeneration of SNpc dopaminergic cells and presence of SN phospho-α-synuclein-containing Lewy bodies. Lrp10 was expressed in mouse SNpc dopaminergic neurons. WT LRP10 downregulated α-synuclein mRNA, and Lrp10 deficiency elevated α-synuclein mRNA via augmenting transcription of α-synuclein gene in dopaminergic neurons. Lrp10 deficiency-induced elevation of α-synuclein mRNA upregulated pathological α-synuclein and α-synuclein oligomers within SNpc dopaminergic neurons of Lrp10 or Lrp10 mice. Macroautophagy activator rapamycin prevented Lrp10 paucity-induced upregulation of SN α-synuclein, PD neurological and neuropathological phenotypes observed in Lrp10 or Lrp10 knockout mice. Lrp10 insufficiency-induced upregulation of ER and mitochondrial α-synuclein stimulated ER stress and mitochondrial apoptotic cascades in SN of Lrp10 or Lrp10 mice. Lrp10 paucity-evoked elevation of pathologic α-synuclein oligomers activated microglia and NLRP3 inflammasome and upregulated TNF-α, IL-1β and IL-18, which excited RIPK1-RIPK3-MLKL necroptotic pathway and MKK4-JNK -c-Jun/ATF-2 apoptotic signaling in SN of Lrp10 or Lrp10 knockout mice. Our results suggest that heterozygous intronic mutation of LRP10-induced LRP10 haploinsufficiency causes degeneration of SNpc dopaminergic neurons and autosomal dominant PD by upregulating mRNA and protein of neurotoxic α-synuclein.
Electronic cigarette vapor exposure modifies stroke-induced transcriptional and microglial responses in a sex-dependent manner.
Sinder SB, Diaz IC, Patel SH … +7 more , Romagnoli J, Sharma H, Perez GG, Dave KR, Perez-Pinzon MA, Bramlett HM, Raval AP
Neurochem Int · 2026 · PMID 42140561 · Publisher ↗
The global rise in nicotine-containing electronic cigarette (EC) use highlights the need to understand their impact on stroke outcomes. This study examined how EC exposure affects post-ischemic inflammation in adult Spra...
The global rise in nicotine-containing electronic cigarette (EC) use highlights the need to understand their impact on stroke outcomes. This study examined how EC exposure affects post-ischemic inflammation in adult Sprague-Dawley rats. Both sexes were exposed to air or EC vapor (5% nicotine Juul pods) for 16 nights, followed by transient middle cerebral artery occlusion (tMCAO; 90 min) or sham surgery. Animals were divided into two cohorts. In Cohort 1, RNA sequencing of ipsilateral cortex at 16 days post-tMCAO revealed 443 upregulated and 453 downregulated genes in males, and 537 upregulated and 578 downregulated genes in females (p < 0.05). Differentially expressed genes in males were linked to membrane transport, signaling, and immune responses. In females, genes were enriched in pathways related to synaptic structure, cognition, proliferation, and genomic maintenance. In Cohort 2, microglial activation was analyzed 21 days post-tMCAO using Iba-1 immunostaining and Sholl analysis. EC-exposed females exhibited more de-ramified microglia, larger soma size, shorter branch length, and reduced morphological complexity compared to air-exposed controls. Current findings suggest that EC exposure exacerbates post-stroke neuroinflammation and transcriptomic dysregulation, particularly in females. Future studies should investigate whether withdrawal from EC reduces ischemic stroke severity and define the timeframe required for potential recovery.
Soy lysolecithin attenuates hypertension and behavioral impairments in mice fed a high-salt diet through receptor-specific regulation of prostaglandin signaling and arachidonic acid-derived prostaglandin production.
Kubota H, Kunisawa K, Hasegawa M … +10 more , Kurahashi H, Kagotani K, Nakajima K, Fujimoto Y, Hayashi A, Sono R, Tsuji T, Saito K, Nabeshima T, Mouri A
Neurochem Int · 2026 · PMID 42140560 · Publisher ↗
High salt (HS) intake is a major risk factor of hypertension and has been implicated in emotional and cognitive decline. On the other hand, dietary supplementation may represent a potential preventive strategy against he...
High salt (HS) intake is a major risk factor of hypertension and has been implicated in emotional and cognitive decline. On the other hand, dietary supplementation may represent a potential preventive strategy against health risks induced by HS intake. Soybean lecithin is widely used as a phospholipid supplement. Here, we investigated the effects of lysolecithin enriched in lysophosphatidylcholine (>70% of total phospholipids; LPC70) on hypertension and behavioral impairments under high-salt diet (HSD) conditions in mice. To further characterize these effects, we examined changes in prostaglandin (PG)-related pathways by integrating gene expression and lipidomic analyses. Mice were fed an HSD (chow containing 8% NaCl) with or without LPC70 for 10 weeks. HSD elevated systolic blood pressure and impaired social behavior and object recognition memory in mice. Quantitative gene expression analyses revealed that HSD increased renal expression of cyclooxygenase-2 (COX-2) and EP3 (PGE receptor), and reduced expression of DP1 (PGD receptor) in the prefrontal cortex. LPC70 attenuated these changes in behavior, blood pressure, and PG-related gene expression. Furthermore, lipidomic analyses revealed that HSD reduced circulating arachidonic acid (AA) levels, whereas LPC70 increased AA-derived PG, such as PGE and PGD, in HSD-fed mice. These findings demonstrate that LPC70 may protect against hypertension and behavioral impairments under HSD conditions in mice, potentially in association with modulation of PG signaling. LPC70 may serve as a functional dietary component that reshapes lipid mediator signaling under HSD conditions.
The impact of long-term feeding with curcuminoids phospholipids enriched diet on disease progression of fALS.
Purushotham SS, Chesworth R, Keembiyage N … +3 more , Münch G, Gyengesi E, Buskila Y
Neurochem Int · 2026 · PMID 42134658 · Publisher ↗
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal neurodegenerative disease characterised by the progressive loss of motor functions affecting both upper and lower motor neurons. Although considered multifa...
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal neurodegenerative disease characterised by the progressive loss of motor functions affecting both upper and lower motor neurons. Although considered multifactorial with an unclear aetiology, it is believed that the interplay between genetic and environmental factors, with neuroinflammation playing a key role in disease progression, contributes to its development. There is currently no effective treatment for ALS. Curcumin has been recently highlighted for its potential therapeutic role in treating neurodegenerative diseases. Curcumin phospholipids, a highly bioavailable form of curcumin that allow the curcumin to be absorbed into the bloodstream more effectively than standard curcumin extracts, is considered as a natural cytokine-suppressive anti-inflammatory compound (CSAID) that is well-known for its therapeutic properties and is considered safe for humans and rodents at low to moderate concentrations. In this study, we investigated whether a long-term feeding regimen incorporating curcuminoids phospholipids-enriched diet early in disease progression could mitigate motor deficits and affect the lifespan of the SOD1 mouse model of familial ALS (fALS). Our results indicate sex-differences regarding the effect of curcumin supplementation on motor deficits and anxiety-like behaviour. While long-term feeding with curcuminoids phospholipids enriched diet had a complex effect on SOD1 female mice expressed as reduced anxiety like behaviour and motor deficits at the walking beam test, it had no effect on SOD1 male mice. Moreover, curcuminoids supplementation had a limited effect on disease onset and progression in SOD1 mice model for fALS.
Nature-origin phthalides for Parkinson's disease drug development.
Vinayagam J, Kalaivani D, Senthilkumar GP
Neurochem Int · 2026 · PMID 42134657 · Publisher ↗
Parkinson's disease (PD) is a neurodegenerative disorder characterised by neuronal loss in the substantia nigra, α-synuclein accumulation, mitochondrial impairment, oxidative stress, neuroinflammation, and apoptotic cell...
Parkinson's disease (PD) is a neurodegenerative disorder characterised by neuronal loss in the substantia nigra, α-synuclein accumulation, mitochondrial impairment, oxidative stress, neuroinflammation, and apoptotic cell death. Although various pharmacological treatments, including levodopa and dopamine receptor agonists, can ameliorate PD symptoms, no disease-modifying agents with neuroprotective effects are currently available to prevent progression of neurodegeneration. As a result, there is a growing need for novel disease-modifying agents, particularly for agents with multi-target neuroprotective activity. Lactone derivatives, collectively called phthalides, from various medicinal plants, particularly from compounds of Ligusticum chuanxiong and Angelica sinensis, have been lately identified as promising drugs in this context. In the following review, a comprehensive discussion is given about the etiology of PD, its progression, molecular correlations with the pathogenesis process, latest pharmacological treatments, adverse effects with prolonged administration of drugs, etiology, and relevance of naturally occurring phthalide compounds such as DL-3-n-butylphthalide, ligustilide, senkyunolide H, sedanolide, neocnidilide, among others, with regards to their activity as neuroprotective agents in animal studies of Parkinson's disease. Results from in vitro as well as animal studies highlight their anti-oxidative, anti-inflammatory, anti-ferroptotic, anti-α-synuclein, as well as anti-MAO-B activity, and their roles as multi-target drugs in the context of disease pathogenesis.
TDP-43 expression in the cytoplasm leads to early synaptic and mitochondrial abnormalities in an inducible mouse model of ALS/FTD.
Vassallu F, López M, López Ambrosioni F … +3 more , Casal J, Caltana L, Igaz LM
Neurochem Int · 2026 · PMID 42134656 · Publisher ↗
TDP-43 proteinopathy is the primary pathology associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), indicating that these neurodegenerative diseases have common underlying mechanisms. We...
TDP-43 proteinopathy is the primary pathology associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), indicating that these neurodegenerative diseases have common underlying mechanisms. We have previously shown that transgenic (Tg) mice conditionally overexpressing a cytoplasmic form of human TDP-43 protein (TDP-43-ΔNLS) in forebrain neurons replicate key features of FTD/ALS, including altered cognitive, motor and social behaviors. These behavioral phenotypes and changes in plasticity-related gene expression can be detected as early as 1 month after Tg induction, before overt neurodegeneration occurs. To assess early ultrastructural features in this model, we performed Transmission Electron Microscopy (TEM) analysis in the cortex (Ctx) and hippocampus (Hp) of Tg animals and their non-Tg controls. TEM evaluation of Ctx and Hp revealed that synaptic density was significantly decreased and synapse length was increased in both regions of Tg animals. Synaptic cleft thickness was increased and post-synaptic density thickness was decreased only in the Ctx of Tg mice, revealing differential regional effects in synaptic morphology. We analyzed mitochondrial density and we found an increase in the Ctx and a decrease in the Hp of Tg animals, with preserved individual mitochondrial area. Lastly, transcriptomic and proteomic analysis from both Tg TDP-43-ΔNLS mice and human proteinopathy showed widespread decreased expression of synaptic structure and function genes. The alterations in synaptic density and architecture reported here, combined with the mRNA/protein expression data, suggest that TDP-43-ΔNLS mice may exhibit abnormal synaptic transmission and that ultrastructural changes play a role in the early behavioral deficits observed in this model.
Let-7a-5p targets MAP3K1 to regulate the MAPK signaling pathway in a depression model.
Fei S, Li Q, Xiang J … +2 more , Wang H, Shang X
Neurochem Int · 2026 · PMID 42134655 · Publisher ↗
Depression is a complex and multifactorial psychiatric disorder involving the dysregulation of multiple biological processes, including inflammation, apoptosis, and synaptic plasticity. Increasing evidence suggests that...
Depression is a complex and multifactorial psychiatric disorder involving the dysregulation of multiple biological processes, including inflammation, apoptosis, and synaptic plasticity. Increasing evidence suggests that microRNAs (miRNAs) play crucial roles in the pathogenesis of depression by regulating gene expression at the post-transcriptional level. In this study, bioinformatics analysis identified let-7a-5p as a hub miRNA associated with depression. Target prediction and dual-luciferase reporter assays confirmed that let-7a-5p directly targets MAP3K1, an upstream kinase of the MAPK signaling pathway. Overexpression of let-7a-5p significantly activated the MAPK cascade, leading to downstream alterations in inflammatory cytokine expression, neuronal apoptosis, and synaptic plasticity-related signaling. Western blot analysis further verified changes in MAP3K1, p-ERK/ERK, and p-p38/p38, as well as inflammation-related proteins (IL-6, TNF-α, IL-1β) and apoptosis-associated proteins (Caspase-3, Bcl-2, Bax). In addition, synaptic plasticity markers including BDNF, NR2A, and PSD95 were also affected, indicating that MAPK activation may regulate neuronal adaptability and connectivity. These findings suggest that let-7a-5p regulates depression-like cellular processes by modulating the MAP3K1-MAPK signaling axis, thereby influencing inflammation, apoptosis, and synaptic plasticity. This study provides novel insights into the molecular mechanisms and potential therapeutic targets of depression.
Parkinson's disease as a disorder of synaptic raft integrity: A unified explanation for motor subtypes and non-motor symptoms.
Sakoda S
Neurochem Int · 2026 · PMID 42134654 · Publisher ↗
Parkinson's disease (PD) has traditionally been attributed to nigrostriatal dopaminergic neurodegeneration; however, neuronal loss alone does not adequately account for the diversity of motor subtypes, variability in tre...
Parkinson's disease (PD) has traditionally been attributed to nigrostriatal dopaminergic neurodegeneration; however, neuronal loss alone does not adequately account for the diversity of motor subtypes, variability in treatment responses, or the wide spectrum of non-motor symptoms. Converging evidence from both raft-focused and network-level lipidomic studies suggests a shared upstream membrane dysfunction characterized by coordinated disruptions in raft-enriched lipids. In this conceptual review, I propose that PD may be conceptualized as a disorder of synaptic lipid raft integrity ("raftopathy") affecting both dopaminergic and non-dopaminergic systems. Within this framework, clinical heterogeneity may be understood along a multidimensional spectrum reflecting the relative contributions of presynaptic and postsynaptic dysfunction, as well as involvement of non-dopaminergic networks. Presynaptic raft disruption may preferentially impair dopamine release and contribute to akinetic-rigid phenotypes with limited pharmacological responsiveness, whereas postsynaptic raft instability may increase receptor signaling variability, potentially underlying tremor-dominant features, wearing-off phenomena, and dyskinesia. Furthermore, neuronal degeneration is hypothesized to represent a downstream consequence of sustained synaptic dysfunction rather than the primary initiating event. This raft-centered framework may provide a conceptual basis for developing therapeutic strategies that extend beyond dopamine replacement, particularly for addressing treatment-related complications and non-motor symptoms.
TRIM31 attenuates microglia-mediated neuroinflammation via targeting TAK1 in vitro and in vivo.
Zhao X, Zhang C, Zhang D … +3 more , Wang P, Zhang L, Fan M
Neurochem Int · 2026 · PMID 42119685 · Publisher ↗
Neuroinflammation represents a central pathogenic driver in a spectrum of central nervous system disorders, predominantly mediated by microglial activation and the ensuing release of inflammatory cytokines. While the E3...
Neuroinflammation represents a central pathogenic driver in a spectrum of central nervous system disorders, predominantly mediated by microglial activation and the ensuing release of inflammatory cytokines. While the E3 ubiquitin ligase TRIM31 is implicated in peripheral immunity, its precise function within neuroinflammation defies precise delineation. In this study, we define the role of TRIM31 in microglia-driven neuroinflammation and clarify its molecular mechanism. Utilizing both cellular and murine models of lipopolysaccharide-induced neuroinflammation, we detected a marked induction of TRIM31 expression with LPS stimulation. Genetic knockdown of TRIM31 exacerbated the LPS-triggered upregulation of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β. Conversely, TRIM31 overexpression potently suppressed cytokines release and attenuated neuroinflammatory responses in vitro and in vivo. Mechanistic investigations combining transcriptomic profiling and immunoblotting manifested that TRIM31 directly interacts with TAK1, catalyzing its K48-linked polyubiquitination and subsequent proteasomal degradation. This action provokes the downregulation of the NF-κB activation cascade. Collectively, our findings identify TRIM31 as a critical negative regulator of neuroinflammation and underscore its therapeutic potential for treating neuroinflammatory diseases via targeted degradation of TAK1.
GluN2B-containing NMDA receptors in the infralimbic cortex and sleep modulate compensatory contextual fear memory after dorsal hippocampal damage.
Kant D, Jha SK
Neurochem Int · 2026 · PMID 42107608 · Publisher ↗
Fear memories are highly persistent, and identifying the neural mechanisms that support their formation is essential in understanding trauma-related neuropsychiatric disorders. Although the dorsal hippocampus (DH) plays...
Fear memories are highly persistent, and identifying the neural mechanisms that support their formation is essential in understanding trauma-related neuropsychiatric disorders. Although the dorsal hippocampus (DH) plays a crucial role in contextual-fear-conditioned (CxFC) memory formation, repeated exposure can engage hippocampus-independent circuits that support fear memory even after DH damage. Compensatory CxFC memory is formed in the infralimbic cortex (IL) in the absence of the DH; however, the glutamatergic receptor subtypes and state-dependent factors that modulate this process remain unclear. Here, we examined the role of (i) GluN2A and GluN2B subunits of NMDA receptor in the IL, and (ii) sleep-dependent development of compensatory-CxFC memory in the DH-lesioned rats. The DH of Wistar rats was bilaterally damaged with ibotenic acid. Thereafter, the animals were fear-conditioned through two separate contextual fear-conditioning sessions, each separated by a three-day interval. The fear memory was assessed during a subsequent test. Pharmacological inhibition of the IL using 'Ro25-6981', a NMDA-GluN2B blocker, during the first session disrupted compensatory fear memory, whereas PEAQX, a NMDA-GluN2A blocker, had no effect. In another cohort, sleep deprivation between sessions abolished compensatory CxFC memory formation in DH-lesioned rats, while non-sleep-deprived DH-lesioned animals displayed robust compensatory CxFC memory. Together, these findings demonstrate the significance of GluN2B-dependent NMDA receptors in the IL and identify sleep as a crucial modulator of hippocampus-independent compensatory contextual fear memory formation, although the underlying detailed molecular mechanism remains to be studied.
Microglia derived cold-inducible RNA-binding protein play a critical role in neuroinflammation and neuronal damage after cardiac arrest and resuscitation in rats.
Gao Y, Liu H, Ang Y … +5 more , Tan X, Cai S, Duan M, Zeng Q, Sun J
Neurochem Int · 2026 · PMID 42107607 · Publisher ↗
Cardiac arrest (CA) is a global health problem that accounts for more deaths than many other diseases. Global cerebral ischemia-reperfusion injury resulting from CA and resuscitation remains a critical issue that urgentl...
Cardiac arrest (CA) is a global health problem that accounts for more deaths than many other diseases. Global cerebral ischemia-reperfusion injury resulting from CA and resuscitation remains a critical issue that urgently requires further investigation. Neuroinflammation-related cytokines play a central role in exacerbating neuronal injury in conditions involving global cerebral ischemia-reperfusion. As a newly discovered damage-associated molecular pattern (DAMP), cold-inducible RNA-binding protein (CIRP) contributes significantly to various inflammatory diseases. However, the mechanism of CIRP in cardiac arrest and resuscitation associated neuroinflammation remains unclear. This study aims to investigate the role of microglia derived CIRP in neuroinflammation and neuron damage. We established a rat model of CA and hippocampal neuron/BV2 microglia cells oxygen-glucose deprivation/reoxygenation (OGDR) model. In animal experiments, we observed an increase in CIRP expression of hippocampus after CA and resuscitation. Moreover, elevated CIRP level can activate microglia to release more inflammatory factors, thereby damaging neurons. RNA sequencing analysis indicated that the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway may serve as a downstream pro-inflammatory signaling pathway of CIRP. In cell experiments, microglial cells subjected to OGDR secreted numerous exosomes containing CIRP. These exosomes acted on the cells' own inflammatory pathways in an autocrine manner, intensifying the inflammatory response. Moreover, they directly damaged neighboring neurons through paracrine action. Inhibiting the synthesis or secretion of CIRP alleviated neuroinflammation. This study enhances to understand the role of CIRP in the neuroinflammation induced by global cerebral ischemia reperfusion and has identifies potential targets for brain resuscitation therapy following CA.
Neurometabolite changes in cingulate cortex regions in healthy Indian population and effect of Bacopa monnieri intervention: a H MRS study.
Singh AD, Kumar M, Bh S … +3 more , P B, Godbole A, Khushu S
Neurochem Int · 2026 · PMID 42102930 · Publisher ↗
The present study investigates the age-related neuro-metabolite changes in anterior-cingulate cortex (ACC) and posterior-cingulate cortex (PCC) and their correlation with cognitive performance. The study also probes the...
The present study investigates the age-related neuro-metabolite changes in anterior-cingulate cortex (ACC) and posterior-cingulate cortex (PCC) and their correlation with cognitive performance. The study also probes the impact of formulations of Brahmi (Bacopa monnieri (L.) Wettst.), a well-known nootropic, on neuro-metabolite concentration, cognitive performance and brain health. We performed H MRS from ACC and PCC and neuropsychological test on three cohorts, younger age (25-40 years, n = 37), middle age (41-55 years, n = 28) and older age group (56-85 years, n = 31). In addition, the subjects with age 50 years and above from the cohorts received three months interventions of Brahmi Ghrita (BG) (n = 9), Brahmi extract (n = 9), and Plain Ghee (n = 8). MRS data were analysed using analysis of covariance (ANCOVA) and Bonferroni post-hoc-tests for comparisons between age-groups, and paired-t-test was performed for pre- and post-intervention comparisons. Partial correlations were performed between neurometabolites and neuropsychological scores, controlling SNR, gender. Our results showed increased concentration of tCho, tCr, mI and tNAA in anterior and posterior cingulate cortex with aging. The increased concentration of these metabolites correlated positively with the age whereas metabolites tCho, tCr, and mI correlated inversely with auditory verbal learning (AVL), immediate recall, and delayed recall memory. The preliminary post-intervention findings revealed that the dietary fat-based formulation of Bacopa monnieri (BG) partially reversed the increase concentration of tCho, tCr, mI and improved AVL, digit span forward (DS-F) cognitive function performance. Overall, the results of the study suggest that BG can be potential prophylactic intervention for brain, especially in ageing population.
Targeted stabilization of astrocytic Cx43 gap junctions reverses depression-like behaviors via dual restoration of syncytial networks and glutamatergic homeostasis.
Li XM, Zhang M, Xing Z … +8 more , Yang XY, Lai HQ, Wang YC, Jiang H, Yan X, Chu SF, Chen NH, Wang ZZ
Neurochem Int · 2026 · PMID 42102929 · Publisher ↗
Depression, a debilitating global mental disorder affecting millions of people worldwide, is characterized by persistent low mood and anhedonia. Growing evidence identifies astrocyte dysfunction and glutamate metabolism...
Depression, a debilitating global mental disorder affecting millions of people worldwide, is characterized by persistent low mood and anhedonia. Growing evidence identifies astrocyte dysfunction and glutamate metabolism imbalance as core pathological features of this condition. Notably, astrocytic connexin 43 (Cx43) downregulation and subsequent gap junction (GJ) impairment constitute recognized pathological features of depression. However, the development of direct therapeutic strategies targeting Cx43-GJ remains underexplored, representing a significant gap in current antidepressant drug discovery. Here, using integrated in vitro (corticosterone-induced dysfunctional astrocytes) and in vivo (chronic unpredictable stress [CUS]-induced mice) systems, we demonstrate that chronic stress depletes Cx43-GJs, driving astrocyte atrophy, disrupting syncytial network integrity, and dysregulating synaptic glutamate-glutamine cycling. Functional magnetic resonance imaging further revealed widespread impairment of whole-brain functional connectivity in CUS mice, while microRNA sequencing additionally confirmed glutamatergic synaptic dysfunction. Treatment with ZP1609, a selective Cx43-GJ stabilizer that preserves Cx43-GJ functionality without modulating connexin hemichannel activity, ameliorated depressive-like behaviors and specifically restored hippocampus-centered functional connectivity in CUS mice. Mechanistic investigation revealed ZP1609 exerts its effects through dual pathways: (ⅰ) stabilizing Cx43-GJs to maintain intercellular communication and reverse astrocyte structural atrophy, thereby restoring syncytial network integrity; and (ⅱ) normalizing astrocytic glutamate-glutamine cycling to mitigate synaptic excitotoxicity and protect glutamatergic synaptic function. Our findings suggest Cx43-GJ stabilization as a novel therapeutic strategy that simultaneously rectifies astrocyte network failure and glutamatergic synaptic impairment, providing preclinical evidence for Cx43-GJ-targeted antidepressants development.
Microglia beyond boundaries: Paradigm shifts in origin, distribution, state diversity, and therapeutic regeneration.
Lan Z, Liu H, Huang C … +6 more , Li J, Dai Z, Yuan Y, He C, Qin S, Su Z
Neurochem Int · 2026 · PMID 42097369 · Publisher ↗
Microglia have undergone a fundamental redefinition, transitioning from traditional CNS-restricted scavengers to a highly dynamic and systemically distributed immune lineage. This review synthesizes recent paradigm shift...
Microglia have undergone a fundamental redefinition, transitioning from traditional CNS-restricted scavengers to a highly dynamic and systemically distributed immune lineage. This review synthesizes recent paradigm shifts that challenge long-standing concepts in neuroimmunology. We first discuss the revision of the classical vascular extravasation model by a newly identified integrin-dependent pial surface migration route for embryonic microglial progenitors. Second, we introduce the expanded concept of the "microglial lineage," which includes transcriptionally and ontogenetically homologous cells residing not only in the CNS but also in peripheral tissues such as the skin, heart, and peripheral nervous system, suggesting broader physiological functions. Third, we highlight the transition from the obsolete M1/M2 polarization model to a microenvironment-driven, dynamic multimodal framework that captures the complex and context-dependent nature of microglial states in health and disease. Finally, we review breakthroughs in regenerative therapy, from pharmacologically induced repopulation to exogenous replacement using iPSC-derived or gene-corrected microglia, offering new hope for genetic microgliopathies such as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Collectively, these advances position microglia as central mediators of neuro-immune crosstalk and open novel avenues for treating neurodegenerative, neuroinflammatory, and developmental brain disorders.
JNK inhibition suppresses microglial NLRP3 activation and oxidative stress but unexpectedly worsens pain in diabetic neuropathy: insights from a combined in vitro and in vivo pharmacological study.
Ling L, Ali T, Li X … +5 more , Gui S, Zhao H, Zeng X, Lv M, Duan C
Neurochem Int · 2026 · PMID 42092483 · Publisher ↗
Diabetic neuropathy (DN) is driven by neuroinflammation and oxidative stress, with c-Jun N-terminal kinase (JNK) as a key mediator; however, the effects of JNK inhibition on neuropathic pain remain unclear. Therefore, we...
Diabetic neuropathy (DN) is driven by neuroinflammation and oxidative stress, with c-Jun N-terminal kinase (JNK) as a key mediator; however, the effects of JNK inhibition on neuropathic pain remain unclear. Therefore, we investigated the therapeutic potential of the JNK inhibitor SP600125 in a type 2 diabetic mouse model using combined in vitro and in vivo approaches. BV2 microglia were exposed to high glucose, lipopolysaccharide, palmitic acid, or hydrogen peroxide (HO) with or without SP600125 (10 nM). The PPARγ antagonist GW9662 was used for mechanistic dissection. Diabetic mice received SP600125 (15 mg/kg/day) or vehicle for 7 weeks. In vitro, SP600125 attenuated JNK phosphorylation and suppressed pro-inflammatory activation via NF-κB and NLRP3 in a PPARγ-dependent manner. SP600125 reduced palmitate-induced oxidative stress but exacerbated HO-induced injury (p < 0.0001), revealing context-dependent redox modulation. In vivo, SP600125 reduced diabetes-induced lipid accumulation and microglial reactivity while shifting microglia to an anti-inflammatory phenotype; however, it did not alter NLRP3, ASC, IKKα, or PPARγ expression. Despite these effects, SP600125 paradoxically worsened mechanical allodynia and thermal hyperalgesia. Together, these findings indicate that JNK inhibition provides anti-inflammatory and anti-lipid effects but paradoxically exacerbates pain, revealing a critical dissociation between neuroprotection and pain modulation in diabetic neuropathy.
Elamipretide (SS-31) promotes recovery by preserving mitochondrial bioenergetics and neural remodeling after spinal cord injury.
Song Z, Ban Z, Zhao H … +1 more , Mei X
Neurochem Int · 2026 · PMID 42082001 · Publisher ↗
Spinal cord injury (SCI) induces secondary damage characterized by mitochondrial dysfunction, oxidative stress, and apoptosis, which collectively impede neurological recovery. Elamipretide (SS-31) is a mitochondria-targe...
Spinal cord injury (SCI) induces secondary damage characterized by mitochondrial dysfunction, oxidative stress, and apoptosis, which collectively impede neurological recovery. Elamipretide (SS-31) is a mitochondria-targeting peptide with potential neuroprotective effects. Here, we investigated whether SS-31 improves functional outcomes after contusive SCI and explored associated mechanisms. In a mouse thoracic contusion model, SS-31 treatment significantly enhanced locomotor recovery and gait performance. Histological analyses showed reduced lesion pathology and increased neuronal preservation in the injured spinal cord. Early after injury, SS-31 attenuated apoptosis signaling, evidenced by reduced cleaved caspase-3 and Bax and increased Bcl-2. At the chronic stage, SS-31 was associated with diminished astrogliosis and enhanced markers of axonal and synaptic remodeling. In oxidatively stressed PC12 cells, SS-31 preserved mitochondrial membrane potential, reduced ROS accumulation, and supported oxidative phosphorylation-related protein integrity. Collectively, these findings suggest that SS-31 promotes recovery after SCI, potentially by mitigating early apoptotic injury and supporting mitochondrial homeostasis and neural remodeling.
Overexpression of Thioredoxin-1 alleviates morphine-induced neuroinflammation in BV-2 cells and the ventral tegmental area of mice.
Lu Z, Long Y, Li X … +2 more , Zhang L, Bai J
Neurochem Int · 2026 Jun · PMID 42066906 · Publisher ↗
The clinical utility of morphine is limited by the development of tolerance and addiction. These processes are linked to neuroinflammation involved microglial responses. Thioredoxin-1 (Trx-1) is a crucial endogenous anti...
The clinical utility of morphine is limited by the development of tolerance and addiction. These processes are linked to neuroinflammation involved microglial responses. Thioredoxin-1 (Trx-1) is a crucial endogenous antioxidant with neuroprotective properties, and our previous work has shown that Trx-1 overexpression blocks morphine-induced conditioned place preference (CPP). However, the role of Trx-1 in morphine-induced microglial inflammatory responses remains unclear. Here, we investigated the effects and underlying mechanisms of Trx-1 overexpression on morphine-induced microglial pro-inflammatory shifts, both in the microglial cell line BV-2 and in the ventral tegmental area (VTA) of mice. In vitro, morphine treatment increased intracellular reactive oxygen species (ROS) in BV-2 cells, upregulated markers associated with microglial reactivity (IBA-1 and MHC-II), activated the NF-κB pathway (evidenced by increased p-IκBα and nuclear p65 translocation), and elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) while reducing the anti-inflammatory cytokine IL-10. Overexpression of Trx-1 via adenoviral transduction reversed all these morphine-induced effects. In vivo, using a CPP paradigm, we confirmed that morphine CPP was blocked in Trx-1 transgenic (TG) mice. Biochemical analysis of the VTA from these mice revealed that Trx-1 overexpression similarly attenuated morphine-induced upregulation of IBA-1, MHC-II, and pro-inflammatory cytokines, consistent with in vitro results. Mechanistically, co-immunoprecipitation assays demonstrated an endogenous interaction between Trx-1 and the mu-opioid receptor (MOR). Overexpression of Trx-1 significantly enhanced this interaction and was associated with increased MOR expression. These results reveal that overexpression of Trx-1 suppresses morphine-induced neuroinflammation by binding MOR and reducing ROS-driven NF-κB activation in microglia. This mechanism positions Trx-1 as a potential therapeutic target for improving the clinical safety and efficacy of opioid addiction.
IL-33/ST2 deficiency induces depression-like behaviors through neuroinflammation in the medial prefrontal cortex and hippocampus.
Wang H, Yang S, Dai J … +10 more , Zheng F, Luo Y, Zhao J, Du E, Lei K, Lei J, Liu J, Xiao Y, Chen H, Sun Y
Neurochem Int · 2026 Jun · PMID 42061726 · Publisher ↗
Depression remains a leading cause of global disability, yet its precise neurobiological underpinnings are incompletely understood. While inflammatory cytokines have been implicated in depressive pathology, the specific...
Depression remains a leading cause of global disability, yet its precise neurobiological underpinnings are incompletely understood. While inflammatory cytokines have been implicated in depressive pathology, the specific role of Interleukin-33 (IL-33) and its receptor ST2 in modulating microglial-mediated neuroinflammation has remained elusive. In this study, we reveal that deficiency of the IL-33/ST2 signaling axis in naive adult male mice selectively induces depression-like behaviors without impairing memory, motor coordination, or balance. This behavioral phenotype is mechanistically linked to heightened microglial activation, increased branching complexity, and exacerbated neuronal loss within the medial prefrontal cortex (mPFC) and dentate gyrus (DG). Furthermore, we demonstrate that IL-33 counteract LPS-induced microglial activation, nuclear translocation, and subsequent neuroinflammatory responses in vitro. Collectively, these findings delineate a novel neuroimmune pathway wherein IL-33/ST2 deficiency precipitates microglia-driven neuroinflammation, thereby contributing to depressive phenotypes.
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