Neurochem. Res. [JOURNAL]
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200 papers
MST4 Regulates Microglia Neuroinflammation via Targeting PKM2 Nuclear Translocation in Epilepsy: An In Vivo and In Vitro Study.
Fu J, Zhang S, Chu Y … +2 more , Li J, Chen X
Neurochem Res · 2026 Jul · PMID 42400665 · Publisher ↗
Microglia-mediated neuroinflammation is closely associated with the pathogenesis of epilepsy. Mammalian sterile-20-like kinase 4 (MST4) has been suggested a regulator of inflammation. However, the effect of MST4 on micro...
Microglia-mediated neuroinflammation is closely associated with the pathogenesis of epilepsy. Mammalian sterile-20-like kinase 4 (MST4) has been suggested a regulator of inflammation. However, the effect of MST4 on microglia neuroinflammation in epilepsy remains unclear. A pilocarpine-induced rat epilepsy model was constructed and a lipopolysaccharide (LPS)-stimulated microglia cell model was applied in the current research. Knockdown or overexpression of MST4 was established using lentivirus transfection. Electroencephalograph (EEG) was employed to measure brain activities of rats. The protein and mRNA expressions were detected using western blot and qRT-PCR, respectively. Immunofluorescent staining was conducted to detect the distribution of the proteins. TUNEL staining was performed to evaluate cell apoptosis. The protein interaction was evaluated with Co-IP assay. Our results showed that MST4 and nuclear PKM2 expressions were increased in epileptic rats compared to control and colocalized with microglia. MST4 overexpression inhibited microglia activation, the release of TNF-α and IL-1β, and improved neuronal apoptosis in epileptic rats. Furthermore, MST4 interacted with PKM2 and regulated PKM2 nuclear translocation. Inhibiting PKM2 nuclear translocation by TEPP-46 reversed the promoting effect of MST4 knockdown on microglia neuroinflammation. In summary, our study demonstrated that MST4 alleviated microglia-mediated neuroinflammation in epilepsy, and the mechanism of MST4-mediated anti-neuroinflammatory effects may be associated with the inhibition of PKM2 nuclear translocation.
Correction to: Dual Antioxidant DH-217 Mitigated Cerebral Ischemia-Reperfusion Injury by Targeting IKKβ/Nrf2/HO-1 Signal Axis.
Shen M, Zheng Y, Li G … +4 more , Chen Y, Huang L, Wu J, Hong C
Neurochem Res · 2026 Jul · PMID 42384271 · Publisher ↗
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Microglia-Dependent BDNF Signaling in the Dentate Gyrus Underlies the Antidepressant Effects of Gardiquimod, a Toll-Like Receptor 7 Agonist, in Chronically Stressed Mice.
Gu J, Hong J, Lu X … +6 more , Liu N, Lu H, Tong L, Liu H, Zhang Y, Huang C
Neurochem Res · 2026 Jun · PMID 42371226 · Publisher ↗
Accumulating evidence suggests that pharmacological restoration of microglial homeostasis in the hippocampus may be a promising strategy for treating depression. In this study, we evaluated whether gardiquimod (GDQ), a s...
Accumulating evidence suggests that pharmacological restoration of microglial homeostasis in the hippocampus may be a promising strategy for treating depression. In this study, we evaluated whether gardiquimod (GDQ), a selective Toll-like receptor 7 (TLR7) agonist, produces antidepressant effects in mice subjected to chronic unpredictable stress (CUS). A single intraperitoneal injection of GDQ at 1 or 1.5 mg/kg, but not 0.5 mg/kg, improved depression-related behaviors within 5 h of administration. Time-course analyses showed that the antidepressant efficacy of GDQ (1.5 mg/kg) appeared between 5 and 8 h, persisted for up to 7 days, and diminished by 14 days after a single dose. Notably, a second GDQ injection at 14 days restored the behavioral improvements, indicating sustained responsiveness to the drug. Mechanistically, the antidepressant effects of GDQ were abolished by both pharmacological inhibition (minocycline) and genetic depletion (PLX3397) of microglia, highlighting the necessity of these cells. Furthermore, GDQ reversed the CUS-induced reduction in brain-derived neurotrophic factor (BDNF) protein levels in the dentate gyrus in a microglia-dependent manner. The critical role of BDNF signaling was confirmed by three complementary approaches: intra-hippocampal infusion of a BDNF-neutralizing antibody, genetic disruption of activity-dependent BDNF release via the Val68Met knock-in mutation, and pharmacological blockade of the TrkB receptor with K252a. Each intervention abolished the behavioral effects of GDQ. Together, these findings identify GDQ as a promising candidate for antidepressant development and highlight the restoration of microglia-supported BDNF signaling in the dentate gyrus as a key mechanism underlying TLR7-mediated mood regulation.
Cryptotanshinone Targets Ferroptosis in Glioma via the EGFR/ROS Signaling Pathway.
Hu J, Liang X, Liao Y
Neurochem Res · 2026 Jun · PMID 42348047 · Publisher ↗
To investigate the regulatory effects of cryptotanshinone (CTS) on the biological behavior of glioma cells and its underlying molecular mechanisms, with a particular focus on the role of the epidermal growth factor recep...
To investigate the regulatory effects of cryptotanshinone (CTS) on the biological behavior of glioma cells and its underlying molecular mechanisms, with a particular focus on the role of the epidermal growth factor receptor/reactive oxygen species (EGFR/ROS) pathway in ferroptosis-mediated antitumor activity. Glioma cell behaviors were monitored through Cell Counting Kit-8 (CCK-8), colony formation, wound healing, and Transwell assays. Intracellular and tumor tissue levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ferrous iron (Fe²⁺), glutathione/glutathione disulfide (GSH/GSSG) ratio, and malondialdehyde (MDA) were assessed. Glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), acyl-CoA synthetase long-chain family member 4 (ACSL4), epidermal growth factor receptor (EGFR), and Ki67 expression was examined using western blotting and immunohistochemistry. Network pharmacology and molecular docking were employed to predict potential cryptotanshinone targets. An in vivo glioma model was created by implanting tumor cells into nude mice. CTS inhibited glioma cell malignant phenotype, while promoting ROS accumulation, MMP loss, Fe²⁺ elevation, and GSH depletion. CTS also modulated ferroptosis-associated molecules, characterized by downregulation of GPX4 and SLC7A11 and upregulation of ACSL4. EGFR was identified as a central target, which was experimentally validated to mediate the antitumor and ferroptosis-inducing effects of CTS. In vivo, CTS suppressed tumor growth and activated ferroptosis, whereas EGFR overexpression partially reversed these protective effects. CTS induces ferroptosis in glioma cells by inhibiting EGFR and enhancing ROS signaling, thereby suppressing tumor proliferation and invasion.
Combined Puerarin and Magnesium Acetyl Taurate Intervention Mitigates Autism-Like Pathology Through Glutamatergic and MAPK Pathway Regulation.
Gupta S, Mehan S, Gupta AK … +5 more , Kumar A, Gupta GD, Narula AS, Samant R, Tongra M
Neurochem Res · 2026 Jun · PMID 42348037 · Publisher ↗
Autism is a multifactorial neurodevelopmental disorder characterized by social deficits, stereotypical behaviour, and neurotransmitter imbalance. This study evaluated the neuroprotective potential of Puerarin (PUN) and M...
Autism is a multifactorial neurodevelopmental disorder characterized by social deficits, stereotypical behaviour, and neurotransmitter imbalance. This study evaluated the neuroprotective potential of Puerarin (PUN) and Magnesium Acetyl Taurate (MGAT) in a propionic acid (PPNA)-induced rat model of autism. PPNA was administered intracerebroventricularly for 11 consecutive days to induce autism-like features, followed by a 44-day treatment period with PUN (300 mg/kg, i.p.) and MGAT (500 mg/kg, p.o.). A comprehensive assessment was conducted, including behavioural analysis, biochemical and molecular evaluations, cerebrospinal fluid and plasma profiling, and histopathology. Treatment with PUN and MGAT, particularly in combination, improved behavioural outcomes, restored neurotransmitter balance, reduced neuroinflammation and apoptotic signaling, and attenuated activation of the glutaminase-glutamate/NMDAR and MAPK pathways (C-JNK, ERK1/2, P38 MAPK). Additionally, treatment increased magnesium levels and PSD-95 expression, indicating significant neuroprotection. These findings support the potential of PUN and MGAT as a multitarget therapeutic strategy for autism and warrant further translational investigation.
Long-Term Impact of Early-Life Stress on Hippocampal Apoptotic Gene Expression in BALB/c Mice.
Barokah AN, Gürsoy İK, Dönmez MH … +3 more , Fitremann J, Bayram A, Bayram KK
Neurochem Res · 2026 Jun · PMID 42347997 · Full text
Early-life stress (ELS), such as maternal separation, has been associated with neuronal apoptosis and impaired hippocampal function in rodent models. This study investigated the long-term effects of two ELS paradigms-unp...
Early-life stress (ELS), such as maternal separation, has been associated with neuronal apoptosis and impaired hippocampal function in rodent models. This study investigated the long-term effects of two ELS paradigms-unpredictable maternal separation (MS) and MS combined with unpredictable maternal stress (MSUS)-on the hippocampal mRNA expression of proapoptotic (Bax, Tp53 and Casp3) and prosurvival (Bcl2) genes in offspring, both in vivo and in a complementary in vitro neuronal culture model. The study included three groups (Control, MS and MSUS groups), with ELS applied from postnatal days 1 to 14 to BALB/c mice. For the in vitro experiments, total RNA from the MSUS hippocampus was nucleofected at different concentrations into healthy mouse hippocampal cells, followed by 3D neuronal cell culture using N-heptyl-D-galactonamide (GalC7) hydrogels. Quantitative real-time PCR was used to assess gene expression, which was analyzed via the comparative Ct method (2). This study revealed that Bax mRNA expression was significantly lower in the MS group than in the control group, whereas both the MS and MSUS groups presented significant increases in Bcl2 mRNA expression. In addition, the expression ratio of Bcl2/Bax was significantly greater in the MS and MSUS groups. No significant differences in Tp53 or Casp3 mRNA expression levels were detected between the groups. Although the in vitro mRNA expression levels were not significantly different, the mRNA expression ratio of Bcl2/Bax reached equilibrium as the concentration of total RNA nucleofected increased. Our results suggested that, in response to ELS, hippocampal cells adapt to prioritize survival over apoptosis.
Minute-Resolution Sampling Reveals Rapid and Stimulus-Specific IL-1β Dynamics During Acute Epileptiform Activity.
Martínez-Gallegos SM, Medina-Ceja L, Morales-Villagrán A … +1 more , Pardo-Peña K
Neurochem Res · 2026 Jun · PMID 42329302 · Publisher ↗
Brain inflammation is increasingly recognized as a critical contributor to seizure generation and neuronal hyperexcitability. Among proinflammatory mediators, interleukin-1β (IL-1β) has been implicated in epileptogenesis...
Brain inflammation is increasingly recognized as a critical contributor to seizure generation and neuronal hyperexcitability. Among proinflammatory mediators, interleukin-1β (IL-1β) has been implicated in epileptogenesis; however, its acute temporal dynamics during seizure initiation remain poorly characterized because of limitations in conventional sampling approaches. In this study, we investigated the minute-by-minute intracerebral dynamics of IL-1β in a rat model of acute epileptiform activity induced by 4-aminopyridine (4-AP) and compared it with that induced by a classical inflammatory stimulus, lipopolysaccharide (LPS). Adult male Wistar rats (10-12 weeks old) were implanted with a push-pull guide cannula in the right lateral ventricle and electrodes over the ipsilateral and contralateral cortices to enable simultaneous cerebrospinal fluid (CSF) sampling and electroencephalographic (EEG) recordings. IL-1β concentrations were quantified at one-minute resolution using a nanodot blot immunodetection method, while epileptiform activity was assessed through EEG amplitude analysis and discharge train identification. Intraventricular administration of 4-AP (75 mM) induced robust epileptiform activity accompanied by a rapid and transient surge in IL-1β levels, reaching a peak concentration of 199 ± 28 ng/mL within 14 min (p < 0.05 vs. NaCl) and closely coinciding with the onset of epileptiform discharges. In contrast, intraventricular administration of LPS (25 µg/µL) elicited a delayed and sustained increase in IL-1β which was statistically significant at 240 and 300 min post-administration and did not induce epileptiform activity during the evaluated period. Although cumulative IL-1β exposure was comparable between 4-AP and LPS groups, their temporal profiles were markedly distinct. These findings demonstrate that acute epileptiform activity is associated with a rapid release of IL-1β that temporally coincides with seizure-like events, supporting a role for early cytokine signaling in seizure initiation. Moreover, this study highlights the importance of minute-resolution approaches for identifying neuroinflammatory processes that are otherwise obscured by conventional sampling strategies.
Sex-Specific Hippocampal Phosphoproteomic Features Associated with Stress-Induced Phenotypes in Mice Exposed to Chronic Restraint Stress.
Liu Y, Wang T, Zhao W … +8 more , Yang C, Zhao Y, Lu F, Cai X, Wang L, Li S, Zhou J, He Z
Neurochem Res · 2026 Jun · PMID 42322444 · Publisher ↗
Chronic stress significantly contributes to anxiodepression, with marked sex differences in hippocampal dysfunction. This study investigated the interplay between sex and stress phenotype in shaping hippocampal phosphory...
Chronic stress significantly contributes to anxiodepression, with marked sex differences in hippocampal dysfunction. This study investigated the interplay between sex and stress phenotype in shaping hippocampal phosphorylation landscapes in a chronic restraint stress model of anxiodepression. Hippocampal phosphoproteomes of female and male mice, classified as anxiodepression-susceptible (AD-Sus) and insusceptible (Insus), were analyzed using 4D label-free quantitative proteomics. Distinct phosphorylation profiles associated with sex and phenotype were identified, with the corresponding phosphoproteins primarily linked to the MAPK signaling pathway. Females exhibited significant enrichment in the thyroid hormone signaling pathway and long-term potentiation. In contrast, males showed notable enrichment in the serotonergic synapse pathway, which suggests a sex-specific difference in serotonin-mediated emotional responses. GABAergic synapses were more prevalent in the Insus group than in the AD-Sus group, while the cGMP-PKG signaling pathway was enriched in both female and male AD-Sus groups. MAPK1 was identified as the kinase with the highest number of phosphorylated substrates across all groups, indicating its potential central role. Key phosphorylation targets included Stmn1 (S38) and Pdha1 (S232) in the female AD-Sus and Insus groups, and Stmn1 (S38) and Mapt (T523) in the female and male Insus groups. The Insus group exhibited additional kinases linked to numerous substrates, indicating a more complex kinase regulation mechanism compared to the AD-Sus group, where MAPK1 played a more pronounced role. Our findings demonstrate distinct sex- and phenotype-specific phosphorylation patterns, highlighting novel molecular mechanisms underlying stress-induced anxiodepression and resilience.
STAT3 Signaling in Spinal Cord Injury: Neurochemical Mechanisms Linking Neuroinflammation, Mitochondrial Stress, and Glial Remodeling.
Wei D, Yang J, He X … +3 more , Li K, Lv C, Gao K
Neurochem Res · 2026 Jun · PMID 42313207 · Full text
Spinal cord injury (SCI) is a devastating neurological disorder marked by profound disturbances in cytokine signaling, redox balance, mitochondrial homeostasis, and glial-neuronal communication. Although many therapeutic...
Spinal cord injury (SCI) is a devastating neurological disorder marked by profound disturbances in cytokine signaling, redox balance, mitochondrial homeostasis, and glial-neuronal communication. Although many therapeutic strategies have been explored to attenuate secondary injury, effective molecularly targeted interventions remain limited. Increasing evidence identifies signal transducer and activator of transcription 3 (STAT3) as a central signaling node in the neurochemical response to SCI. Recent studies indicate that STAT3 exhibits pronounced spatiotemporal and cell-type-specific activation after SCI. Depending on the upstream trigger and cellular compartment involved, STAT3 can amplify or restrain neuroinflammation, shape astrocyte and microglial reactivity, influence mitochondrial bioenergetics and oxidative stress, modulate ferroptosis and apoptosis, and alter the regenerative state of the injured spinal cord. In this review, we frame STAT3 not simply as a downstream effector of the JAK/STAT cascade, but as an integrative regulator of SCI neurochemistry that links cytokine-driven signaling to metabolic stress, glial remodeling, and axonal repair. We emphasize how injury phase, cell type, and subcellular localization influence STAT3-dependent outcomes, discuss emerging therapeutic strategies that converge on STAT3-centered pathways, and outline the key challenges that must be addressed for precise translational targeting.
Molecular Mechanism of M2 Macrophage-Derived Extracellular Vesicles in Alleviating Inflammation in Rats with Spinal Cord Injury.
Li J, Liang S, Luo J … +1 more , Rao Y
Neurochem Res · 2026 Jun · PMID 42301587 · Publisher ↗
Spinal cord injury (SCI) is a severe condition with high disability. We aimed to explore the role and mechanism of M2-EVs in SCI-induced inflammation in rats, providing novel treatment methods for SCI. Primary macrophage...
Spinal cord injury (SCI) is a severe condition with high disability. We aimed to explore the role and mechanism of M2-EVs in SCI-induced inflammation in rats, providing novel treatment methods for SCI. Primary macrophages were differentiated into M2 macrophages. M2-EVs were extracted, followed by morphology detection and measurement of CD63, TSG101, and Calnexin. SCI rats were injected with M2-EVs, followed by assessment of hind limb motor ability, pathological changes, nerve cell morphology, and proinflammatory factor expression. LPS-stimulated spinal astrocytes were treated with M2-EVs. Cell viability, ROS levels, LDH and MDA contents, the expression of lncRNA FTX, FTX, KDM3A, and KLF3, the binding of FTX to KDM3A, and KDM3A enrichment and H3K9me2 on the KLF3 promoter were detected. Results exhibited that M2-EVs treatment increased BBB score, recovered the damaged spinal cord structure, reduced neuronal loss and proinflammatory factor expression. M2-EVs treatment increased cell viability and decreased inflammation. Mechanistically, M2-EVs delivered FTX into cells. FTX bound to KDM3A and inhibited KLF3 expression via blocking H3K9me2 demethylation. KDM3A and KLF3 overexpression partially reversed the inhibitory effect of M2-EVs on inflammation in SCI. In conclusion, M2-EVs suppress SCI inflammation by delivering FTX into cells and inhibiting the KDM3A/KLF3 axis.
Electroacupuncture Ameliorates Neuroinflammatory Damage and Cognitive Impairment in Vascular Dementia by Promoting Shh Signaling-Mediated Microglial M2 Polarization.
Wen T, Shang M, Wang R … +2 more , Zhou J, Wen Y
Neurochem Res · 2026 Jun · PMID 42301370 · Publisher ↗
Electroacupuncture (EA) has been documented to exert therapeutic benefits in vascular dementia (VD). This study seeks to elucidate the therapeutic efficacy and underlying molecular mechanisms of EA in VD. A VD model was...
Electroacupuncture (EA) has been documented to exert therapeutic benefits in vascular dementia (VD). This study seeks to elucidate the therapeutic efficacy and underlying molecular mechanisms of EA in VD. A VD model was induced in rats, which received EA with or without an Shh pathway inhibitor. An in vitro VD model was generated by exposing BV2 microglial cells to oxygen-glucose deprivation (OGD). A battery of tests was employed: cognitive function (novel object recognition and morris water maze), histopathology (H&E and TUNEL staining), synaptic ultrastructure (transmission electron microscope), microglial activation/polarization (immunofluorescence), inflammatory cytokine secretion (ELISA), protein expression (immunoblotting), and cellular viability (CCK-8). VD model rats exhibited attenuated Shh signaling in brain tissues, which was effectively restored by EA treatment in a duration-dependent manner. EA intervention observably improved cognitive performance, mitigated neuronal damage, enhanced synaptic plasticity, suppressed pro-inflammatory responses, and promoted microglial M2 polarization. These therapeutic effects were abolished by the Shh pathway inhibitor cyclopamine. Furthermore, Shh overexpression in microglia attenuated OGD-induced pro-inflammatory activation and reduced its detrimental impact on neuronal cells. Collectively, these data indicate that the cognitive benefits of EA in VD are critically dependent on Shh-driven reprogramming of microglial responses, which in turn resolves neuroinflammation and mitigates neuronal injury, thereby informing future therapeutic strategies.
Dentate Gyrus ERK1/2-BDNF Signaling is Required for the Antidepressant Effect of Microglial Stimulation in a Male Mouse Model of Depression Induced by Adolescent Nicotine Exposure.
Ji W, Wu S, Ye M … +7 more , Zhang L, Hong J, Yan L, Pan H, Huang C, Zhang Y, Wang H
Neurochem Res · 2026 Jun · PMID 42295462 · Publisher ↗
Adolescent nicotine exposure can reduce microglial populations in the adult mouse dentate gyrus, a change causally linked to early-stage microglial hyper-activation and reversible by treatment with low-dose lipopolysacch...
Adolescent nicotine exposure can reduce microglial populations in the adult mouse dentate gyrus, a change causally linked to early-stage microglial hyper-activation and reversible by treatment with low-dose lipopolysaccharide (LPS). However, the mechanisms by which LPS mediates this reversal remain unclear. Here, we identify a previously unrecognized requirement for dentate gyrus extracellular signal-regulated kinase 1/2 (ERK1/2)-brain-derived neurotrophic factor (BDNF) signaling in this process, distinct from but mechanistically parallel to our previous findings in chronic stress models. We show that low-dose LPS administration restored dorsal dentate gyrus BDNF levels reduced by adolescent nicotine exposure, and its antidepressant effects in adult mice previously exposed to nicotine during adolescence were abolished by intra-hippocampal delivery of a BDNF-neutralizing antibody, administration of the TrkB antagonist K252a, or introduction of the BDNF Val68Met loss-of-function mutation. Additionally, low-dose LPS reversed the decreased phospho-ERK1/2 in the dorsal dentate gyrus of adult mice with a history of adolescent nicotine exposure. Inhibition of ERK1/2 by SL327 prevented the reversal effect of LPS on adolescent nicotine exposure-induced depression-like behaviors and decrease in BDNF levels, suggesting that ERK1/2 functions upstream of BDNF signaling in mediating the antidepressant effect of LPS. When microglia were inhibited by minocycline, the beneficial effects of LPS, including the amelioration of depression-like behaviors and the up-regulation of dentate gyrus p-ERK1/2 and BDNF, were eliminated. These findings indicate that the antidepressant action of low-dose LPS in a mouse model of depression resulting from adolescent nicotine exposure requires intact microglial function and depends on ERK1/2-BDNF signaling within the dorsal dentate gyrus.
Correction: A Primary Spinal Cord Mixed Culture Method for In Vitro Analysis of Glial Heterogeneity and Inflammatory Responses.
de Oliveira Santos Costa CC, de Jesus Nunes C, Pedreira ACNR … +2 more , Costa SL, do Nascimento RP
Neurochem Res · 2026 Jun · PMID 42287483 · Full text
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Role of the P2X7-Nrf2 Pathway in Hyperalgesia Induced by Chronic Compression of the Dorsal Root Ganglion.
Tang S, Wang C, Yang Y … +6 more , Zhou L, Li Y, Ding X, Meng Y, Fan X, Ning L
Neurochem Res · 2026 Jun · PMID 42283887 · Publisher ↗
The aim of the present study was to test the hypothesis that purinergic P2X7 receptor (P2X7) is involved in neuropathic pain by influencing the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. The chronic comp...
The aim of the present study was to test the hypothesis that purinergic P2X7 receptor (P2X7) is involved in neuropathic pain by influencing the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. The chronic compression of the dorsal root ganglion (DRG) model (hereafter termed CCD) was used to investigate the hypothesis. We analyzed the effect of P2X7 on Nrf2 activation and the expression of downstream molecules, heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1), in the DRG following CCD. We further assessed the role of extracellular signal-regulated kinases 5 (ERK5) in the development of hyperalgesia mediated by P2X7-Nrf2 pathway in CCD. In this study, phosphorylated Nrf2 (pNrf2) expression in CCD male rats was upregulated by treatment with the P2X7 agonist BzATP but reduced by administration of the P2X7 antagonist A438079. Furthermore, BzATP-induced pNrf2 upregulation was suppressed by ERK5 blockade using the antagonist BIX02189. Expression changes in HO-1 and NQO1 mirrored those of pNrf2. These results indicated that P2X7 participated in neuropathic pain that was associated with the activation of the ERK5-Nrf2 pathway in rats.
Rotenone in Drug-Resistant Epilepsy Models: Powerful Tool or Problematic Paradigm?
Khedpande N, Barve K
Neurochem Res · 2026 Jun · PMID 42283792 · Publisher ↗
The rotenone adjuvant kindling paradigm replicates key clinical features of drug-resistant epilepsy (DRE), including broad-spectrum pharmacoresistance, neuroinflammation, and oxidative stress, by combining mitochondrial...
The rotenone adjuvant kindling paradigm replicates key clinical features of drug-resistant epilepsy (DRE), including broad-spectrum pharmacoresistance, neuroinflammation, and oxidative stress, by combining mitochondrial complex I inhibition with pentylenetetrazol (PTZ) or corneal kindling. PTZ, a GABA receptor antagonist, induces seizures by reducing inhibitory neurotransmission and is widely used to model kindling and seizure susceptibility; in this paradigm, its repeated subconvulsive dosing facilitates progressive epileptogenesis and enhances network hyperexcitability. Rotenone-induced microglial activation and mitochondrial dysfunction further potentiate PTZ sensitivity, limiting the penetration and effectiveness of antiseizure drugs by promoting cytokine release, disrupting the blood-brain barrier, and overexpressing efflux transporters. In comparison to traditional DRE models, this paradigm's construct, face, and predictive validity are strengthened by its recapitulation of neuropsychiatric comorbidities and spontaneous recurrent seizures. Comparative findings suggest greater clinical relevance and improved suitability for evaluating mechanism-based therapies targeting mitochondrial dysfunction, GABAergic imbalance, and inflammatory signaling; however, concerns regarding systemic toxicity, mortality, and inter-animal variability remain important limitations. Overall, the rotenone adjuvant PTZ-kindling model represents a promising, though imperfect, translational platform for the development of novel therapies for DRE.
β-Lapachone-Induced Oxidative Stress Causes PARP-Dependent NAD-Depletion that Affects the Energy Metabolism of Cultured Primary Rat Astrocytes.
Willker JE, Dringen R
Neurochem Res · 2026 Jun · PMID 42277481 · Full text
Oxidative stress has been connected with many brain pathologies. As brain astrocytes have a strong antioxidative potential, we have investigated the consequences of β-lapachone-induced oxidative stress on the cell metabo...
Oxidative stress has been connected with many brain pathologies. As brain astrocytes have a strong antioxidative potential, we have investigated the consequences of β-lapachone-induced oxidative stress on the cell metabolism of cultured astrocytes by determining the cellular levels of important components of the cellular redox and energy metabolism. β-Lapachone exposure induced a rapid oxidation of cellular NADH and NADPH followed by a time- and concentration-dependent loss in the total cellular NADx content and an increase in the total cellular NADPx content, while the cell viability was not compromised. In addition, the treated cells were partially depleted of ATP and lost their ability to upregulate glycolytic lactate production after exposure to the respiratory chain inhibitor antimycin A. All these consequences were prevented in the presence of ES936 which inhibits the NQO1-mediated reduction of β-lapachone. Inhibition of poly(ADP-ribose) polymerases (PARPs) by PJ34 or AZD-2461 did not affect the strong cellular accumulation of glutathione disulfide, but significantly lowered the oxidative stress-induced loss in the cellular NADx and ATP contents, maintained the ability of the cells to upregulate glycolytic lactate production during incubation with antimycin A, and doubled the increase in the cellular NADPx content. After removal of the β-lapachone-induced oxidative stress, astrocytes were able to restore their initial cellular content of NADx in the presence of the NAD precursor nicotinamide. This restoration was accompanied by the reestablishment of the ability to upregulate glycolytic lactate production during antimycin A exposure. The results obtained show that oxidative stress has severe consequences on various fundamental metabolic parameters of astrocytes, but also demonstrate the high potential of these cells to recover after severe oxidative stress.
Olfactory Mucosa MSCs-Derived Exosomal RPL6 Attenuates Seizure-Induced Neuronal Damage via FGF2-Mediated Oxidative Stress and Mitophagy.
Wang Z, Hu X, Liang Y … +5 more , Tan G, Fan W, Peng J, Ma YN, Xia Y
Neurochem Res · 2026 Jun · PMID 42277443 · Publisher ↗
Evidence suggests that olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) can benefit epilepsy treatment in both clinical patients and mouse models, although their precise mechanism remains unclear. Given the adva...
Evidence suggests that olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) can benefit epilepsy treatment in both clinical patients and mouse models, although their precise mechanism remains unclear. Given the advantages of exosomes in precise cellular regulation, ease of storage, and long-term stability, this study investigated the role of OM-MSCs-derived exosomes (OM-MSCs-exos) in status epilepticus (SE) models. Here, SE mouse models were induced by intraperitoneal injection of pilocarpine. OM-MSCs, differentially treated OM-MSCs-exos, and recombinant FGF2 protein were injected into SE model mice to investigate the effects of OM-MSCs-exos on SE models and their potential mechanisms. Functionally, treatment with OM-MSCs and OM-MSCs-exos significantly improved cognitive function, as evidenced by increased target quadrant duration, decreased escape latency, increased average speed, and more platform crossings in behavioral tests. Furthermore, this treatment further alleviated hippocampal tissue damage by reversing pilocarpine-induced oxidative damage, neuronal injury, and excessive mitophagy. Consistent outcomes were confirmed in vitro. Mechanistically, RPL6 was screened and confirmed as a key protein in OM-MSCs-exos, which interacts with FGF2 to promote FGF2 expression, thereby alleviating oxidative stress and mitochondrial dysfunction induced by HO. In conclusion, the RPL6 protein derived from OM-MSCs-exos improves neuronal damage post-SE by activating FGF2 to suppress oxidative stress and mitophagy, laying a theoretical foundation for the development of exosome-related drugs for treating epilepsy clinically.
Ischemic Stroke Induces Ferroptosis and Neuroinflammation via Activation of the Microglial Tbp-Lpl Transcriptional Axis.
Wang Z, Xiong J, Lv R
Neurochem Res · 2026 Jun · PMID 42268517 · Publisher ↗
This study elucidates the role of microglia in ferroptosis and neuroinflammation following ischemic stroke and defines the underlying molecular mechanisms. Single-cell transcriptomic analysis revealed that multiple brain...
This study elucidates the role of microglia in ferroptosis and neuroinflammation following ischemic stroke and defines the underlying molecular mechanisms. Single-cell transcriptomic analysis revealed that multiple brain cell types in the MCAO mouse model exhibited ferroptosis-related signatures, with microglia showing the most pronounced changes. Differentially expressed genes in post-stroke microglia were significantly enriched in ferroptosis-associated pathways. Further investigations demonstrated that both in vivo (tMCAO/R) and in vitro (OGD/R-treated microglia) models exhibited marked upregulation of the transcription factor Tbp and the lipid metabolism enzyme Lpl, accompanied by increased expression of pro-inflammatory chemokines CCL2, CCL3, and CCL4. Ultrastructural, biochemical, and molecular analyses confirmed canonical features of ferroptosis, including mitochondrial damage, elevated lipid peroxidation, increased ACSL4 and NCOA4 levels, and reduced GPX4 expression. Mechanistically, Tbp directly bound to and transcriptionally activated the Lpl promoter. Activation of the Tbp-Lpl axis by OGD/R promoted pro-inflammatory polarization and chemokine release in microglia and was associated with exacerbated ferroptotic injury, whereas Tbp knockdown effectively reversed these effects. Collectively, these findings demonstrate that ischemic stroke activates the Tbp-Lpl transcriptional regulatory axis in microglia, coordinately driving lipid metabolic reprogramming, amplifying inflammation, and promoting ferroptosis. This study provides new mechanistic insights into post-stroke neuronal injury and identifies Tbp as a potential therapeutic target for modulating microglial ferroptosis and neuroinflammation.
Neurochemical Mechanisms Underlying Tanshinone-Mediated Neuroprotection and Formulation Strategies in Cerebral Ischemia/Reperfusion Injury.
Park JH
Neurochem Res · 2026 Jun · PMID 42260052 · Publisher ↗
Cerebral ischemia/reperfusion (I/R) injury represents a major pathological component of ischemic stroke and is driven by a complex cascade of neurochemical and molecular events, including excitotoxicity, oxidative and ni...
Cerebral ischemia/reperfusion (I/R) injury represents a major pathological component of ischemic stroke and is driven by a complex cascade of neurochemical and molecular events, including excitotoxicity, oxidative and nitrosative stress, neuroinflammation, blood-brain barrier (BBB) disruption, mitochondrial dysfunction, and regulated cell death pathways such as apoptosis and ferroptosis. Tanshinones, a class of lipophilic diterpenoid quinones derived from Salvia miltiorrhiza (Danshen), have attracted increasing attention as multi-target neuroprotective agents in experimental models of cerebral I/R. Accumulating evidence demonstrates that major tanshinones, including tanshinone I, tanshinone IIA, tanshinone IIB, cryptotanshinone, and dihydrotanshinone I, modulate key neurochemical processes underlying cerebral I/R injury, including redox homeostasis, inflammatory signaling cascades, mitochondrial function, BBB integrity, and cell death regulatory networks. In parallel, recent advances in formulation strategies, including chemically modified derivatives (e.g., sodium tanshinone IIA sulfonate and the cryptotanshinone derivative DST-3), as well as microemulsions, liposomes, and nanoparticle-based delivery systems, have markedly improved aqueous solubility, pharmacokinetic behavior, and brain bioavailability of tanshinones, thereby potentially enhancing their neuroprotective effects in experimental models. This review comprehensively summarizes current evidence on the neurochemical and molecular mechanisms of tanshinones and their formulations in cerebral I/R injury, with an emphasis on signaling pathway modulation, redox regulation, mitochondrial protection, and formulation-driven improvements in brain delivery, and discusses remaining mechanistic challenges and future research directions.
8-Gingerol Mitigates MPP-Induced α-Synuclein Aggregation and NLRP3 Inflammasome Activation by Inducing the Insulin Signaling Pathway in SH-SY5Y Cells.
Shih YC, Kuo TY, Chang C … +4 more , Lin CY, Liao CH, Hsiao YJ, Tsai CW
Neurochem Res · 2026 Jun · PMID 42258088 · Publisher ↗
Impaired insulin signaling facilitates α-synuclein aggregation and exacerbates neuroinflammation related to Parkinson's disease (PD). This study investigated whether 8-gingerol from ginger could protect against MPP⁺-indu...
Impaired insulin signaling facilitates α-synuclein aggregation and exacerbates neuroinflammation related to Parkinson's disease (PD). This study investigated whether 8-gingerol from ginger could protect against MPP⁺-induced α-synuclein aggregation and neuroinflammation in SH-SY5Y cells via the insulin signaling pathway. MTT assay showed that MPP⁺ markedly reduced SH-SY5Y cell viability at 0.5-2 mM. Treatment of cells with 6-gingerol and 8-gingerol, but not 6-shogaol, significantly attenuated MPP⁺-induced cytotoxicity. The concentration at 20 µM showed the strongest neuroprotective effect. Immunoblots showed that 8-gingerol treatment attenuated the accumulation of p-α-synuclein and p-Tau induced by MPP⁺ for 24 h. Furthermore, 8-gingerol normalized the aberrant phosphorylation of IRS-1, Akt, and GSK-3β induced by MPP⁺. It also suppressed the MPP⁺-induced expression of inflammasome-associated proteins, including FoxO1, TXNIP, NLRP3, and cleaved-caspase 1. Pre-treatment with the PI3K/Akt inhibitor wortmannin abrogated the protective effects by increasing p-α-synuclein and NLRP3 inflammasome protein levels. These results indicated that 8-gingerol protects SH-SY5Y cells against MPP⁺-induced the α-synuclein aggregation and NLRP3 inflammasome activation is mediated through the insulin signaling pathway.
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