Neurochem. Res. [JOURNAL]
Sun
200 papers
Esketamine Suppresses Astrocyte-Driven Neuroinflammation in Traumatic Brain Injury via the METTL5/c-Myc/PD-L1.
Luo L, Yu M, Li X … +9 more , Bi Y, Duan P, Meng Y, Jin Z, Feng W, Li L, Xing Y, Chen J, Zhang B
Neurochem Res · 2026 Mar · PMID 41824127 · Full text
Traumatic brain injury (TBI) is a major global health issue leading to high mortality and disability. Activated astrocytes are one of the pivotal driving factors in the neuroinflammatory cascade following TBI. This study...
Traumatic brain injury (TBI) is a major global health issue leading to high mortality and disability. Activated astrocytes are one of the pivotal driving factors in the neuroinflammatory cascade following TBI. This study aims to investigate the role of esketamine on TBI and the underlying mechanism. Mice received a mouse weight-drop cortical impact or sham surgery and TBI mice were treated with either vehicle or esketamine at 2 h post-injury for 7 consecutive days. The modified Neurological Severity Scoring system, Rotarod test, Open Field test and Novel Object Recognition test were used to assess the neurological function after TBI. And cortical tissues surrounding focal trauma were obtained for Nissl staining, immunofluorescence, ELISA assay and western blotting. In vitro, astrocytes were induced with LPS, followed by the addition of esketamine to the culture medium. After a 24 h exposure, the astrocytes were collected for CCK-8 assay, qRT-PCR, western blotting, immunofluorescence and Co-IP analysis. Esketamine dramatically improved the neurological outcome of mice and reduced neuronal cell death (P < 0.05) and neuroinflammation after TBI. Its anti-inflammatory benefits stem from its ability to suppress astrocyte activation (P < 0.05), inhibit pro-inflammatory A1 astrocyte differentiation (P < 0.01), and promote the formation of protective A2 astrocytes (P < 0.01). Esketamine exerts its effects by inhibiting the METTL5/c-Myc/PD-L1 signaling pathway. Esketamine can effectively alleviate activated astrocytes and promote the polarization of activated astrocytes toward A2 following TBI by inhibiting the METTL5/c-Myc/PD-L1, demonstrating significant anti-inflammatory and neuroprotective effects.
Spinal Cord Stimulation Alleviates Spinal Cord Injury-Induced Neuropathic Pain Via mC-Dependent Regulation of TRAF2.
Tao K, Yu Z, Cheng Z … +1 more , Ye Q
Neurochem Res · 2026 Mar · PMID 41824110 · Publisher ↗
Spinal cord injury (SCI) often results in neuropathic pain (NP), which remains a major clinical challenge. Spinal cord stimulation (SCS) has emerged as a promising therapy for SCI-induced NP; however, its underlying mech...
Spinal cord injury (SCI) often results in neuropathic pain (NP), which remains a major clinical challenge. Spinal cord stimulation (SCS) has emerged as a promising therapy for SCI-induced NP; however, its underlying mechanisms are not fully elucidated. 5-Methylcytosine (m5C) modification plays a critical role in various pathological processes, yet its involvement in SCI-induced NP has not been explored. This study aimed to investigate whether the therapeutic effects of SCS on SCI-induced NP are associated with m5C modification. An SCI mouse model was induced. Behavioral tests (evaluating mechanical allodynia and thermal hyperalgesia), enzyme-linked immunosorbent assays (measuring inflammatory cytokines), and histopathological analyses (hematoxylin and eosin staining and TUNEL staining) were performed. Bioinformatics analysis of the GSE256472 dataset was conducted to identify m5C-related genes involved in NP. Lentiviral-mediated overexpression or knockdown of NOP2/Sun RNA methyltransferase 2 (NSUN2) or TNF receptor-associated factor 2 (TRAF2) was employed to validate their functional roles. In vitro, BV2 microglial cells were transfected to modulate NSUN2 expression, followed by m⁵C-RNA immunoprecipitation, dual-luciferase reporter assays, and RNA stability assays to dissect the molecular mechanism. SCS significantly reversed mechanical allodynia and thermal hyperalgesia, suppressed neuroinflammation, and attenuated neuronal apoptosis in SCI mice. Bioinformatics and experimental validation revealed that NSUN2—a core m⁵C methyltransferase—was markedly upregulated in both SCI-induced NP patients and mice, and this elevation was normalized by SCS. Functional studies demonstrated that NSUN2 overexpression abolished the analgesic and neuroprotective benefits of SCS, whereas NSUN2 knockdown mimicked SCS effects. Mechanistically, NSUN2 directly deposited m⁵C modifications at position 929 of TRAF2 mRNA, enhancing its stability and expression. TRAF2 overexpression counteracted the therapeutic effects of NSUN2 inhibition, reinstating inflammation, apoptosis, and pain hypersensitivity. SCS alleviated SCI-induced NP by downregulating NSUN2, thereby reducing m⁵C-mediated stabilization of TRAF2 mRNA and subsequent activation of pro-inflammatory and pro-apoptotic pathways. The NSUN2/TRAF2 axis represents a novel epitranscriptomic mechanism in NP and a potential target for precision interventions in SCI-related pain management.
RIP1 Exacerbates BBB Disruption by Impairing Autophagy-Mediated A2 Astrocyte Polarization in Hypertension-Induced Cerebral Microhemorrhage in Mice.
Hu G, Shi R, Li Y … +5 more , Wang L, Zhao J, Liu L, Wei D, Zhang X
Neurochem Res · 2026 Mar · PMID 41817888 · Publisher ↗
Cerebral microhemorrhages (CMHs) contribute to cognitive decline and motor deficits. Inhibiting A1 astrocyte polarization can attenuate brain injury and promote recovery after experimental intracerebral hemorrhage. Despi...
Cerebral microhemorrhages (CMHs) contribute to cognitive decline and motor deficits. Inhibiting A1 astrocyte polarization can attenuate brain injury and promote recovery after experimental intracerebral hemorrhage. Despite RIP1 is a known mediator of neurological impairment in hemorrhage models, it is not known whether it regulates astrocytic phenotypic switching to influence CMH progression. Here, a mouse model of hypertension-induced CMHs was established by co-administration of Ang II and L-NAME. Following hypertension induction, daily neurological assessments showed progressively declining scores, indicating ongoing CMH development. RIP1 silencing delayed CMH onset, reduced cumulative incidence, and alleviated hypertension-induced deficits including gait abnormalities, impaired spatial learning and memory, blood-brain barrier (BBB) dysfunction, and A1 astrocyte polarization. In vitro, primary mouse astrocytes were exposed to hemoglobin to simulate the microhemorrhagic microenvironment. RIP1 silencing attenuated hemoglobin-induced A1 polarization and promoted a shift toward the A2 phenotype. Furthermore, RIP1 knockdown counteracted the detrimental effects of A1-polarized astrocytes on endothelial function, as evidenced by improved endothelial cell proliferation, migration, and tube formation. Mechanistically, RIP1 knockdown facilitated the transition from A1 to A2 astrocytic phenotype by activating autophagy and suppressing the NF-κB-NLRP3 inflammasome pathway, thereby mitigating hypertension-induced BBB disruption following CMHs. In conclusion, RIP1 silencing alleviates BBB disruption following hypertension-induced CMHs by promoting autophagy-mediated A2 astrocyte polarization.
Neuroprotective Role of Morin Hydrate in Stress-Re-stress (SRS) Rat Model of PTSD: Mitigation of Cognitive Dysfunction, Anxiety, and Depression via Regulation of Oxidative Stress and Neuroinflammation.
Mamidi SR, Danduga RCSR
Neurochem Res · 2026 Mar · PMID 41811531 · Publisher ↗
Post-traumatic stress disorder (PTSD) is a chronic psychiatric condition linked with abnormal fear responses, oxidative imbalance, inflammation, and neuronal injury. The present work examined the protective effects of mo...
Post-traumatic stress disorder (PTSD) is a chronic psychiatric condition linked with abnormal fear responses, oxidative imbalance, inflammation, and neuronal injury. The present work examined the protective effects of morin hydrate (MH), a natural flavonoid known for its antioxidant and neuroprotective properties, in a stress-re-stress (SRS) rat model of PTSD. Male Wistar rats were exposed to repeated stress cues and then treated with vehicle, paroxetine (10 mg/kg, p.o.), or MH (15 and 30 mg/kg, p.o.). Behavioral outcomes were assessed using fear conditioning, elevated plus maze, open field, Y-maze, novel object recognition, forced swim, and sucrose preference tests. Animals exposed to SRS developed pronounced fear retention, anxiety-like and depressive behaviors, and cognitive impairment. Treatment with MH, especially at 30 mg/kg, improved exploratory activity, reduced immobility, and enhanced memory performance. Biochemical studies showed reduced lipid peroxidation and restoration of glutathione, superoxide dismutase, and catalase. MH also lowered pro-inflammatory cytokines (TNF-α, IL-1β) and increased hippocampal brain-derived neurotrophic factor (BDNF). Histological analysis confirmed preservation of neuronal density in CA1 and CA2 regions of the hippocampus. In summary, MH produced behavioral, biochemical, and structural improvements in the SRS model, suggesting its value as a natural therapeutic candidate for PTSD.
Glibenclamide Attenuates Brain Edema After Intracerebral Hemorrhage Through Preservation of Blood-Brain Barrier Integrity and Glymphatic Function.
Du C, Wu Y, Geng Y … +4 more , Ali A, Li Z, Liu Z, Ma C
Neurochem Res · 2026 Mar · PMID 41806094 · Publisher ↗
Brain edema is a major contributor to secondary injury following intracerebral hemorrhage (ICH). Neurochemical disturbances, including disruption of blood-brain barrier (BBB) tight junctions and altered aquaporin-4 (AQP4...
Brain edema is a major contributor to secondary injury following intracerebral hemorrhage (ICH). Neurochemical disturbances, including disruption of blood-brain barrier (BBB) tight junctions and altered aquaporin-4 (AQP4) polarization, are central to post-hemorrhagic fluid imbalance. However, their association with glymphatic dysfunction and tissue-level alterations remains incompletely understood. A rat model of ICH was established and treated with glibenclamide. BBB integrity, glymphatic function, and AQP4 polarization were systematically evaluated using molecular, histological, and tracer-based approaches. Brain edema and perihematomal tissue mechanical properties were assessed. ICH was associated with marked disruption of BBB integrity, characterized by reduced tight junction protein expression and increased permeability, along with impaired AQP4 polarization and diminished glymphatic influx and clearance. These coordinated neurochemical alterations were accompanied by secondary changes in cerebrospinal fluid composition, brain water accumulation, and tissue mechanical properties. Glibenclamide treatment was associated with preservation of tight junction protein expression, restoration of AQP4 polarization, and improved glymphatic transport dynamics, accompanied by attenuation of edema formation and partial normalization of perihematomal tissue mechanics. Functional performance was correspondingly improved in treated animals. These findings indicate that experimental ICH was accompanied by coordinated changes in BBB integrity, AQP4 polarization, and fluid transport dynamics. Glibenclamide treatment was associated with parallel improvements across molecular, physiological, and functional domains. Collectively, the data highlight a coordinated pattern of neurovascular and fluid homeostasis alterations that may be involved in edema progression after hemorrhagic injury.
Astrocyte States in Brain Aging and Neurodegeneration: At the Crossroads of Senescence and Reactivity.
Pacca-Corrêa JBL, Fernandes BM, Siqueira M … +5 more , Schafbenker R, Baumart GJ, Damico IV, Gomes FCA, Matias I
Neurochem Res · 2026 Mar · PMID 41803335 · Full text
Brain aging involves progressive disruption of tissue homeostasis and susceptibility to neurodegenerative disorders. Within this context, astrocytes are key determinants of region-specific physiology, given their roles i...
Brain aging involves progressive disruption of tissue homeostasis and susceptibility to neurodegenerative disorders. Within this context, astrocytes are key determinants of region-specific physiology, given their roles in metabolic support, synapse regulation, proteostasis, neuroinflammation, and blood-brain barrier maintenance. Aging is accompanied by broad transcriptional and functional remodeling in astrocytes, leading to the emergence of distinct cellular states that cannot be defined by classical morphological criteria alone. This review discusses how aging modifies astrocyte identities toward reactive and senescence-like states. We summarize core features of astrocyte senescence, including altered secretory signaling, impaired neuronal support, and changes in mitochondrial and proteostatic pathways, while integrating recent single-cell and regionally transcriptomic studies that delineate multiple reactive states associated with aging and pathological contexts. We further address evidence that reactivity and senescence are not mutually exclusive endpoints, but may coexist, arise sequentially, or partially overlap depending on timing, brain region, biological sex, and pathological insults. Finally, we define key open questions and experimental priorities required to establish the temporal and causal relationships among astrocyte states. We argue that resolving these issues is essential for advancing therapeutic strategies that specifically target defined astrocyte phenotypes, rather than nonspecifically suppressing astrocyte activity, in aging and neurodegenerative diseases.
Intranasal Diazepam Outperforms Midazolam and Lorazepam in Early Seizure Control in Pilocarpine-Induced Mice Model.
Tong AH, Zhao J, Li J … +5 more , Ban W, Wang RJ, Xie Y, Zhang Y, Zuo Z
Neurochem Res · 2026 Mar · PMID 41784904 · Full text
Epilepsy is a central nervous system disease characterized by the sudden onset of seizures, loss of consciousness, or confusion. In recent years, many non-intravenous routes of administration of benzodiazepines have been...
Epilepsy is a central nervous system disease characterized by the sudden onset of seizures, loss of consciousness, or confusion. In recent years, many non-intravenous routes of administration of benzodiazepines have been developed for seizure control, with intranasal administration being an attractive route of choice. However, for such a route of administration, there is a lack of evidence on the choice of the epilepsy drug. This study aims to compare the intranasal formulations of three first-line drugs for seizure control, namely midazolam, diazepam, and lorazepam, via an ideal intranasal treatment. A pilocarpine-induced seizure model in mice was used to compare drug efficacy. The three drugs were administered intranasally to 36 C57 mice at a single dose of 1 mg/kg, followed by inducing the seizures via intraperitoneal injection of pilocarpine. The subsequent seizure scores were observed for either 10-100 min. After sacrificing the mice at 10/100 minutes post-dosing, whole brain tissue and plasma were collected to analyze the drug concentrations as well as brain-to-plasma concentration ratios. In addition, effects of these intranasally delivered drugs on neuroinflammation-associated molecules were monitored and compared via the mRNA levels and/or protein expression of GABARα1, TNF-α, and IL-1β in the cortex and hippocampus. Additionally, drug bindings to plasma and brain tissue obtained using the ultrafiltration method were compared, and drug binding affinities towards the GABA receptor, as determined via the computer docking technique, were also compared. Among the three tested drugs, our results suggested that intranasal diazepam, with the highest brain-to-plasma ratio, was the best in seizure control at 10 min. Although all three drugs showed good stability, similar brain binding and receptor binding affinity, diazepam demonstrated the greatest efficacy in reducing TNF-α mRNA and protein levels, and lowest plasma protein binding, which could contribute to its higher brain-to-plasma ratio and better acute epilepsy control compared to the other two drugs. Our pilot in vivo experiments in the pilocarpine-induced mice seizure model for the first time demonstrated that intranasally administered benzodiazepines are effective for seizure control at the early stage, with intranasally delivered diazepam being the most potent one.
Antidepressant-like effect of hydroxytyrosol in a 1-methyl-4-phenylpyridinium model of Parkinson's disease in rats.
Pérez-Barrón G, Sánchez-González K, Cruz SL … +6 more , López-Rubalcava C, Soria JM, García-Esparza MÁ, Montes S, Ríos C, Monroy-Noyola A
Neurochem Res · 2026 Mar · PMID 41784840 · Publisher ↗
This study (a) used the forced swim test in a rat model of Parkinson’s disease (PD) to characterise the antidepressant-like effect of hydroxytyrosol (Hty) against 1-methyl-4-phenylpyridinium (MPP+) and (b), studied dopam...
This study (a) used the forced swim test in a rat model of Parkinson’s disease (PD) to characterise the antidepressant-like effect of hydroxytyrosol (Hty) against 1-methyl-4-phenylpyridinium (MPP+) and (b), studied dopamine and serotonin levels in the striatum. Rats were intravenously administered 1.5 mg/kg Hty via the tail vein 5 min before an intra-striatal infusion of 10 µg MPP+; control animals received saline. After 6 days, locomotor activity was assessed in an open-field test and antidepressant-like effects were tested using the forced swim test. On day 6, all the animals received apomorphine (1 mg/kg, s.c.) and ipsilateral rotations were recorded for an hour before sacrifice and removal of striatal tissues for dopamine and serotonin quantification. Neither MPP+ injection nor Hty altered locomotor activity. Hty pretreatment significantly reduced immobility time, increased climbing time in the forced swim test, and diminished the number of ipsilateral rotations induced by apomorphine in rats treated with MPP+. These effects were consistent with an increase in dopamine and serotonin levels. These results show that Hty had antidepressant-like activity in the forced swim test in the rat MPP+ model and protected against MPP+ neurotoxicity, suggesting its potential utility in the treatment of neurodegenerative diseases such as PD and depression.
Crocin Mitigates Glutamate Excitotoxicity and Tau Hyperphosphorylation by Modulating EAAT2 and Akt/Tau Pathway in a Scopolamine-induced Rat Model of Alzheimer's Disease.
El-Baga SE, Hassan MH, Awadalla EA … +1 more , Abd El-Kader AEM
Neurochem Res · 2026 Mar · PMID 41784832 · Full text
Alzheimer's disease (AD) is characterized by glutamatergic dysregulation and excitotoxicity, largely associated with impaired activity of the excitatory amino acid transporter 2 (EAAT2). Downregulation of EAAT2 results i...
Alzheimer's disease (AD) is characterized by glutamatergic dysregulation and excitotoxicity, largely associated with impaired activity of the excitatory amino acid transporter 2 (EAAT2). Downregulation of EAAT2 results in glutamate accumulation, N-Methyl-D-Aspartate (NMDA) receptor overactivation, and neuronal injury. Crocin (Cr), a carotenoid compound extracted from saffron (Crocus sativus), exhibits potent antioxidant and neuroprotective properties, particularly in experimental models of neurodegeneration. Forty-eight adult male rats were divided into six groups: control (saline), crocin (50 mg/kg), scopolamine (3 mg/kg for 7 days), scopolamine followed by memantine (M) (20 mg/kg), scopolamine followed by crocin, and scopolamine followed by both memantine and crocin. This study aimed to evaluate the therapeutic potential of crocin, alone and in combination with memantine, in a scopolamine-induced rat model of Alzheimer's disease, with a focus on EAAT2 modulation. Scopolamine administration significantly elevated glutamate, NMDAR and p-tau levels while reducing p-Akt, GABA and EAAT2 levels, accompanied by marked hippocampal neurodegeneration. In contrast, crocin treatment, either alone or in combination with memantine, restored neurotransmitter balance, downregulated NMDAR, upregulated EAAT2, increased p-Akt expression level and reduced tau phosphorylation. Histological analysis further confirmed notable structural recovery of hippocampal neurons.
Analysis of Serum VCAN-AS1 Expression Level in Patients with Cerebral Infarction Secondary Epilepsy and Its Mechanism by Regulating miR-885-3p/NTNG1.
Lin Y, Zhang K, Zhang M … +7 more , Yin L, Liu Z, Meng Y, Li Y, Meng J, Yin X, Wang L
Neurochem Res · 2026 Mar · PMID 41779276 · Publisher ↗
VCAN-AS1 is a novel long non-coding RNA that participates in diverse disease processes, but the mechanism of its action in cerebral infarction secondary epilepsy (CISE) is unclear. The potential action mechanism of VCAN-...
VCAN-AS1 is a novel long non-coding RNA that participates in diverse disease processes, but the mechanism of its action in cerebral infarction secondary epilepsy (CISE) is unclear. The potential action mechanism of VCAN-AS1 in CISE was explored by this study. VCAN-AS1 and its downstream targets, namely miR-885-3p and Netrin G1 (NTNG1), were screened by the GEO, LncRNASNP2, and miRDB databases. The epileptic mouse and cell models were constructed using pilocarpine and the Mg-free medium, respectively. ELISA kits or RT-qPCR was used for the measurement of TNF-α/IL-1/IL-6 levels. The levels of Fe, GSH, and ROS were detected by the specific biochemical kits. GPX4 expression was analyzed by RT-qPCR. Dual-luciferase reporter assay was used to detect the interactions between miR-885-3p and VCAN-AS1 or NTNG1. Meanwhile, the expression levels of VCAN-AS1, miR-885-3p, and NTNG1 were detected by RT-qPCR. Elevated serum levels of VCAN-AS1 were observed in patients with CISE, and silencing of VCAN-AS1 attenuated inflammation and ferroptosis in epilepsy-associated neurons and the hippocampus of epileptic mice. VCAN-AS1 negatively regulated miR-885-3p which subsequently repressed NTNG1 expression. Up-regulation of miR-885-3p inhibited inflammation and ferroptosis in epileptic mouse and cell models, and overexpression of NTNG1 reversed these effects of miR-885-3p. The suppression of VCAN-AS1 expression mitigated neuronal inflammation and ferroptosis in epileptic conditions by targeting the miR-885-3p/NTNG1 regulatory axis, which may be an important molecular mechanism of CISE.
Focal Estrogen Therapy in Male Rats Promotes Neuronal Survival and Reduces Denervation Atrophy After Spinal Cord Injury via Modulation of β-Catenin and NF-κB.
Haque A, Zaman V, Drasites KP … +5 more , Sawant S, Vertegel A, Varma A, Green C, Banik NL
Neurochem Res · 2026 Mar · PMID 41779271 · Publisher ↗
Spinal cord injury (SCI) initiates a devastating vicious cycle characterized by the secondary degeneration of motor neurons in the spinal cord and progressive denervation atrophy in the skeletal muscle they innervate. Wh...
Spinal cord injury (SCI) initiates a devastating vicious cycle characterized by the secondary degeneration of motor neurons in the spinal cord and progressive denervation atrophy in the skeletal muscle they innervate. While the hormone 17β-estradiol (E2) has recognized neuroprotective properties, its capacity to simultaneously halt the distinct degenerative pathways in both the nervous and muscular systems, remains largely unexplored. This study elucidates a novel, dual mechanism through which E2 coordinately protects the entire motor unit. It was first established that a direct myoprotective role exists for E2 in vitro, demonstrating its ability to attenuate IFN-γ-induced upregulation of reactive oxygen species, the critical atrophy ligands MuRF1 and MAFbx in L6 myoblasts. In a contusion SCI model in male rats, we have demonstrated that E2 treatment comprehensively suppressed post-injury proteolytic and apoptotic signaling in skeletal muscle, thus normalizing the Bax: Bcl-2 and calpain: calpastatin ratios and reducing the expression of MAFbx and MuRF1. Mechanistically, this anti-atrophic effect was driven by the inhibition of NF-κB nuclear translocation in muscle tissue. Furthermore, E2 functionally preserved the neuromuscular junction, reducing the expression of MuRF1 and the denervation marker acetylcholinesterase while restoring presynaptic cholineacetyltransferase. Most significantly, our study demonstrated that focal delivery of a sustained-release E2 formulation directly to the site of the injured spinal cord activated the canonical Wnt/β-catenin pro-survival pathway, as evidenced by the stabilization of β-catenin and AKT proteins and a marked increase in the survival of β-catenin-positive motor neurons. Our findings reveal that E2 therapy confers comprehensive protection after SCI by operating on two fronts: it directly blocks NF-κB-driven proteolysis in skeletal muscle while concurrently activating Wnt/β-catenin signaling to promote motor neuron survival. This coordinated, dual-arm mechanism underscores the significant therapeutic potential of targeted E2 delivery to disrupt the self-perpetuating cycle of neuromuscular degeneration following spinal cord injury in male rats.
Berberine Attenuates Intracranial Aneurysm Formation by Activating SIRT1 to Suppress HMGB1 Acetylation and NF-κB Signaling.
Tan J, Zeng Y, Zhu H … +3 more , Xiao Z, Zhao Y, Li M
Neurochem Res · 2026 Mar · PMID 41779228 · Publisher ↗
The formation of intracranial aneurysms (IAs) is linked to metabolic problems and functional abnormalities in vascular smooth muscle cells (VSMCs). Berberine (BBR), a tetracyclic alkaloid having anti-inflammatory, antiox...
The formation of intracranial aneurysms (IAs) is linked to metabolic problems and functional abnormalities in vascular smooth muscle cells (VSMCs). Berberine (BBR), a tetracyclic alkaloid having anti-inflammatory, antioxidant, and energy metabolism regulatory capabilities, has an unknown impact in IA progression. The purpose of this study is to look at the effects of BBR on IA development and the molecular mechanisms that drive it. An elastase-induced rat IA model was established as previously described, with in vivo measurements of aneurysm incidence, rupture rates, and artery structural integrity. An in vitro damage model was created by using primary VSMCs treated with Ang II. Inflammatory reactions, oxidative stress, mitochondrial function, and energy metabolism were investigated. The SIRT1/HMGB1/NF-κB signaling axis was investigated by Western blotting, immunofluorescence, pharmacological inhibition (EX-527), genetic manipulation (SIRT1 overexpression or HMGB1 knockdown/overexpression), and mitochondrial-targeted therapies (Antimycin A, MitoTEMPO). BBR dramatically reduced IA development and rupture in rats, reducing arterial inflammation and structural damage. In vitro, BBR restored Ang II-induced VSMC dysfunction, including mitochondrial depolarization, ROS overproduction, glycolytic shift, and inflammation, by upregulating SIRT1, increasing its binding to HMGB1, and decreasing HMGB1 acetylation, cytoplasmic translocation, and NF-κB activity. EX-527 eliminated these benefits, whereas SIRT1 overexpression replicated them, revealing SIRT1's important involvement. Loss- and gain-of-function studies revealed that HMGB1 operates downstream of SIRT1, and that mitochondrial integrity is critical: Antimycin A inhibited BBR's actions, but MitoTEMPO mimicked them. BBR promotes SIRT1 to deacetylate HMGB1, preventing its cytoplasmic translocation and NF-κB-mediated inflammation. Importantly, mitochondrial dysfunction caused by Ang II or IA disease is a primary driver of metabolic dysregulation and inflammatory activation in VSMCs. By maintaining mitochondrial integrity, BBR restores bioenergetic and redox equilibrium, breaking the inflammatory-metabolic vicious cycle. These coordinated responses inhibit the formation and evolution of cerebral aneurysms.
Single Intraperitoneal Injection of Dexamethasone Alerts Region-Specific Neurotransmitter Metabolism in Rat Brain.
Tiutiunnik TV, Obukhova DA, Vilnikova VA … +2 more , Muruzheva ZM, Karpenko MN
Neurochem Res · 2026 Mar · PMID 41779097 · Publisher ↗
Synthetic glucocorticoids, such as dexamethasone, are widely used in therapy; however, their administration at high doses may be associated with effects on the central nervous system, particularly on neurotransmitter sys...
Synthetic glucocorticoids, such as dexamethasone, are widely used in therapy; however, their administration at high doses may be associated with effects on the central nervous system, particularly on neurotransmitter systems, yet the molecular mechanisms underlying these phenomena remain poorly understood. In this study, we investigated the effects of a single intraperitoneal administration of dexamethasone (8 mg/kg) on the metabolism of key monoamines and the expression of their metabolic enzymes in various rat brain regions (striatum, hippocampus, and prefrontal cortex) using high-performance liquid chromatography and real-time quantitative reverse transcription polymerase chain reaction. We found that dexamethasone exerts a pronounced, region-specific impact on neurotransmitter systems. In the striatum, dexamethasone increased dopamine and serotonin levels while simultaneously reducing their catabolism, which was associated with decreased messenger ribonucleic acid expression of monoamine oxidase A, monoamine oxidase B, tryptophan hydroxylase and increased expression of tyrosine hydroxylase. In the hippocampus, dexamethasone elevated serotonin levels and reduced its turnover despite an increase in monoamine oxidase A messenger ribonucleic acid expression, suggesting the potential involvement of post-transcriptional regulation or alternative metabolic pathways. In the prefrontal cortex, dexamethasone induced a reduction in norepinephrine levels, accompanied by a decrease in monoamine oxidase A and catechol-O-methyltransferase messenger ribonucleic acid expression. This study highlights the importance of considering region-specific cerebral effects of glucocorticoids for the development of personalized therapeutic and neuroprotective strategies, including the potential use of dexamethasone in conditions such as Parkinson's disease due to its ability to elevate striatal dopamine levels.
Esketamine Alleviates Postoperative Cognitive Dysfunction via Rock2/Add1 Signaling Pathway in Aged Mice.
Xu C, Zhang Y, Liu Y … +7 more , Niu X, Zhang C, Zhao N, Wu Y, Ma H, Wen Y, Ni X
Neurochem Res · 2026 Mar · PMID 41779095 · Publisher ↗
Postoperative cognitive dysfunction (POCD) is common in elderly surgical patients, and it can prolong recovery time and affect the quality of life. Although esketamine has been reported to alleviate POCD, its specific me...
Postoperative cognitive dysfunction (POCD) is common in elderly surgical patients, and it can prolong recovery time and affect the quality of life. Although esketamine has been reported to alleviate POCD, its specific mechanism is not yet fully understood. This study investigates the effects of esketamine on POCD and its underlying molecular mechanisms. After exploratory laparotomy under isoflurane anesthesia, aged mice were treated with 10 mg/kg of esketamine via intraperitoneal injection. The findings of this study indicate that intraperitoneal administration of esketamine could alleviate POCD, as demonstrated through a suite of behavioral tests. Moreover, we collected hippocampal samples and used proteomics to obtain differentially expressed proteins, then cross-referenced them with the GO database to identify Rho-associated coiled-coil kinase 2 (Rock2) as a potential target molecule for esketamine to alleviate POCD. We further confirmed using Western blotting that esketamine downregulates the increase in Rock2 expression and the phosphorylation of the Ser726 site on alpha-adducin (S726-Add1) induced by anesthesia and surgery in aged mice. Furthermore, the damage to dendritic spine density, dendritic complexity, and synaptic plasticity in the hippocampal region caused by anesthesia and surgery showed improvement to a certain extent after esketamine treatment, as demonstrated by Golgi staining, transmission electron microscopy, and electrophysiological assessments. In summary, esketamine improved POCD in aged mice, indicating that its mechanism may involve the protection of synaptic plasticity through the Rock2/Add1 pathway. This research may provide new perspectives for the pharmacological treatment of POCD.
Nitric Oxide Synthase Dysregulation in Hyperammonemia: Opportunities and Challenges Toward Therapeutic Targeting to Combat Neurological Complications.
Dhiman P, Kumar R, Singh D
Neurochem Res · 2026 Feb · PMID 41762344 · Publisher ↗
Hyperammonemia (HA) is a metabolic disorder characterized by elevated ammonia levels in the blood. Ammonia produced from the metabolism of amino acids is mainly detoxified in the liver through the urea cycle. However, de...
Hyperammonemia (HA) is a metabolic disorder characterized by elevated ammonia levels in the blood. Ammonia produced from the metabolism of amino acids is mainly detoxified in the liver through the urea cycle. However, defects in this cycle result in the buildup of ammonia in the blood, which is highly neurotoxic and disrupts multiple signaling pathways in the brain, including nitric oxide (NO). NO is produced from the enzyme nitric oxide synthase (NOS), which exists in three different isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). NO is an important signaling molecule that plays a crucial role in various physiological functions, like neurotransmission, synaptic plasticity, learning and memory, regulation of cerebral blood flow, and immune responses. The role of NO in HA pathophysiology remains debated, with evidence supporting both neurotoxic and neuroprotective effects. The present review explains the relationship between HA and different NOS isoforms in the discrete brain regions, highlighting their effects on NO production in both acute and chronic HA conditions. HA impairs the glutamate-NO-cGMP pathway through multiple mechanisms, including tonic NMDAR activation, CaMKII-mediated modulation of nNOS, neurosteroids, and neurotransmitter imbalances. Moreover, alterations in arginine transport via the y⁺LAT2 transporter, and elevated levels of methylarginine derivatives, such as asymmetric dimethylarginine, contribute to reduced NOS activity, leading to reduced NO production, increased oxidative stress, and an increased inflammatory response in HA. Understanding these multiple mechanisms underlying NOS modulation may provide new therapeutic strategies to improve neurological impairments associated with HA.
Roflumilast Elicits Therapeutic and Neuroprotective Effects in 3-Nitropropionic Acid-Induced Huntington's Disease-Like Neurodegeneration in Rats by Mitigating NLRP3 Inflammasome-Mediated Pyroptosis, Ferroptosis, and Glial Activation.
Taha M, Salah D, Abdou K … +1 more , Senousy MA
Neurochem Res · 2026 Feb · PMID 41762337 · Full text
Huntington’s disease (HD) pathogenesis involves diverse cellular mechanisms, yet the contributions of pyroptosis and ferroptosis remain elusive. Roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor, has shown neuroprotec...
Huntington’s disease (HD) pathogenesis involves diverse cellular mechanisms, yet the contributions of pyroptosis and ferroptosis remain elusive. Roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor, has shown neuroprotective effects, but its precise mechanisms are yet to be elucidated. We evaluated the potential neuroprotective and therapeutic effects of roflumilast in 3-nitropropionic acid (3-NP)-induced HD-like neurodegeneration, focusing on pyroptotic and ferroptotic cell death signaling. Adult male Wistar rats were assigned to five groups: normal control (saline + 0.5% carboxymethyl cellulose), roflumilast-control (1 mg/kg/day, p.o. for 21 days), 3-NP (20 mg/kg/day, i.p. for seven days), roflumilast-prophylactic (1 mg/kg/day, p.o. for 21 days prior to 3-NP), and roflumilast-treatment (1 mg/kg/day, p.o. for 21 days post-3-NP). Behavioral outcomes of the open-field, rotarod, and grip strength tests were assessed. Striatal PDE-4, total and p-CREB, BDNF, interleukin-1β, and markers of pyroptosis (NLRP3, caspase-1, and gasdermin D) and ferroptosis (iron, GPx4, GSH, and malondialdehyde) were measured alongside histopathological alterations and GFAP and Iba-1 immunohistochemical staining. Bioinformatics was used to visualize the target genes’ protein-protein interaction network. Behavioral assessments revealed impaired locomotion, motor coordination, and muscle strength in the 3-NP-injected rats. Biochemical analysis showed increased striatal PDE-4 expression and decreased p-CREB/BDNF axis alongside NLRP3 inflammasome/caspase-1/gasdermin D activation and elevated interleukin-1β. In parallel, ferroptosis was evidenced by increased striatal iron and malondialdehyde levels, along with reduced GPx4 and GSH. Histopathological examination revealed pronounced striatal neurodegeneration, accompanied by enhanced GFAP and Iba-1 immunostaining, indicating astrogliosis and microglial activation. Roflumilast, administered prophylactically or therapeutically, significantly improved functional and behavioral abnormalities while ameliorating biochemical, histopathological, and immunohistochemical derangements induced by 3-NP. The therapeutic regimen exhibited superior efficacy relative to prophylaxis. Conclusively, roflumilast exerts therapeutic and neuroprotective effects in HD-like neurodegeneration by mitigating pyroptosis and ferroptosis, attenuating astrogliosis, microglial activation, and neuroinflammation, and restoring synaptic plasticity.
Prenatal Stress Induces Changes in Behavior, HPA Axis, Inflammation, and Oxidative Stress in Adult Rats Offspring.
Aguiar-Geraldo JM, Peper-Nascimento J, Cararo JH … +5 more , Possamai-Della T, Zugno AI, Pillai A, Quevedo J, Valvassori SS
Neurochem Res · 2026 Feb · PMID 41762310 · Full text
Prenatal stress is related to the development of psychiatric disorders involving inflammation, oxidative stress, and hypothalamic-pituitary-adrenal (HPA) axis. Therefore, the aim of the present study was to evaluate the...
Prenatal stress is related to the development of psychiatric disorders involving inflammation, oxidative stress, and hypothalamic-pituitary-adrenal (HPA) axis. Therefore, the aim of the present study was to evaluate the effects of prenatal stress on behavior, inflammation, oxidative stress, and the HPA-axis in the dams and their offspring treated with lithium. Thirteen pregnant Wistar rats were exposed to a prenatal chronic unpredictable stress protocol from the 14th day of gestation until birth. At the 60th postnatal day (PND), a treatment protocol was carried out in the offspring with lithium (intraperitoneally - 47.5 mg/kg) or saline for seven days (twice a day). The behavior was assessed in the open field test to evaluate free movements. The dams (21 PND) and offspring (after open field) were euthanized, their brains were dissected in frontal cortex, hippocampus, and striatum, and the serum was collected. In the brain and/or serum, the levels of oxidative stress, inflammation, and HPA axis parameters were evaluated. Female offspring from stressed dams showed hyperactivity. Besides behavior alterations, offspring brain and serum showed an increase in pro-inflammatory cytokines, oxidative damage markers, and HPA axis hormones levels. Lithium administration only reduced the biochemical alterations. The prenatal stress protocol induced long-lasting behavior, inflammatory, oxidative stress, and HPA-axis alterations in the offspring which could underlie the development of psychiatric disorders.
Repeated Oral Methylphenidate Administration Evokes Changes in Brain Plasticity Proteins in Juvenile Wistar Kyoto Rats: Evidence for Sex-Related Differences.
Soares-Couto P, Sá SI, Costa VM … +5 more , Dias-Carvalho A, Ferreira M, Carvalho FD, Meisel A, Capela JP
Neurochem Res · 2026 Feb · PMID 41746535 · Full text
Methylphenidate (MPH) is first-line pharmacotherapy for Attention Deficit Hyperactivity Disorder (ADHD). Misdiagnosis and misuse raise concerns about exposing children and adolescents to MPH. This study aimed to assess h...
Methylphenidate (MPH) is first-line pharmacotherapy for Attention Deficit Hyperactivity Disorder (ADHD). Misdiagnosis and misuse raise concerns about exposing children and adolescents to MPH. This study aimed to assess how clinically relevant oral doses of MPH influence the expression of brain proteins involved in synaptic plasticity and neuronal growth in both sexes. Thirty-seven Wistar-Kyoto (WKY) rats (18 males and 19 females) were divided into an MPH group (daily oral dose of 5 mg/kg MPH in a 5% sucrose solution) and a control group (equivalent volume of 5% sucrose solution). Daily gavage administration started on postnatal day (PND) 15 and lasted for 15 days, with sacrifice at PND 30. In five brain regions [prefrontal cortex (PFC), striatum, hippocampus, cerebellum, and diencephalon], GAP43, GAPDH and PSD-95 levels were measured by Western blot. Additionally, MAP2 and synaptophysin levels were assessed in the PFC, motor cortex, ventral and dorsal striatum, and hippocampus (including CA1, CA3, hilus, and dentate gyrus) using immunohistochemistry.In MPH-treated males, GAP43 and synaptophysin levels were reduced in the cerebellum and CA1 region, respectively, while PSD-95 and GAPDH levels increased in the striatum and diencephalon. MPH-treated females showed only a significant decrease in PSD-95 levels in the PFC. Regarding MAP2 levels, no significant changes were observed in any of the analyzed regions or sexes. In control animals, males exhibited higher MAP2 levels in the striatum compared to females. In conclusion, MPH in healthy rats can alter proteins associated with synaptic plasticity differently, highlighting the importance of sex as a variable.
Neuroprotective Effects of Citropten Against Scopolamine-Induced Cognitive Impairment and Oxidative Stress in a Rat Model.
Jadhav VP, Mohanty PK
Neurochem Res · 2026 Feb · PMID 41746530 · Publisher ↗
Alzheimer’s disease (AD) is a chronic and progressive neurological degeneration marked by cognitive impairment and memory deficits, with oxidative stress and disturbances in the cholinergic system serving as key patholog...
Alzheimer’s disease (AD) is a chronic and progressive neurological degeneration marked by cognitive impairment and memory deficits, with oxidative stress and disturbances in the cholinergic system serving as key pathological factors. The current investigation sought to evaluate the neuroprotective and cognition-enhancing properties of Citropten (5,7-dimethoxycoumarin), a bioactive compound belonging to the coumarin class, in a scopolamine-induced cognitive impairment model. Wistar rats were divided into vehicle control, scopolamine alone, standard drug, and two Citropten-treated groups (12.5 and 25 mg/kg), and treated orally once daily for 18 days. Cognitive impairments were induced by daily scopolamine administration (2 mg/kg, i.p.) from Day 8 onward. Behavioral performance was analysed with the Novel Object Recognition (NOR), Elevated Plus Maze (EPM) and Morris Water Maze (MWM). Post-behavioral testing, brain tissues were analysed for acetylcholinesterase (AChE) activity, level of malondialdehyde (MDA), reduced glutathione (GSH), and catalase (CAT) activity. Scopolamine significantly impaired spatial, and recognition memory, as well as EPM-based learning memory performance, increased AChE activity and MDA levels, and reduced GSH and CAT activity compared with vehicle control group. Citropten treatment dose-dependently improved escape latency and target quadrant time spent in the MWM, enhanced the discrimination index in NOR test, and reduced transfer latency in the EPM. Biochemically, Citropten significantly reduced AChE and MDA levels while restoring GSH and CAT activity, showing effects comparable to the standard drug, Donepezil. Our findings demonstrate that Citropten exhibits multi-targeted neuroprotective agent, with potential relevance for mitigating cognitive dysfunction associated with cholinergic and oxidative stress pathways in scopolamine-induced cognitive impairment model.
Retraction Note: ACE2 Rescues Impaired Autophagic Flux Through the PI3K/AKT Pathway After Subarachnoid Hemorrhage.
Pang L, Liu Z, Zhou K … +4 more , Chen P, Pan E, Che Y, Qi X
Neurochem Res · 2026 Feb · PMID 41739352 · Publisher ↗
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