Neurochemical Research最新文献

Triggering receptor expressed on myeloid cells 2 (TREM2) located on microglial membranes and its downstream PI3K/PKB signaling pathway are involved in epilepsy. We have synthesized a novel carbazole-based H₂S donor (HS-D2023) which was synthesized from N-Ethyl-3-carbazolecarboxaldehyde and has ideal safety with stable release of H₂S. The H₂S donor has been demonstrated to suppress seizures in pilocarpine-induced status epilepticus model in mice. However, its mechanism remains to be explored. The aim of the current study is to investigate whether the antiepileptic effects of the novel H₂S donor involve TREM2 and PI3K/PKB signaling. We found that the H₂S donor pretreatment prevented the down-regulation of TREM2 expression levels in the hippocampus in pilocarpine-induced epileptic mice. The effects of the H₂S donor on latent period, duration and severity of seizures and EEG epileptic waves were significantly attenuated in TREM2-KO epileptic mice compared to WT epileptic mice, suggesting that the H₂S donor exerted antiepileptic effects through TREM2-dependent signaling. The effects of the H₂S donor on epileptic seizures and EEG epileptic waves were prevented by the PI3K inhibitor LY294002. The H₂S donor could significantly rescue the attenuated expression levels of p-PI3K and p-PKB in WT, but not TREM2-KO epileptic mice. The H₂S donor also failed to restore the balance between pro- and anti-inflammatory factors in TREM2-KO epileptic mice. These results suggested that the H₂S donor could upregulate TREM2 expression and subsequent activate the PI3K/PKB signaling pathway to suppress seizures. The finding may provide a prospective target for the treatment of epilepsy.

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, is increasingly recognized as a critical contributor to the pathogenesis of various neurological disorders. Mitochondria, the powerhouses of cells, play dual roles as both initiators and mediators of ferroptosis by integrating lipid peroxidation cascades, oxidative stress responses, and iron homeostasis dysregulation. This review first comprehensively explores the multifaceted mechanisms by which mitochondria mediate ferroptosis in neurological diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Friedreich’s ataxia (FRDA), amyotrophic lateral sclerosis (ALS), epilepsy, stroke, and brain injury, with a focus on mitochondrial lipid peroxidation and iron metabolism dysregulation. Building on these mechanistic insights, we further discuss emerging evidence suggesting that targeting mitochondrial pathways may represent a promising therapeutic strategy for mitigating ferroptosis-associated neuronal damage. By synthesizing these findings, our review establishes a conceptual foundation for developing innovative neuroprotective interventions through precise modulation of mitochondrial function within ferroptotic pathways.

Traumatic brain injury (TBI) is a severe form of cranial trauma that is associated with high disability and mortality rates, imposing substantial physical, psychological, and economic burdens on affected individuals. Formononetin (FN), a well-characterized phytoestrogen, exhibits diverse biological activities, most notably anti-inflammatory and antioxidant effects, and has demonstrated neuroprotective potential in TBI scenarios. Previous studies have shown that FN is capable of upregulating the expression of microRNA-155 (miR-155), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in TBI rat models. However, the precise function of miR-155 and its interaction with the Nrf2/HO-1 pathway remain incompletely elucidated. Herein, we investigated the therapeutic impact of FN on TBI pathophysiology and its underlying neuroprotective mechanisms, with a specific focus on miR-155 inhibition. Our findings showed that FN treatment notably improved neurological function, reduced cerebral edema, attenuated histopathological damage at the site of injury, decreased neuronal apoptosis, enhanced the performance in the Morris water maze, decreased inflammatory cytokine levels, and upregulated the expression of miR-155, Nrf2, and HO-1 in TBI rats. These observations suggest that FN has neuroprotective effects in TBI. Notably, when miR-155 was inhibited, the neuroprotective effects of FN were partially abrogated, accompanied by downregulated Nrf2 and HO-1 expression. This suggests that the protective effects of FN are likely mediated by miR-155-dependent modulation of the Nrf2/HO-1 pathway, providing valuable insights into the potential therapeutic use of FN and its derivatives for TBI management.

Methylphenidate (MP) is commonly prescribed to treat attention deficit hyperactivity disorder (ADHD). ADHD and depression are often comorbid, leading to simultaneous use of serotonin reuptake inhibitors (SSRIs), such as Fluoxetine (FLX). Previous studies have shown MP increases microglial activation, which has been linked to neuroinflammation, but little is known about these two medications in combination. To address this gap in our knowledge, 3-week-old male Sprague Dawley rats were randomly assigned into four groups receiving either water, MP, FLX, or MP + FLX orally using a previously established dosing regimen. After four weeks of treatment the animal’s brains were collected for in vitro [³H] PK11195 autoradiography. Chronic treatment with MP and MP + FLX resulted in significantly increased [³H] PK11195 binding in somatosensory regions including the cortex limbs somatosensory (S(Limbs)), facial somatosensory (S(Face)), dorsal caudate putamen (D CPU), and ventral caudate putamen (V CPU). Chronic treatment with MP increased microglial activation in specific brain regions; however, these effects were not amplified by co-administration with fluoxetine. These findings emphasize the importance of further investigating the interactions between SSRIs and MP, particularly as their combined use becomes more prevalent.

Anxiety disorders are among the most prevalent neuropsychiatric conditions, with oxidative stress, neuroinflammation, and serotonergic dysfunction contributing to their pathogenesis. Novel therapeutic approaches targeting these mechanisms are urgently required. The present study evaluated the anxiolytic potential of syringic acid (SA), nifuroxazide (NFU), and their combinations in a restraint stress-induced mouse model of anxiety. Behavioral parameters were assessed using the elevated plus maze, light–dark box, open field, and marble burying tests. Biochemical markers of oxidative stress, including superoxide dismutase (SOD) and glutathione (GSH), were quantified, along with pro-inflammatory mediators NLRP3, NF-κB, TNF-α, and IL-1β. Serotonin levels were measured by ELISA. Molecular docking studies were performed to explore the binding interactions of SA with NLRP3 and NFU with NF-κB. Restraint stress induced significant anxiety-like behavior, oxidative imbalance, and upregulation of inflammatory markers, accompanied by reduced serotonin levels. SA treatment significantly improved behavioral performance, restored SOD and GSH activity, and reduced NLRP3, NF-κB, TNF-α, and IL-1β levels. NFU alone showed minimal behavioral and biochemical benefits but, in combination with SA (particularly at full dose), produced marked anxiolytic effects, attenuated inflammation, and partially restored serotonin concentrations. Docking studies supported these findings, revealing stable interactions of SA with NLRP3 and NFU with NF-κB. Syringic acid demonstrates potent anxiolytic activity, mediated through antioxidant, anti-inflammatory, and serotonergic modulation. Its combination with nifuroxazide further enhances these effects, highlighting a promising therapeutic strategy against anxiety disorders.

Graphical Abstract

Cerebral ischemia-reperfusion injury (CIRI) represents a critical pathological mechanism underlying ischemic stroke, yet effective therapeutic interventions remain limited. Neurotoxic astrocytes, activated by inflammatory mediators such as interleukin-17 A (IL-17 A), exacerbate neuronal damage. Although electroacupuncture (EA) has demonstrated neuroprotective properties, its influence on IL-17 A signaling and subsequent astrocyte-mediated neurotoxicity in CIRI remains unclear. This study aims to investigate whether EA mitigates CIRI by downregulating IL-17 A to suppress the activation of neurotoxic astrocyte. A mouse model of middle cerebral artery occlusion and reperfusion (MCAO/R) was established employing the Zea-Longa modified ligation method. EA was applied to the Baihui (GV20) and Fengfu (GV16) acupoints. Neurological and behavioral evaluations were performed using the Modified Neurological Severity Score (mNSS), foot fault test, and balance beam test. Cerebral infarction volume was quantified via TTC staining, and neuronal ultrastructure was examined by transmission electron microscopy. Laser speckle imaging was employed to monitor cerebral blood flow before and after modeling and EA treatment. Western blotting was used to analyze protein expression levels of IL-17 A, IL-17RA, NF-κB p65, Bax, Bcl-2, and cleaved-Caspase-3/Caspase-3. Co-localization of IL-17 A with GFAP and C3, as well as IL-17RA with GFAP, was assessed via immunofluorescence staining. qPCR was performed to quantify IL-17 A mRNA levels, while TUNEL staining assessed neuronal apoptosis. ELISA was used to determine the concentrations of IL-17 A, TNF-α, and IL-1β in brain tissue. EA significantly improved neurological function, reduced cerebral infarct size, and alleviated neuronal apoptosis. Compared to the MCAO/R group, EA markedly downregulated IL-17 A expression and its related signaling proteins, inhibited neurotoxic astrocyte activation (C3⁺/GFAP⁺), and suppressed the release of proinflammatory cytokines. Notably, administration of recombinant IL-17 A reversed the neuroprotective effects of EA. These findings suggest that EA mitigates ischemic brain injury by inhibiting IL-17 A-mediated neurotoxic astrocyte activation and neuroinflammation, highlighting its potential as a therapeutic strategy for CIRI.

Graphical Abstract

ABCB1 and ABCG2 are major efflux transporters at the blood–brain barrier, regulating CNS exposure to xenobiotics and therapeutic agents. Chronic exposure to cigarette smoke and e-cigarette vapor contains toxicants capable of modulating their expression. Adult rats were exposed to cigarette smoke or e-cigarette vapor for two months. Abcb1 and Abcg2 mRNA expression in the amygdala and hippocampus was assessed using quantitative PCR (qPCR), and protein levels were quantified using ELISA. Statistical analysis was performed with one-way ANOVA. Both cigarette smoke and e-cigarette vapor significantly upregulated Abcb1 and Abcg2 mRNA and protein expression in the amygdala and hippocampus compared to controls. Long-term exposure to cigarette smoke and e-cigarette vapor causes a significant increase in transcriptional and translational upregulation of ABCB1 and ABCG2 in limbic brain regions. This change is probably mediated by oxidative stress and xenobiotic-sensing transcription factors. While this may enhance neuroprotection, it could also limit CNS drug penetration and disrupt neurochemical homeostasis, with potential implications for cognition, mood, and therapeutic efficacy.

Non-Alcoholic Fatty Liver Disease (NAFLD) is increasingly recognized as a systemic disorder with implications far beyond the liver, notably in the progression of cognitive decline and neurodegenerative disorders such as Alzheimer’s disease (AD) and traumatic brain injury (TBI). At the center of this liver-brain axis lies Saroglitazar (SGZ), a dual PPAR-α/γ agonist initially developed for diabetic dyslipidemia. Emerging evidence suggests that SGZ exerts neuroprotective effects via multiple molecular mechanisms, including modulation of oxidative stress, inflammation, and mitochondrial integrity. This review critically evaluates the mechanistic intersections of SGZ’s hepatic and neural actions and proposes a unified framework for its therapeutic impact. We contextualize SGZ’s role alongside alternative therapies, explore its translational readiness, and propose testable hypotheses to guide future research. While preclinical evidence is promising, robust human studies are essential to validate SGZ’s potential in mitigating NAFLD-associated cognitive impairment. This article aims to advance a novel conceptual synthesis and call for integrative strategies targeting the hepato-neuro axis.

Up-to-date data on roles of ATP‑sensitive potassium (KATP) channels indicate their emerging roles in neurodegeneration. The aim of present study was to evaluate the significance of KATP channels on cell viability, calcium dynamics, and mitochondrial morphology with the accent on their intracellular localization. We distinguished between whole-cell KATP effects and specific effects of mitochondrial KATP under both physiological conditions and pathological conditions simulating in vitro Parkinson´s-type neurodegeneration. SH‑SY5Y cells with its high fidelity to dopaminergic neurons were treated for 24 h with the non‑selective KATP opener pinacidil and blocker glibenclamide, or with the mitochondrial KATP opener diazoxide and blocker 5‑hydroxydecanoate (5HD). The effects of modulators were analysed alone or alongside with rotenone, which is widely used as an inducer of Parkinson´s-type neurodegeneration. Intracellular calcium distribution and mitochondrial rebuild pattern was evaluated using the cell segmentation performed by fluorescent confocal microscopy. Although none of the KATP modulators reversed the negative effects of rotenone, significant and selective effects of mitochondrial KATP modulation on calcium homeostasis and mitochondrial morphology were observed. For antagonists, both compounds showed consistent effects, with non-selective glibenclamide exerting stronger effects, particularly in elevating calcium. More distinctive results were obtained for agonists: both reduced calcium concentration; however, pinacidil tended to induce mitochondrial fragmentation, an effect absent in diazoxide-treated cells. Furthermore, strong correlations were identified between calcium levels and several mitochondrial and cell viability parameters.

Sevoflurane, the primary anesthetic employed in pediatric populations, has been associated with neurotoxic effects in neonatal mice. However, the precise mechanisms underlying these effects remain to be fully elucidated. The present study utilizes single-nucleus RNA sequencing to investigate the impact of neonatal exposure to sevoflurane on the heterogeneity and intercellular communication of hippocampal astrocytes and neurons in neonatal mice. The results suggest that sevoflurane anesthesia leads to cognitive impairments, which are associated with a decreased population of neurons and astrocytes in the hippocampus of neonatal mice. The heightened activity of inflammatory and neurodevelopmental response pathways in the hippocampal astrocytes of mice displaying cognitive deficits, coupled with the enrichment of differentially expressed genes within neuronal subpopulations across various neurogenesis-related disorders, highlights the critical role of astrocytes in influencing neuronal function in the context of sevoflurane-induced neurotoxicity. Furthermore, our findings demonstrated that the interaction between astrocytes and neurons through NLGN1-NRXN1 inhibits the PI3K-Akt signaling pathway of neurons and contributes to the process of sevoflurane-induced neurotoxicity. In summary, our study identifies a novel intercellular communication mechanism in sevoflurane-induced cognitive impairment, providing insights into the molecular processes that could be targeted for therapeutic intervention.

Graphical Abstract

Single-nucleus RNA sequencing analysis revealed that repeated sevoflurane exposure disrupts the characteristic NRXN1-NLGN1 synaptic interaction between astrocytes and neurons, subsequently impairing the activation of PI3K/Akt signaling pathway and ultimately culminating in neurodevelopmental impairment in neonatal mice.