Neurochemical Research最新文献

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.

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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.

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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.

Epilepsy affects over 65 million individuals worldwide, with approximately 30% of patients resistant to conventional antiepileptic drugs (AEDs). Neuroinflammation and oxidative stress are recognized contributors to epileptogenesis and seizure severity. Ammi visnaga (toothpick plant), traditionally used for its anti-inflammatory and antioxidant properties, remains understudied in the context of seizure-related neuroinflammation. This study aimed to investigate the neuroprotective, anticonvulsant, anti-inflammatory, and antioxidant properties of Ammi visnaga fruit hydroalcoholic extract in a pentylenetetrazole (PTZ)-induced seizure model in mice, with a particular focus on hippocampal oxidative stress and cytokine modulation. Forty adult male NMRI mice were randomized into Six groups including: both healthy negative control and PTZ + saline control, PTZ-only, phenobarbital-treated, and Ammi visnaga-treated (25, 50, and 100 mg/kg). Seizure latency, hippocampal expression of IL-6 and TNF-α (via qPCR) and oxidative stress biomarkers (MDA, nitrite, TAC) were assessed. Seizure latency significantly increased with Ammi visnaga treatment in a dose-dependent manner (P < 0.0001), with the 100 mg/kg group showing a robust delay compared to the PTZ group. Cytokine mRNA expression (IL-6 and TNF-α, measured by qPCR) were markedly downregulated in all extract-treated groups, reaching levels comparable to healthy controls (P < 0.001). Oxidative stress markers showed clear modulation; MDA and nitrite levels were significantly reduced in the hippocampus and serum at 100 mg/kg (P < 0.01 and P < 0.05, respectively). Total antioxidant capacity (TAC) was substantially enhanced in both serum and hippocampal tissue, particularly in the 50 and 100 mg/kg groups (P < 0.0001). In contrast, phenobarbital elevated seizure threshold but had minimal impact on oxidative stress biomarkers. Ammi visnaga fruit hydroalcoholic extract demonstrated potent, dose-dependent neuroprotective effects in a PTZ-induced seizure model through dual anti-inflammatory and antioxidative mechanisms. Its ability to suppress IL-6 and TNF-α expression and restore redox balance positions it as a promising adjunctive therapeutic candidate for epilepsy management, especially in drug-resistant cases driven by neuroinflammation and oxidative stress.

Tramadol, a widely used opioid analgesic, has been linked to neuropsychiatric side effects, including anxiety, when used chronically. These effects are believed to arise from disruptions in multiple neurotransmitter systems, including GABA, glutamate, dopamine, and serotonin. Valproic Acid (VAL), known for its mood-stabilizing and neuroprotective properties, may have the potential to counteract these effects. This study aimed to investigate the behavioral and neurochemical changes induced by chronic tramadol administration in rats and to evaluate the therapeutic potential of VAL in reversing these effects. Twenty-four male Sprague Dawley rats were divided into four groups: Control, Tramadol (TRA), Valproic Acid (VAL), and Tramadol + Valproic Acid (TRA + VAL). Behavioral assessments were conducted using the Open Field Test (OFT) and Light/Dark Box (LDT). After testing, levels of GABA, glutamate, dopamine, serotonin, acetylcholine, and norepinephrine were measured in the hypothalamus and cerebral cortex using LC-MS/MS. Chronic tramadol treatment led to anxiety-like behaviors, as seen in reduced center time in the OFT and shorter latency to enter dark areas in the LDT. These behavioral disruptions were accompanied by decreased levels of GABA in the hypothalamus and cerebral cortex. Co-treatment with VAL restored GABA levels and normalized behavior. The levels of most other neurotransmitters were also affected by tramadol, but not normalized by valproate. VAL mitigates tramadol-induced neurobehavioral disturbances by restoring key neurotransmitter imbalances in GABA. These findings support the therapeutic potential of VAL in managing opioid-induced mood and behavioral disruptions in opioid use disorder.

In the current study, we investigated the effects of 3-carene administration on basal brain activity and 4-aminopyridine (4-AP) induced epileptiform activity. Additionally, we examined the effects of asprosin on ECoG band powers. Thirty-five male Wistar rats were divided into five groups as follows: control (DMSO), 4-AP (2.5 mg/kg i.p.), 3-carene 10 mg/kg (i.p), 3-carene 50 mg/kg (i.p), 3-carene 50 mg/kg (i.p) post-treatment. Recordings lasting 60–70 min were conducted for all groups under ketamine/xylazine (90/10 mg/kg) anesthesia. Furthermore, we used thick acute horizontal hippocampal slices obtained from 30‑ to 35‑day‑old rats for in vitro experiments. Extracellular field potential recordings were evaluated in the CA1 region of the hippocampus. In vivo recordings revealed that intraperitoneal administration of 3-carene (10 mg/kg and 50 mg/kg) significantly suppressed basal brain activity across delta, theta, alpha, and beta bands. However, 3-carene failed to reduce epileptiform discharges induced by 4-AP. Complementary in vitro experiments using hippocampal and entorhinal cortex slices further confirmed the lack of anticonvulsant effect, as 3-carene did not alter the frequency or duration of 4-AP-induced ictal or interictal events. These findings suggest that while 3-carene modulates resting-state cortical oscillations, it lacks efficacy in suppressing seizure-like activity. The results highlight its potential as a neuromodulatory agent rather than a standalone anticonvulsant.