Neurochemical Research最新文献

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.

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.

Previous research revealed a reduction in the VGF immunoreactivity within the substantia nigra (SN) of rats with a 60–90% dopaminergic neuron loss and in the plasma of newly diagnosed Parkinson’s disease (PD) patients. Hence, our aim was to explore whether central and peripheral proVGF changes occur during early dopaminergic dysfunction. To investigate this, we employed a rat model mimicking early-stage PD by injecting the SN unilaterally with an adeno-associated virus (AAV) carrying either the human α-synuclein (α-syn; n = 19) or green fluorescent protein (GFP; n = 18) gene. After conducting motor assessments and sacrificing the animals, brain and blood samples were collected. Tyrosine hydroxylase (TH)-, glutamic acid decarboxylase (GAD)-, and phosphorylated (p)-α-syn antibodies were used for immunohistochemistry (IHC), while an antibody targeting the C-terminus of proVGF was employed for IHC, western blot (WB), and enzyme linked immunosorbent asssay (ELISA). The α-syn overexpression caused a modest (~ 30%) reduction in TH immunoreactivity within the SN—without affecting the striatum—and did so without producing overt motor symptoms, effectively modeling a pre-symptomatic PD stage. This early dopaminergic dysfunction was accompanied by decreased immunostaining for both proVGF C-trerminus and GAD in the SN, but not the striatum. Reduction in plasma proVGF levels were also observed, indicating systemic changes during initial dopaminergic impairment. Analysis using WB confirmed a decrease in a 70 kDa band consistent with proVGF in both SN and plasma. These findings suggest proVGF as a promising early biomarker for PD, opening new avenues for intervention before the onset of clinical symptoms.

Changes in hippocampal neurons are known to play a critical role in social memory deficits associated with autism spectrum disorders (ASD). Although the theory of excitatory-inhibitory imbalance in autism pathogenesis is well established, early developmental alterations in the hippocampus remain insufficiently characterized. Alterations in gamma-aminobutyric acid (GABA)ergic neurons and their markers are thought to underlie synaptic changes in inhibitory circuits. Therefore, this study was designed to: (1) quantify glutamatergic and GABAergic neuron populations in the hippocampus; (2) characterize inhibitory postsynaptic currents (IPSCs) in primary hippocampal neurons; and (3) assess gene expression of selected GABAergic markers in two autism-like animal models, namely Shank3-deficient mice and prenatally valproate (VPA)-exposed rats. A reduced proportion of GABAergic neurons was observed in the hippocampus of both models. An increase in the number of glutamatergic neurons was found only in the hippocampus of prenatally VPA-exposed rats. This was accompanied by a decrease in IPSC frequency in primary hippocampal neurons from prenatally VPA-exposed rats, while no significant changes were found in Shank3-deficient mice. Altered temporal dynamics of inhibitory synaptic transmission were demonstrated in both models by a decreased cumulative probability of inter-event intervals for inhibitory currents. Furthermore, reduced gene expression levels of Gabarap and Gabarapl1 were detected in Shank3-deficient mice, whereas decreased Gat1 expression level was found in prenatally VPA-exposed rats at postnatal day 5. These findings strongly support the excitatory-inhibitory imbalance hypothesis in ASD. Thus, genetic or environmentally induced GABAergic changes in the hippocampus may underlie hippocampus-dependent social memory alterations in ASD.