Neuroreport最新文献

Background: Neuroinflammation plays a critical role in the pathogenesis and progression of Parkinson's disease. Verminoside (VMS) is a natural iridoid exhibiting anti-inflammatory properties. We aimed to investigate the effects of VMS on neuroinflammation and neuronal death in lipopolysaccharide (LPS)-treated BV2 microglial cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse models.

Methods: The production of inflammatory mediators, including nitric oxide, inducible nitric oxide synthase, tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, were measured by Griess assay, ELISA, or real-time PCR. The protein levels of IκBα and nuclear factor kappa B (NF-κB) were determined by western blot. Cell viability and apoptotic rate were assessed using a cell viability assay and flow cytometry, respectively. Immunofluorescence was employed to label Iba-1-positive microglia and tyrosine hydroxylase-positive dopaminergic neurons. In addition, the motor function of mice was evaluated using the rotarod and traction tests.

Results: Our results demonstrated that VMS effectively suppressed the upregulation of inflammatory mediators induced by LPS in BV2 cells. VMS also inhibited the nuclear translocation of NF-κB and eliminated NF-κB activity. Moreover, VMS mitigated the toxicity of conditioned media from LPS-treated BV2 cells. In MPTP-treated mice, VMS decreased the number of Iba-1-positive microglia, reduced the production of inflammatory mediators, preserved tyrosine hydroxylase-positive dopaminergic neurons, and ameliorated motor deficits.

Conclusion: In summary, VMS prevents dopaminergic neuron degeneration and alleviates behavioral impairments by suppressing NF-κB-mediated neuroinflammation, highlighting its potential as a therapeutic drug for Parkinson's disease.

Background: Cognitive impairment is highly prevalent in people with diabetes. Electroacupuncture improves diabetes-associated cognitive impairment (DACI), but its regulatory mechanism remains unclear.

Methods: The DACI model was established in rats via high-fat diet combined with low-dose intraperitoneal streptozocin. The acupuncture points Yishu (EX-B3), Zusanli (ST36), and Neiting (ST44) were chosen for electroacupuncture therapy. Cognitive function was assessed by Morris water maze test. Staining with hematoxylin and eosin was used to find the pathological changes in the hippocampus. The expression levels of relative proteins were analyzed by Western blot and immunofluorescence. In addition, ELISA was used to measure the levels of lactate and pyruvate in the hippocampus.

Results: Electroacupuncture can improve the learning and memory ability of DACI model rats (P<0.01) and hippocampal morphology; electroacupuncture can significantly increase the phosphorylated protein ratios of P-insulin receptor substrates 1 (P-IRS1)/IRS1, P-phosphoinositide 3-kinase (P-PI3K)/PI3K, and P-protein kinase B (P-AKT)/AKT (P < 0.001) and mean fluorescence intensity of P-IRS1, P-PI3K, and P-AKT (P < 0.01); electroacupuncture can promote the expression of glucose transporters (GLUTs) (P < 0.01) and monocarboxylic transporters (MCTs) (P < 0.01) and improves the contents of pyruvate and lactate in the hippocampus of DACI model rats (P < 0.01); Signaling pathway inhibitor LY294002 attenuated the above improvement (P < 0.05).

Conclusion: Electroacupuncture's mechanism may be involved in activating the IRS1/PI3K/AKT pathway, promoting the expression of GLUTs and MCTs, and regulating hippocampal energy metabolism.

Objective: This study aimed to elucidate the role of P2X3 receptors on type II spiral ganglion neurons (SGNs) in mediating the enhancement of the medial olivocochlear (MOC) reflex following long-term noise exposure.

Methods: We utilized four groups of male CBA/Ca mice: control, ouabain, ouabain noise, and ouabain noise + AF-353. The ouabain group received local cochlear application of ouabain to selectively induce apoptosis of type I SGNs. The ouabain noise group was then exposed to moderate noise [80 dB sound pressure level (SPL)] for 6 h daily over 4 weeks, while the ouabain noise + AF-353 group received the P2X3 receptor blocker AF-353 before noise sessions. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were measured to assess hearing. The MOC reflex was evaluated via contralateral and ipsilateral suppression of DPOAEs. Immunofluorescence visualized P2X3 receptor expression.

Results: Ouabain-treated mice exposed to noise displayed a significantly enhanced MOC reflex, which was attenuated by AF-353. ABR thresholds were elevated and wave I amplitude was reduced, suggesting hearing impairment, whereas DPOAE thresholds were unchanged. Immunofluorescence indicated a marked upregulation of P2X3 receptors in the cochlea's middle turn after noise exposure, an effect decreased by AF-353.

Conclusion: The enhanced MOC reflex induced by long-term moderate noise exposure is mediated by the upregulation of P2X3 receptors on type II SGNs. The selective ablation of type I SGNs confirms the pivotal role of type II SGNs in this adaptive neural plasticity.

Objective: This study aimed to investigate the therapeutic effects of minocycline on neuropathic pain by examining its regulatory influence on hippocampal proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels, given the established involvement of neuroinflammation and BDNF dysregulation in the pathogenesis of neuropathic pain and associated neurological dysfunctions.

Methods: This study used a rat model of neuropathic pain induced by L5 spinal nerve transection (L5-SNT). Forty-eight male Sprague-Dawley rats were divided into four groups: naive, sham-operated, model + saline, and model + minocycline. Minocycline was administered intraperitoneally at 40 mg/kg daily. Mechanical allodynia was assessed using the von Frey test, while real-time reverse transcription and ELISA were employed to quantify hippocampal expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, and BDNF at various time points postsurgery.

Results: L5-SNT induced significant mechanical allodynia in the model + saline group, which was significantly attenuated by minocycline treatment in the model + minocycline group on days 3, 7, and 11 postsurgery (P < 0.05). Minocycline significantly reduced TNF-α, IL-6, and BDNF levels in the hippocampus, particularly on day 7 post-SNT (P < 0.05); however, minocycline did not significantly affect IL-1β levels. These findings suggest that minocycline's analgesic effects may be mediated through the downregulation of key proinflammatory cytokines and BDNF in the hippocampus.

Conclusion: Minocycline administration significantly mitigates mechanical allodynia and modulates hippocampal neuroinflammatory markers in a rat model of neuropathic pain. These results highlight minocycline's potential as a therapeutic option for neuropathic pain, particularly in targeting neuroinflammation within the hippocampus.

Objective: How neuronal oscillatory activity in Parkinson's disease (PD) is organized and coordinated is not yet known. We hypothesized that cross-frequency phase synchrony (CFS) in the beta and gamma frequencies measured over the motor cortex [using electroencephalography (EEG)] at rest would be elevated in people with PD compared with healthy controls. ON- versus OFF-medication tests in the PD group were further compared with the hypothesis that elevated CFS would be found in the OFF-medication state.

Methods: CFS in beta and gamma frequencies was estimated in EEG recordings from 15 people with mild-moderate Parkinson's and in 15 control participants.

Results: Beta-gamma CFS in the motor cortices was increased in the PD OFF tests compared with tests of the control group. As a whole-brain control analysis, large-scale beta-gamma CFS in all 32 channels was found to not differ between groups, thereby isolating abnormal beta-gamma CFS to the motor cortex in PD OFF.

Conclusion: New evidence describes brain oscillatory patterns in people with mild-moderate PD, which might pave avenues for early diagnosis and treatments.

Background: Epilepsy is a central nervous system disorder characterized by abnormal brain activity, leading to seizures or periods of unusual behavior, sensations, and, in some cases, loss of awareness. Cannabidiol, a phytocannabinoid, has recently gained approval as an adjunctive seizure treatment, partly through modulation of G protein-coupled receptor 55 (GPR55), transient receptor potential vanilloid 1, and 5-hydroxytryptamine (5-HT) receptors. Similar to phytocannabinoids, endocannabinoids may also possess therapeutic potential for seizure management; however, no studies have investigated the effects of the endocannabinoid 2-linoleoylglycerol (2-LG). In the present study, we investigated the effects of 2-LG on pentylenetetrazol (PTZ)-induced seizures in mice.

Methods: Mice were pretreated with 0 (vehicle), 15, or 30 mg/kg 2-LG intraperitoneally, and saline or 60 mg/kg PTZ was administered 30 min later. Vehicle, WAY-100635 (0.01 mg/kg), or rimonabant (1 mg/kg) were administered 30 min before 2-LG (30 mg/kg) administration, and then saline or 60 mg/kg PTZ was administered 30 min later.

Results: Administration of 2-LG (30 mg/kg) significantly reduced seizure scores induced by PTZ. In addition, pretreatment with the 5-HT1A receptor antagonist WAY-100635 reversed the 2-LG antiseizure effect. We also demonstrated that PTZ-induced fluorescence intensity of the GPR55 ligand T1117 in the hippocampus was decreased by 2-LG treatment, and this effect was reversed by WAY-100635 pretreatment. Similarly, the cannabinoid receptor type 1 inverse agonist rimonabant inhibited the antiseizure activity of 2-LG, although it did not significantly affect T1117 fluorescence.

Conclusion: These results suggest that 2-LG exerts an antiseizure effect through interactions between the 5-HT1A receptor and GPR55.

Background: Diabetes significantly elevates the risk of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, indicating shared pathophysiological mechanisms. While ferroptosis is increasingly implicated in neurodegeneration, microglia - highly vulnerable to ferroptosis - may mediate this link. However, it remains unknown whether high glucose (HG) directly induces microglial ferroptosis.

Methods: Using HG-treated BV2 microglia, we integrated multiomics profiling (RNA-seq and targeted lipidomics), functional assays, and genetic manipulation of pyruvate dehydrogenase kinase 4 (PDK4) to investigate its role in HG-associated ferroptosis.

Results: HG-induced microglial ferroptosis, characterized by iron overload, elevated malondialdehyde and mitochondrial reactive oxygen species, glutathione peroxidase 4 (GPX4) downregulation, and mitochondrial damage, including loss of membrane potential and ultrastructural disintegration. This was accompanied by upregulated PDK4 expression. PDK4 overexpression attenuated ferroptosis by preserving GPX4, reducing lipid peroxidation, and maintaining mitochondrial integrity; these protective effects were reversed by n-6 polyunsaturated fatty acid (PUFA) supplementation. Conversely, PDK4 knockdown exacerbated ferroptosis via amplified n-6 PUFA synthesis and oxidative stress. Mechanistically, PDK4 acts as a metabolic gatekeeper by restricting acetyl-CoA availability for the synthesis of pro-ferroptotic PUFAs, thereby curtailing iron-dependent lipid peroxidation.

Conclusion: PDK4 is a critical regulator of HG-induced microglial ferroptosis, thereby bridging hyperglycemia-induced metabolic dysfunction and neurodegeneration. Our findings nominate PDK4 as a promising therapeutic target for diabetes-linked neurodegenerative diseases.

Objectives: Acid-sensing ion channels (ASICs) are rapidly inactivated following activation by acidic extracellular pH. Consequently, mechanisms beyond ASICs are likely involved in modulating neuronal excitability under sustained acidic conditions. Therefore, this study investigated the impact of sustained acidic pH on neuronal excitability.

Methods: Membrane current and voltage changes induced by acidic pH were recorded from acutely isolated rat medullary dorsal horn neurons using the whole-cell patch-clamp technique.

Results: The steady-state inactivation relationship for extracellular pH revealed that most ASICs were completely inactivated at pH ≤ 6.5. Acidic pH depolarized medullary dorsal horn neurons with high affinity (EC50 of pH 6.9), a process mediated by ASIC activation. Acidic pH (≤6.9) also generated instantaneous action potentials; however, they immediately disappeared owing to the inactivation of voltage-gated Na⁺ channels. Action potentials reemerged depending on pH level, even under sustained acidic conditions. This reappearance of action potentials correlated with the extent to which acidic pH inhibited the persistent Na⁺ current mediated by voltage-gated Na⁺ channels.

Conclusion: These findings suggest that under pathological conditions characterized by sustained extracellular pH reduction, such as inflammation, a persistent Na⁺ current may serve as a sensor for modulating neuronal excitability in response to prolonged acidic pH levels.

Objective: This study investigated abnormal short- and long-range functional connectivity density (FCD) and resting-state functional connectivity (rsFC) within and outside the cortico-striatal-thalamic (CST) loop in patients with obsessive-compulsive disorder (OCD).

Methods: Ninety-two patients with OCD and 75 healthy controls underwent multimodal MRI. Clinical assessments included the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Beck Anxiety Inventory, and Beck Depression Inventory. Voxel-based FCD analysis explored local and distant nodal changes, followed by seed-based rsFC analysis and correlation with clinical variables.

Results: Compared with healthy controls, patients with OCD showed decreased short-range FCD in the bilateral postcentral gyrus, left superior temporal gyrus, and right insula, but increased short-range FCD in the left caudate nucleus. Long-range FCD increased in the right orbitofrontal gyrus and left middle frontal gyrus. Seed-based analysis revealed enhanced rsFC between the right orbitofrontal gyrus and right calcarine fissure and surrounding cortex, and between the left middle frontal gyrus and right anterior cingulate and paracingulate gyri, as well as the right paracentral lobule. Left caudate FCD values negatively correlated with Y-BOCS scores, while left middle frontal gyrus FCD values positively correlated with illness duration.

Conclusion: Patients with OCD exhibit widespread connectivity abnormalities in multiple brain regions within and beyond the classic CST loop, involving sensorimotor networks, emotion-cognitive regulation, executive control, error monitoring, and visual processing systems. These findings suggest that OCD pathophysiology extends beyond the traditional CST loop, providing new insights into the neural mechanisms underlying this disorder.

Objective: Butyrate, a short-chain fatty acid produced by intestinal microbial fermentation of dietary fiber, serves as an endogenous ligand for the G protein-coupled receptors. Previous studies have confirmed the neuroprotective effects of sodium butyrate (NaB) in ischemic stroke, but its role in subarachnoid hemorrhage (SAH) remains unclear. Here, we investigated the potential therapeutic efficacy and underlying mechanisms of NaB in a rat SAH model.

Methods: NaB was administered intranasally 1 h post-SAH, and neurological function and neuronal apoptosis were evaluated 24 h post-SAH.

Results: During the early brain injury (EBI) phase after SAH, GPR41 was predominantly expressed in neuronal cells, and its expression levels increased significantly, peaking at 24 h post-SAH. NaB treatment attenuated neurological deficits after SAH, reduced brain edema, and alleviated neuronal damage and apoptosis. Furthermore, NaB elevated the levels of GPR41, phosphorylated Akt, and the antiapoptotic protein Bcl-2, while suppressing the expression of the proapoptotic protein Bax. Notably, the neuroprotective effects of NaB were partially reversed by GPR41 siRNA knockdown and pharmacological inhibition of PI3K with LY294002.

Conclusions: These findings suggest that NaB may mitigate EBI after SAH by inhibiting neuronal apoptosis, with the underlying mechanism potentially involving activation of the GPR41/PI3K/Akt signaling pathway.