Neural Inflammation Research Articles

Donepezil improves skeletal muscle insulin resistance in obese mice via the AMPK/FGF21-mediated suppression of inflammation and ferroptosis.

Donepezil has traditionally been used in Alzheimer's disease treatment and is known for its ability to alleviate neural inflammation and apoptosis. However, its impact on insulin signaling remains unexplored. This study sought to elucidate the novel role of donepezil in mitigating skeletal muscle insulin resistance under hyperlipidemic conditions. Western blot analysis was used to assess the expression of various proteins of interest, whereas a glucose uptake assay was performed in skeletal muscle cells via commercially available kits. An in vitro model of obesity was developed using palmitate. These in vitro findings were corroborated in vivo via insulin resistance models established through high-fat diet (HFD) feeding in mice. Intraperitoneal glucose tolerance tests and insulin tolerance tests were performed on the experimental mice. The results revealed that donepezil treatment improved insulin signaling and inflammation in palmitate-treated C2C12 myocytes and the skeletal muscle of HFD-fed mice. Notably, donepezil treatment augmented FGF21 expression and AMPK phosphorylation in the myocytes and skeletal muscle of HFD-fed mice. Knockdown of FGF21 or AMPK via siRNA reversed the effects of donepezil on insulin signaling and inflammation in cultured myocytes. We also found that donepezil ameliorated skeletal muscle insulin resistance via the FGF21-mediated suppression of ferroptosis under hyperlipidemic conditions. These findings suggest that donepezil enhances the FGF21/AMPK axis, thereby mitigating inflammation and insulin resistance in skeletal muscle. This study introduces a novel therapeutic approach for treating Alzheimer's disease patients with insulin resistance.

Additive effect of high transportation noise exposure and socioeconomic deprivation on stress-associated neural activity, atherosclerotic inflammation, and cardiovascular disease events.

Noise exposure and lower socioeconomic status (SES) are both independently linked to increased cardiovascular disease (CVD) risk. Although these factors frequently coexist, their combined impact and the underlying pathophysiological mechanisms remain poorly understood. This study aimed to evaluate the joint effects of high transportation noise exposure and lower SES on major adverse cardiovascular events (MACE) and the role of the neural-arterial axis in mediating this relationship. We retrospectively analyzed data from 507 individuals who underwent clinical 18F-FDG-PET/CT imaging at a single center. SES was evaluated using local median income (as a primary measure) and area deprivation index (ADI, as a secondary measure). Participants were classified into three groups based on transportation noise exposure and income/ADI: low noise/higher SES, high noise or lower SES, and high noise/lower SES. Cox models assessed MACE risks. Linear regression models evaluated associations with stress-related neural activity (SNA) and arterial inflammation (ArtI). The combination of high noise exposure and low income (vs. neither exposure) associated with increased MACE risk (HR [95% CI]: 5.597 [2.201-14.233], p < 0.001). SNA (standardized β [95% CI]: 0.389 [0.192-0.586], p < 0.001) and ArtI (0.151 [0.005-0.298], p = 0.043) were greater in this group. Mediation analysis showed that the neural-arterial axis contributes to increased exposure-related MACE risk and accounts for 8% of the overall effect. Similar results were found with ADI. Our study uniquely demonstrates how combined high transportation noise and lower socioeconomic status additively increases cardiovascular disease risk through specific biological pathways, particularly via effects on stress-associated neural activity and arterial inflammation. As such, the research offers novel insights into the interplay between environmental and socioeconomic factors in cardiovascular health. This underscores an urgent need for integrated public health strategies that address both noise pollution and socioeconomic disparities and provides a foundation for targeted interventions aimed at reducing the burden of cardiovascular disease in vulnerable populations. Central illustration of hypothesized mechanistic pathways linking transportation noise/SES exposure groups and MACE. SNA stress related neural activity (as AmygAc-ratio of amygdala to background cortical activity), MACE major adverse cardiovascular events, ArtI arterial inflammation, ADI Area Deprivation Index, SES socioeconomic status.

White matter protection with insulin-like growth factor-1 after hypoxia-ischaemia in preterm foetal sheep.

Perinatal hypoxia-ischaemia in extremely preterm infants is associated with long-term neurodevelopmental impairment, for which there is no specific treatment. Insulin-like growth factor-1 can reduce acute brain injury, but its effects on chronic white matter injury after hypoxia-ischaemia are unclear. Preterm-equivalent foetal sheep (0.6 gestation) received either sham-asphyxia or asphyxia induced by umbilical cord occlusion for 30 min, and recovered for either 3 or 35 days after asphyxia. The 35 day recovery groups received either an intracerebroventricular infusion of insulin-like growth factor-1 (1 µg/24 h) or vehicle, from 3 to 14 days after asphyxia. Asphyxia was associated with ventricular enlargement, and loss of frontal and parietal white matter area (P < 0.05 versus sham-asphyxia). This was associated with reduced area fraction of myelin basic protein and numbers of oligodendrocyte transcription factor 2 and mature, anti-adenomatous polyposis coli-positive oligodendrocytes in periventricular white matter (P < 0.05), with persistent inflammation and caspase-3 activation (P < 0.05). Four of eight foetuses developed cystic lesions in temporal white matter. Prolonged infusion with insulin-like growth factor-1 restored frontal white matter area, improved numbers of oligodendrocyte transcription factor 2-positive and mature, anti-adenomatous polyposis coli-positive oligodendrocytes, with reduced astrogliosis and microgliosis after 35 days recovery (P < 0.05 versus asphyxia). One of four foetuses developed temporal cystic lesions. Functionally, insulin-like growth factor-1-treated foetuses had faster recovery of EEG power, but not spectral edge. Encouragingly, these findings show that delayed, prolonged, insulin-like growth factor-1 treatment can improve functional maturation of periventricular white matter after severe asphyxia in the very immature brain, at least in part by suppressing chronic neural inflammation.

Role of Amniotic Fluid Toxicity in the Pathophysiology of Myelomeningocele: A Narrative Literature Review.

Myelomeningocele is a birth defect whose clinical manifestations are due both to incomplete neural tube closure and the progressive destruction of exposed neuroepithelium during pregnancy. Two hypotheses have been formulated to explain the spinal cord damage in utero: mechanical trauma and chemical factors. The objective of this review was to summarize the current insights about the potential role of amniotic fluid in spinal cord damage in myelomeningocele. Numerous histological and clinical data on animals and humans strongly suggest a progressive degeneration of neural tissue including loss of neural cells, astrogliosis, inflammation, and loss of normal architecture. However, few data have been published about the direct toxicity of amniotic fluid in this neural degeneration, including the potentially toxic effect of meconium. Finally, the chemical and cellular modifications of amniotic fluid composition in myelomeningocele could reflect both the process (toxic effect of meconium) and the consequences of neuroepithelium destruction (release of neural cells). Fetal surgery not only stops the leakage of the cerebrospinal fluid but also reduces the toxic effect of amniotic fluid by restoring the intrauterine environment. Identification of amniotic fluid neurotoxic factors could lead to the development of therapeutic agents designed to protect spinal tissue and improve fetal myelomeningocele outcomes.

Neuroprotective effects of all-trans-retinoic acid are mediated via downregulation of TLR4/NF-κB signaling in a rat model of middle cerebral artery occlusion.

To determine the effects of all-trans-retinoic acid (ATRA) on the post-stroke inflammatory response and elucidate the underlying molecular mechanisms. This animal experiment was conducted at Central Laboratory, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China during 2020-2022. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5h, and treated with ATRA at 2 and 24h after reperfusion. Neurological deficit scores on behavioral tests, and cerebral infarct volume, microglial polarization, and the expression levels of inflammatory cytokines and proteins associated with TLR4/NF-κB signaling were assessed. The ATRA administration reduced cerebral infarct volume and ameliorated neurological deficit scores in MCAO rats. Additionally, ATRA relieved cerebral edema and downregulated the secretion of proinflammatory cytokines after stroke. Finally, ATRA attenuated the polarization of the microglia toward the M1 phenotype and promoted the activation of the beneficial M2 phenotype; the underlying mechanism potentially involved the suppression of the TLR4/NF-κB signaling pathway. The ATRA treatment promoted functional recovery in an experimental model of ischemic stroke by attenuating neural inflammation. ATRA potentially modulated microglia-mediated neuroinflammation via the downregulation of the TLR4/NF-κB signaling pathway, which makes it a candidate treatment for post-stroke neuroinflammation.

Methyltransferase METTL3 regulates neuropathic pain through m6A methylation modification of SOCS1

The mechanisms of neuropathic pain (NP) are considered multifactorial. Alterations in the suppressor of cytokine signaling 1 (SOCS1) play a critical role in neural damage and inflammation. Epigenetic RNA modifications, specifically N6-methyladenosine (m6A) methylation, have increasingly been observed to impact the nervous system. Nevertheless, there is a scarcity of studies investigating the connection between m6A methylation and SOCS1 in the molecular mechanisms of NP. This study investigates the roles and potential mechanisms of the m6A methyltransferase like 3 (METTL3) and SOCS1 in female rats with spinal nerve ligation (SNL)-induced NP. It was found that in NP, both METTL3 and overall m6A levels were downregulated, leading to the activation of pro-inflammatory cytokines, such as interleukin-1β, interleukin 6, and tumor necrosis factor-α. Notably, The SOCS1 mRNA is significantly enriched with m6A methylation modifications, with the most prevalent m6A methyltransferase METTL3 stabilizing the downregulation of SOCS1 by targeting m6A methylation modifications at positions 151, 164, and 966.Exogenous supplementation of METTL3 improved NP-related neuroinflammation and behavioral dysfunctions, but these effects could be reversed by the absence of SOCS1. Additionally, the depletion of endogenous SOCS1 promoted NP progression by inducing the toll-like receptor 4 (TLR4) signaling pathway. The dysregulation of METTL3 and the resulting m6A modification of SOCS1 form a crucial epigenetic regulatory loop that promotes the progression of NP. Targeting the METTL3/SOCS1 axis might offer new insights into potential therapeutic strategies for NP.

Utilizing diffusion tensor imaging as an image biomarker in exploring the therapeutic efficacy of forniceal deep brain stimulation in a mice model of Alzheimer’s disease

Objective.With prolonged life expectancy, the incidence of memory deficits, especially in Alzheimer's disease (AD), has increased. Although multiple treatments have been evaluated, no promising treatment has been found to date. Deep brain stimulation (DBS) of the fornix area was explored as a possible treatment because the fornix is intimately connected to memory-related areas that are vulnerable in AD; however, a proper imaging biomarker for assessing the therapeutic efficiency of forniceal DBS in AD has not been established.Approach.This study assessed the efficacy and safety of DBS by estimating the optimal intersection volume between the volume of tissue activated and the fornix. Utilizing a gold-electroplating process, the microelectrode's surface area on the neural probe was increased, enhancing charge transfer performance within potential water window limits. Bilateral fornix implantation was conducted in triple-transgenic AD mice (3 × Tg-AD) and wild-type mice (strain: B6129SF1/J), with forniceal DBS administered exclusively to 3 × Tg-AD mice in the DBS-on group. Behavioral tasks, diffusion tensor imaging (DTI), and immunohistochemistry (IHC) were performed in all mice to assess the therapeutic efficacy of forniceal DBS.Main results.The results illustrated that memory deficits and increased anxiety-like behavior in 3 × Tg-AD mice were rescued by forniceal DBS. Furthermore, forniceal DBS positively altered DTI indices, such as increasing fractional anisotropy (FA) and decreasing mean diffusivity (MD), together with reducing microglial cell and astrocyte counts, suggesting a potential causal relationship between revised FA/MD and reduced cell counts in the anterior cingulate cortex, hippocampus, fornix, amygdala, and entorhinal cortex of 3 × Tg-AD mice following forniceal DBS.Significance.The efficacy of forniceal DBS in AD can be indicated by alterations in DTI-based biomarkers reflecting the decreased activation of glial cells, suggesting reduced neural inflammation as evidenced by improvements in memory and anxiety-like behavior.

Urinary kallikrein reverses neuropathic pain by inhibiting ectopic neural discharges, neural inflammation and oxidative stress.

Neuropathic pain is a refractory disease and badly impacts the lives of patients. Urinary kallikrein (UK) acted as a glycoprotein has been discovered to play a pivotal role in neuroprotection. However, the regulatory impacts and correlative pathways of UK in the progression of neuropathic pain remain dimness. The chronic constriction injury (CCI) rat model was firstly established to mimic neuropathic pain. The withdrawal threshold was measured through the Von Frey test. The levels of TNF-α, IL-1β and IL-6 were determined through ELISA. The levels of ROS, GSH, SOD and GSH-Px were examined through the commercial kits. The ectopic discharges were assessed. The protein expressions were inspected through western blot. It was demonstrated that withdrawal threshold was reduced in CCI rat model, but this change was reversed after UK treatment, indicating that UK relieved mechanical allodynia. Moreover, UK alleviated the inflammatory response through reducing TNF-α, IL-1β and IL-6 levels. It was uncovered that oxidative stress was strengthened in CCI rat model, but this impact was restrained after UK treatment. Additionally, UK suppressed ectopic discharge. At last, it was proved that UK triggered the Nrf2/ARE signaling pathway in CCI rat model. This study manifested that UK reversed neuropathic pain by inhibiting ectopic neural pathways, neural pathways and oxidation via the Nrf2/ARE pathway. This study may offer useful proofs the regulatory functions of UK in the cure of neuropathic pain.

ARMCX3 regulates ROS signaling, affects neural differentiation and inflammatory microenvironment in dental pulp stem cells

BackgroundThe neural differentiation of dental pulp stem cells (DPSCs) exhibits great potential in the treatment of dental pulp repair and neurodegenerative diseases. However, the precise molecular mechanisms underlying this process remain unclear. This study was designed to reveal the roles and regulatory mechanisms of the armadillo repeat-containing X-linked 3 (ARMCX3) in neural differentiation and inflammatory microenvironment in human DPSCs (hDPSCs). MethodsWe treated hDPSCs with porphyromonas gingivalis lipopolysaccharide (Pg-LPS) to simulate the inflammatory microenvironment. Then the lentiviral vectors were introduced to construct stable cell lines with ARMCX3 knockdown or overexpression. The expression of neural-specific markers, ARMCX3 and inflammation factors were estimated by immunofluorescence (IF), quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) assays. Additionally, we used IF assays and specific kits to investigate the regulatory role of ARMCX3 on reactive oxygen species (ROS) signaling. Moreover, a ROS inhibitor was utilized to verify whether ROS inhibition reversed the effects of ARMCX3 in Pg-LPS-treated hDPSCs. ResultsThis work illustrated that Pg-LPS treatment significantly enhanced ARMCX3 expression and inflammatory response, and inhibited neural differentiation in hDPSCs. ARMCX3 knockdown effectively accelerated neural differentiation and controlled inflammatory cytokines at a lower level in hDPSCs in the presence of Pg-LPS. Additionally, knockdown of ARMCX3 notably reduced ROS production and ROS inhibition effectively eliminated the roles of ARMCX3 overexpression in hDPSCs. Besides, all results were proved to be statistically significant. ConclusionThis investigation proved that ARMCX3 affected neural differentiation and inflammation microenvironment in hDPSCs at least partly by mediating ROS signal. These findings provided a new perspective on the mechanism of neural differentiation of hDPSCs and help to better explore the therapeutic schedule of pulpitis and neurodegenerative diseases.

Linarin inhibits microglia activation-mediated neuroinflammation and neuronal apoptosis in mouse spinal cord injury by inhibiting the TLR4/NF-κB pathway

To investigate the mechanism underlying the neuroprotective effect of linarin (LIN) against microglia activation-mediated inflammation and neuronal apoptosis following spinal cord injury (SCI). Fifty C57BL/6J mice (8- 10 weeks old) were randomized to receive sham operation, SCI and linarin treatment at 12.5, 25, and 50 mg/kg following SCI (n=10). Locomotor function recovery of the SCI mice was assessed using the Basso Mouse Scale, inclined plane test, and footprint analysis, and spinal cord tissue damage and myelination were evaluated using HE and LFB staining. Nissl staining, immunofluorescence assay and Western blotting were used to observe surviving anterior horn motor neurons in injured spinal cord tissue. In cultured BV2 cells, the effects of linarin against lipopolysaccharide (LPS)‑induced microglia activation, inflammatory factor release and signaling pathway changes were assessed with immunofluorescence staining, Western blotting, RT-qPCR, and ELISA. In a BV2 and HT22 cell co-culture system, Western blotting was performed to examine the effect of linarin against HT22 cell apoptosis mediated by LPS-induced microglia activation. Linarin treatment significantly improved locomotor function (P < 0.05), reduced spinal cord damage area, increased spinal cord myelination, and increased the number of motor neurons in the anterior horn of the SCI mice (P < 0.05). In both SCI mice and cultured BV2 cells, linarin effectively inhibited glial cell activation and suppressed the release of iNOS, COX-2, TNF-α, IL-6, and IL-1β, resulting also in reduced neuronal apoptosis in SCI mice (P < 0.05). Western blotting suggested that linarin-induced microglial activation inhibition was mediated by inhibition of the TLR4/NF- κB signaling pathway. In the cell co-culture experiments, linarin treatment significantly decreased inflammation-mediated apoptosis of HT22 cells (P < 0.05). The neuroprotective effect of linarin is medicated by inhibition of microglia activation via suppressing the TLR4/NF‑κB signaling pathway, which mitigates neural inflammation and reduce neuronal apoptosis to enhance motor function of the SCI mice.

Isoquercitrin attenuates neuroinflammation in LPS-stimulated BV2 microglia cells via p38MAPK/NF-κB pathway

Abstract Objectives Microglia mediated neuronal inflammation has been reported to be responsible for neurodegenerative disease. Isoquercitrin (IQC), widely found in fruits, vegetables and foods, has high bioavailability and offers many benefits of humans. Although IQC has been shown to possess pleiotropic biological activities, but its anti-inflammatory mechanism in microglia at molecular level remains largely unclear. Therefore, this study aimed to investigate IQC’s inhibition on inflammation within BV2 microglia cells induced by lipopolysaccharide (LPS) and the underlying mechanism. Methods The cell viability was tested by using the MTT assay and the NO production was measured by Griess reagent. Inflammatory cytokines expression was determined by RT-qPCR and the expression of iNOS、COX2 and correlation factor of NF-κB and MAPK pathway were determined by RT-qPCR and western blotting. Results IQC does not affect the viability of LPS-stimulated microglia. IQC treatment inhibited LPS-triggered NO and PGE2 production, iNOS and COX2 expression and affected the mRNA levels of relative inflammatory cytokines. Moreover, IQC inhibited nuclear factor kappa B(NF-κB) and MAPK pathway activation mediated by LPS, thereby inhibiting the levels of inflammatory cytokines. Conclusions IQC exhibited remarkable anti-inflammatory effects and promised therapeutic potential for neural inflammation associated diseases.

Sleep Deprivation Triggers Mitochondrial DNA Release in Microglia to Induce Neural Inflammation: Preventative Effect of Hydroxytyrosol Butyrate.

Sleep deprivation (SD) triggers mitochondrial dysfunction and neural inflammation, leading to cognitive impairment and mental issues. However, the mechanism involving mitochondrial dysfunction and neural inflammation still remains unclear. Here, we report that SD rats exhibited multiple behavioral disorders, brain oxidative stress, and robust brain mitochondrial DNA (mtDNA) oxidation. In particular, SD activated microglia and microglial mtDNA efflux to the cytosol and provoked brain pro-inflammatory cytokines. We observed that the mtDNA efflux and pro-inflammatory cytokines significantly reduced with the suppression of the mtDNA oxidation. With the treatment of a novel mitochondrial nutrient, hydroxytyrosol butyrate (HTHB), the SD-induced behavioral disorders were significantly ameliorated while mtDNA oxidation, mtDNA release, and NF-κB activation were remarkably alleviated in both the rat brain and the N9 microglial cell line. Together, these results indicate that microglial mtDNA oxidation and the resultant release induced by SD mediate neural inflammation and HTHB prevents mtDNA oxidation and efflux, providing a potential treatment for SD-induced mental issues.

Recent Advances in Understanding and Managing Alzheimer's Disease: from Pathogenesis to Treatment

Objective: The objective of this article is to conduct a comprehensive review of recent advances in understanding the pathogenesis of Alzheimer's disease (AD) and innovations in its management, emphasizing how these developments can inform more effective therapeutic strategies. Initially, this study explores contemporary findings related to the molecular and cellular mechanisms contributing to AD pathology, including the aggregation of beta-amyloid and tau, neural inflammation, synaptic dysfunction, as well as the impact of genetic and environmental factors. Theoretical Framework: Alzheimer's disease (AD) presents itself as a growing challenge for global public health, given its rising prevalence and the significant impact on the affected individuals, their families, and the healthcare systems. Method: A systematic review was conducted using major scientific databases to collect relevant articles on recent advances in the understanding and management of Alzheimer's disease, from pathogenesis to treatment. Specific keywords were used to identify studies addressing new findings and interdisciplinary therapeutic strategies. This enabled the synthesis of effective approaches and the identification of research gaps, supporting evidence-based clinical practices. Results and Discussion: Recent research has identified novel genetic markers linked to Alzheimer's disease, enhancing early diagnosis. Studies have also demonstrated the efficacy of integrated cognitive therapies in slowing disease progression. Additionally, new pharmacological treatments targeting amyloid plaques have shown promise in clinical trials. However, challenges in uniform treatment efficacy across diverse populations highlight the need for tailored therapeutic approaches.

GDF11 improves hippocampal neurogenesis and cognitive abilities in diabetic mice by reducing neural inflammation

BackgroundThe cognitive decline associated with type 2 diabetes (T2D) is often attributed to compromised hippocampal neurogenesis and exacerbated neural inflammation. This study investigates the therapeutic potential of growth differentiation factor 11 (GDF11) in reversing these neurodegenerative processes in diabetic mice. ResultWe utilized a murine model of T2D and examined the effects of GDF11 on learning, memory, neurogenesis, and neuroinflammatory markers. Our results indicate that diabetic mice exhibit significant deficits in cognitive function, mirrored by reduced hippocampal neurogenesis and increased neuroinflammation. Chronic administration of GDF11 was observed to significantly enhance cognitive abilities, as evidenced by improved performance in learning and memory tasks. Concurrently, GDF11 treatment restored neural activity and promoted the regeneration of new neurons within the hippocampus. Inflammatory profiling revealed a reduction in neuroinflammatory markers, which was further supported by reduced microglia numbers. To delineate the role of neuroinflammation, we pharmacologically depleted microglia, leading to a restoration of neurogenesis and cognitive functions in diabetic mice. ConclusionThese findings endorse the hypothesis that GDF11 exerts its beneficial effects by modulating neuroinflammatory pathways. Consequently, GDF11 represents a promising intervention to ameliorate diabetes-induced cognitive impairments and neural degeneration through its anti-inflammatory properties.

Repeated epidural delivery of Shinbaro2: effects on neural recovery, inflammation, and pain modulation in a rat model of lumbar spinal stenosis.

The choice of treatment for lumbar spinal stenosis (LSS) depends on symptom severity. When severe motor issues with urinary dysfunction are not present, conservative treatment is often considered to be the priority. One such conservative treatment is epidural injection, which is effective in alleviating inflammation and the pain caused by LSS-affected nerves. In this study, Shinbaro2 (Sh2), pharmacopuncture using natural herbal medicines for patients with disc diseases, is introduced as an epidural to treat LSS in a rat model. The treatment of primary sensory neurons from the rats' dorsal root ganglion (DRG) neurons with Sh2 at various concentrations (0.5, 1, and 2mg/mL) was found to be safe and non-toxic. Furthermore, it remarkably stimulated axonal outgrowth even under H2O2-treated conditions, indicating its potential for stimulating nerve regeneration. When LSS rats received epidural injections of two different concentrations of Sh2 (1 and 2mg/kg) once daily for 4 weeks, a significant reduction was seen in ED1+ macrophages surrounding the silicone block used for LSS induction. Moreover, epidural injection of Sh2 in the DRG led to a significant suppression of pain-related factors. Notably, Sh2 treatment resulted in improved locomotor recovery, as evaluated by the Basso, Beattie, and Bresnahan scale and the horizontal ladder test. Additionally, hind paw hypersensitivity, assessed using the Von Frey test, was reduced, and normal gait was restored. Our findings demonstrate that epidural Sh2 injection not only reduced inflammation but also improved locomotor function and pain in LSS model rats. Thus, Sh2 delivery via epidural injection has potential as an effective treatment option for LSS.

Antiseizure properties of fenamate NSAIDs determined in mature human stem-cell derived neuroglial circuits.

Repeated and uncontrolled seizures in epilepsy result in brain cell loss and neural inflammation. Current anticonvulsants primarily target ion channels and receptors implicated in seizure activity. Identification of neurotherapeutics that can inhibit epileptiform activity and reduce inflammation in the brain may offer significant benefits in the long-term management of epilepsy. Fenamates are unique because they are both non-steroidal anti-inflammatory drugs (NSAIDs) and highly subunit selective modulators of GABAA receptors. In the current study we have investigated the hypothesis that fenamates have antiseizure properties using mature human stem cell-derived neuro-glia cell cultures, maintained in long-term culture, and previously shown to be sensitive to first, second and third generation antiepileptics. Mefenamic acid, flufenamic acid, meclofenamic acid, niflumic acid, and tolfenamic acid (each tested at 10-100μM) attenuated 4-aminopyridine (4-AP, 100μM) evoked epileptiform activity in a dose-dependent fashion. These actions were as effective diazepam (3-30μM) and up to 200 times more potent than phenobarbital (300-1,000μM). The low (micromolar) concentrations of fenamates that inhibited 4-AP evoked epileptiform activity correspond to those reported to potentiate GABAA receptor function. In contrast, the fenamates had no effect on neural spike amplitudes, indicating that their antiseizure actions did not result from inhibition of sodium-channels. The antiseizure actions of fenamates were also not replicated by either of the two non-fenamate NSAIDs, ibuprofen (10-100μM) or indomethacin (10-100μM), indicating that inhibition of cyclooxygenases is not the mechanism through which fenamates have anticonvulsant properties. This study therefore shows for the first time, using functionally mature human stem cell-derived neuroglial circuits, that fenamate NSAIDs have powerful antiseizure actions independent of, and in addition to their well-established anti-inflammatory properties, suggesting these drugs may provide a novel insight and new approach to the treatment of epilepsy in the future.

Periodic heat waves-induced neuronal etiology in the elderly is mediated by gut-liver-brain axis: a transcriptome profiling approach

Heat stress exposure in intermittent heat waves and subsequent exposure during war theaters pose a clinical challenge that can lead to multi-organ dysfunction and long-term complications in the elderly. Using an aged mouse model and high-throughput sequencing, this study investigated the molecular dynamics of the liver-brain connection during heat stress exposure. Distinctive gene expression patterns induced by periodic heat stress emerged in both brain and liver tissues. An altered transcriptome profile showed heat stress-induced altered acute phase response pathways, causing neural, hepatic, and systemic inflammation and impaired synaptic plasticity. Results also demonstrated that proinflammatory molecules such as S100B, IL-17, IL-33, and neurological disease signaling pathways were upregulated, while protective pathways like aryl hydrocarbon receptor signaling were downregulated. In parallel, Rantes, IRF7, NOD1/2, TREM1, and hepatic injury signaling pathways were upregulated. Furthermore, current research identified Orosomucoid 2 (ORM2) in the liver as one of the mediators of the liver-brain axis due to heat exposure. In conclusion, the transcriptome profiling in elderly heat-stressed mice revealed a coordinated network of liver-brain axis pathways with increased hepatic ORM2 secretion, possibly due to gut inflammation and dysbiosis. The above secretion of ORM2 may impact the brain through a leaky blood–brain barrier, thus emphasizing intricate multi-organ crosstalk.

An Amino Acids and Dipeptide Injection Inhibits the TNF-α/HMGB1 Inflammatory Signaling Pathway to Reduce Pyroptosis and M1 Microglial Polarization in POCD Mice: the Gut to the Brain.

Peripheral surgery-induced neural inflammation is a key pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the mechanism underlying neuroinflammation and associated neural injury remains elusive. Surgery itself can lead to gut damage, and the occurrence of POCD is accompanied by high levels of TNF-α in the serum and blood‒brain barrier (BBB) damage. Reductions in stress, inflammation and protein loss have been emphasized as strategies for enhanced recovery after surgery (ERAS). We designed an amino acids and dipeptide (AAD) formula for injection that could provide intestinal protection during surgery. Through the intraoperative infusion of AAD based on the ERAS concept, we aimed to explore the effect of AAD injection on POCD and its underlying mechanism from the gut to the brain. Here, we observed that AAD injection ameliorated neural injury in POCD, in addition to restoring the function of the intestinal barrier and BBB. We also found that TNF-α levels decreased in the ileum, blood and hippocampus. Intestinal barrier protectors and TNF-α inhibitors also alleviated neural damage. AAD injection treatment decreased HMGB1 production, pyroptosis, and M1 microglial polarization and increased M2 polarization. In vitro, AAD injection protected the impaired gut barrier and decreased TNF-α production, alleviating damage to the BBB by stimulating cytokine transport in the body. HMGB1 and Caspase-1 inhibitors decreased pyroptosis and M1 microglial polarization and increased M2 polarization to protect TNF-α-stimulated microglia in vitro. Collectively, these findings suggest that the gut barrier-TNF-α-BBB-HMGB1-Caspase-1 inflammasome-pyroptosis-M1 microglia pathway is a novel mechanism of POCD related to the gut-brain axis and that intraoperative AAD infusion is a potential treatment for POCD.

Dangers of the chronic stress response in the context of the microbiota-gut-immune-brain axis and mental health: a narrative review.

More than 20% of American adults live with a mental disorder, many of whom are treatment resistant or continue to experience symptoms. Other approaches are needed to improve mental health care, including prevention. The role of the microbiome has emerged as a central tenet in mental and physical health and their interconnectedness (well-being). Under normal conditions, a healthy microbiome promotes homeostasis within the host by maintaining intestinal and brain barrier integrity, thereby facilitating host well-being. Owing to the multidirectional crosstalk between the microbiome and neuro-endocrine-immune systems, dysbiosis within the microbiome is a main driver of immune-mediated systemic and neural inflammation that can promote disease progression and is detrimental to well-being broadly and mental health in particular. In predisposed individuals, immune dysregulation can shift to autoimmunity, especially in the presence of physical or psychological triggers. The chronic stress response involves the immune system, which is intimately involved with the gut microbiome, particularly in the process of immune education. This interconnection forms the microbiota-gut-immune-brain axis and promotes mental health or disorders. In this brief review, we aim to highlight the relationships between stress, mental health, and the gut microbiome, along with the ways in which dysbiosis and a dysregulated immune system can shift to an autoimmune response with concomitant neuropsychological consequences in the context of the microbiota-gut-immune-brain axis. Finally, we aim to review evidenced-based prevention strategies and potential therapeutic targets.

Advantages of edaravone dextrosanol in elderly patients with acute cerebral infarction versus edaravone: a preliminary study

Objective To analyze and compare the application advantages of Edaravone and Edaravone Dextrosanol in elderly patients with acute cerebral infarction (ACI). Methods A retrospective analysis of clinical data from 113 elderly AIS patients admitted to our hospital between January 2022 and January 2023 was conducted. Based on the treatment interventions received, patients were divided into a control group (n = 56) and an observation group (n = 57). The control group received Edaravone in addition to routine treatment, while the observation group received Edaravone Dextrosanol in addition to routine treatment. compared clinical outcomes, motor and neurological function, self-care ability, neural damage indicators, inflammatory markers, and adverse reactions between the two groups. Results ① Total effective rate in the observation group (91.23%) was significantly higher than that in the control group (75.00%) (p < 0.05). ② After treatment, higher FMA and Barthel scores, lower NDS score in observation group vs control group (p < 0.05). ③ After treatment, lower NSE and MMP-9 levels in observation group vs control group (p < 0.05). ④ After treatment, lower IL-1β, IL-6, and hs-CRP levels in observation group vs control group (p < 0.05). ⑤ No significant difference in adverse reaction incidence between groups (p > 0.05). Conclusion Edaravone Dextrosanol proves effective in treating elderly AIS patients. Compared to Edaravone, it boosts effectiveness, neurological recovery, motor & self-care abilities, and reduces neural damage & inflammation markers. Its safety profile is comparable to Edaravone, without significantly increasing adverse reactions. These findings suggest that Edaravone Dextrosanol is worthy of clinical promotion.