Neurological Inflammation Research Articles

Treatment of neurologic pathology and inflammation in Machado-Joseph disease through in vivo self-assembled siRNA.

Machado-Joseph disease, also known as Spinocerebellar ataxia type 3 (MJD/SCA3), is a fatal autosomal dominant hereditary ataxia characterized by cerebellar ataxia resulting from the abnormal expansion of CAG repeats in exon 10 of the ATXN3 gene. Presently, there is no effective treatment for SCA3. Small interfering RNAs (siRNAs) are emerging as potential therapeutic strategies to specifically target the disease-causing mutant ATXN3 (mATXN3) protein. However, the delivery efficiency of siRNAs remains a major obstacle for clinical application, particularly in brain disorders. This study aimed to develop a synthetic biology strategy to reprogram the host liver as a tissue chassis to induce and deliver in vivo self-assembled siRNAs (IVSA-siRNAs) to target the ATXN3 gene. A synthetic construct directed by a cytomegalovirus promoter was designed to encode a neuron-targeting rabies virus glycoprotein tag and mATXN3-siRNA. After intravenous injection, the synthetic construct was taken up by mouse livers, which were then reprogrammed to enable the self-assembly, production, and secretion of small extracellular vesicles (sEVs) encapsulating mATXN3-siRNA. The sEV-encapsulated mATXN3-siRNA was further transported through the endogenous circulating system of sEVs, crossing the blood-brain barrier and reaching the cerebellar cortex and spinal cerebellar tract, where they silenced the ATXN3 gene. Treatment with the synthetic construct for 8 or 12 weeks led to significant improvements in motor balance ability and reduction of cerebellar atrophy in YACMJD84.2 transgenic mice. The number of Purkinje cells in the cerebellar cortex was significantly increased, and the loss of myelin basic protein was reduced. Moreover, the quantity of neurotoxic nuclear inclusion bodies and the expression of glial fibrillary acidic protein, which promotes neuroinflammation in activated astrocytes, were decreased significantly. The synthetic construct facilitated the generation and delivery of IVSA-siRNA to the cerebellar cortex and spinal cerebellar tract, thereby inhibiting the expression of mATXN3 protein. This treatment successfully addressed motor impairments, alleviated neuropathological phenotypes, and mitigated neuroinflammation in YACMJD84.2 transgenic mice. Our strategy effectively overcomes the primary challenges associated with siRNA therapy for cerebellar ataxia, offering a promising avenue for future clinical treatments.

Inflammation and Elevated Osteopontin in Plasma and CSF in Cerebral Malaria Compared to Plasmodium-Negative Neurological Infections.

Cerebral malaria in young African children is associated with high mortality, and persisting neurological deficits often remain in survivors. Sequestered Plasmodium-infected red blood cells lead to cerebrovascular inflammation and subsequent neuroinflammation. Brain inflammation can play a role in the pathogenesis of neurologic sequelae. Therefore, we assessed a select set of proinflammatory analytes (IP10, IL23, MIP3α, GRO, MCP-1, and osteopontin in both the plasma and cerebrospinal fluid(CSF) of Zambian children with cerebral malaria and compared this with children with neurological symptoms that were negative for Plasmodium falciparum (non-cerebral malaria). Several similarities in plasma and CSF levels were found, as were some striking differences. We confirmed that IP10 levels were higher in the plasma of cerebral malaria patients, but this was not found in CSF. Levels of osteopontin were elevated in both the plasma and CSF of CM patients compared to the non-CM patients. These results show again a highly inflammatory environment in both groups but a different profile for CM when compared to non-cerebral malaria. Osteopontin may play an important role in neurological inflammation in CM and the resulting sequelae. Therefore, osteopontin could be a valid target for further biomarker research and potentially for therapeutic interventions in neuroinflammatory infections.

Regulation of miR-590-5p on Neurological Inflammation and Oxidative Stress and Its Biomarker Role in Parkinson’s Disease

Regulation of miR-590-5p on Neurological Inflammation and Oxidative Stress and Its Biomarker Role in Parkinson’s Disease

P15-12 Omega-3 fatty acid metabolite resolvin D1 modulates organic dust-induced pulmonary and neurological inflammation

P15-12 Omega-3 fatty acid metabolite resolvin D1 modulates organic dust-induced pulmonary and neurological inflammation

Diallyl trisulfide regulates PGK1/Nrf2 expression and reduces inflammation to alleviate neurological damage in mice after traumatic brain injury

BackgroundDiallyl trisulfide (DATS) has a direct antioxidant capacity and emerges as a promising neuroprotective agent. This study was designed to investigate the role of DATS in traumatic brain injury (TBI). MethodsTBI mouse models were established using the controlled cortical impact, followed by DATS administration. The effects of DATS on neurological deficit, brain damage, inflammation and phosphoglycerate kinase 1 (PGK1) expression were detected using mNSS test, histological analysis, TUNEL assay, enzyme-linked immunosorbent assay and immunofluorescence. PC12 cells were subjected to H2O2-induced oxidative injury after pre-treatment with DATS, followed by cell counting kit-8 assay, flow cytometry and ROS production detection. Apoptosis-related proteins and the PGK1/nuclear factor erythroid-2 related factor 2 (Nrf2) pathway were examined using Western blot. ResultsDATS ameliorated the cerebral cortex damage, neurological dysfunction and apoptosis, as well as decreased PGK1 expression and expressions of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) in mice after TBI. DATS also enhanced viability, blocked apoptosis and inhibited ROS production in H2O2-induced PC12 cells. DATS downregulated Cleaved-Caspase3, Bax and PGK1 levels, and upregulated Bcl-2 and Nrf2 levels in TBI mouse models and the injured cells. ConclusionDATS regulates PGK1/Nrf2 expression and inflammation to alleviate neurological damage in mice after TBI.

Midkine: A Cancer Biomarker Candidate and Innovative Therapeutic Approaches.

Midkine (MDK) is a protein that contributes to both physiological and pathological processes. Several studies provide insight into the different roles of MDK in development, tissue repair, neural plasticity, and health and disease processes. This research further examined how MDK contributed to conditions, including neurological diseases, inflammation, and ischaemia. Furthermore, MDK overexpression has been reported in many kinds of cancer and MDK is recognized as a malignancy marker. MDK stimulates pro-tumor activity by regulating a number of signaling pathways, which increase cancer cell proliferation, survival, metastasis, and treatment resistance. However, studies have shown that MDK also functions as a molecule that regulates drug resistance. Several cancer therapy techniques have been suggested to modify MDK function, including antibody-based therapies, oligonucleotides, oncolytic viruses, and small compounds. Further research and experimentation will be required to establish the therapeutic relevance and efficacy of these treatments. This review focuses on the role of MDK in cancer biology, as well as its multiple different roles in health and disease processes.

Genome Mining Leads to Diverse Sesquiterpenes with Anti-inflammatory Activity from an Arctic-Derived Fungus.

With the advancement of bioinformatics, the integration of genome mining with efficient separation technology enables the discovery of a greater number of novel bioactive compounds. The deletion of the key gene responsible for triterpene cyclase biosynthesis in the polar strain Eutypella sp. D-1 instigated metabolic shunting, resulting in the activation of dormant genes and the subsequent production of detectable, new compounds. Fifteen sesquiterpenes were isolated from the mutant strain, with eight being new compounds. The structural elucidation of these compounds was obtained through a combination of HRESIMS, NMR spectroscopy, and ECD calculations, revealing six distinct skeleton types. Compound 7 possessed a unique skeleton of 5/10 macrocyclic ether structure. Based on the gene functions and newly acquired secondary metabolites, the metabolic shunting pathway in the mutant strain was inferred. Compounds 6, 8, 11, 14, and 15 exhibited anti-inflammatory effects without cytotoxicity through the release of nitric oxide from lipopolysaccharide-stimulated RAW264.7 cells. Notably, acorane-type sesquiterpene 8 inhibited nitric oxide production and modulated the MAPK and NLRP3/caspase-1 signaling pathways. Compound 8 also alleviated the CuSO4-induced systemic neurological inflammation symptoms in a transgenic fluorescent zebrafish model.

Biomarkers for neuroprognostication after standard versus extracorporeal cardiopulmonary resuscitation – A sub-analysis of Prague-OHCA study

BackgroundLimited evidence exists for prognostic performance of biomarkers in patients resuscitated from out-of-hospital cardiac arrest (OHCA) with extracorporeal CPR (ECPR). We hypothesized that (1) the time course and (2) prognostic performance of biomarkers might differ between CPR and ECPR in a sub-analysis of Prague-OHCA study. MethodsPatients received either CPR (n = 164) or ECPR (n = 92). The primary outcome was favorable neurologic survival at 180 days [cerebral performance category (CPC) 1–2]. Secondary outcomes included biomarkers of neurologic injury, inflammation and hemocoagulation. ResultsFavorable neurologic outcome was not different between groups: CPR 29.3% vs. ECPR 21.7%; p = 0.191. Biomarkers exhibited similar trajectories in both groups, with better values in patients with CPC 1–2. Procalcitonin (PCT) was higher in ECPR group at 24–72 h (all p < 0.01). Neuron-specific enolase (NSE), C-reactive protein and neutrophil-to-lymphocyte ratio did not differ between groups. Platelets, D-dimers and fibrinogen were lower in ECPR vs. CPR groups at 24–72 h (all p < 0.001). ROC analysis (24–48–72 h) showed the best performance of NSE in both CPR and ECPR groups (AUC 0.89 vs. 0.78; 0.9 vs. 0.9; 0.91 vs. 0.9). PCT showed good performance specifically in ECPR (0.72 vs. 0.84; 0.73 vs. 0.87; 0.73 vs. 0.86). Optimal cutoff points of NSE and PCT were higher in ECPR vs. CPR. ConclusionsBiomarkers exhibited similar trajectories although absolute values tended to be higher in ECPR. NSE had superior performance in both groups. PCT showed a good performance specifically in ECPR. Additional biomarkers may have modest incremental value. Prognostication algorithms should reflect the resuscitation method.

Biomimetic Self-Propelled Asymmetric Nanomotors for Cascade-Targeted Treatment of Neurological Inflammation.

The precise targeted delivery of therapeutic agents to deep regions of the brain is crucial for the effective treatment of various neurological diseases. However, achieving this goal is challenging due to the presence of the blood‒brain barrier (BBB) and the complex anatomy of the brain. Here, a biomimetic self-propelled nanomotor with cascade targeting capacity is developed for the treatment of neurological inflammatory diseases. The self-propelled nanomotors are designed with biomimetic asymmetric structures with a mesoporous SiO2 head and multiple MnO2 tentacles. Macrophage membrane biomimetic modification endows nanomotors with inflammatory targeting and BBB penetration abilities The MnO2 agents catalyze the degradation of H2O2 into O2, not only by reducing brain inflammation but also by providing the driving force for deep brain penetration. Additionally, the mesoporous SiO2 head is loaded with curcumin, which actively regulates macrophage polarization from the M1 to the M2 phenotype. All in vitro cell, organoid model, and in vivo animal experiments confirmed the effectiveness of the biomimetic self-propelled nanomotors in precise targeting, deep brain penetration, anti-inflammatory, and nervous system function maintenance. Therefore, this study introduces a platform of biomimetic self-propelled nanomotors with inflammation targeting ability and active deep penetration for the treatment of neurological inflammation diseases.

MSR405: Inhibiting Neuroinflammation after Spinal Cord Injury in Rats.

The treatment of spinal cord injury (SCI) is often ineffective. Additionally, SCI-induced inflammation leads to secondary injury. Current anti-inflammatory hydrophilic drugs fail to reach the nerve injury site due to the blood-brain barrier. Here, we synthesized MSR405, a new lipophilic unsaturated fatty acid derivative of Radix Isatidis and investigated its therapeutic effect in SCI model rats. Furthermore, we systematically investigated its structure, toxicity, anti-inflammatory effect, and the underlying mechanism. MSR405 was injected into the abdominal cavity of the Sprague Dawley SCI model rats, and the effect on their behavioral scores and pathology was estimated to assess the status of neurological inflammation. Our data show that MSR405 treatment significantly improved the motor function of SCI rats, and markedly suppressed the associated neuroinflammation. Moreover, MSR405 could attenuate LPS-induced inflammatory response in BV2 cells (Mouse microglia cells) in vitro. Mechanistically, MSR405 inhibits proinflammatory cytokines, supporting the anti-inflammatory response. Additionally, MSR405 can significantly block the TLR4/NF-κB signaling pathway and nitric oxide production. In summary, MSR405 reduces inflammation in SCI rats through the TLR4/NF-κB signal cascade and can inhibit neuroinflammation after spinal cord injury.

Ripks and Neuroinflammation.

Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).

Structural mechanisms of α7 nicotinic receptor allosteric modulation and activation

The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of α7-modulator complexes, revealing partially overlapping binding sites but varying conformational states. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. We extend the study using a time-resolved cryoelectron microscopy (cryo-EM) approach to reveal asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily.

Automated Retinal Vessel Analysis Based on Fundus Photographs as a Predictor for Non-Ophthalmic Diseases-Evolution and Perspectives.

The study of retinal vessels in relation to cardiovascular risk has a long history. The advent of a dedicated tool based on digital imaging, i.e., the retinal vessel analyzer, and also other software such as Integrative Vessel Analysis (IVAN), Singapore I Vessel Assessment (SIVA), and Vascular Assessment and Measurement Platform for Images of the Retina (VAMPIRE), has led to the accumulation of a formidable body of evidence regarding the prognostic value of retinal vessel analysis (RVA) for cardiovascular and cerebrovascular disease (including arterial hypertension in children). There is also the potential to monitor the response of retinal vessels to therapies such as physical activity or bariatric surgery. The dynamic vessel analyzer (DVA) remains a unique way of studying neurovascular coupling, helping to understand the pathogenesis of cerebrovascular and neurodegenerative conditions and also being complementary to techniques that measure macrovascular dysfunction. Beyond cardiovascular disease, retinal vessel analysis has shown associations with and prognostic value for neurological conditions, inflammation, kidney function, and respiratory disease. Artificial intelligence (AI) (represented by algorithms such as QUantitative Analysis of Retinal vessel Topology and siZe (QUARTZ), SIVA-DLS (SIVA-deep learning system), and many others) seems efficient in extracting information from fundus photographs, providing prognoses of various general conditions with unprecedented predictive value. The future challenges will be integrating RVA and other qualitative and quantitative risk factors in a unique, comprehensive prediction tool, certainly powered by AI, while building the much-needed acceptance for such an approach inside the medical community and reducing the "black box" effect, possibly by means of saliency maps.

MiR-30c-5p-Targeted Regulation of GNAI2 Improves Neural Function Injury and Inflammation in Cerebral Ischemia-Reperfusion Injury.

MiRNAs are related to neuronal proliferation and apoptosis following cerebral ischemia-reperfusion injury (CIRI). This study focused on miR-30c-5p in the disease.An oxygen-glucose deprivation/re-oxygenation (OGD/R) model was prepared in HT22 cells and transfected to overexpress miR-30c-5p and G Protein Subunit Alpha I2 (GNAI2) respectively or co-transfected to silence miR-30c-5p and GNAI2. Meanwhile, a middle cerebral artery occlusion (MCAO) model was constructed in mice, and miR-30c-5p and GNAI2 were silenced in vivo simultaneously. The mice were evaluated for neurological damage, apoptosis, and inflammation. HT22 cells were tested for cytotoxicity, proliferation, apoptosis, and inflammatory factors. The interaction between miR-30c-5p and GNAI2 was predicted, analyzed, and confirmed. MiR-30c-5p was found to be downregulated in both experimental models. miR-30c-5p reduced lactate dehydrogenase production, inflammatory response, inhibit apoptosis, and enhanced neuronal proliferation, while GNAI2 overexpression showed the opposite results. Downregulated miR-30c-5p worsened neurological function, apoptosis, and inflammation of MCAO mice while silencing GNAI2 attenuated the influence of downregulated miR-30c-5p. MiR-30c-5p can improve neuronal apoptosis and inflammatory response caused by CIRI and is neuroprotective by targeting GNAI2, providing a new target for treating CIRI.

Neurokinin-2 receptor negatively modulates substance P responses by forming complex with Neurokinin-1 receptor

BackgroundTachykinins and their cognate receptors, neurokinin receptors (NKs) including NK1, NK2, and NK3 play vital roles in regulating various physiological processes including neurotransmission, nociception, inflammation, smooth muscle contractility, and stimulation of endocrine and exocrine gland secretion. Their abnormal expression has been reported to be associated with neurological disorders, inflammation, and cancer. Even though NKs are expressed in the same cells with their expression being inversely correlated in some conditions, there is no direct evidence to prove their interaction. Understanding the functional crosstalk between NKs in mediated downstream signaling and cellular responses may elucidate the roles of each receptor in pathophysiology.ResultsIn this study, we showed that NKs were co-expressed in some cells. However, different from NK3, which only forms homodimerization, we demonstrated a direct interaction between NK1 and NK2 at the protein level using co-immunoprecipitation and NanoBiT-based protein interaction analysis. Through heterodimerization, NK2 downregulated substance P-stimulated NK1 signals, such as intracellular Ca2+ mobilization and ERK phosphorylation, by enhancing β-arrestin recruitment, even at the ligand concentration that could not activate NK2 itself or in the presence of NK1 specific antagonist, aprepitant. In A549 cells with receptors deleted and reconstituted, NK2 exerted a negative effect on substance P/NK1-mediated cell migration.ConclusionOur study has provided the first direct evidence of an interaction between NK1 and NK2, which highlights the functional relevance of their heterodimerization in cellular responses. Our findings demonstrated that through dimerization, NK2 exerts negative effects on downstream signaling and cellular response mediated by NK1. Moreover, this study has significant implications for understanding the complexity of GPCR dimerization and its effect on downstream signaling and cellular responses. Given the important roles of tachykinins and NKs in pathophysiology, these insights may provide clues for developing NKs-targeting drugs.

Abstract 242: Assessment of Biomarkers After Standard Cardiopulmonary Resuscitation versus Extracorporeal Cardiopulmonary Resuscitation

Background: Multiple biomarkers have been used in prognostication of outcome after out-of-hospital cardiac arrest (OHCA) and standard cardiopulmonary resuscitation (CPR). Limited evidence exists for patients resuscitated with extracorporeal CPR (ECPR). We hypothesized that (1) the time course and (2) prognostic performance of biomarkers will differ between CPR and ECPR. Methods: This is a pre-planned sub-analysis of Prague-OHCA study. Patients were randomized to either CPR or ECPR. The primary outcome was poor neurologic outcome at 180 days, defined as a cerebral performance category (CPC) of 3-5. Secondary outcomes included assessment of biomarkers of neurologic injury (NSE), inflammation (procalcitonin - PCT, C-reactive protein - CRP, neutrophil-lymphocyte ratio - NLR) and hematology (platelets - Plt, D-dimers - D-dim, and fibrinogen - Fg) using Mann-Whitney test with Bonferroni correction, and ROC analysis of data at 24-72 h. Results: In as-treated analysis, ECPR was used in 92 patients. The primary outcome was not different between groups: CPR, CPC 1-2 48 (29.3%) vs CPC 3-5 116 (70.7%); ECPR, CPC 1-2 20 (21.7%) vs CPC 3-5 72 (78.3%); p= 0.191. In general, individual biomarkers exhibited similar trajectories over 72 h, with worse values in patients with CPC 3-5 in both CPR and ECPR groups. PCT was higher in ECPR group at 24-72 h (all p&lt;0.01). NSE, CRP and NLR did not differ between groups. Plt, D-dim and Fg were lower in ECPR vs CPR groups at 24-72 h (all p&lt;0.001). ROC analysis showed the best performance of NSE in both CPR and ECPR groups (AUC 24 h: 0.89 vs 0.78; 48 h: 0.9 vs 0.9; 72 h: 0.91 vs 0.9). PCT showed good performance specifically in ECPR (AUC 24 h: 0.72 vs 0.84; 48 h 0.73 vs 0.87; 72 h: 0.73 vs 0.86). Optimal cutoff points were higher in ECPR vs CPR in NSE (24 h: 60 vs 84; 48 h: 65 vs 61; 72 h: 39 vs 57) and PCT (24 h: 1.8 vs 11, 48 h: 1.0 vs 5.3, 72 h: 0.9 vs 5.6). Conclusions: Biomarkers have similar trajectories after OHCA rescued with either CPR or ECPR although absolute values were higher in ECPR. NSE had superior prognostic value in both groups while PCT showed a good prognostic performance specifically in the ECPR group. Additional studied biomarkers may have modest incremental value. Prognostication algorithms using biomarkers should reflect a mode of resuscitation.

Electroacupuncture Alleviates Neuroinflammation by Regulating Microglia Polarization via STAT6/PPARγ in Ischemic Stroke Rats.

Previous study showed that electroacupuncture (EA) produced a protective effect on cerebral ischemia-reperfusion injury (CIRI) in rats and may correlate with the anti-inflammatory effects of microglia. This study aimed to investigate further whether EA could modulate neuroinflammation by targeting the Signal Transducer and Activator of Transcription 6 (STAT6) and Peroxisome Proliferator-Activated Receptor γ (PPARγ) pathway, the key regulator of microglia. Middle cerebral artery occlusion (MCAO) rats were used, and 6h after reperfusion, EA interventions were performed in Chize (LU 5), Hegu (LI 4), Sanyinjiao (SP 6), and Zusanli (ST 36) on the affected side of the rats, the group that received EA+STAT6 phosphorylation inhibitor AS1517499 was used as a parallel control. The degree of neurological impairment, infarct volume, microglia polarization, inflammation levels and activity of STAT6/PPARγ pathway were then assessed by neurological deficit score, triphenyl tetrazolium chloride (TTC) staining, immunofluorescence, western blotting (WB), quantitative real-time PCR (qPCR) and Enzyme linked immunosorbent assay (ELISA). The data showed that EA significantly alleviated nerve injury, reduced infarct volume, enhanced the expression and activity of STAT6/PPARγ pathway, inhibited NF-κB activity, increased M2 microglia numbers and anti-inflammatory factor release, and inhibited microglia M1-type polarization and pro-inflammatory factor expression. In contrast, inhibition of STAT6 phosphorylation exacerbated neural damage, inhibited STAT6/PPARγ pathway activity, promoted microglia M1-type polarization and exacerbated neuroinflammation, resulting in an attenuated positive effect of EA intervention. Therefore, we concluded that EA intervention could attenuate microglia-associated neuroinflammation by enhancing the expression and activity of STAT6/PPARγ pathway, thereby reducing CIRI in MCAO rats.

Alcohol spiked with zolpidem and midazolam potentiates inflammation, oxidative stress and organ damage in a mouse model.

Crime-related spiking of alcoholic drinks with prescription drugs is quite common and has been happening for centuries. This study, therefore, evaluated the effects of oral administration of alcohol spiked with the zolpidem and midazolam potent sedatives on inflammation, oxidative stress and various organ damage in male Swiss albino mice. Mice were randomly assigned into six treatment groups; the first group constituted the normal control, the second group received 50mg/kg body weight of zolpidem only, the third group received 50mg/kg body weight zolpidem dissolved in 5g/kg alcohol, the fourth group received 50mg/kg midazolam only, the fifth group received midazolam (50mg/kg) dissolved in 5g/kg alcohol and the sixth group received 5g/kg alcohol. Alcohol-induced significant reduction in neurological function and altered blood hematological indicators. Such neurological impairment and negative effects on blood were exacerbated in mice administered with spiked alcohol. Additionally, midazolam and zolpidem enhanced alcohol-driven elevation of liver function markers; the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) gamma glutamyltransferase (GGT), total bilirubin and alkaline phosphatase. Exposure to alcohol and/or spiked alcohol led to significant augmentation of nitric oxide and malonaldehyde, with concomitant depletion of liver glutathione (GSH) levels. Similarly, serum levels of pro-inflammatory cytokines tumor necrosis factor alpha and interferon-gamma were increased by co-exposure with midazolam or zolpidem. Alcohol-induced hepatotoxicity and nephrotoxicity were amplified by exposure to alcohol spiked with midazolam/zolpidem. Exposure to alcohol spiked with midazolam or zolpidem appears to exacerbate neurological deficits, inflammation, oxidative stress, and organ damage.

The Neuroprotective Effects and Probable Mechanisms of Everolimus in a Rat Model of Intracerebral Hemorrhage.

Mammalian target of rapamycin (mTOR) is a central regulator of cellular growth and homeostasis. Changes in mTOR activity are often observed in many neurological diseases, such as stroke. Intracerebral hemorrhage (ICH) is associated with high mortality and morbidity. However, there are currently no treatments that have been shown to enhance outcomes following ICH, so new treatments are urgently required. In this study, a selective mTOR inhibitor, everolimus, was applied to investigate the outcome after ICH and the possible underlying mechanism. The ICH model was established by autologous blood injection. Everolimus (50 and 100µg/kg) was administered intraperitoneally for 14 consecutive days' post-operation. The neurological functions were examined at 3, 7, and 14days' post-ICH. Samples of brain tissue were collected to perform histopathological and immunohistochemical (NF-k-positive cell) examinations. Besides, the striatum was used to evaluate parameters related to oxidative stress (superoxide dismutase (SOD) activity, malondialdehyde (MDA), and total thiol levels) and inflammation markers (TNF-α and NO). Everolimus ameliorated ICH-induced neurological deficits. In addition, treatment with everolimus reduced infarct volume and NF-k-β positive cells as compared to the ICH group. Furthermore, everolimus significantly increased total thiol content and SOD activity while significantly reducing MDA, NO, and TNF- levels as compared to the ICH group. Collectively, our investigation showed that everolimus improves ICH outcome and modulates oxidative stress and inflammation after ICH. Treatment with rapamycin reduced neurological deficient, oxidative stress, and inflammation in a rat model of intracerebral hemorrhage.

MiR-122-5p Promotes Peripheral and Central Nervous System Inflammation in a Mouse Model of Intracerebral Hemorrhage via Disruption of the MLLT1/PI3K/AKT Signaling.

Intracerebral hemorrhage (ICH) is a recognized central nervous system inflammation complication. Several microRNAs (miRNAs or miRs) have been documented to be vital modulators in peripheral and central nervous system inflammation. Based on whole transcriptome sequencing and bioinformatics analysis, this study aims to reveal the possible molecular mechanisms by which miR-122-5p affects the inflammatory response in the peripheral and central nervous system in a mouse model of ICH. Differentially expressed ICH-related miRNAs were screened. Adeno-associated viral vectors were used to knock down miR-122-5p in mice to evaluate the effect of miR-122-5p on peripheral and central nervous system inflammation. The downstream target gene of miR-122-5p was analyzed. Neurons were isolated from mice and treated with hemin to construct an in vitro model of ICH, followed by transduction with miR-122-5p mimic or combined with oe-MLLT1. The neurons were then co-cultured with microglia BV2 to assess their activation. It was found that miR-122-5p was highly expressed in ICH, and MLLT1 was lowly expressed. In vivo experiments showed that miR-122-5p knockdown decreased neurological deficits, BBB permeability, and inflammation in the peripheral and central nervous system in ICH mice. It involved its binding to MLLT1 and downregulation of the activity of the PI3K/AKT pathway. In vitro data exhibited that miR-122-5p stimulated the generation of inflammatory factors and microglia activation by targeting MLLT1 and inhibiting the PI3K/AKT pathway. Collectively, our work reveals a novel miR-122-5p/MLLT1-mediated regulatory network in ICH that may be a viable target for neuroinflammation alleviation.