Neuronal Apoptosis Research Articles

Neuroprotective Effect of Rosuvastatin Calcium Combined with Hyperbaric Oxygen Mediated p38MAPK Pathway in Rats with Leukoaraiosis.

This study explored the neuroprotective mechanism of rosuvastatin calcium (RSC) combined with hyperbaric oxygen (HBO) in rats with leukoaraiosis (LA), and its impact on the p38MAPK signaling pathway (SPW). Clean-grade male SD rats were used as subjects, which were assigned into Sham group (SG), LA group (LAG), RSC group (RSCG), HBO group (HBOG), and RSC + HBO group (combination group, CG), 20 rats in each. At 14 d post-modeling, the effects of RSC, HBO, and RSC + HBO treatment on the cognitive function, brain neuronal cell apoptosis, brain tissue matrix metalloproteinases (MMPs) family gene expression, and the status of the p38MAPK SPW in LA rats were analyzed. As against the LAG, the escape latency (EL) was shortened, the count of platform crossings was augmented, the number of brain neuronal cell apoptosis decreased, the relative expression (RE) of brain TIMP-1, MMP-2, MMP-3, and MMP-9 mRNA were reduced (P < 0.05), and the RE of brain cleaved caspase (Cas)-3 and p-p38MAPK proteins were reduced in the RSCG, HBOG, and CG (P < 0.05); As against the RSCG and HBOG, the CG showed more visible improvements in all indicators (P < 0.05). The combination of RSC and HBO can inhibit brain neuronal cell apoptosis and the expression of the MMPs family genes in rats with LA by suppressing the overactivation of the p38MAPK SPW, which is beneficial for the recovery of the rats' cognitive function.

Dexmedetomidine alleviates sevoflurane-induced neurotoxicity during late pregnancy by modulating apoptotic pathways and BDNF receptor expression.

To investigate the associations between the neurotoxicity of sevoflurane and the neuroprotection provided by dexmedetomidine, we measured apoptotic gene and protein expression, brain-derived neurotrophic factor (BDNF) levels, and receptor expression, and neuronal apoptosis. Pregnant rats were treated with dexmedetomidine, 2.5% sevoflurane for 6h, or a combination of 2.5% sevoflurane for 6h with dexmedetomidine on gestational day 18 (G18). The apoptotic genes and proteins expression, BDNF and receptor expression, and neuronal apoptosis were assessed in offspring hippocampi on postnatal day 1 (P1) and P41. Dendritic spine density, synaptophysin protein fluorescence staining, and cognitive function were evaluated on P41. Maternal sevoflurane exposure increased Bax mRNA and protein expression, decreased Bcl-2 mRNA and protein expression, enhanced neuronal apoptosis, decreased the ratio of mature BDNF (mBDNF) to proBDNF, reduced mBDNF and tropomyosin receptor kinase B (TrkB) protein expression, and increased p75 neurotrophin receptor (p75NTR) protein expression in the hippocampi of neonatal rats. In juvenile rats, maternal sevoflurane exposure reduced mBDNF and TrkB protein expression, dendritic spine density, the proportion of time spent in the target quadrant, and the number of crossings over the platform while increasing escape latency in the Morris water maze. All abnormalities induced by maternal sevoflurane exposure, except for mBDNF levels on P41, were alleviated by dexmedetomidine. Dexmedetomidine mitigates sevoflurane-induced neuronal development abnormalities and cognitive impairments during late pregnancy by improving hippocampal Bcl-2 and Bax mRNA and protein expression, as well as proBDNF-p75NTR and mBDNF-TrkB protein expression in offspring.

Glabridin as a selective Kv2.1 inhibitor ameliorates DPN pathology by disrupting the Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau pathway.

Diabetic peripheral neuropathy (DPN) is a common diabetic complication. DPN has a complicated pathogenesis, and the currently clinical drugs against this disease show only limited efficacy and undesirable side effects. Thus, it is of great challenges to discover effective targets and drugs against DPN. Glabridin (GLA) is a natural prenylated isoflavone from the roots of Glycyrrhiza glabra. It exhibits a wide range of pharmacological activities including anti-inflammatory, antioxidant, cardiovascular protective, neuroprotective, hepatoprotective, anti-obesity and anti-diabetic effects, etc. In this study we investigated the beneficial effects of GLA on late-stage DPN and the underlying mechanisms. Using electrophysiological recording from CHO-Kv2.1 cells, we identified GLA as a new Kv2.1-selective inhibitor with an IC50 value of 2.07 μM. We showed that oral administration of GLA (30, 60 mg·kg-1·d-1) for 4 weeks significantly improved all neurological dysfunctions and peripheral vascular dysfunctions in DPN mice. Furthermore, we demonstrated that GLA administration improved intraepidermal nerve fiber (IENF) density damage and myelin sheath injury, promoted neurite outgrowth of DRG neurons and alleviated the apoptosis of DRG neurons in DPN mice. All these beneficial effects of GLA were deprived in Kv2.1-knockdown DPN mice specifically in the DRG and sciatic nerve tissues by injection of adeno associated virus AAV8-Kv2.1-RNAi (AAV8-Kv2.1). We showed that the levels of Aβ and hyperphosphorylated tau proteins (p-Tau) were pathologically increased in serum of DPN patients. We demonstrated that Kv2.1 channels bridged Aβ to activate NLRP3 inflammasome in Schwann cells and promote p-Tau production in DRG neurons through Schwann cells/DRG neurons crosstalk. GLA interrupted Aβ/Kv2.1/NLRP3/p-Tau axis to ameliorate the DPN-like pathology in mice. Our results support that Kv2.1 inhibition is a therapeutic strategy for DPN and highlight the potential of GLA in treating this disease.

Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ1-42-induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease.

BackgroundAlzheimer's disease (AD) is a chronic brain degenerative disease that leads to dementia.ObjectiveThe aim of the present study is to investigate the neuroprotective impact of sodium-glucose cotransporter-2 inhibitors (SGLT2i) (empagliflozin and dapagliflozin) on tau phosphorylation, oxidative stress, and neuroinflammation.MethodsWe used MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, annexin-V-FITC kit, and DCFH-DA (dichloro-dihydro-fluorescein diacetate) to respectively evaluate the effect of the SGLT2i (empagliflozin and dapagliflozin) on amyloid-β (Aβ)1-42-induced neuronal death, apoptosis, and oxidative stress. The expression of NLRP3-inflammasome, phospho-Tau181, glycogen synthase kinase-3 beta (GSK-3β), cyclin-dependent kinase 5 (CdK5), and histone deacetylase 6 (HDAC6), was quantified by flow cytometry. Drug distribution in the mice's brains was assessed by liquid chromatography-mass spectrometry (LC-MS).ResultsAβ1-42 significantly reduced cell viability and increased apoptosis, which was reversed by using gliflozins. SGLT2i significantly reduced Aβ1-42-induced reactive oxygen species generation, downregulated NLRP3-inflammasome, and diminished tau pathology. Mechanistically, the last effect involved the modulation of GSK-3β and CdK5 protein expression. However, the tested treatments did not modify the Aβ1-42-stimulating effect of HDAC6. Gliflozins are substrates of drug transporters ATP-binding cassette sub-family B member 1 and/or ATP binding cassette subfamily G member 2 (ABCB1 and ABCG2), and Elacridar significantly enhances their brain distribution.ConclusionsSGLT2i empagliflozin and dapagliflozin exhibited neuroprotective actions against human Aβ1-42-induced neurotoxicity.

Disruption of Oligodendroglial Autophagy Leads to Myelin Morphological Deficits, Neuronal Apoptosis, and Cognitive Decline in Aged Mice.

The aging central nervous system (CNS) is often marked by myelin degeneration, yet the underlying mechanisms remain elusive. This study delves into the previously unexplored role of autophagy in maintaining CNS myelin during aging. We generated the transgenic mouse line plpCreERT2; atg5f/f, enabling selective deletion of the core autophagic component Atg5 in oligodendrocytes (OLs) following tamoxifen administration in adulthood, while analysis was conducted on aged mice. Our findings reveal that oligodendroglial autophagy inactivation leads to significant alterations in myelin protein levels. Moreover, the ultrastructural analysis revealed pronounced myelin deficits and increased degeneration of axons, accompanied by apoptosis, as confirmed by immunohistochemistry. Behaviorally, aged knockout (cKO) mice exhibited marked deficits in learning and memory tasks, indicative of cognitive impairment. Additionally, we observed increased activation of microglia, suggesting an inflammatory response linked to the absence of autophagic activity in OLs. These results underscore the critical role of autophagy in OLs for the preservation of CNS myelin and axonal integrity during aging. Our study highlights autophagy as a vital mechanism for neural maintenance, offering potential therapeutic avenues for combating age-related neurodegenerative diseases.

Ceftaroline + Rifampin Versus Vancomycin + Rifampin in the Treatment of Methicillin-Resistant Staphylococcus aureus Meningitis in an Experimental Rabbit Model.

Background/Aim: To compare the effectiveness ceftaroline-rifampicin (CR) and vancomycin-rifampicin (VR), against methicillin-resistant Staphylococcus aureus (MRSA) in a rabbit meningitis model, to compare the effects on brain tissues in terms of inflammation and apoptosis and to test the antibiotics via in vitro time-kill and synergy tests. Method: Meningitis was induced using MRSA strain ATCC 43300. After 28 hours, the rabbits were split into three groups: control, VR, and CR. A CSF culture was taken at the start (T0) and end of treatment (EOT)-the 24th hour of treatment. At EOT, the animals' brain tissues were examined for inflammation and apoptosis. The study strain was tested for a 24-hour time kill assay. Results: At the EOT, statistically significant differences were observed between the treatment groups in terms of reducing the cerebrospinal fluid (CSF) bacterial count, achieving partial or complete treatment response, and exhibiting lower levels of neuronal apoptosis compared with the control group. However, there was no significant difference in all three parameters and in survival between the two treatment groups. The CR group exhibited a noticeable decrease in inflammation than the control group, but no significant difference was found between the control group versus VR and VR versus CR group. Rifampicin did not improve antibacterial efficacy in the in vitro time-kill assay. Conclusion: The CR arm showed better complete response and inflammation, but both treatments were similar in other parameters. CR combination was found as effective as VR combination for treating MRSA meningitis.

PI3K/AKT Pathway: A Potential Therapeutic Target in Cerebral Ischemia-Reperfusion Injury.

PI3K/AKT Pathway: A Potential Therapeutic Target in Cerebral Ischemia-Reperfusion Injury.

Correlation Between Neuronal Apoptosis Inhibitory Protein (NAIP), SMN2, and SMA Phenotypes: A Tertiary Care Centre Experience From India.

SMN2 copy number fails to answer variability in the SMA phenotype completely. We aimed to evaluate the copy number variation in NAIP and SMN2: c.859G>C and A-44G variants as disease modifiers and their correlation with the SMA phenotype. Based on the motor milestones achieved, patients with homozygous deletion of SMN1 exon 7 were classified into SMA Types I-IV. The copy numbers of SMN1 exon 8, SMN2, and NAIP were determined using the MLPA assay. Sanger sequencing was performed for the SMN2 variants. The cohort of 142 patients included nearly equal numbers of patients of SMA Types I, II, and III. The disease severity correlated with the SMN2 and NAIP copy number, with a lower copy number predicting a worse outcome. In addition, we evaluated the SMA genotype (SMN1 exon 8, SMN2 copy number, and NAIP copy number) as a predictor of SMA severity and found that most of the SMA Type I patients had a genotype of 0-2-0, SMA Type II patients had a genotype of 0-3-1, Type III patients had a genotype of 0-3-2 and 0-3-1, and Type IV patients had a genotype of 0-4-2. None of the patients from the cohort had the two modifier variants. The combined genotype of SMN1 exon 8 copy number-SMN2 copy number-NAIP copy number could accurately predict the SMA phenotype. The absence of SMN2: c.859G>C and A-44G variants in any of our patients points to the rarity of these variants in the Indian population.

Exosomes derived from olfactory mucosa mesenchymal stem cells attenuate cognitive impairment in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, and endoplasmic reticulum (ER) stress. In recent years, exosomes have garnered significant attention as a potential therapeutic tool for neurodegenerative diseases. This study, for the first time, investigates the neuroprotective effects of exosomes derived from olfactory mucosa mesenchymal stem cells (OM-MSCs-Exos) in AD and further explore the potential role of low-density lipoprotein receptor-related protein 1 (LRP1) in this process. Using an Aβ1-42-induced AD mouse model, we observed that OM-MSCs-Exos significantly improved cognitive function in behavioral tests, reduced neuroinflammatory responses, alleviated ER stress, and decreased neuronal apoptosis. Further analysis revealed that OM-MSCs-Exos exert neuroprotective effects by modulating the activation of microglia and astrocytes and influencing the ER stress response, a process that may involve LRP1. Although these findings support the potential neuroprotective effects of OM-MSCs-Exos, further studies are required to explore their long-term stability, dose dependency, and immunogenicity to assess their feasibility for clinical applications.

METTL3/IGF2BP2/IκBα axis participates in neuroinflammation in Alzheimer's disease by regulating M1/M2 polarization of microglia.

METTL3/IGF2BP2/IκBα axis participates in neuroinflammation in Alzheimer's disease by regulating M1/M2 polarization of microglia.

MALAT1 promotes microglia activation and neuronal apoptosis through via the miR-124-3p/ SGK1 axis mediating experimental autoimmune encephalomyelitis disease progression in mice.

MALAT1 promotes microglia activation and neuronal apoptosis through via the miR-124-3p/ SGK1 axis mediating experimental autoimmune encephalomyelitis disease progression in mice.

Genetic deletion of G protein-coupled receptor 56 aggravates traumatic brain injury through the microglial CCL3/4/5 upregulation targeted to CCR5

Traumatic brain injury (TBI) is a significant global health concern that often results in death or disability, and effective pharmacological treatments are lacking. G protein-coupled receptor 56 (GPR56), a potential drug target, is crucial for neuronal and glial cell function and therefore plays important roles in various neurological diseases. Here, we investigated the potential role and mechanism of GPR56 in TBI-related damage to gain new insights into the pharmacological treatment of TBI. Our study revealed that TBI caused a significant decrease in GPR56 expression and that the deletion of Gpr56 exacerbated neurological function deficits and blood‒brain barrier (BBB) damage following TBI. Additionally, Gpr56 deletion led to increased microgliosis, increased infiltration of peripheral T cells and macrophages, and increased release of cerebral inflammatory cytokines and chemokines after TBI. Furthermore, Gpr56 deletion induced neuronal apoptosis, impaired autophagy, and exacerbated neurological function deficits through microglial-to-neuronal CCR5 signaling after TBI. Overall, these results indicate that Gpr56 knockout exacerbates neurological deficits, neuroinflammation and neuronal apoptosis following TBI through microglial CCL3/4/5 upregulation targeted to CCR5, which indicates that GRP56 may be a potential new pharmacological target for TBI.

Interplay between PI3k/AKT signaling and caspase pathway in Alzheimer disease: mechanism and therapeutic implications.

Alzheimer's disease, a neurodegenerative disorder, is characterized by cognitive impairment, neuronal loss, and synaptic dysfunction. The interplay between the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and the caspase-mediated apoptotic cascade plays a pivotal role in its progression. The signaling pathway responsible for neuronal survival also regulates synaptic plasticity and resistance to oxidative stress, whereas caspase activation accelerates neurodegeneration by triggering cell death and inflammation. Dysregulation of these pathways leads to amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, and mitochondrial dysfunction, creating a negative feedback loop and accelerating disease progression. Emerging treatment methods that target PI3K/AKT activation and caspase inhibition have showed promise in preclinical models, preventing neuronal apoptosis while retaining cognitive function. This review investigates the molecular processes driving PI3K/AKT and caspase crosstalk, their significance in Alzheimer's disease, and prospective therapeutic strategies aiming at regulating these pathways to improve disease outcomes.

Neurotoxic Effects of Atrazine on Dopaminergic System via miRNAs and Energy-Sensing Pathways.

Atrazine (ATR, 2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine) is a globally prevalent herbicide known to induce dopaminergic neurotoxicity at high concentrations. MicroRNAs (miRNAs), pivotal in regulating gene expression post-transcriptionally, play essential roles in neuronal differentiation, proliferation, and apoptosis. This study investigates the effects of ATR on the dopaminergic system and behavioral responses in rats, with a particular focus on critical dopaminergic proteins such as tyrosine hydroxylase (TH), nuclear receptor related-1 protein (NURR1), and α-synuclein. The results reveal that ATR exposure significantly reduces the expression of TH and NURR1, while elevating levels of α-synuclein. Through miRNA sequencing and proteomic analysis, we identify alterations in miRNA and protein profiles that are intricately linked to the development of the dopaminergic system. Notably, treatment with ATR results in a marked increase in AMPK levels concurrent with a decrease in miR-322-5p. The differentially expressed genes associated with ATR exposure primarily influence the dopaminergic system by engaging in critical pathways such as AMPK, mTOR, autophagy, FoxO, and HIPPO. This study underscores the neurotoxic impact of ATR on the dopaminergic system via miRNA regulatory mechanisms and energy-sensing pathways, including AMPK and SIRT1, providing a molecular foundation for developing strategies to prevent and treat neurotoxicity induced by ATR exposure.

TREM2 Modulates Postoperative Cognitive Function in Aged Mice by Inhibiting the NLRP3/caspase-1 Pathway and Apoptosis via PLCγ2 Activation.

Postoperative cognitive dysfunction (POCD) is a prevalent complication in elderly patients, with neuroinflammation identified as a key contributing factor. This study investigates the therapeutic potential of the TREM2-PLCγ2 signaling pathway in mitigating neuroinflammation, neuronal apoptosis and cognitive impairment following surgery. We employed both in vivo and in vitro models to investigate the effects of TREM2 activation and its interaction with PLCγ2. Mice subjected to surgery were pre-treated with the TREM2-activating peptide COG1410, and subsequently evaluated for neuroinflammation, neuronal apoptosis, and cognitive function. In vitro studies using microglial cells were conducted to examine the mechanistic relationship between TREM2 and PLCγ2 phosphorylation via SYK. Knockdown experiments and SYK inhibition were performed to determine the hierarchical interaction between TREM2, PLCγ2, and their downstream influence on the NLRP3 inflammasome. Surgery significantly elevated the activation of the NLRP3 inflammasome, along with increased Cleaved Caspase-1, IL-1β, IL-18, and neuronal apoptosis markers. Pre-treatment with COG1410 effectively reduced these pro-inflammatory and pro-apoptotic markers, while alleviating cognitive impairment. TREM2 activation promoted SYK-dependent phosphorylation of PLCγ2, which inhibited NLRP3 inflammasome activation and reduced neuroinflammation. TREM2 knockdown exacerbated microglial inflammation, while PLCγ2 knockdown suppressed NLRP3 activation. Inhibition of SYK impaired the protective effects of the TREM2-PLCγ2 pathway and delayed cognitive recovery in mice. RNA-sequencing further revealed significant alterations in pathways related to neuroinflammation and apoptosis. TREM2 modulates PLCγ2 activity through SYK phosphorylation, thereby alleviating microglial-driven neuroinflammation and neuronal apoptosis, and improving cognitive impairment following surgery. Targeting the TREM2-PLCγ2 pathway presents a promising strategy for the prevention and treatment of POCD.

Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures across the Alzheimer disease continuum.

Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures across the Alzheimer disease continuum.

Establishment and application of a wild neonatal mouse model infected with an Echovirus 30 isolate

BackgroundEchovirus 30 (E30) is a significant pathogen associated with various illnesses such as viral meningitis, viral myocarditis. Currently, there are no specific drugs or vaccines targeting this virus. An appropriate animal model is imperative for assessing drug and vaccine efficacy.MethodsThis investigation aimed to establish a neonatal mouse model using a clinical isolate E30/A538 and apply it to screen anti-E30 drugs. The study involved evaluating the susceptibility of different mouse strains to the isolate, determining the infectious dose, transmission route, and optimal age of the mice. This model was then used to assess antiviral efficacy.ResultsNeonatal ICR mice infected intracranially with 5LD50 of E30/A538 at one-day-old displayed clinical symptoms such as tremors, lethargy, limb paralysis, and mortality. Importantly, the E30/A538-infected mice exhibited brain neuron apoptosis and severe myocardial necrolysis, closely resembling human infections. Elevated levels of viral RNA and positive antigen presence were predominantly detected in the brains and hearts of infected mice. Using this model to assess antiviral efficacy, it was demonstrated that interferon-α2a inhibited E30/A538 replication in vivo, mitigated histopathological changes in the brain, spinal cord, and myocardium, and enhanced the survival rate of neonatal mice.ConclusionsIn summary, this research established a wild neonatal mouse model of E30/A538 isolate infection that mirrors the characteristics of human infection. The model demonstrated the efficacy of interferon-α2a in combating E30. This model would serve as a foundation for investigating the pathogenesis of E30, as well as for assessing the efficacy of vaccines and other antiviral treatments against E30.

10% carbon dioxide improves cognitive function after subarachnoid hemorrhage in rats: inhibiting neuronal apoptosis through the PI3K/AKT signaling pathway.

Many patients experience long-term cognitive dysfunction after subarachnoid hemorrhage (SAH), and effective treatments are currently lacking. Carbon dioxide (CO2), an inexpensive and easily produced gas, forms carbonic acid when dissolved in water. Studies have suggested that hypercapnia may have neuroprotective effects. However, the optimal concentration of CO2 for therapeutic inhalation is still unclear. This study aimed to investigate the effects of various CO2 concentrations on cognitive function in SAH rats and to explore the potential molecular mechanisms involved. In this study, we established a rat model of SAH by endovascular perforation of the internal carotid artery. The rat models inhaled CO2 at concentrations of 10%, 20%, or 30%, for 1 hour after modeling. The results showed that inhalation of 10% CO2 improved cortical blood flow following SAH, while higher concentrations of CO2 (20% and 30%) worsened cortical hypoperfusion. The partial pressure of CO2 did not change 1 hour after SAH, but it significantly increased with the inhalation of 10% CO2. Additionally, 10% CO2 effectively inhibited neuronal apoptosis, enhanced locomotor activity, and improved memory and learning abilities in SAH rats. Moreover, 10% CO2 upregulated the phosphorylation of phosphatidylinositol 3 kinase) and protein kinase B, increased the expression of Bcl-2, and decreased the expression of Bax. In conclusion, inhaling 10% CO2 restores cerebral perfusion, inhibits neuronal apoptosis, and improves cognitive function in SAH rats. In contrast, higher concentrations of CO2 led to worsened hypoperfusion. The neuroprotective effect of 10% CO2 may occur through the activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.

Role of γ-Aminobutyric Acid (GABA) as an Inhibitory Neurotransmitter in Diabetes Management: Mechanisms and Therapeutic Implications

GABA (γ-Aminobutyric Acid), a well-established inhibitory neurotransmitter in the central nervous system, has garnered considerable interest for its potential role in diabetes management, particularly due to its presence in pancreatic islets. This review aims to explore the therapeutic role of GABA in diabetes management and its potential mechanisms for antidiabetic effects. Relevant studies were searched across databases such as PubMed and ScienceDirect, applying strict eligibility criteria focused on GABA administration methods and diabetic models. The collective results showed that the administration of GABA in diabetic models resulted in remarkable enhancements in glucose and insulin homeostasis, favorable modifications in lipid profiles, and amelioration of dysfunctions across neural, hepatic, renal, and cardiac systems. The findings from the literature demonstrated that GABAergic signaling within pancreatic tissues can significantly contribute to the stimulation of β cell proliferation through the facilitation of a sustained trans-differentiation process, wherein glucagon-secreting α cells are converted into insulin-secreting β-like cells. In addition, activated GABAergic signaling can trigger the initiation of the PI3K/AKT signaling pathway within pancreatic tissues, leading to improved insulin signaling and maintained glucose homeostasis. GABAergic signaling can further function within hepatic tissues, promoting inhibitory effects on the expression of genes related to gluconeogenesis and lipogenesis. Moreover, GABA may enhance gut microbiota diversity by attenuating gut inflammation, attributable to its anti-inflammatory and immunomodulatory properties. Furthermore, the neuroprotective effects of GABA play a significant role in ameliorating neural disorders associated with diabetes by facilitating a substantial reduction in neuronal apoptosis. In conclusion, GABA emerges as a promising candidate for an antidiabetic agent; however, further research is highly encouraged to develop a rigorously designed framework that comprehensively identifies and optimizes the appropriate dosages and intervention methods for effectively managing and combating diabetes.

The immunomodulatory effects of GLP-1 receptor agonists in neurogenerative diseases and ischemic stroke treatment

Glucagon-like peptide-1 (GLP-1) receptor is widely distributed in the digestive system, cardiovascular system, adipose tissue and central nervous system. Numerous GLP-1 receptor-targeting drugs have been investigated in clinical studies for various indications, including type 2 diabetes and obesity (accounts for 70% of the total studies), non-alcoholic steatohepatitis, Alzheimer's disease, and Parkinson's disease. This review presented fundamental information regarding two categories of GLP-1 receptor agonists (GLP-1RAs): peptide-based and small molecule compounds, and elaborated their potential neuroprotective effects by inhibiting neuroinflammation, reducing neuronal apoptosis, and ultimately improving cognitive function in various neurodegenerative diseases. As a new hypoglycemic drug, GLP-1RA has a unique role in reducing the concurrent risk of stroke in T2D patients. Given the infiltration of various peripheral immune cells into brain tissue, particularly in the areas surrounding the infarct lesion, we further investigated the potential immune regulatory mechanisms. GLP-1RA could not only facilitate the M2 polarization of microglia through both direct and indirect pathways, but also modulate the quantity and function of T cell subtypes, including CD4, CD8, and regulatory T cells, resulting into the inhibition of inflammatory responses and the promotion of neuronal regeneration through interleukin-10 secretion. Therefore, we believe that the "Tregs-microglia-neuron/neural precursor cells" axis is instrumental in mediating immune suppression and neuroprotection in the context of ischemic stroke. Given the benefits of rapid diffusion, favorable blood-brain barrier permeability and versatile administration routes, these small molecule compounds will be one of the important candidates of GLP-1RA. We look forward to the further clinical evidence of small molecule GLP-1RA intervention in ischemic stroke or T2D complicated by ischemic stroke.