The dysregulation of blood-brain barrier (BBB) activates pathological mechanisms such as neuroinflammation after traumatic brain injury (TBI), and glymphatic system dysfunction accelerates toxic waste accumulation after TBI. It is essential to find an effective way to inhibit inflammation and repair BBB and glymphatic system after TBI; however, effective and lasting drug therapy remains challenging because BBB severely prevents drugs from being delivered to central nervous system. Transferrin receptors (TfRs) are mainly expressed on brain capillary endothelial cells. Here, we report a TfR-targeted nanomedicine for TBI treatment by penetrating BBB and delivering fluvoxamine (Flv). The TfR-targeted polypeptide liposome loaded with Flv (TPL-Flv) implements cell targeting ability on human umbilical vein endothelial cells (HUVECs) in vitro detected by flow cytometry, and drug safety was proved through cell viability analysis and blood routine and biochemistry analysis. Afterwards, we established a controlled cortical impact model to explore TPL-Flv administration effects on TBI mice. We confirmed that TPL-Flv could stimulate CXCR4/SDF-1 signaling pathway, activate Treg cells, and inhibit inflammation after TBI. TPL-Flv treatment also alleviated BBB disruption and restored aquaporin-4 (AQP4) polarization, as well as reversed glymphatic dysfunction. Furthermore, TPL-Flv accomplished remarkable improvement of motor and cognitive functions. These findings demonstrate that TPL-Flv can effectively cross BBB and achieve drug delivery to cerebral tissue, validating its potential to improve therapeutic outcomes for TBI.

Stroke is the second leading cause of death from cardiovascular diseases. Brain microvascular endothelial cells (BMECs) are crucial in the treatment of cerebral ischemic stroke, as their functional status directly affects the integrity of the blood-brain barrier (BBB). This review systematically discusses the central role of BMECs in ischemia. The mitochondrial dysfunction and activation of apoptosis/necrosis pathways in BMECs directly disrupt the integrity of the BBB and the degradation of junctional complexes (such as TJs and AJs) further exacerbates its permeability. In the neurovascular unit (NVU), astrocytes, microglia, and pericytes regulate the function of BMECs by secreting cytokines (such as TGF-β and VEGF), showing dual effects of promoting repair and damage. The dynamic changes of transporters, including those from the ATP-binding cassette and solute carrier families, as well as ion channels and exchangers, such as potassium and calcium channels, offer novel insights for the development of targeted drug delivery systems.

Peripheral surgery evokes neuroimmune activation in the central nervous system and modulates immune cell polarization in the ischemic brain. However, the phenotypic change of microglia and myeloid cells within post-surgical ischemic brain tissue remain poorly defined. Using an integrated approach that combines single-cell RNA sequencing with comprehensive biological analysis in a perioperative ischemic stroke (PIS) model, we identified a distinct Spp1-positive macrophage/microglia (Spp1+ Mac/MG) subgroup that exhibit enriched anti-inflammatory pathways with distinct lipid metabolic reprogrammed profile. Moreover, using immunofluorescence staining, we identified the expression of Glucagon-like peptide-1 receptor (GLP1R) in Spp1+F4/80+ cells and Spp1+Iba-1+ cells. Intraperitoneal administration of semaglutide, a GLP1R agonist clinically approved for the treatment of type 2 diabetes mellitus, resulted in a significant reduction of cerebral infarct volume in PIS mice compared to that in ischemic stroke (IS) mice. Meanwhile, semaglutide treatment also increased the proportion of Spp1+Edu+Iba-1+ cells 3 days after PIS. Using high-parameter flow cytometry, immunofluorescence staining and RNA sequencing, we demonstrated that semaglutide treatment significantly attenuated the expression of neuroinflammatory markers in mice following PIS. We also found that semaglutide treatment significantly ameliorated sensorimotor dysfunction up to 3 days after PIS in mice. Our current finding reveal a novel protective Spp1+Mac/MG subset after PIS and demonstrated that it can be upregulated by semaglutide. We propose that targeting Spp1+Mac/MG subsets using semaglutide could serve as a promising strategy to attenuate the exacerbated neuroinflammation in PIS.

Astrocytes play a pivotal role in the inflammatory response triggered by traumatic brain injury (TBI). They are not only involved in the initial inflammatory response following injury but also significantly contribute to Astrocyte activation and inflammasome release are key processes in the pathophysiology of TBI, significantly affecting the progression of secondary injury and long-term outcomes. This comprehensive review explores the complex triggering mechanisms of astrocyte activation following TBI, the intricate pathways controlling the release of inflammasomes from activated astrocytes, and the subsequent neuroinflammatory cascade and its multifaceted roles after injury. The exploration of these processes not only deepens our understanding of the neuroinflammatory cascade but also highlights the potential of astrocytes as critical therapeutic targets for TBI interventions. We then evaluate cutting-edge research aimed at targeted therapeutic approaches to modulate pro-inflammatory astrocytes and discuss emerging pharmacological interventions and their efficacy in preclinical models. Given that there has yet to be a relevant review elucidating the specific intracellular mechanisms targeting astrocyte release of inflammatory substances, this review aims to provide a nuanced understanding of astrocyte-mediated neuroinflammation in TBI and elucidate promising avenues for therapeutic interventions that could fundamentally change TBI management and improve patient outcomes. The development of secondary brain injury and long-term neurological sequelae. By releasing a variety of cytokines and chemokines, astrocytes regulate neuroinflammation, thereby influencing the survival and function of surrounding cells. In recent years, researchers have concentrated their efforts on elucidating the signaling crosstalk between astrocytes and other cells under various conditions, while exploring potential therapeutic interventions targeting these cells. This paper highlights the specific mechanisms by which astrocytes produce inflammatory mediators during the acute phase post-TBI, including their roles in inflammatory signaling, blood-brain barrier integrity, and neuronal protection. Additionally, we discuss current preclinical and clinical intervention strategies targeting astrocytes and their potential to mitigate neurological damage and enhance recovery following TBI. Finally, we explore the feasibility of pharmacologically assessing astrocyte activity post-TBI as a biomarker for predicting acute-phase neuroinflammatory changes.

Chronic cerebral hypoperfusion (CCH) represents a key pathogenic contributor to neurocognitive disorders. It can lead to multifaceted pathological alterations including neuroinflammation, neuronal apoptosis, blood-brain barrier disruption, synaptic plasticity deficits, and mitochondrial dysfunction. The glucagon-like peptide-1 receptor (GLP-1R), ubiquitously expressed across multiple organ systems, exerts neuroprotective effects by maintaining intracellular homeostasis and mitigating neuronal damage triggered by oxidative stress, inflammatory cascades, apoptotic signaling, and ischemic insults. Furthermore, GLP-1R activity is modulated by gut microbiota composition and short-chain fatty acid abundance, implicating the gut-brain axis in its regulatory influence on neurological function. This review systematically examines the pathophysiological mechanisms underlying CCH and highlights the therapeutic potential of GLP-1R activation. Specifically, GLP-1R-targeted interventions attenuate hypoperfusion-induced damage through pleiotropic pathways and gut-brain crosstalk, thereby offering novel perspectives for advancing both fundamental research and clinical management of neurocognitive disorders.

Ischemic stroke (IS) is the leading cause of worldwide death while the discovery and effective delivery of neuroprotective agents for satisfied IS treatment is still challenging.

In this study, we discover that celery seed (CS) derived reconstituted lipid nanoparticles (CS-rLNPs) can effectively penetrate across blood-brain barrier (BBB) with increased distribution to the brain. Especially, CS-rLNPs show innate neuron-targeting ability to primarily bind to neuron in the cerebral ischemic area, which is not reported by any parallel studies. Moreover, CS-rLNPs are found to exert therapeutic effects on IS, which effectively restore the function of model mice. Further studies reveal that the therapeutic effects are realized through TLR4/MyD88/NF-κB p65 pathway regulated anti-inflammation and anti-apoptosis mechanisms.

Therefore, CS-rLNPs can serve as a neuron-targeted neuroprotective nanomedicine for IS treatment.

Intravenous thrombolysis remains the cornerstone for restoring cerebral reperfusion post-stroke. Despite recombinant tissue plasminogen activator (rtPA) achieving arterial reperfusion within 6 h, persistent microcirculatory blood flow reduction often hampers recovery. Exendin-4, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has demonstrated potential for improving stroke outcomes, though its mechanisms remain partially unclear. This study investigated the role of Exendin-4 in restoring microcirculatory blood flow post-stroke. Using ischemic stroke models in 8-week-old male C57BL/6j mice, induced by transient middle cerebral artery occlusion or bilateral common carotid artery ligation, Exendin-4 (150 μg/kg) was administered intravenously. Infarct size and neurological deficits were evaluated using TTC staining and neurological severity scores. Real-time cerebral blood flow (CBF) and microvascular changes were measured with laser speckle imaging and two-photon microscopy. Mechanistic studies employed immunofluorescence and infrared differential interference contrast microscopy. Our findings demonstrated that Exendin-4 significantly reduced infarct size and improved neurological outcomes, independent of blood glucose levels. Immunofluorescence revealed GLP-1 receptor expression in arteriolar smooth muscle cells, endothelial cells, and pericytes. Exendin-4 enhanced microvascular blood flow via vasodilation, confirmed through real-time imaging. In vitro, Exendin-4 relaxed pre-constricted vessels, an effect that was abolished by eNOS and adenylate cyclase (AC) inhibitors. However, guanylate cyclase (GC) inhibition failed to block Exendin-4-induced vasodilation, suggesting a non-cGMP-dependent NO pathway may be involved. Furthermore, prostaglandin E2 (PGE2) signaling via EP4 receptors was identified as a critical contributor to Exendin-4's vasodilatory effect, highlighting the involvement of multiple signaling pathways. These findings suggest that Exendin-4 preserves cerebral microcirculation through a multifaceted mechanism involving GLP-1R-mediated AC-cAMP signaling, PGE2-EP4 signaling, and a non-cGMP-dependent NO pathway. This study positions GLP-1 receptor agonists as promising therapeutic candidates for enhancing cerebral microcirculation and improving outcomes following stroke.

Sensitive and accurate methods for early detection of acute ischemic stroke (AIS) are essential for timely treatment and prognostic assessment of patients. In this study, we report a microfluidics-based ultrasensitive surface-enhanced Raman scattering (SERS) immunoassay device for the quantitative determination of multiplex biomarkers in AIS. By preparing 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) antibody-modified gold nanoparticles (AuNPs) on SERS devices as SERS probes, the biomarkers in whole blood of AIS were accurately captured and further visualized for SERS signal intensity quantitative analysis of six biomarkers in the blood samples. It is worth mentioning that the limit of detection (LOD) of the method can reach the level of fg/mL, with excellent sensitivity and selectivity. Meanwhile, the analytical comparison with ELISA method showed that the detection results of both methods were consistent, which verified the feasibility of the assembled device. The SERS immunoassay device detection provides a powerful strategy for the prediction, early diagnosis and dynamic monitoring of prognosis of AIS with a wide range of clinical practice prospects.

The last two decades have proffered many remarkable choices in managing type 1 and type 2 diabetes mellitus. Leading the list are glucagon-like peptide-1 receptor agonists (GLP1RAs), the first of which, exenatide, was approved by the FDA in 2005. Two other major classes of drugs have also entered the market: dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly known as gliptins and approved in 2006, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, with the first approval occurring in 2013. These drugs have revolutionized the treatment of diabetes. Additionally, on the horizon, the once-weekly basal insulin analog insulin icodec and the once-weekly combination of insulin icodec and semaglutide are expected to be available in the future. Beyond glycemic control, GLP1RAs have exhibited benefits in conditions associated with diabetes, including hypertension, dyslipidemia, non-alcoholic steatohepatitis, as well as in neurodegenerative diseases such as Alzheimer's disease. Additionally, emerging research suggests potential roles in certain types of cancer, infertility, and associative learning. Major cardiovascular events seem to be lower in patients on GLP1RAs. While some evidence is robust, other findings remain tenuous. It is important that clinicians are familiar with current research in order to provide optimal evidence-based care to patients. In the not-too-distant future, there may be a case to prescribe these drugs for benefits outside diabetes.

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.

Ischemic stroke is the most common cerebrovascular disease and the leading cause of permanent disability worldwide. Recent studies have shown that stroke development and prognosis are closely related to abnormal tryptophan metabolism. Here, significant downregulation of 3-hydroxy-kynurenamine (3-HKA) in stroke patients and animal models is identified. Supplementation with 3-HKA improved long-term neurological recovery, reduced infarct volume, and increased ipsilateral cerebral blood flow after distal middle cerebral artery occlusion (MCAO). 3-HKA promoted angiogenesis, functional blood vessel formation, and blood-brain barrier (BBB) repair. Moreover, 3-HKA inhibited A1-like (neurotoxic) astrocyte activation but promoted A2-like (neuroprotective) astrocyte polarization. Proteomic analysis revealed that 3-HKA inhibited AIM2 inflammasome activation after stroke, and co-labeling studies indicated that AIM2 expression typically increased in astrocytes at 7 and 14 days after stroke. Consistently, in co-cultures of primary mouse brain microvascular endothelial cells and astrocytes, 3-HKA promoted angiogenesis after oxygen-glucose deprivation (OGD). AIM2 overexpression in astrocytes abrogated 3-HKA-driven vascular remodeling in vitro and in vivo, suggesting that 3-HKA may regulate astrocyte-mediated vascular remodeling by impeding AIM2 inflammasome activation. In conclusion, 3-HKA may promote post-stroke vascular remodeling by regulating A1/A2 astrocyte activation, thereby improving long-term neurological recovery, suggesting that supplementation with 3-HKA may be an efficient therapy for stroke.

Acute ischemic stroke (AIS) is associated with a high incidence and significant rates of disability, making it a critical focus of clinical research. The current review investigates the role of serum inflammatory markers in the pathogenesis and prognosis of AIS. By quantitatively analyzing specific inflammatory markers, this study aims to enhance the understanding of the pathophysiological mechanisms underlying AIS, support early diagnosis, improve disease assessment, and establish a scientific foundation for targeted treatment strategies to optimize clinical outcomes. From a pathophysiological perspective, multiple inflammatory markers are involved in the inflammatory response that occurs within brain tissue following cerebral ischemia. The serum levels of various inflammatory markers were measured in individuals with AIS, revealing strong correlations between these markers and disease severity. The findings indicate that these markers can serve as reliable indicators of disease progression. Further analysis demonstrated their prognostic value in predicting functional recovery and the risk of recurrence. Notably, during a 3-month follow-up, each 0.32 ng/mL increase in matrix metalloproteinases-9 levels was associated with a 16 % increase in the risk of disability and mortality after AIS. The findings of this review contribute to a more comprehensive understanding of the pathological and physiological mechanisms of AIS and offer a foundation for advancing early diagnostic methods, disease assessment tools, and personalized treatment strategies. Monitoring inflammatory marker levels may enable clinicians to more accurately evaluate disease severity and develop tailored therapeutic interventions, potentially reducing disability and recurrence rates while improving quality of life for individuals with AIS. The findings highlight the potential of precision medicine approaches based on inflammatory markers to shape future AIS treatment paradigms.

JOURNAL/nrgr/04.03/01300535-202502000-00029/figure1/v/2024-05-28T214302Z/r/image-tiff Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis. Human-induced pluripotent stem cell-derived neural stem cell exosomes (hiPSC-NSC-Exos) have shown potential for brain injury repair in central nervous system diseases. In this study, we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism. Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits, enhanced blood-brain barrier integrity, and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage. Additionally, hiPSC-NSC-Exos decreased immune cell infiltration, activated astrocytes, and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α post-intracerebral hemorrhage, thereby improving the inflammatory microenvironment. RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion, thereby improving blood-brain barrier integrity. Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects. In summary, our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity, in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.

High-fat diet (HFD) currently is reported that in connection with cognitive impairment. Tirzepatide is a novel dual receptor agonist for glycemic control. But whether Tirzepatide exerts a protective effect in HFD-related cognitive impairment remains to be explore.

During the study, the cognitive dysfunction mice model induced by HFD were established. The expressions synapse-associated protein and other target proteins were detected. The oxidative stress parameters, levels of inflammatory cytokine were also detected.

Our findings proved that Tirzepatide administration attenuates high fat diet-related cognitive impairment. Tirzepatide administration suppresses microglia activation, alleviates oxidative stress as well as suppressed the expression of NLRP3 in HFD mice by up-regulating SIRT3 expression. In conclusion, Tirzepatide attenuates HFD-induced cognitive impairment through reducing oxidative stress and neuroinflammation via SIRT3-NLRP3 signaling.

This study suggest that Tirzepatide has neuroprotective effects in HFD-related cognitive dysfunction mice model, which provides a promising treatment of HFD-related cognitive impairment.

This review explores the intricate connections between Drosophila models and the human blood-brain barrier (BBB) with nanoparticle-based approaches for neurological treatment. Drosophila serves as a powerful model organism due to its evolutionary conservation of key biological processes, particularly in the context of the BBB, which is formed by glial cells that share structural and functional similarities with mammalian endothelial cells. Recent advancements in nanoparticle technology have highlighted their potential for effective drug delivery across the BBB, utilizing mechanisms such as passive diffusion, receptor-mediated transcytosis, and carrier-mediated transport. The ability to engineer nanoparticles with specific physicochemical properties-such as size, surface charge, and functionalization-enhances their targeting capabilities, particularly towards astrocytes, which play a crucial role in maintaining BBB integrity and responding to neuroinflammation. Insights gained from Drosophila studies have informed the design of personalized nanomedicine strategies aimed at treating neurodegenerative diseases, including Alzheimer's, Parkinson's disease etc. As research progresses, the integration of findings from Drosophila models with emerging humanized BBB systems will pave the way for innovative therapeutic approaches that improve drug delivery and patient outcomes in neurological disorders.

Parkinson's disease (PD) is a chronic, progressive neurological disorder primarily affecting motor control, clinically characterized by resting tremor, bradykinesia, rigidity, and other symptoms that significantly diminish the quality of life. Currently, available treatments only alleviate symptoms without halting or delaying disease progression. There is a significant association between PD and type 2 diabetes mellitus (T2DM), possibly due to shared pathological mechanisms such as insulin resistance, chronic inflammation, and mitochondrial dysfunction. PD is caused by a deficiency of dopamine, a neurotransmitter in the brain that plays a critical role in the control of movement. Glucose metabolism and energy metabolism disorders also play an important role in the pathogenesis of PD. This review investigates the neuroprotective mechanisms of glucagon-like peptide-1 (GLP-1) and its receptor agonists, offering novel insights into potential therapeutic strategies for PD. GLP-1 class drugs, primarily used in diabetes management, show promise in addressing PD's underlying pathophysiological mechanisms, including energy metabolism and neuroprotection. These drugs can cross the blood-brain barrier, improve insulin resistance, stabilize mitochondrial function, and enhance neuronal survival and function. Additionally, they exhibit significant anti-inflammatory and antioxidative stress effects, which are crucial in neurodegenerative diseases like PD. Research indicates that GLP-1 receptor agonists could improve both motor and cognitive symptoms in PD patients, marking a potential breakthrough in PD treatment and prevention. Further exploration of GLP-1's molecular mechanisms in PD could provide new preventive and therapeutic approaches, especially for PD patients with concurrent T2DM. By targeting both metabolic and neurodegenerative pathways, GLP-1 receptor agonists represent a multifaceted approach to PD treatment, offering hope for better disease management and improved patient outcomes.

Spinal cord swelling commonly occurs following SCI. Previous studies suggest that PBM may reduce inflammation and scar formation after SCI. However, whether PBM can alleviate post-spinal cord injury edema and its underlying mechanisms have not yet been reported. This study aims to investigate the effects of PBM on spinal cord swelling in rats following SCI and explore the underlying mechanisms.

A rat model of SCI was established, and the rats received continuous PBM therapy for two weeks. Tissue hydration, motor function, AQP4 expression, and pathological changes in the spinal cord were evaluated at different time points. In vitro, astrocytes were subjected to PBM and treated with either cucurbitacin I or TGN020 following OGD.

The results indicate that PBM reduces tissue swelling in rats with SCI, improves motor function recovery, and inhibits the upregulation of AQP4 and GFAP associated with SCI. In vitro, PBM reduces abnormal activation of the JAK2/STAT3 signaling pathway in astrocytes, leading to decreased AQP4 synthesis and astrocyte activation.

These findings suggest that PBM reduces spinal cord swelling in rats after injury. This effect is associated with the inhibition of JAK2/STAT3 signaling pathway activation in astrocytes and the reduction in AQP4 expression.

Astrocytes are the most numerous type of glial cells found in the nervous system. They regulate energy homeostasis in collaboration with the neuronal circuits involved in energy balance. These glial cells are equipped with sensors and receptors for nutrients and metabolic hormones in order to control energy homeostasis. Astrocytes, like hypothalamic appetite-regulating neurons, are vulnerable to the negative consequences of a high-fat diet (HFD) feeding, which is associated with an inflammatory response and transforms them into a reactive astrocyte state, consequently leading to the disruption of energy balance. Additionally, these cells have sexually dimorphic characteristics, which will lead to different metabolic outcomes in males and females. In this review, we will discuss the various physiological and pathophysiological roles of astrocytes in regulating energy balance. Finally, we will discuss the sexual dimorphism in astrocytes and the impact of estrogen on eliciting distinct responses.

Uncontrolled and chronic inflammatory states in the Central Nervous System (CNS) are the hallmark of neurodegenerative pathology and every injury or stroke-related insult. The key mediators of these neuroinflammatory states are glial cells known as microglia, the resident immune cell at the core of the inflammatory event, and astroglia, which encapsulate inflammatory insults in proteoglycan-rich scar tissue. Since the majority of neuroinflammation is exclusively based on the responses of said glia, their phenotypes have been identified to be on an inflammatory spectrum encompassing developmental, homeostatic, and reparative behaviors as opposed to their ability to affect devastating cell death cascades and scar tissue formation. Recently, research groups have focused on peptide discovery to identify these phenotypes, find novel mechanisms, and mediate or re-engineer their actions. Peptides retain the diverse function of proteins but significantly reduce the activity dependence on delicate 3D structures. Several peptides targeting unique phenotypes of microglia and astroglia have been identified, along with several capable of mediating deleterious behaviors or promoting beneficial outcomes in the context of neuroinflammation. A comprehensive review of the peptides unique to microglia and astroglia will be provided along with their primary discovery methodologies, including top-down approaches using known biomolecules and naïve strategies using peptide and phage libraries.

The blood-brain barrier (BBB) strictly limits the entry of most exogenous therapeutic drugs into the brain, which brings great challenges to the drug treatment of refractory central diseases, including the treatment of ischemic stroke. Our previous studies have shown that specific mode electroacupuncture stimulation (SMES) can temporarily open the BBB, but with the mechanisms largely unknown. This study explored whether SMES opens the BBB in the infarcted border zone of rats during middle cerebral artery occlusion/reperfusion recovery, and whether this is related to p65 or vascular endothelial growth factor A (VEGFA) modulation of tight junction protein expression through in vivo and in vitro studies. Evans blue, FITC-dextran, mouse-derived nerve growth factor (NGF), and transendothelial electrical resistance values were used to evaluate the permeability of the BBB. Additionally, microvascular endothelial cells and astrocytes were utilized for in vitro study. Immunofluorescence, immunohistochemistry, western blot, and ELISA were employed to assess related protein expression. SMES significantly increased vascular permeability for Evans blue and NGF in the infarcted border zone, and increased the expression of VEGFA by activating p-p65, thereby reducing the expression of tight junction proteins Occludin and ZO-1. Correspondingly, oxygen glucose deprivation/reoxygenation activated p-p65 in and induced VEGFA secretion from astrocytes in vitro. Their conditioned medium reduced the expression of Occludin in bEnd.3 cells and increased the permeability of FITC-dextran. The mechanism of SMES opening infarcted border zone BBB is partly related to its actions on p65, VEGFA, and tight junction proteins.

Ischemic stroke (IS) remains one of the most serious threats to human life. Early blood-brain barrier damage (BBB) is the cause of parenchymal cell damage. Repair of the structure and function of the BBB is beneficial for the treatment of IS. The traditional prescription ginseng aconitum decoction (GAD) has a long history in the treatment of cardiovascular and cerebrovascular diseases, however, the effect of GAD on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, in vitro models of BBB were established with brain endothelial cells (bEnd.3). We found that GAD reduced the leakage of the fluorescent probe FITC-dextran (P < 0.01) and increased the expression of tight junction proteins (Claudin-5, ZO-1) (P < 0.05) in the BBB model in vitro. Furthermore, to investigate the BBB protective effects of GAD in vivo. A total of 25 male C57/BL6 mice (20 - 22 g) were randomly divided into 5 groups (n = 5 per group): (1) Sham group (saline), (2) MCAO group (saline), (3) MCAO + CG group (Chinese ginseng 8 mg/kg/day), (4) MCAO + AC group (aconite 8 mg/kg/day), (5) MCAO + GAD group (GAD 8 mg/kg/day).We constructed IS model in mice and found that GAD treatment reduced IgG leakage (P < 0.05), up-regulated the expression of tight junction proteins Claudin-5, Occludin, and ZO-1 (P < 0.05). Further mechanism study showed that fatty acid oxidation (FAO) of vascular endothelial cells is involved in the protection of the BBB after IS, and GAD regulates FAO (P < 0.05) to protect BBB. In addition, we found the effect of GAD was stronger than that of Chinese ginseng (CG) (P < 0.05) and aconite (AC) (P < 0.01) alone. We concluded that GAD ameliorated the BBB dysfunction by regulating FAO involving vascular endothelial cells after IS. At the same time, the prescription is more effective than single traditional Chinese medicine.

As terrorist incidents and underground explosion events have become more frequent around the world, brain injury caused by thoracic blast exposure has been more highlighted due to its injured organ, subsequent social and economic burden. It has been reported dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays important roles in regulating vascular endothelial injury repair and angiogenesis, but its role in thoracic blast-induced brain injury remains to be explained. This study seeks to investigate the mechanism of DDAH1 on thoracic blast-induced brain injury. 40 C57BL/6 wild type mice and 40 DDAH1 knockout mice were randomly and equally divided into control group and blast group, respectively. The integrity of blood-brain barrier (BBB) was detected by Evans blue test. The serum inflammatory factors, nitric oxide (NO) contents, and asymmetric dimethylarginine (ADMA) levels were determined through ELISA. HE staining and reactive oxygen species (ROS) detection were performed for histopathological changes. Western blot was used to detect the proteins related to oxidative stress, tight junction, focal adhesion, vascular endothelial injury, and the DDAH1/ADMA/eNOS signaling pathway. DDAH1 deficiency aggravated thoracic blast-induced BBB leakage, inflammatory response, and the increased levels of inflammatory-related factors. Additionally, DDAH1 deficiency also increased ROS generation, MDA and IRE-α expression. Regarding cerebral vascular endothelial dysfunction, DDAH1 deficiency increased the expression of MCAM, FN1, LIMK1, VEGF, MMP9, Vimentin and N-cadherin, while lowering the expression of FMR1, Occludin, claudin-3, claudin-5, Lyn, LIMA1, Glrb, Sez6, Dystrophin, and phosphorylation of VASP. Also, DDAH1 deficiency exacerbated explosion-induced increase of ADMA and decrease of eNOS activity and NO contents. Thus, we conclude that DDAH1 could prevent cerebral vascular endothelial dysfunction and related injury by inhibiting ADMA signaling and increasing eNOS activity in thoracic blast induced brain injury.

Despite implementation of therapeutic hypothermia (TH) for infants with neonatal encephalopathy (NE), a significant proportion of infants suffer neurodevelopmental impairment (NDI). Remote ischemic conditioning (RIC) is a proposed neuroprotective maneuver that has been studied in adults with brain injury, but it has not been previously investigated in infants with NE.

We performed a prospective, randomized, safety and dose escalation study in 32 neonates with NE. Four cohorts of consecutive patients were randomized to RIC therapy, including four cycles of limb ischemia and reperfusion on progressive days of TH, or sham. Clinical, biochemical, and safety outcomes were monitored in both groups.

All patients received the designated RIC therapy without interruption or delay. RIC was not associated with increased pain, vascular, cutaneous, muscular, or neural safety events. There was no difference in the incidence of seizures, brain injury, or mortality between the two groups with the escalation of RIC dose and frequency.

We found that RIC is a safe and feasible adjunctive therapy for neonates with NE undergoing TH.

This pilot study establishes critical safety and feasibility data that are necessary for the design of future studies to investigate the potential efficacy of RIC to reduce NDI.

Remote ischemic conditioning (RIC) is a possible neuroprotective intervention in infants with hypoxic-ischemic encephalopathy (HIE). RIC can be administered concurrently with therapeutic hypothermia without any notable adverse events. Future studies will need to address potential efficacy of RIC to improve neurodevelopmental outcomes, as well as consider the ideal temporal window and dose for RIC in this patient population.

Readily available nutrient-rich foods exploit our inherent drive to overconsume, creating an environment of overnutrition. This transformative setting has led to persistent health issues, such as obesity and metabolic syndrome. The development of glucagon-like peptide-1 receptor (GLP-1R) agonists reveals our ability to pharmacologically manage weight and address metabolic conditions. Obesity is directly linked to chronic low-grade inflammation, connecting our metabolic environment to neurodegenerative diseases. GLP-1R agonism in curbing obesity, achieved by impacting appetite and addressing associated metabolic defects, is revealing additional benefits extending beyond weight loss. Whether GLP-1R agonism directly impacts brain health or does so indirectly through improved metabolic health remains to be elucidated. In exploring the intricate connection between obesity and neurological conditions, recent literature suggests that GLP-1R agonism may have the capacity to shape the neurovascular landscape. Thus, GLP-1R agonism emerges as a promising strategy for addressing the complex interplay between metabolic health and cognitive well-being.

Chronic pain often coincides with changes in gut microbiota composition. Yet, the role of gut microbiota in bone cancer pain (BCP) is still not fully understood. This study investigated the role of gut microbiota in BCP and the effect of oxymatrine (OMT) on gut microbiota in BCP. A BCP mice model was developed to assess gut microbiota composition, serum and brain tissue butyric acid levels, and blood-brain barrier (BBB) permeability. Microbiota transplantation was used to restore gut microbiota, and the effect of Clostridium butyricum or sodium butyrate (NaB) supplementation on pain-related behaviors and BBB integrity was evaluated. The potential benefits of OMT on gut microbiota composition, peroxisome proliferator-activated receptor gamma (PPARγ)/cyclooxygenase-2 (COX-2) signaling, BBB integrity, and pain-related behaviors were also explored. BCP significantly altered gut microbiota composition and reduced serum and brain tissue butyric acid levels. Additionally, BBB permeability increased considerably in the BCP group compared with sham and control mice. Microbiota transplantation, as well as C butyricum or NaB supplementation, ameliorated pain-related behaviors and BBB integrity; the supplementation of C butyricum or NaB boosted brain-tight-junction protein expression, potentially through modulating PPARγ/COX-2 signaling. OMT influenced gut microbiota composition and regulated PPARγ/COX-2 signaling in the BCP model, improving pain-related behaviors and BBB integrity. BCP affects gut microbiota composition and butyric acid levels. Modulating gut microbiota and butyric acid levels through transplantation or supplementation may alleviate BCP. OMT shows potential as a treatment by altering gut microbiota composition and regulating PPARγ/COX-2 signaling. These findings provide new insights into BCP pathophysiology and possible treatments. PERSPECTIVE: This study explores the impact of gut microbiota on BCP. Microbiota transplantation alleviates BCP and enhances BBB integrity. Also, C butyricum or NaB improves BBB via PPARγ/COX-2. OMT, a BCP treatment, modifies microbiota by regulating PPARγ/COX-2, in turn improving pain and BBB integrity. These findings suggest a therapeutic approach, emphasizing clinical relevance in targeting gut microbiota and restoring butyric acid levels.

Most central nervous diseases are accompanied by astrocyte activation. Autophagy, an important pathway for cells to protect themselves and maintain homeostasis, is widely involved in regulation of astrocyte activation. Reactive astrocytes may play a protective or harmful role in different diseases due to different phenotypes of astrocytes. It is an urgent task to clarify the formation mechanisms of inflammatory astrocyte phenotype, A1 astrocytes. Sestrin2 is a highly conserved protein that can be induced under a variety of stress conditions as a potential protective role in oxidative damage process. However, whether Sestrin2 can affect autophagy and involve in A1 astrocyte conversion is still uncovered. In this study, we reported that Sestrin2 and autophagy were significantly induced in mouse hippocampus after multiple intraperitoneal injections of lipopolysaccharide, with the elevation of A1 astrocyte conversion and inflammatory mediators. Knockdown Sestrin2 in C8-D1A astrocytes promoted the levels of A1 astrocyte marker C3 mRNA and inflammatory factors, which was rescued by autophagy inducer rapamycin. Overexpression of Sestrin2 in C8-D1A astrocytes attenuated A1 astrocyte conversion and reduced inflammatory factor levels via abundant autophagy. Moreover, Sestrin2 overexpression improved mitochondrial structure and morphology. These results suggest that Sestrin2 can suppress neuroinflammation by inhibiting A1 astrocyte conversion via autophagy, which is a potential drug target for treating neuroinflammation.

A1 polarization of astrocytes mediated prolonged inflammation contributing to brain injury in ischemic stroke. We have previously shown that AD16 protects against neonatal hypoxic-ischemic brain damage in vivo and oxygen-glucose deprivation in vitro. More recently, AD16 has demonstrated safety, tolerability, and favorable pharmacokinetics in a randomized controlled phase I trial. In this study, we utilized a rat model of transient middle cerebral artery occlusion (tMCAO) to explore whether the anti-inflammatory compound AD16 protects against ischemic brain injury by regulating A1 polarization and its underlying mechanisms. Our results showed that AD16 treatment significantly reduced the brain infarcted volume and improved neurological function in tMCAO rats. GO analysis results show that differential genes among the Sham, tMCAO and AD16 treatment groups are involved in the regulation of cytokine and inflammatory response. KEGG enrichment pathways analysis mainly enriched in cytokine-cytokine receptor interaction, viral protein interaction with cytokine-cytokine receptor, TNF, chemokine, NF-κB and IL-17 signaling pathway. Furthermore, AD16 treatment decreased the permeability of the blood-brain barrier and suppressed neuroinflammation. AD16 treatment also significantly reduced the polarization of A1 and inhibited NF-κB and JAK2/STAT3 signaling pathways. This study demonstrates that AD16 protects against brain injury in ischemic stroke by reducing A1 polarization to suppress neuroinflammation through downregulating NF-κB and JAK2/STAT3 signaling. Our findings uncover a potential molecular mechanism for AD16 and suggest that AD16 holds promising therapeutic potential against cerebral ischemia.

Failure to achieve target-specific delivery to ischemic brain sites has hampered the clinical efficacy of newly developed therapies for ischemic stroke. Emodin, an active ingredient isolated from traditional Chinese medicine, has been indicated to alleviate ischemic stroke; however, the underlying mechanism remains unclear. In this study, we aimed to achieve brain-targeted delivery of emodin to maximize its therapeutic efficacy and elucidate the mechanisms by which emodin alleviates ischemic stroke. A polyethylene glycol (PEG)/cyclic Arg-Gly-Asp (cRGD)-modified liposome was used to encapsulate emodin. TTC, HE, Nissl staining, and immunofluorescence staining were employed to evaluate the therapeutic efficacy of brain-targeting emodin in MCAO and OGD/R models. Inflammatory cytokine levels were determined using ELISA. Immunoprecipitation, immunoblotting, and RT-qPCR were utilized for clarifying the changes in key downstream signaling. Lentivirus-mediated gene restoration was employed to verify the core effector of emodin for relieving ischemic stroke. Encapsulating emodin in a PEG/cRGD-modified liposome enhanced its accumulation in the infarct region and substantially raised its therapeutic efficacy. Furthermore, we demonstrated that AQP4, the most abundant water transporter subunit expressed in astrocytes, plays a crucial role in mediating the mechanisms by which emodin inhibits astrocyte swelling, neuroinflammatory blood-brain barrier (BBB) breakdown in vivo and in vitro, and brain edema in general. Our study unveiled the critical target of emodin responsible for alleviating ischemic stroke and a localizable drug delivery vehicle in the therapeutic strategy for ischemic stroke and other brain injuries.

Studies have indicated that medium- to long-duration spaceflight may adversely affect astronauts' emotional and social functioning. Emotion modulation can significantly impact astronauts' well-being, performance, mission safety and success. However, with the increase in flight time, the potential alterations in emotional and social performance during spaceflight and their underlying mechanisms remain to be investigated, and targeted therapeutic and preventive interventions have yet to be identified. We evaluated the changes of emotional and social functions in mice with the extension of the time in simulated space complex environment (SSCE), and simultaneously monitored changes in brain tissue of vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and inflammation-related factors. Furthermore, we assessed the regulatory role of repetitive transcranial magnetic stimulation (rTMS) in mood and socialization with the extension of the time in SSCE, as well as examining alterations of VEGF signaling in the medial prefrontal cortex (mPFC). Our findings revealed that mice exposed to SSCE for 7 days exhibited depressive-like behaviors, with these changes persisting throughout SSCE period. In addition, 14 days of rTMS treatment significantly ameliorated SSCE-induced emotional and social dysfunction, potentially through modulation of the level of VEGF signaling in mPFC. These results indicates that emotional and social disorders increase with the extension of SSCE time, and rTMS can improve the performance, which may be related to VEGF signaling. This study offers insights into potential pattern of change over time for mental health issues in astronauts. Further analysis revealed that rTMS modulates emotional and social dysfunction during SSCE exposure, with its mechanism potentially being associated with VEGF signaling.

We aim to deal with the Hub-genes and signalling pathways connected with Sepsis-associated encephalopathy (SAE).

The raw datasets were acquired from the Gene Expression Omnibus (GEO) database (GSE198861 and GSE167610). R software filtered the differentially expressed genes (DEGs) for hub genes exploited for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Hub genes were identified from the intersection of DEGs via protein-protein interaction (PPI) network. And the single-cell dataset (GSE101901) was used to authenticate where the hub genes express in hippocampus cells. Cell-cell interaction analysis and Gene Set Variation Analysis (GSVA) analysis of the whole transcriptome validated the interactions between hippocampal cells.

A total of 161 DEGs were revealed in GSE198861 and GSE167610 datasets. Biological function analysis showed that the DEGs were primarily involved in the phagosome pathway and significantly enriched. The PPI network extracted 10 Hub genes. The M2 Macrophage cell decreased significantly during the acute period, and the hub gene may play a role in this biological process. The hippocampal variation pathway was associated with the MAPK signaling pathway.

Hub genes (Pecam1, Cdh5, Fcgr, C1qa, Vwf, Vegfa, C1qb, C1qc, Fcgr4 and Fcgr2b) may paticipate in the biological process of SAE.

Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1β and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.

The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus.

Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or liraglutide treatment (n = 20), and in healthy subjects (n = 13).

At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group.

Weight loss following treatment with liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with liraglutide.

The morbidity rate of ischemic stroke is increasing annually with the growing aging population in China. Astrocytes are ubiquitous glial cells in the brain and play a crucial role in supporting neuronal function and metabolism. Increasing evidence shows that the impairment or loss of astrocytes contributes to neuronal dysfunction during cerebral ischemic injury. The mitochondrion is increasingly recognized as a key player in regulating astrocyte function. Changes in astrocytic mitochondrial function appear to be closely linked to the homeostasis imbalance defects in glutamate metabolism, Ca2+ regulation, fatty acid metabolism, reactive oxygen species, inflammation, and copper regulation. Here, we discuss the role of astrocytic mitochondria in the pathogenesis of brain ischemic injury and their potential as a therapeutic target.

Poststroke inflammation is essential in the mechanism of secondary injury, and it is orchestrated by resident microglia, astrocytes, and circulating immune cells. Edaravone dexborneol (EDB) is a combination of edaravone and borneol that has been identified as a clinical protectant for stroke management. In this study, we verified the anti-inflammatory effect of EDB in the mouse model of ischemia and investigated its modulatory action on inflammation-related cells. C57BL/6 male mice, which had the transient middle cerebral artery occlusion (tMCAO), were treated (i.p.) with EDB (15 mg/kg). EDB administration significantly reduced the brain infarction and improved the sensorimotor function after stroke. And EDB alleviated the neuroinflammation by restraining the polarization of microglia/macrophages and astrocyte toward proinflammatory phenotype and inhibiting the production of proinflammatory cytokines (such as IL-1β, TNF-α, and IL-6) and chemokines (including MCP-1 and CXCL1). Furthermore, EDB ameliorated the MCAO-induced impairment of Blood-brain barrier (BBB) by suppressing the degradation of tight junction protein and attenuated the accumulation of peripheral leukocytes in the ischemic brain. Additionally, systemic EDB administration inhibited the macrophage phenotypic shift toward the M1 phenotype and the macrophage-dependent inflammatory response in the spleen and blood. Collectively, EDB protects against ischemic stroke injury by inhibiting the proinflammatory activation of microglia/macrophages and astrocytes and through reduction by invasion of circulating immune cells, which reduces central and peripheral inflammation following stroke.

Claudin-5 (CLDN5) is an endothelial tight junction protein essential for blood-brain barrier (BBB) formation. Abnormal CLDN5 expression is common in brain disease, and knockdown of Cldn5 at the BBB has been proposed to facilitate drug delivery to the brain. To study the consequences of CLDN5 loss in the mature brain, we induced mosaic endothelial-specific Cldn5 gene ablation in adult mice (Cldn5iECKO). These mice displayed increased BBB permeability to tracers up to 10 kDa in size from 6 days post induction (dpi) and ensuing lethality from 10 dpi. Single-cell RNA sequencing at 11 dpi revealed profound transcriptomic differences in brain endothelial cells regardless of their Cldn5 status in mosaic mice, suggesting major non-cell-autonomous responses. Reactive microglia and astrocytes suggested rapid cellular responses to BBB leakage. Our study demonstrates a critical role for CLDN5 in the adult BBB and provides molecular insight into the consequences and risks associated with CLDN5 inhibition.

Although a wide variety of mechanisms take part in the secondary injury phase of spinal cord injury (SCI), inflammation is the most important factor implicated in the sequelae after SCI. Being central to the inflammation reaction, macrophages and their polarization are a topic that has garnered wide interest in the studies of SCI secondary injury. The glucagon-like peptide 1 (GLP-1) receptor agonist exenatide has been shown to enhance the endoplasmic reticulum stress response and improve motor function recovery after spinal cord injury (SCI). Since exenatide has also been reported to induce the production of M2 cells in models of cerebral infarction and neurodegenerative diseases, this study was conducted to examine the effects of exenatide administration on the inflammation process that ensues after spinal cord injury. In a rat contusion model of spinal cord injury, the exenatide group received a subcutaneous injection of 10 μg exenatide immediately after injury while those in the control group received 1 mL of phosphate-buffered saline. Quantitative RT-PCR and immunohistochemical staining were used to evaluate the effects of exenatide administration on the macrophages infiltrating the injured spinal cord, especially with regard to macrophage M1 and M2 profiles. The changes in hind limb motor function were assessed based on Basso, Beattie, Bresnahan locomotor rating scale (BBB scale) scores. The improvement in BBB scale scores was significantly higher in the exenatide group from day 7 after injury and onwards. Quantitative RT-PCR revealed an increase in the expression of M2 markers and anti-inflammatory interleukins in the exenatide group that was accompanied by a decrease in the expression of M1 markers and inflammatory cytokines. Immunohistochemical staining showed no significant difference in M1 macrophage numbers between the two groups, but a significantly higher number of M2 macrophages was observed in the exenatide group on day 3 after injury. Our findings suggest that exenatide administration promoted the number of M2-phenotype macrophages after SCI, which may have led to the observed improvement in hind limb motor function in a rat model of SCI.