Chuanzhitongluo capsule improves cognitive impairment in mice with chronic cerebral hypoperfusion via the cholinergic anti-inflammatory pathway.

Vascular cognitive impairment (VCI) has become a common disease-causing cognitive deficit in humans, second only to Alzheimer's Disease (AD). Chuanzhitongluo capsule (CZTL) is a Traditional Chinese Medicine (TCM) preparation known for its effective protection against cerebral ischemia. However, its potential to ameliorate VCI remains unclear. This study aimed to investigate the cognitive improvement effects of CZTL in a mouse model of VCI. Chronic cerebral hypoperfusion (CCH) was induced in mice by bilateral common carotid artery stenosis (BCAS) to simulate the pathological changes associated with VCI. Spatial learning and memory abilities were assessed using the Morris Water Maze (MWM). RNA sequencing (RNA-Seq) was employed to identify differentially expressed genes (DEGs) in the hippocampus. Levels of inflammatory factors were measured through enzyme-linked immunosorbent assay (ELISA), while immunofluorescence (IF) determined the expression intensity of target proteins. Western Blot (WB) confirmed the final action pathway. Results indicated that CZTL significantly improved the spatial learning and memory abilities of CCH mice, along with alterations in gene expression profiles in the hippocampus. It also reduced neuroinflammation in the hippocampus and upregulated the choline acetyltransferase (ChAT) and α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR), which are in synaptic plasticity and neuronal development. Moreover, CZTL inhibited the NF-κB signaling pathway. In conclusion, CZTL may alleviate neuroinflammation induced by CCH and improve cognitive impairment in CCH mice by regulating the cholinergic anti-inflammatory pathway (CAIP) involving ChAT/α7nAChR/NF-κB.

Inosine pretreatment of pregnant rats ameliorates maternal inflammation-mediated hypomyelination in pups via microglia polarization switch.

Periventricular leukomalacia (PVL) is a neurological condition observed in premature infants, characterized by hypomyelination and activation of microglia. Maternal inflammation-induced brain injury in offspring significantly contributes to the development of PVL. Currently, there are no clinical pharmaceutical interventions available for pregnant women to prevent maternal inflammation-mediated brain injury in their offspring. Inosine has been shown to modulate the immune response in diverse stressful circumstances, such as injury, ischemia, and inflammation. The aim of this investigation was to examine the potential prophylactic impact of inosine on offspring PVL induced by maternal inflammation. This was accomplished by administering a 1 mg/ml inosine solution (40 ml daily) to pregnant Sprague-Dawley (SD) rats for 16 consecutive days prior to their intraperitoneal injection of lipopolysaccharide (350 µg/kg, once a day, for two days). The results showed that maternal inosine pretreatment significantly reversed the reduction in MBP and CNPase (myelin-related markers), CC-1 and Olig2 (oligodendrocyte-related markers) in their PVL pups (P7), suggesting that inosine administration during pregnancy could improve hypomyelination and enhance the differentiation of oligodendrocyte precursor cells (OPCs) in their PVL pups. Furthermore, the protective mechanism of inosine against PVL is closely associated with the activation and polarization of microglia. This is evidenced by a notable reduction in the quantity of IBA 1-positive microglia, a decrease in the level of CD86 (a marker for M1 microglia), an increase in the level of Arg 1 (a marker for M2 microglia), as well as a decrease in the level of pro-inflammatory factors TNF-α, IL-1ß, and IL-6, and an increase in the level of anti-inflammatory factors IL-4 and IL-10 in the brain of PVL pups following maternal inosine pretreatment. Taken together, inosine pretreatment of pregnant rats can improve hypomyelination in their PVL offspring by triggering the M1/M2 switch of microglia.

Corrigendum: Differences in resting-state brain networks and gray matter between APOE ϵ2 and APOE ϵ4 carriers in non-dementia elderly.

[This corrects the article DOI: 10.3389/fpsyt.2023.1197987.].

Thiazolidine-2,4-dione derivatives as potential α-glucosidase inhibitors: Synthesis, inhibitory activity, binding interaction and hypoglycemic activity.

In order to find effective α-glucosidase inhibitors, a series of thiazolidine-2,4-dione derivatives (C1 âˆ¼ 36) were synthesized and evaluated for α-glucosidase inhibitory activity. Compared to positive control acarbose (IC50 = 654.35 ± 65.81 µM), all compounds (C1 âˆ¼ 36) showed stronger α-glucosidase inhibitory activity with IC50 values of 0.52 ± 0.06 âˆ¼ 9.31 ± 0.96 µM. Among them, C23 with the best anti-α-glucosidase activity was a reversible mixed-type inhibitor. Fluorescence quenching suggested the binding process of C23 with α-glucosidase in a static process. Fluorescence quenching, CD spectra, and 3D fluorescence spectra results also implied that the binding of C23 with α-glucosidase caused the conformational change of α-glucosidase to inhibit the activity. Molecular docking displayed the binding interaction of C23 with α-glucosidase. Compound C23 (8 âˆ¼ 64 µM) showed no cytotoxicity against LO2 and 293 cells. Moreover, oral administration of C23 (50 mg/kg) could reduce blood glucose and improve glucose tolerance in mice.

Chuanzhitongluo Inhibits Neuronal Apoptosis in Mice with Acute Ischemic Stroke by Regulating the PI3K/AKT Signaling Pathway.

BACKGROUND AND PURPOSE: Apoptosis is involved in the occurrence and development of acute ischemic stroke (AIS). This study aimed to assess whether Chuanzhitongluo (CZTL), a multi-target and multi-pathway compound preparation, plays a neuroprotective role in AIS by modulating neuronal apoptosis via the PI3K/AKT signaling pathway. METHODS: A mouse model of AIS was established by photochemical processes. Cerebral infarction volume was measured by 2% staining with 2, 3, and 5-triphenyl tetrazole chloride (TTC). Neuron apoptosis was assessed by TUNEL staining. Apoptosis RNA arrays were used to detect changes in apoptosis-related gene expression profiles. Western blotting was used to detect proteins involved in the PI3K/AKT signaling pathway. RESULTS: The study demonstrated that CZTL could potentially mitigate neuronal apoptosis in AIS mice. This appears to be achieved via the up-regulation of certain genes such as BCL-2, Birc6, and others, coupled with the down-regulation of genes like BAX, Bid, and Casp3. Further validation revealed that CZTL could enhance the expression of BCL-2 and reduce the expression of Cleaved Caspase-3 and BAX at both the gene and protein levels. The study also found that CZTL can enhance the phosphorylation level of the PI3K/AKT signaling pathway. In contrast to these findings, the PI3K inhibitor LY294002 notably amplified neuronal apoptosis in AIS mice. CONCLUSIONS: These findings imply that CZTL's ability to inhibit neuronal apoptosis may be linked to the activation of AIS's PI3K/AKT signaling pathway.

Subtyping treatment response of tirofiban in acute ischemic stroke based on neuroimaging features.

In a previously published clinical trial, we demonstrated that tirofiban was effective and safe in acute ischemic stroke (AIS) patients who did not undergo early recanalization treatments. We aimed to evaluate neuroimaging characteristics and their clinical significance to guide tirofiban treatment. In this post hoc analysis, location of infarcts (anterior circulation stroke [ACS] vs. posterior circulation stroke [PCS]), degree of cerebral artery stenosis (≤69% vs. ≥70% or occlusion), total infarct volume, and ASPECTS were used to predict the treatment effects of tirofiban, defined as the proportions of excellent and favorable functional outcome (modified Rankin Scale [mRS] score of 0-1, 0-2) at 90 days. ACS patients were more likely to achieve excellent (OR 2.08; 95% CI 1.25-3.45; p = 0.004) and favorable functional outcome (OR 2.28; 95% CI 1.24-4.22; p = 0.008) when treated with tirofiban. However, there was no significant difference in PCS patients between tirofiban and the control group. For patients with severe stenosis (≥70% or occlusion), tirofiban treatment improved the proportion of good outcomes (OR 2.84; 95% CI 1.44-5.60; p = 0.002 for mRS 0-1; OR 2.42; 95% CI 1.22-4.77; p = 0.011 for mRS 0-2). Meanwhile, we found that tirofiban improved outcome in patients with ASPECTS 8-10 and was independent of total infarct volume. These findings support the hypothesis that patients with ACS and severe stenosis may be recommended for tirofiban treatment, which can be predicted independent of total infarct volume.

Synthesis and biological evaluation of indole derivatives containing thiazolidine-2,4-dione as α-glucosidase inhibitors with antidiabetic activity.

In order to develop potential α-glucosidase inhibitors with antidiabetic activity, twenty-six indole derivatives containing thiazolidine-2,4-dione were synthesized. All compounds presented potential α-glucosidase inhibitory activities with IC50 values ranging from 2.35 ± 0.11 to 24.36 ± 0.79 µM, respectively compared to acarbose (IC50 = 575.02 ± 10.11 µM). Especially, compound IT4 displayed the strongest α-glucosidase inhibitory activity (IC50 = 2.35 ± 0.11 µM). The inhibition mechanism of compound IT4 on α-glucosidase was clarified by the investigation of kinetics studies, fluorescence quenching, CD spectra, 3D fluorescence spectra, and molecular docking. In vivo antidiabetic experiments demonstrated that oral administration of compound IT4 would suppress fasting blood glucose level and ameliorate their glucose tolerance and dyslipidemia in diabetic mice.

Necrostatin-1s Suppresses RIPK1-driven Necroptosis and Inflammation in Periventricular Leukomalacia Neonatal Mice.

Periventricular leukomalacia (PVL), a predominant form of brain injury in preterm survivors, is characterized by hypomyelination and microgliosis and is also the major cause of long-term neurobehavioral abnormalities in premature infants. Receptor-interacting protein kinase 1 (RIPK1) plays a pivotal role in mediating cell death and inflammatory signaling cascade. However, very little is known about the potential effect of RIPK1 in PVL and the underlying mechanism. Herein, we found that the expression level of RIPK1 was drastically increased in the brain of PVL neonatal mice models, and treatment of PVL neonatal mice with Necrostatin-1s (Nec-1s), an inhibitor of RIPK1, greatly ameliorated cerebral ischemic injury, exhibiting an increase of body weights, reduction of cerebral infarct size, neuronal loss, and occurrence of necrosis-like cells, and significantly improved the long-term abnormal neurobehaviors of PVL. In addition, Nec-1s significantly suppressed hypomyelination and promoted the differentiation of oligodendrocyte precursor cells (OPCs), as demonstrated by the increased expression levels of MBP and Olig2, the decreased expression level of GPR17, a significant increase in the number of CC-1-positive cells, and suppression of myelin ultrastructure impairment. Moreover, the mechanism of neuroprotective effects of Nec-1s against PVL is closely associated with its suppression of the RIPK1-mediated necrosis signaling molecules, RIPK1, PIPK3, and MLKL. More importantly, inhibition of RIPK1 could reduce microglial inflammatory injury by triggering the M1 to M2 microglial phenotype, appreciably decreasing the levels of M1 marker CD86 and increasing the levels of M2 markers Arg1 or CD206 in PVL mice. Taken together, inhibition of RIPK1 markedly ameliorates the brain injury and long-term neurobehavioral abnormalities of PVL mice through the reduction of neural cell necroptosis and reversing neuroinflammation.

Differences in resting-state brain networks and gray matter between APOE ε2 and APOE ε4 carriers in non-dementia elderly.

Background: Apolipoprotein E (APOE) ε2 and APOE ε4 are the most distinct alleles among the three APOE alleles, both structurally and functionally. However, differences in cognition, brain function, and brain structure between the two alleles have not been comprehensively reported in the literature, especially in non-demented elderly individuals. Methods: A neuropsychological test battery was used to evaluate the differences in cognitive performance in five cognitive domains. Independent component analysis (ICA) and voxel-based morphometry (VBM) were used separately to analyze resting-state functional magnetic resonance imaging (rs-fMRI) data and the structure MRI data between the two groups. Finally, correlations between differential brain regions and neuropsychological tests were calculated. Results: APOE ε2 carriers had better cognitive performance in general cognitive, memory, attention, and executive function than APOE ε4 carriers (all p < 0.05). In ICA analyses of rs-fMRI data, the difference in the resting-state functional connectivity (rsFC) between two groups is shown in 7 brain networks. In addition, VBM analyses of the T1-weighted image revealed that APOE ε2 carriers had a larger thalamus and right postcentral gyrus volume and a smaller bilateral putamen volume than APOE ε4 carriers. Finally, differences in brain function and structure may be might be the reason that APOE ε2 carriers are better than APOE ε4 carriers in cognitive performance. Conclusion: These findings suggest that there are significant differences in brain function and structure between APOE ε2 carriers and APOE ε4 carriers, and these significant differences are closely related to their cognitive performance.

Inhibition of inflammatory factor TNF-α by ferrostatin-1 in microglia regulates necroptosis of oligodendrocyte precursor cells.

OBJECTIVE: Inflammation of the surrounding environment is a major reason causing loss or injury of oligodendrocyte precursor cells (OPCs) in myelin-associated diseases. Lipopolysaccharide-activated microglia can release various inflammatory factors such as tumor necrosis factor-α (TNF-α). One of the ways of OPC death is necroptosis, which can be triggered by TNF-α, a death receptor ligand, by activating receptor-interacting protein kinase 1 (RIPK1)/RIPK3/mixed lineage kinase domain-like protein (MLKL) signaling pathway. This study investigated whether inhibiting microglia ferroptosis can decrease TNF-α release to alleviate OPC necroptosis. METHODS: Lipopolysaccharide and Fer-1 stimulate BV2 cells. The expressions of GPX4 and TNF-α were detected by western blot and quantitative real-time PCR; malondialdehyde, glutathione, iron, and reactive oxygen species were measured by the assay kits. After lipopolysaccharide stimulation of BV2 cells, the supernatant was taken to culture OPC. The protein expression levels of RIPK1, p-RIPK1, RIPK3, p-RIPK3, MLKL, and p-MLKL were detected by western blot. RESULTS: Lipopolysaccharide administration could induce ferroptosis in microglia by decreasing ferroptosis marker GPX4, while ferroptosis inhibitor Fer-1 could significantly increase GPX4 level. Fer-1 prevented oxidative stress and iron concentration elevation and alleviated mitochondrial damage in lipopolysaccharide-induced BV2 cells. The results revealed that Fer-1 downregulated the release of lipopolysaccharide-induced TNF-α in microglia and attenuated OPC necroptosis by significantly decreasing the expression levels of RIPK1, p-RIPK1, MLKL, p-MLKL, RIPK3, and p-RIPK3. CONCLUSION: Fer-1 may be a potential agent for inhibiting inflammation and treating myelin-related diseases.

Risk factors and protective factors for nonsuicidal self-injury in adolescents: A hospital- and school-based case-control study.

OBJECTIVE: Nonsuicidal Self-Injury (NSSI) in China has increasingly interested clinicians, although few studies have investigated its risk and protective factors. This study examined the risk factors of NSSI among Chinese adolescents. METHODS: The researchers recruited adolescent participants with NSSI from a hospital outpatient clinic to form a case group and recruited adolescents without NSSI who provided informed consent from the school to form a control group. Participants completed a questionnaire, and data were analyzed using logistic regression. RESULTS: A total of 138 cases and 276 controls participated in this study. Binary multivariate logistic regression analysis with adjusting for age and sex showed that domestic violence (OR = 8.615, 95%CI: 3.081-24.091), parental overconcern (OR = 6.995, 95%CI: 3.447-14.192), guilt (OR = 4.949, 95%CI: 2.227-10.996), and school bullying (OR = 21.676, 95%CI: 6.799-69.109) increased the risk of NSSI, while peer support (OR = 0.068, 95%CI: 0.030-0.150) and living in an urban environment (OR = 0.157, 95%CI: 0.056-0.437) decreased the risk of NSSI. CONCLUSION: Some psychosocial factors were confirmed to be independent risk and protective factors for NSSI in this study. However, the clinical significance of the results needs to be interpreted with caution due to sample size limitations.

Retraction: Down-regulation of HOXB5 inhibits TGF-ß-induced migration and invasion in hepatocellular carcinoma cells via inactivation of the PI3K/Akt pathway.

[This retracts the article DOI: 10.1039/C8RA06860G.].

Chuanzhitongluo regulates microglia polarization and inflammatory response in acute ischemic stroke.

BACKGROUND AND PURPOSE: Chuanzhitongluo (CZTL), a traditional Chinese medicine mixture, is used in the recovery period of acute ischemic stroke (AIS), and effectively improves the prognosis of AIS patients. This study aims to evaluate whether CZTL regulates microglia polarization and inflammatory response to reduce brain damage in the acute phase of AIS. METHODS: A mouse model of AIS was prepared by the photochemical method. Cerebral infarct volume was detected by 2,3,5-Triphenyltetrazolium chloride (TTC) staining. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to assess neuronal apoptosis. Gene expression profile change was explored by Gene chip. Inflammatory factors were analyzed by Protein microarray. The Immunofluorescence double-labeling assay was executed to elucidate the effects of CD16+ / Iba-1+ and CD206+ / Iba-1+ in the peripheral area of cerebral ischemia. RESULTS: Results revealed that CZTL treatment alleviated the neurological impairment, reduced cerebral infarct volume, and inhibited neuronal apoptosis. CZTL altered gene expression profiles, which indicate that CZTL may be involved in regulating neuroinflammation. CZTL restrained inflammatory responses by down-regulated pro-inflammatory cytokines expression and enhanced anti-inflammatory cytokines level. Further experiments demonstrated that CZTL inhibited the activation of NLRP3 inflammasome, which decreasing the inflammatory response. In addition, CZTL promoted the transformation of microglia from M1 to M2 phenotype. CONCLUSIONS: These results indicate that CZTL alleviates neuroinflammation and brain damage after AIS in mice, which may be mediated by modulating microglia polarization.

Research on Haze Image Enhancement based on Dark Channel Prior Algorithm in Machine Vision.

According to the characteristics of foggy images, such as high noise, low resolution, and uneven illumination, an improved foggy image enhancement method based on dark channel priority is proposed. First, the new algorithm refines the transmittance and optimizes the atmospheric light value and converts the restored image to HSV space. Second, the brightness V component is enhanced by MSRCR algorithm improved by bilateral filtering, and the saturation S is improved by adaptive stretching algorithm. Finally, the image is converted from HSV space to RGB space to complete image enhancement. The new method solves the problems of that the color of large area is uneven and the overall color of the image is dark when the traditional dark channel prior method is used to remove fog. The experimental results show that from subjective evaluation and quantitative analysis the new algorithm overcomes the shortcomings of noise amplification and edge blur when the conventional enhancement algorithm enhances the image. It can improve image darkening and avoid image distortion in JPEG, BMP, GIF, PNG, PSD, and TIFF formats. By comparing with other image enhancement algorithms, the improved algorithm performs better than DCP, SSR, MSR, MSRCR, and CLAHE algorithm in PSNR, SSIM, and IE evaluation indexes. It has a good effect on preserving the edge information and has good adaptability and stability for heavily polluted haze image enhancement.

Assessment of Willingness to Pay for Pollution Prevention, Health and Happiness: A Case Study of Punjab, Pakistan.

Air pollution has been notoriously held accountable for a substantial number of deaths in several countries. Moreover, its negative impact on people's health and well-being has also been witnessed in countries where air pollution is below the recommended national levels. The urban cities of Pakistan are among the worst South Asian areas in terms of air pollution. Because of this problem, the health and well-being of citizens are affected. The present study investigates the impact of air pollution on urban residents' happiness and health. It analyzes their willingness to pay for pollution prevention and its determinants by employing the data obtained through a primary survey. Pakistanis are unaware of air pollution's effect on health and quality of life, therefore only 12.5% consider this problem very serious. The results confirm the significantly negative effect of air pollution on happiness. Concerning the willingness to pay, it is differentiated in the form of tax and social contribution. Pakistanis are willing to pay more in social contribution in return for different environmental attributes. The results show that only 13% of respondents are not willing to pay for income contribution to improve air quality reporting indifferent attitude and insufficient knowledge of the environment. Our findings suggest that their apprehension concerning the environment influences people's willingness to pay. The study concludes that despite Pakistan's underdeveloped economic stature and its poor and flexible budgetary allocation for the betterment of air quality, most Pakistanis showed their willingness to pay for environmental protection. The government and environmental organizations ought to generate consensus among the general population about environmental importance, individual responsibility, and social duties thereby lessening the free-rider problem and reducing air pollution for better social welfare.

Upregulation of PGC-1α Attenuates Oxygen-Glucose Deprivation-Induced Hippocampal Neuronal Injury.

Hippocampal neuronal damage likely underlies cognitive impairment in vascular dementia (VaD). PPARγ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. However, the role and the precise mechanism of how PGC-1α alleviates hippocampal neuronal injury remain unknown. To address this question, HT-22 cells, an immortalized hippocampal neuron cell line, with or without PGC-1α overexpression were subjected to oxygen-glucose deprivation (OGD), which mimics the circumstance of chronic cerebral hypoperfusion in VaD. After OGD, cell viability was assessed using the MTS assay. The mitochondrial function and reactive oxygen species (ROS) were both detected. ChIP-Seq analysis was employed to discover the underlying molecular mechanism of PGC-1α-mediated neuroprotective effects. Our results showed that mitochondrial membrane potentials were increased and ROS production was decreased in PGC-1α overexpressing cells, which increased cell viability. The further bioinformatics analysis from ChIP-Seq data indicated that PGC-1α may participate in the regulation of apoptosis, autophagy, and mitophagy pathways in HT-22 cells. We found that PGC-1α promoted the LC3-II formation and reduced the neuronal apoptosis determined by TUNEL staining. In addition, PGC-1α upregulated the expressions of mitochondrial antioxidants, including SOD2, Trx2, and Prx3. In summary, our findings indicate that PGC-1α may attenuate OGD-induced hippocampal neuronal damage by regulating multiple mechanisms, like autophagy and mitochondrial function. Thus, PGC-1α may be a potential therapeutic target for hippocampal damage associated with cognitive impairment.

Corrigendum: The Effects of rs405509 on APOEε4 Non-carriers in Non-demented Aging.

[This corrects the article DOI: 10.3389/fnins.2021.677823.].

Activation of A2B adenosine receptor protects against demyelination in a mouse model of schizophrenia.

The purpose of the present study was to explore the effects of A2B adenosine receptor (A2BAR) on learning, memory and demyelination in a dizocilpine maleate (MK-801)-induced mouse model of schizophrenia (SCZ). BAY 60-6583, an agonist of A2BAR, or PSB 603, an antagonist of A2BAR, was used to treat SCZ in this model. The Morris Water Maze (MWM) was utilized to determine changes in cognitive function. Moreover, western blotting, immunohistochemistry and immunofluorescence were conducted to investigate the myelination and oligodendrocyte (OL) alterations at differentiation and maturation stages. The MWM results showed that learning and memory were impaired in SCZ mice, while subsequent treatment with BAY 60-6583 alleviated these impairments. In addition, western blot analysis revealed that myelin basic protein (MBP) and chondroitin sulphate proteoglycan 4 (NG2) expression levels were significantly decreased in MK-801-induced mice, while the expression of G protein-coupled receptor 17 (GPR17) was increased. Additionally, the number of anti-adenomatous polyposis coli clone CC-1/OL transcription factor 2 (CC-1+/Olig2+) cells was also decreased. Notably, BAY 60-6583 administration could reverse these changes, resulting in a significant increase in MBP and NG2 protein expression, and in the number of CC-1+/Olig2+ cells, while GPR17 protein expression levels were decreased. The present study indicated that the selective activation of A2BAR using BAY 60-6583 could improve the impaired learning and memory of SCZ mice, as well as protect the myelin sheath from degeneration by regulating the survival and maturation of OLs.

A2B adenosine receptor inhibition ameliorates hypoxic-ischemic injury in neonatal mice via PKC/Erk/Creb/HIF-1α signaling pathway.

Periventricular leukomalacia (PVL), the dominant cerebral white matter injury disease, is induced by hypoxia-ischemia and inflammation in premature infants. The activation of A2B adenosine receptor (A2BAR) is shown to involve into inflammation, ischemia, and other typical stress reactions, but its exact function in PVL has not been clarified. We gained initial insight from PVL mouse model (P9) by the induction of hypoxia-ischemia with right carotid ligation followed by exposure to hypoxia and intraperitoneal (i.p.) injection of Lipopolysaccharide (LPS). The results showed that treatment of PSB-603, an A2BAR selective antagonist, greatly ameliorated cerebral ischemic injury by increasing bodyweights, reducing infarct volume, brain injury,inflammation andcontributing to long-term learning memory functionalrecoveryof the PVL mice. Meanwhile, PSB-603 treatment suppressed neurons apoptosis as characterized byreducing of Caspase-3 level, inhibited microglia activation and attenuated hypomyelination through promoting MBP expression and oligodendrocytes differentiation. A2BAR inhibition also augmented PKC expression, the activity of PKC downstream signaling molecules were then explored. Erk expression and Creb phosphorylation exhibited upregulation in PSB-603 treatment group compared with the control group. Hypoxia Inducible Factor-1α (HIF-1α), a direct target of hypoxia, which is a key regulator of adenosine signaling by binding to the A2BAR promoter to induce expression of A2BAR, was shown to be decreased by PSB-603. Taken together, A2BAR inhibition can ameliorate hypoxic-ischemic injury in PVL mice maybe through PKC/Erk/Creb/HIF-1α signaling pathway.