AR and traumatic brain injury.

Accumulating evidence has revealed the adenosine 2A receptor is a key tuner for neuropathological and neurobehavioral changes following traumatic brain injury by experimental animal models and a few clinical trials. Here, we highlight recent data involving acute/sub-acute and chronic alterations of adenosine and adenosine 2A receptor-associated signaling in pathological conditions after trauma, with an emphasis of traumatic brain injury, including neuroinflammation, cognitive and psychiatric disorders, and other severe consequences. We expect this would lead to the development of therapeutic strategies for trauma-related disorders with novel mechanisms of action.

Targeting the adenosine A receptor for neuroprotection and cognitive improvement in traumatic brain injury and Parkinson's disease.

Adenosine exerts its dual functions of homeostasis and neuromodulation in the brain by acting at mainly 2 G-protein coupled receptors, called A and A receptors. The adenosine A receptor (AR) antagonists have been clinically pursued for the last 2 decades, leading to final approval of the istradefylline, an AR antagonist, for the treatment of OFF-Parkinson's disease (PD) patients. The approval paves the way to develop novel therapeutic methods for AR antagonists to address 2 major unmet medical needs in PD and traumatic brain injury (TBI), namely neuroprotection or improving cognition.

Inhibition of the interaction between microglial adenosine 2A receptor and NLRP3 inflammasome attenuates neuroinflammation posttraumatic brain injury.

Aims: Adenosine 2A receptor (A R) is widely expressed in the brain and plays important roles in neuroinflammation, and the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a crucial component of the innate immune system while the regulation of A R on it in the central nervous system (CNS) has not been clarified.

Methods: The effects of microglial A R on NLRP3 inflammasome assembly and activation were investigated in wild-type, A R- or NLRP3-knockout primary microglia with pharmacological treatment. Microglial A R or NLRP3 conditional knockout mice were used to interrogate the effects of this regulation on neuroinflammation posttraumatic brain injury (TBI).

Knockdown of adenosine A2A receptors in hippocampal neurons prevents post-TBI fear memory retrieval.

The formation of fear memory is crucial in emotional disorders such as PTSD and anxiety. Traumatic brain injury (TBI) can cause emotional disorders with dysregulated fear memory formation; however, their cross-interaction remains unclear and hurdled the treatment against TBI-related emotional disorders. While adenosine A2A receptor(A2AR) contributes to the physiological regulation of fear memory, this study aimed to evaluate the A2AR role and possible mechanisms in post-TBI fear memory formation using a craniocerebral trauma model, genetically modified A2AR mutant mice, and pharmacological A2AR agonist CGS21680 and antagonist ZM241385.

[Activation of the adenosine A2A receptor at the acute stage of moderate traumatic brain injury enhances the neuroprotective effects of oxaloacetate].

The purpose of the present study was to investigate the effect of glutamate scavenger oxaloacetate (OA) combined with CGS21680, an adenosine A2A receptor (A2AR) agonist, on acute traumatic brain injury (TBI), and to elucidate the underlying mechanisms. C57BL/6J mice were subjected to moderate-level TBI by controlled cortical impact, and then were treated with OA, CGS21680, or OA combined with CGS21680 at acute stage of TBI. At 24 h post TBI, neurological severity score, brain water content, glutamate concentration in cerebrospinal fluid (CSF), mRNA and protein levels of IL-1β and TNF-α, mRNA level and activity of glutamate oxaloacetate aminotransferase (GOT), and ATP level of brain tissue were detected.

A 5-HTR agonist alleviates cognitive dysfunction after traumatic brain injury in rats by increasing BDNF expression.

Effective treatment for cognitive dysfunction after traumatic brain injury (TBI) is lacking in clinical practice. Increased brain-derived neurotrophic factor (BDNF) expression in cognitive circuits can significantly alleviate cognitive dysfunction in animal models of TBI. Selective 5-hydroxytryptamine receptor 6 (5-HTR) agonists significantly increase BDNF expression and improve cognitive function.

Overexpressed ski efficiently promotes neurorestoration, increases neuronal regeneration, and reduces astrogliosis after traumatic brain injury.

Traumatic brain injury (TBI) survivors suffer from long-term disability and neuropsychiatric sequelae due to irreparable brain tissue destruction. However, there are still few efficient therapies to promote neurorestoration in damaged brain tissue. This study aimed to investigate whether the pro-oncogenic gene ski can promote neurorestoration after TBI.

High glutamate concentration reverses the inhibitory effect of microglial adenosine 2A receptor on NLRP3 inflammasome assembly and activation.

NLRP3 inflammasome plays a crucial role in the innate immune system. Our group previously reported that the microglial adenosine 2A receptor (AR) regulates canonical neuroinflammation, which is affected by the glutamate concentration. However, the regulatory effect of AR on NLRP3 inflammasome and the effects of glutamate concentration remain unknown.

HMGB1 mediates cognitive impairment caused by the NLRP3 inflammasome in the late stage of traumatic brain injury.

Background: Cognitive impairment in the late stage of traumatic brain injury (TBI) is associated with the NOD-, LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome, which plays an important role in neuroinflammation. Although classical inflammatory pathways have been well-documented in the late stage of TBI (4-8 weeks post-injury), the mechanism by which the NLRP3 inflammasome impairs cognition is still unclear.

Methods: Mice lacking the gene encoding for NLRP3 (NLRP3-knockout mice) and their wild-type littermates were used in a controlled cortical impact model of TBI.

NLRP3 Inflammasome-Dependent Increases in High Mobility Group Box 1 Involved in the Cognitive Dysfunction Caused by Tau-Overexpression.

Tau hyperphosphorylation is a characteristic alteration present in a range of neurological conditions, such as traumatic brain injury (TBI) and neurodegenerative diseases. Treatments targeting high-mobility group box protein 1 (HMGB1) induce neuroprotective effects in these neuropathologic conditions. However, little is known about the interactions between hyperphosphorylated tau and HMGB1 in neuroinflammation.

Axon regeneration after optic nerve injury in rats can be improved via PirB knockdown in the retina.

Background: In the central nervous system (CNS), three types of myelin-associated inhibitors (MAIs) exert major inhibitory effects on nerve regeneration: Nogo-A, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp). MAIs have two co-receptors, Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB). Existing studies confirm that inhibiting NgR only exerted a modest disinhibitory effect in CNS.

A novel method for detecting heteromeric complexes at synaptic level by combining a modified method of proximity ligation assay with transmission electron microscopy.

The heteromeric complexes of adenosine 2A receptor (A2AR) and N-methyl-D-aspartate receptor (NMDAR) have recently been confirmed in cell experiments, while its in situ detection at the subcellular level of brain tissue has not yet been achieved. Proximity Ligation Assay (PLA) enables the detection of low-abundance proteins and their interactions at the cellular level with high specificity and sensitivity, while Transmission electron microscope (TEM) is an excellent tool for observing subcellular structures. To develop a highly efficient and reproducible technique for in situ detection of protein interactions at subcellular levels, in this study, we modified the standard PLA sample preparation method to make the samples suitable for analysis by transmission electron microscopy.

Ski promotes proliferation and inhibits apoptosis in fibroblasts under high-glucose conditions via the FoxO1 pathway.

Objectives: The present study clarified the role and signalling pathway of Ski in regulating proliferation and apoptosis in fibroblasts under high-glucose (HG) conditions.

Materials And Methods: The proliferation and apoptosis of rat primary fibroblasts were assessed using EdU incorporation and TUNEL assays. The protein and phosphorylation levels of the corresponding factors were measured using immunofluorescence staining and Western blotting.

Ski mediates TGF-β1-induced fibrosarcoma cell proliferation and promotes tumor growth.

TGF-β1 promotes cell proliferation in only some tumors and exerts bidirectional regulatory effects on the proliferation of fibroblasts. This study intends to explore whether the mechanism is related to increased expression of Ski. Cell proliferation of the fibrosarcoma cell line L929 was assessed with an ELISA BrdU kit.

Paired Immunoglobulin-like Receptor B Inhibition in Müller Cells Promotes Neurite Regeneration After Retinal Ganglion Cell Injury in vitro.

In the central nervous system (CNS), three types of myelin-associated inhibitors (MAIs) have major inhibitory effects on nerve regeneration. They include Nogo-A, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein. MAIs possess two co-receptors, Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB).

A R inhibition in alleviating spatial recognition memory impairment after TBI is associated with improvement in autophagic flux in RSC.

Spatial recognition memory impairment is an important complication after traumatic brain injury (TBI). We previously found that spatial recognition memory impairment can be alleviated in adenosine A receptor knockout (A R KO) mice after TBI, but the mechanism remains unclear. In the current study, we used manganese-enhanced magnetic resonance imaging and the Y-maze test to determine whether the electrical activity of neurons in the retrosplenial cortex (RSC) was reduced and spatial recognition memory was impaired in wild-type (WT) mice after moderate TBI.

Expression of a short antibody heavy chain peptide effectively antagonizes adenosine 2A receptor in vitro and in vivo.

Background: Adenosine 2A receptor (AR) is involved in many physiological and pathological functions and serves as an important drug target. Inhibition of AR may alleviate symptoms associated with a variety of neuropsychiatric disorders. However, the currently used AR antagonists have specificity limitations.

Altered Energy Metabolism During Early Optic Nerve Crush Injury: Implications of Warburg-Like Aerobic Glycolysis in Facilitating Retinal Ganglion Cell Survival.

Neurons, especially axons, are metabolically demanding and energetically vulnerable during injury. However, the exact energy budget alterations that occur early after axon injury and the effects of these changes on neuronal survival remain unknown. Using a classic mouse model of optic nerve-crush injury, we found that traumatized optic nerves and retinas harbor the potential to mobilize two primary energetic machineries, glycolysis and oxidative phosphorylation, to satisfy the robustly increased adenosine triphosphate (ATP) demand.

Increased ski expression levels are associated with a higher risk and poor prognosis in patients with gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most commonly diagnosed primary mesenchymal tumors of the gastrointestinal tract and 30% of GISTs are associated with a high recurrence risk or metastasis. The current risk classification criteria of the National Comprehensive Cancer Network are based on tumor size, mitotic activity and localization. Investigating additional biomarkers associated with clinical risk may aid in the diagnosis of GIST and improves prediction of patient prognosis.

Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex.

Background: Vacuolar sorting protein 35 (VPS35), a critical component of retromer, is essential for selective endosome-to-Golgi retrieval of membrane proteins. It is highly expressed in microglial cells, in addition to neurons. We have previously demonstrated microglial VPS35's functions in preventing hippocampal, but not cortical, microglial activation, and in promoting adult hippocampal neurogenesis.

PKC Mediates LPS-Induced IL-1β Expression and Participates in the Pro-inflammatory Effect of AR Under High Glutamate Concentrations in Mouse Microglia.

Pathogens such as bacterial lipopolysaccharide (LPS) play an important role in promoting the production of the inflammatory cytokines interleukin-1 beta (IL-1β) and tumour necrosis factor-α (TNF-α) in response to infection or damage in microglia. However, whether different signalling pathways regulate these two inflammatory factors remains unclear. The protein kinase C (PKC) family is involved in the regulation of inflammation, and our previous research showed that the activation of the PKC pathway played a key role in the LPS-induced transformation of the adenosine A receptor (AR) from anti-inflammatory activity to pro-inflammatory activity under high glutamate concentrations.

Exploration of the glutamate-mediated retinal excitotoxic damage: a rat model of retinal neurodegeneration.

Aim: To explore the more suitable concentration of glutamate or N-methyl-D-aspartic acid (NMDA) for intravitreal injection to establish a rat model of retinal neurodegeneration.

Methods: We injected different doses of glutamate (20 or 50 nmol) or NMDA (40 nmol) into the vitreous chambers of rats, then measured the concentration of glutamate and retinal thickness, quantified apoptotic cells and determined the degree of tau hyperphosphorylation at different time points. -test was used for comparison of two groups.

Caffeine attenuates brain injury but increases mortality induced by high-intensity blast wave exposure.

Caffeine is a substance that is consumed worldwide, and it may exert neuroprotective effects against various cerebral insults, including neurotrauma, which is the most prevalent injury among military personnel. To investigate the effects of caffeine on high-intensity blast wave-induced severe blast injury in mice, three different paradigms of caffeine were applied to male C57BL/6 mice with severe whole body blast injury (WBBI). The results demonstrated that chronic caffeine treatment alleviated blast-induced traumatic brain injury (bTBI); however, both chronic and acute caffeine treatments exacerbated blast-induced lung injuries and, more importantly, increased both the cumulative and time-segmented mortalities postinjury.

The ERK/CREB pathway is involved in the c-Ski expression induced by low TGF-β1 concentrations during primary fibroblast proliferation.

Increasing evidence has suggested that bidirectional regulation of cell proliferation is one important effect of TGF-β1 in wound healing. Increased c-Ski expression plays a role in promoting fibroblast proliferation at low TGF-β1 concentrations, but the mechanism by which low TGF-β1 concentrations regulate c-Ski levels remains unclear. In this study, the proliferation of rat primary fibroblasts was assessed with an ELISA BrdU kit.