Sustained antidepressant effects of ketamine metabolite involve GABAergic inhibition-mediated molecular dynamics in aPVT glutamatergic neurons.

Despite the rapid and sustained antidepressant effects of ketamine and its metabolites, their underlying cellular and molecular mechanisms are not fully understood. Here, we demonstrate that the sustained antidepressant-like behavioral effects of (2S,6S)-hydroxynorketamine (HNK) in repeatedly stressed animal models involve neurobiological changes in the anterior paraventricular nucleus of the thalamus (aPVT). Mechanistically, (2S,6S)-HNK induces mRNA expression of extrasynaptic GABAA receptors and subsequently enhances GABAA-receptor-mediated tonic currents, leading to the nuclear export of histone demethylase KDM6 and its replacement by histone methyltransferase EZH2. This process increases H3K27me3 levels, which in turn suppresses the transcription of genes associated with G-protein-coupled receptor signaling. Thus, our findings shed light on the comprehensive cellular and molecular mechanisms in aPVT underlying the sustained antidepressant behavioral effects of ketamine metabolites. This study may support the development of potentially effective next-generation pharmacotherapies to promote sustained remission of stress-related psychiatric disorders.

The defects of the hippocampal ripples and theta rhythm in depression, and the effects of physical exercise on their amelioration.

Adverse environmental stress causes depressive symptoms with the impairments of memory formation, cognition, and motivation, however, their underlying neural bases have not been well understood, especially based on the observation of living animals. In the present study, therefore, the mice model of restraint-induced stress was examined electrophysiologically to investigate the alterations of hippocampal sharp wave ripples (SWRs) and theta rhythms. In addition, the therapeutic effects of physical exercise on the amelioration of those hippocampal impairments were examined in combination with a series of behavioral tests. The data demonstrated that chronic restraint stress caused the reductions of occurrence and amplitude of hippocampal SWRs and the decreases of occurrence, duration, and power of theta rhythms, while physical exercise significantly reverted them to the levels of healthy control. Furthermore, hippocampal adult neurogenesis and microglial activation, previously reported to be involved in the etiology of depression, were histologically examined in the mice. The results showed that the impairment of neurogenesis and alleviation of microglial activation were induced in the depressed mice. On the other hand, physical exercise considerably ameliorated those pathological conditions in the affected brain. Consistently, the data of behavioral tests in mice suggested that physical exercise ameliorated the symptomatic defects of motivation, memory formation, and cognition in the depressed mice. The impairments of hippocampal SWRs and theta rhythms in the affected hippocampus are linked with the symptomatic impairments of cognition and motivation, and the defect of memory formation, respectively, in depression. Taken together, this study demonstrated the implications of impairment of the hippocampal SWRs and theta rhythms in the etiology of depression and their usefulness as diagnostic markers of depression.

Discrete prefrontal neuronal circuits determine repeated stress-induced behavioral phenotypes in male mice.

Chronic stress is a major risk factor for psychiatric disorders, including depression. Although depression is a highly heterogeneous syndrome, it remains unclear how chronic stress drives individual differences in behavioral responses. In this study, we developed a subtyping-based approach wherein stressed male mice were divided into four subtypes based on their behavioral patterns of social interaction deficits and anhedonia, the core symptoms of psychiatric disorders. We identified three prefrontal cortical neuronal projections that regulate repeated stress-induced behavioral phenotypes. Among them, the medial prefrontal cortex (mPFC)→anterior paraventricular thalamus (aPVT) pathway determines the specific behavioral subtype that exhibits both social deficits and anhedonia. Additionally, we identified the circuit-level molecular mechanism underlying this subtype: KDM5C-mediated epigenetic repression of Shisa2 transcription in aPVT projectors in the mPFC led to social deficits and anhedonia. Thus, we provide a set of biological aspects at the cellular, molecular, and epigenetic levels that determine distinctive stress-induced behavioral phenotypes.

Endoscope-Controlled High Frontal Approach for Dural Arteriovenous Fistula in Anterior Cranial Fossa.

BACKGROUND: Currently, surgical obliterations are a mainstay for treating dural arteriovenous fistula (DAVF) in the anterior cranial fossa (ACF), which has high risks of hemorrhage and functional disorder. By introducing an endoscope into a high frontal approach and utilizing its advantages, we attempted to establish it as a new surgical procedure that eliminates the drawbacks of various approaches that have been used to date. METHODS: By using 30 clinical datasets of venous-phase head computed tomography angiogram, measurements and comparisons on a 3-dimensional workstation were performed to identify the appropriate positioning of keyhole craniotomy for endoscope-controlled high frontal approach (EHFA). Based on these data, a cadaver-based surgery was simulated to verify the feasibility of EHFA and develop an efficient procedure. RESULTS: In EHFA, though raising the position of the keyhole craniotomy made the operative field deeper, significant advantages were obtained in the angle between the operative axis and the medial-anterior cranial base and the amount of bone removal required at the anterior edge of craniotomy. Minimally invasive EHFA, performed through a keyhole craniotomy without opening the frontal sinus, proved to be feasible on 10 sides of 5 cadaver heads. Moreover, 3 patients with DAVF in ACF were successfully treated by clipping the fistula via EHFA. CONCLUSIONS: EHFA, which provided a direct corridor to the medial ACF at the level of the foramen cecum and crista galli and the minimum necessary operative field, was found to be a suitable procedure for clipping the fistula of DAVF in ACF.

Conformational change of RNA-helicase DHX30 by ALS/FTD-linked FUS induces mitochondrial dysfunction and cytosolic aggregates.

Genetic mutations in fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS). Although mitochondrial dysfunction and stress granule have been crucially implicated in FUS proteinopathy, the molecular basis remains unclear. Here, we show that DHX30, a component of mitochondrial RNA granules required for mitochondrial ribosome assembly, interacts with FUS, and plays a crucial role in ALS-FUS. WT FUS did not affect mitochondrial localization of DHX30, but the mutant FUS lowered the signal of mitochondrial DHX30 and promoted the colocalization of cytosolic FUS aggregates and stress granule markers. The immunohistochemistry of the spinal cord from an ALS-FUS patient also confirmed the colocalization, and the immunoelectron microscope demonstrated decreased mitochondrial DHX30 signal in the spinal motor neurons. Subcellular fractionation by the detergent-solubility and density-gradient ultracentrifugation revealed that mutant FUS also promoted cytosolic mislocalization of DHX30 and aggregate formation. Interestingly, the mutant FUS disrupted the DHX30 conformation with aberrant disulfide formation, leading to impaired mitochondrial translation. Moreover, blue-native gel electrophoresis revealed an OXPHOS assembly defect caused by the FUS mutant, which was similar to that caused by DHX30 knockdown. Collectively, our study proposes DHX30 as a pivotal molecule in which disulfide-mediated conformational change mediates mitochondrial dysfunction and cytosolic aggregate formation in ALS-FUS.

SGK1 in Schwann cells is a potential molecular switch involved in axonal and glial regeneration during peripheral nerve injury.

Schwann cells play an important role in peripheral myelination, and dysfunction of these cells leads to axonal damage. Schwann cells degenerate following peripheral nerve injury. Immature Schwann cells proliferate, differentiate, and support axonal regeneration and extension during recovery. There are a lot of intracellular signals involved in the myelination process. Although serum- and glucocorticoid-inducible kinase (SGK1) in Schwann cells is supposedly involved in developmental myelination, its significance during peripheral nerve injury and repair remains unknown. In this study, we examined the dynamics of SGK1 during peripheral nerve repair and the potential role of SGK in the process. Axonal crush injury was first generated in the right sciatic nerve under anesthesia in mice, which exhibited apparent paralysis and subsequent recovery of the injured hindlimbs. Immunohistochemical analysis revealed the appearance of glial fibrillary acidic protein (GFAP)-positive immature Schwann cells around injured nerves, and SGK1 was present in these cells. Next, we employed S16 cells, a Schwann cell line, to explore the impact of SGK1 on Schwann cells. Administration of the SGK inhibitor gsk650394 decreased cell proliferation and increased cell size. SGK inhibition did not cause cellular injury, suggesting that it suppresses proliferation and enlarges Schwann cells without causing cell death. Furthermore, quantitative PCR and immunoblotting revealed that SGK inhibition upregulated the gene expression of BDNF, MBP, and Krox20, which are facilitating factors for myelination and neural regeneration, and downregulated that of Sox10. Taken together, these findings indicate that SGK1 inactivation in Schwann cells diverts cell fate from proliferation to differentiation.

Failure of DNA double-strand break repair by tau mediates Alzheimer's disease pathology in vitro.

DNA double-strand break (DSB) is the most severe form of DNA damage and accumulates with age, in which cytoskeletal proteins are polymerized to repair DSB in dividing cells. Since tau is a microtubule-associated protein, we investigate whether DSB is involved in tau pathologies in Alzheimer's disease (AD). First, immunohistochemistry reveals the frequent coexistence of DSB and phosphorylated tau in the cortex of AD patients. In vitro studies using primary mouse cortical neurons show that non-p-tau accumulates perinuclearly together with the tubulin after DSB induction with etoposide, followed by the accumulation of phosphorylated tau. Moreover, the knockdown of endogenous tau exacerbates DSB in neurons, suggesting the protective role of tau on DNA repair. Interestingly, synergistic exposure of neurons to microtubule disassembly and the DSB strikingly augments aberrant p-tau aggregation and apoptosis. These data suggest that DSB plays a pivotal role in AD-tau pathology and that the failure of DSB repair leads to tauopathy.

Sex- and Age-related Differences in Spinal Degeneration: An Anatomical and Magnetic Resonance Imaging Study of the Human Spine.

Objectives: A precise anatomical understanding of the morphology of the spine is indispensable for neck and low back pain therapy including rehabilitation. However, few studies have directly addressed spinal morphology with a focus on the height of the vertebral body and discs. The aim of the current study was to analyze sex- and age-related changes in the spine by measuring the distance between adjacent centers of the intervertebral disc spaces from the posterior aspect in cadavers and by using magnetic resonance imaging (MRI) measurements at the cervical and lumbar vertebral levels. Methods: In the cadaveric study, the posterior distance between the adjacent centers of the disc spaces was measured for 58 spinal canals. The equivalent distances were examined using MRI in 370 and 660 subjects who presented with neck pain and back pain, respectively. Results: The distance between the adjacent centers of the intervertebral disc spaces in male cadavers was larger than that in female cadavers from C3 to L5/S1. The MRI results showed that the distance between the adjacent centers of the intervertebral disc spaces decreased with age in all spinal areas in men and women. Cadaveric values were significantly lower than the MRI values in men, whereas in women, no significant differences were observed. Conclusions: These results suggest that age-related changes in the cervical and lumbar spine are associated with differences between men and women in the degrees of progressive vertebral body and disc degeneration.

Endoscopic High Occipital Interhemispheric Transtentorial Approach for Lesions in the Anterosuperior Cerebellum, Upper Fourth Ventricle, and Upper Dorsal Brain Stem.

BACKGROUND: The occipital transtentorial route is considered the most suitable for surgical treatment of lesions arising from the anterosuperior cerebellum, upper fourth ventricle, and upper dorsal brain stem. Therefore, this study examined the feasibility and effectiveness of the endoscopic high occipital interhemispheric transtentorial approach (EHOTA) for lesions in these areas, in achieving results comparable to the endoscopic occipital interhemispheric transtentorial approach (EOTA). EOTA has recently been reported to be an effective procedure for pineal region tumors, having several advantages that include minimal invasiveness with a small entrance limiting the retraction of the occipital lobe, the elimination of blind spots, and the facilitation of fine manipulation due to the bright, magnified panoramic view. METHODS: By using 30 clinical datasets of venous-phase head computed tomography angiogram, measurements on images were performed and differences between EOTA and EHOTA were identified. In addition, the feasibility of EHOTA was verified with 5 cadaver heads. RESULTS: Although the operative field via EHOTA was considered significantly deeper and less maneuverable than with the procedure via EOTA, beneficial angles for manipulation in the superior cerebellum and the fourth ventricle were obtained in EHOTA, on account of their becoming more obtuse. Using EHOTA, it was possible to reach those regions and effectively manipulate all 10 sides of the 5 cadaveric heads, as well as a case with anterosuperior cerebellar cavernous angioma. CONCLUSIONS: EHOTA, which has the same advantages as EOTA, could prove to be an efficacious procedure for lesions in the anterosuperior cerebellum, upper fourth ventricle, and upper dorsal brain stem.

Arbitrary Ca2+ regulation for endothelial nitric oxide, NFAT and NF-κB activities by an optogenetic approach.

Modern western dietary habits and low physical activity cause metabolic abnormalities and abnormally elevated levels of metabolites such as low-density lipoprotein, which can lead to immune cell activation, and inflammatory reactions, and atherosclerosis. Appropriate stimulation of vascular endothelial cells can confer protective responses against inflammatory reactions and atherosclerotic conditions. This study aims to determine whether a designed optogenetic approach is capable of affecting functional changes in vascular endothelial cells and to evaluate its potential for therapeutic regulation of vascular inflammatory responses in vitro. We employed a genetically engineered, blue light-activated Ca2+ channel switch molecule that utilizes an endogenous store-operated calcium entry system and induces intracellular Ca2+ influx through blue light irradiation and observed an increase in intracellular Ca2+ in vascular endothelial cells. Ca2+-dependent activation of the nuclear factor of activated T cells and nitric oxide production were also detected. Microarray analysis of Ca2+-induced changes in vascular endothelial cells explored several genes involved in cellular contractility and inflammatory responses. Indeed, there was an increase in the gene expression of molecules related to anti-inflammatory and vasorelaxant effects. Thus, a combination of human blue light-activated Ca2+ channel switch 2 (hBACCS2) and blue light possibly attenuates TNFα-induced inflammatory NF-κB activity. We propose that extrinsic cellular Ca2+ regulation could be a novel approach against vascular inflammation.

Modulation of inflammatory responses by fractalkine signaling in microglia.

Reactive microglia are suggested to be involved in neurological disorders, and the mechanisms underlying microglial activity may provide insights into therapeutic strategies for neurological diseases. Microglia produce immunological responses to various stimuli, which include fractalkine (FKN or CX3CL1). CX3CR1, a FKN receptor, is present in microglial cells, and when FKN is applied before lipopolysaccharide (LPS) administration, LPS-induced inflammatory responses are inhibited, suggesting that the activation of the FKN signal is beneficial. Considering the practical administration for treatment, we investigated the influence of FKN on immunoreactive microglia using murine primary microglia and BV-2, a microglial cell line. The administration of LPS leads to nitric oxide (NO) production. NO was reduced when FKN was administered 4 h after LPS administration without a change in inducible nitric oxide synthase expression. In contrast, morphological changes, migratory activity, and proliferation were not altered by delayed FKN treatment. LPS decreases the CX3CR1 mRNA concentration, and the overexpression of CX3CR1 restores the FKN-mediated decrease in NO. CX3CR1 overexpression decreased the NO production that is mediated by LPS even without the application of FKN. ATP and ethanol also reduced CX3CR1 mRNA concentrations. In conclusion, the delayed FKN administration modified the LPS-induced microglial activation. The FKN signals were attenuated by a reduction in CX3CR1 by some inflammatory stimuli, and this modulated the inflammatory response of microglial cells, at least partially.

Adrenergic inhibition facilitates normalization of extracellular potassium after cortical spreading depolarization.

Cortical spreading depolarization (CSD) is a propagating wave of tissue depolarization characterized by a large increase of extracellular potassium concentration and prolonged subsequent electrical silencing of neurons. Waves of CSD arise spontaneously in various acute neurological settings, including migraine aura and ischemic stroke. Recently, we have reported that pan-inhibition of adrenergic receptors (AdRs) facilitates the normalization of extracellular potassium after acute photothrombotic stroke in mice. Here, we have extended that mechanistic study to ask whether AdR antagonists also modify the dynamics of KCl-induced CSD and post-CSD recovery in vivo. Spontaneous neural activity and KCl-induced CSD were visualized by cortex-wide transcranial Ca2+ imaging in G-CaMP7 transgenic mice. AdR antagonism decreased the recurrence of CSD waves and accelerated the post-CSD recovery of neural activity. Two-photon imaging revealed that astrocytes exhibited aberrant Ca2+ signaling after passage of the CSD wave. This astrocytic Ca2+ activity was diminished by the AdR antagonists. Furthermore, AdR pan-antagonism facilitated the normalization of the extracellular potassium level after CSD, which paralleled the recovery of neural activity. These observations add support to the proposal that neuroprotective effects of AdR pan-antagonism arise from accelerated normalization of extracellular K+ levels in the setting of acute brain injury.

The TRPM7 Channel in the Nervous and Cardiovascular Systems.

Transient receptor potential melastatin 7 (TRPM7), along with the closely related TRPM6, are unique channels that have dual operations: cation permeability and kinase activity. In contrast to the limited tissue distribution of TRPM6, TRPM7 is widely expressed among tissues and is therefore implicated in a variety of cellular functions physiologically and pathophysiologically. The discovery of TRPM7's unique structure imparting dual ion channel and kinase activities shed light onto novel and peculiar biological functions, such as Mg2+ homeostasis, cellular Ca2+ flickering, and even intranuclear transcriptional regulation by a cleaved kinase domain translocated to nuclei. Interestingly, at a higher level, TRPM7 participates in several biological processes in the nervous and cardiovascular systems, in which excitatory responses in neurons and cardiomyocytes are critical for their function. Here, we review the roles of TRPM7 in cells involved in the nervous and cardiovascular systems and discuss its potential as a future therapeutic target.

Modulation of microglial activity by salt load and SGK1.

Microglial cells are derived from myelogenous cells and their chronic activation elicits brain inflammation, which influences neurological activity. Comprehensive understanding of the regulation of microglial activation could therefore contribute to overcoming neuropsychiatric disorders. Recently, the importance of serum- and glucocorticoid-inducible kinases (SGKs) has been explored in immune cells such as T cells, dendritic cells and macrophages. We have already shown that SGK1 and SGK3 are expressed in microglial cells and associated with the regulation of lipopolysaccharide (LPS)-induced inflammatory molecules. Here we investigate whether salt load influences expression of SGK1 and inflammatory responses in murine primary microglia and an immortalized microglial cell line, BV-2. Additional amounts of NaCl were administrated and immunoblotting was carried out, and SGK1 was induced in dose- and time-dependent manners. Next, the dynamics of inflammatory mediators iNOS and TNFα were investigated by administration of LPS. iNOS mRNA was induced by LPS application and enhanced by NaCl preload. In support of these results, nitric oxide was produced by LPS and accelerated by NaCl preload. In contrast, however, NaCl preload reduced the release of TNFα, suggesting the modulation of immune responses by salt load. The effects of salt load on both cases were attenuated in SGK1-deleted cells. Taken together, these results indicate that salt load modulates inflammatory responses and that SGK1 assists salt load-induced inflammatory responses.

Differences in postural stability and dynamic visual acuity among healthy young adults in relation to sports activity: a cross sectional study.

[Purpose] Sports activity has been shown to improve postural stability and vestibular function in healthy older adults. The hypothesis was that healthy young adults undertaking sports activity will also have better postural stability and vestibular function compared with healthy young adults who do not undertake sports activity. The purpose of this study was to investigate the differences in postural stability and vestibular function between healthy young adults who undertake sports activity and those who do not undertake such activity. [Participants and Methods] Thirty-nine healthy young adults were recruited and divided into sports and non-sports groups on the basis of their response to a questionnaire concerning regular participation in sports activities over the past 12 months. In both groups, postural stability was measured during quiet standing and standing during head rotation, and dynamic visual acuity was assessed during head rotation. [Results] The results showed significant differences in postural stability during head rotation and dynamic visual acuity between the two groups, whereas no significant differences were found in postural stability during quiet standing. [Conclusion] The results suggest that healthy young adults who undertake sports activity have better postural stability during head rotation and better dynamic visual acuity. The causal effect of these differences is not clear and further investigation is warranted.

Objective measures of physical activity in patients with chronic unilateral vestibular hypofunction, and its relationship to handicap, anxiety and postural stability.

OBJECTIVE: Dizziness is one of the most common symptoms in the general population. Patients with dizziness experience balance problems and anxiety, which can lead to decreased physical activity levels and participation in their daily activities. Moreover, recovery of vestibular function from vestibular injury requires physical activity. Although there are reports that decreased physical activity is associated with handicap, anxiety, postural instability and reduced recovery of vestibular function in patients with chronic dizziness, these data were collected by self-report questionnaires. Therefore, the objective data of physical activity and the relationships between physical activity, handicap, anxiety and postural stability in patients with chronic dizziness are not clear. The purpose of this research was to objectively measure the physical activity of patients with chronic dizziness in daily living as well as handicap, anxiety and postural stability compared to healthy adults. Additionally, we aimed to investigate the relationships between physical activity, handicap, anxiety and postural stability in patients with chronic dizziness. METHODS: Twenty-eight patients with chronic dizziness of more than 3 months caused by unilateral vestibular hypofunction (patient group) and twenty-eight age-matched community dwelling healthy adults (healthy group) participated in this study. The amount of physical activity including time of sedentary behavior, light physical activity, moderate to vigorous physical activity and total physical activity using tri-axial accelerometer, self-perceived handicap and anxiety using questionnaires, and postural stability were measured using computerized dynamic posturography. RESULTS: The results showed worse handicap, anxiety and postural stability in the patient group compared to the healthy group. Objective measures of physical activity revealed that the patient group had significantly longer time of sedentary behavior, shorter time of light physical activity, and shorter time of total physical activity compared to the healthy group; however, time of moderate to vigorous physical activity was not significantly different between groups. Moreover, there were correlations between physical activity and postural stability in the patient group, while there were no correlations between physical activity, handicap or anxiety in the patient group. CONCLUSION: These results suggest that objectively measured physical activity of the patients with chronic unilateral vestibular hypofunction is lower compared to the healthy adults, and less active patients showed decreased postural stability. However, the details of physical activity and causal effect between physical activity and postural stability were not clear and further investigation is needed.

Potential implication of SGK1-dependent activity change in BV-2 microglial cells.

It has recently been established that microglial activation is involved in the pathophysiology of various neurological and psychiatric disorders such as amyotrophic lateral sclerosis and schizophrenia. The pathological molecular machineries underlying microglial activation and its accelerating molecules have been precisely described in the diseased central nervous system (CNS). However, to date, the details of physiological mechanism, which represses microglial activation, are still to be elucidated. Our latest report demonstrated that serum- and glucocorticoid-inducible kinases (SGK1 and SGK3) were expressed in multiple microglial cell lines, and their inhibitor enhanced the toxic effect of lipopolysaccharide on microglial production of inflammatory substances such as TNFα and iNOS. In the present report, we prepared SGK1-lacked microglial cell line (BV-2) and demonstrated that deficiency of SGK1 in microglia induced its toxic conversion, in which it took amoeboid morphology characteristic of reactive microglia, increased CD68 expression, quickened its proliferation, and showed higher susceptibility to ATP and subsequent cell death. Our data indicate that SGK1 plays pivotal roles in inhibiting its pathological activation, and suggest its potential function as a therapeutic target for the treatment of various disorders related to the inflammation in the CNS.

In vivo TSPO and cannabinoid receptor type 2 availability early in post-stroke neuroinflammation in rats: a positron emission tomography study.

BACKGROUND: Upregulated levels of 18-kDa translocator proteins (TSPO) and type 2 endocannabinoid receptors (CB2) are considered to reflect different aspects of microglia-related neuroinflammatory responses in the brain. Relative to the increase in the TSPO expression that occurs slightly later during neuroinflammation in a proinflammatory fashion, CB2 activation is considered to relate to the neuroprotective responses that occurs predominantly at an early stage of brain disorders. These findings, however, were deduced from studies with different animal samples under different experimental settings. Here, we aimed to examined the differences in TSPO binding and CB2 availability at an early stage of stroke in the same animal using positron emission tomography (PET). METHODS: We used a total of eight Sprague-Dawley rats that underwent photothrombotic stroke surgery. The binding levels of a TSPO tracer [11C](R)PK11195 and a CB2 tracer [11C]NE40 were measured at 24 h after the surgery in the same animal using PET in combination with immunohistochemistry for CB2 and several other markers. A morphological inspection was also performed with X-ray computed tomography for small animals. RESULTS: The levels of [11C]NE40 binding potential (BPND) were significantly higher in the cerebral cortical region on the lesion side than those on the non-lesion side, whereas no difference was found in the levels of [11C](R)PK11195 BPND between hemispheres. The tracer influx index (R1) data were all reduced on the lesion side irrespective of tracers. This increase in [11C]NE40 BPND was concomitant with an elevation in CB2 expression mainly within the microglia in the peri-infarct area, as shown by immunohistochemical examinations with Iba-1, CD11b/c+, and NG2+ staining. CONCLUSIONS: The present results provide in vivo evidence of different responses of microglia occurring in the acute state of stroke. The use of the CB2 tracer [11C]NE40 allows us to evaluate the roles played by the neuroprotective aspect of microglia in acute neuroinflammatory processes.

Serum- and glucocorticoid-inducible kinases in microglia.

Microglia are derived from myelogenous cells and contribute to immunological and inflammatory responses in central nervous system. They play important roles not only in infectious diseases and inflammation after stroke, but also in psychiatric diseases such as schizophrenia. While recent studies suggest the significances of serum- and glucocorticoid-inducible kinases (SGKs) in other immune cells such as macrophages, T cells and dendritic cells, their role in microglia remains unknown. Here we, for the first time, report that SGK1 and SGK3 are expressed in multiple microglial cell lines. An SGK inhibitor, gsk650394, inhibits cell viability. In addition, lipopolysaccharide-induced expression of inflammatory regulators iNOS and TNFα was enhanced by gsk650394. Furthermore, translocation of NF-κB was enhanced by gsk650394. Taken together, these findings suggest that SGKs may play an important role in regulating microglial viability and inflammatory responses.