Choi, Doo‐Sup

Non-canonical IκB kinases (IKKs) TBK1 and IKKε have essential roles as regulators of innate immunity and cancer. Recent work has also implicated these kinases in distinctively controlling glucose homeostasis and repressing adaptive thermogenic and mitochondrial biogenic response upon obesity-induced inflammation. Additionally, TBK1 and IKKε regulate pancreatic β-cell regeneration. In this review, we summarize current data on the functions and molecular mechanisms of TBK1 and IKKε in orchestrating inflammation to cancer, obesity, and diabetes.

AbstractAcamprosate is an FDA‐approved medication for the treatment of alcoholism that is unfortunately only effective in certain patients. Although acamprosate is known to stabilize the hyper‐glutamatergic state in alcoholism, pharmacological mechanisms of action in brain tissue remains unknown. To investigate the mechanism of acamprosate efficacy, the authors employ a pharmacoproteomics approach using an animal model of alcoholism, type 1 equilibrative nucleoside transporter (ENT1) null mice. The results demonstrate that acamprosate treatment significantly decreased both ethanol drinking and preference in ENT1 null mice compared to that of wild‐type mice. Then, to elucidate acamprosate efficacy mechanism in ENT1 null mice, the authors utilize label‐free quantification proteomics comparing both genotype and acamprosate treatment effects in the nucleus accumbens (NAc). A total of 1040 protein expression changes are identified in the NAc among 3634 total proteins detected. The proteomics and Western blot result demonstrate that acamprosate treatment decreased EAAT expression implicating stabilization of the hyper‐glutamatergic condition in ENT1 null mice. Pathway analysis suggests that acamprosate treatment in ENT1 null mice seems to rescue glutamate toxicity through restoring of RTN4 and NF‐κB medicated neuroimmune signaling compared to wild‐type mice. Overall, pharmacoproteomics approaches suggest that neuroimmune restoration is a potential efficacy mechanism in the acamprosate treatment of certain sub‐populations of alcohol dependent subjects.

Abstract Although the precise drug mechanism of action of acamprosate remains unclear, its antidipsotropic effect is mediated in part through glutamatergic neurotransmission. We evaluated the effect of 4 weeks of acamprosate treatment in a cohort of 13 subjects with alcohol dependence (confirmed by a structured interview, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) on proton magnetic resonance spectroscopy glutamate levels in the midline anterior cingulate cortex (MACC). We compared levels of metabolites with a group of 16 healthy controls. The Pennsylvania Alcohol Craving Scale was used to assess craving intensity. At baseline, before treatment, the mean cerebrospinal fluid–corrected MACC glutamate (Glu) level was significantly elevated in subjects with alcohol dependence compared with controls (P = 0.004). Four weeks of acamprosate treatment reduced glutamate levels (P = 0.025), an effect that was not observed in subjects who did not take acamprosate. At baseline, there was a significant positive correlation between cravings, measured by the Pennsylvania Alcohol Craving Scale, and MACC (Glu) levels (P = 0.019). Overall, these data would suggest a normalizing effect of acamprosate on a hyperglutamatergic state observed in recently withdrawn patients with alcohol dependence and a positive association between MACC glutamate levels and craving intensity in early abstinence. Further research is needed to evaluate the use of these findings for clinical practice, including monitoring of craving intensity and individualized selection of treatment with antidipsotropic medications in subjects with alcohol dependence.

AbstractBackgroundAdenosine signaling has been implicated in several neurological and psychiatric disorders. Previously, we found that astrocytic excitatory amino acid transporter 2 (EAAT2) and aquaporin 4 (AQP4) are downregulated in the striatum of mice lacking type 1 equilibrative nucleoside transporter (ENT1).MethodsTo further investigate the gene expression profile in the striatum, we preformed Illumina Mouse Whole Genome BeadChip microarray analysis of the caudate–putamen (CPu) and nucleus accumbens (NAc) inENT1 null mice. Gene expression was validated byRT‐PCR, Western blot, and immunofluorescence. Using transgenic mice expressing enhanced green fluorescence protein (EGFP) under the control of the glial fibrillary acidic protein (GFAP) promoter, we examinedEGFPexpression in anENT1 null background.ResultsGlial fibrillary acidic protein was identified as a top candidate gene that was reduced in ENT1 null mice compared to wild‐type littermates. Furthermore, EGFP expression was significantly reduced in GFAP‐EGFP transgenic mice in an ENT1 null background in both the CPu and NAc. Finally, pharmacological inhibition or siRNA knockdown of ENT1 in cultured astrocytes also reduced GFAPmRNAlevels.ConclusionsOverall, our findings demonstrate thatENT1 regulatesGFAPexpression and possibly astrocyte function.

Abstract Aging and the presence of cerebrovascular disease are associated with increased incidence of Alzheimer's disease. A common feature of aging and cerebrovascular disease is decreased endothelial nitric oxide (NO). We studied the effect of a loss of endothelium derived NO on amyloid precursor protein (APP) related phenotype in late middle aged (LMA) (14–15 month) endothelial nitric oxide synthase deficient ( eNOS −/− ) mice. APP, β‐site APP cleaving enzyme (BACE) 1, and amyloid beta (Aβ) levels were significantly higher in the brains of LMA eNOS −/− mice as compared with LMA wild‐type controls. APP and Aβ 1‐40 were increased in hippocampal tissue of eNOS −/− mice as compared with wild‐type mice. LMA eNOS −/− mice displayed an increased inflammatory phenotype as compared with LMA wild‐type mice. Importantly, LMA eNOS −/− mice performed worse in a radial arm maze test of spatial learning and memory as compared with LMA wild‐type mice. These data suggest that chronic loss of endothelial NO may be an important contributor to both Aβ related pathology and cognitive decline. image Cardiovascular risk factors are associated with increased incidence of Alzheimer's disease (AD). A common feature of these risk factors is decreased endothelial nitric oxide (NO). We observed, in mice deficient in endothelial nitric oxide synthase, increased amyloid precursor protein (APP), β‐site APP cleaving enzyme 1, amyloid beta levels, microglial activation, and impaired spatial memory. This suggests chronic loss of endothelial NO may be an important contributor to the pathogenesis of sporadic AD.