S14 * IDENTIFICATION OF NEUROINFLAMMATION IN THE BRAIN IN VIVO AND IN VITRO AND THERAPEUTIC STRATEGIES TO COMBAT ITS PROGRESSION * S14.1 * INFLAMMATORY PROCESSES IN NEURODEGENERATIVE DISEASES

Autor: R. Crichton, D. T. Dexter, R. J. Ward, N. Kalk, E. A. Rabiner, A. R. Lingford-Hughes, R. Ward, P. De Witte, F. Lallemand, X. Noel, S. Campanella, P. Verbank, F. Crews
Rok vydání: 2011
Předmět:
Zdroj: Alcohol and Alcoholism. 46:i13-i14
ISSN: 1464-3502
0735-0414
Popis: Changes in morphology in specific brain regions are observed in various neurodegenerative diseases, e.g. Parkinson's and Alzheimer's diseases as well as in chronic alcohol abusers and adolescents involved in ‘binge dirnking’. Such changes are known to be associated with alterations in motor function as well as in cognitive impairment. The exact triggers for each of these neurodegenerative processes are unknown, although alcohol and its metabolite acetaldehyde contribute to alcohol-induced brain damage. A common factor in all of these diseases is the occurrence of neuroinflammation, which occurs at an early stage of the disease process and drives the disease pathology. The signalling pathways that are involved in such neuroinflammation include various transition metals, iron and copper, mitochondrial dysfunction as well as activation of the innate immune system. Metals as well as alcohol metabolism can generate reactive oxygen species that can initiate lipid peroxidation by attacking polyunsaturated fatty acids in membrane phospholipids, generating a family of reactive aldehydes, which can undergo Michael-type additions to protein thiol, imidazole and amino groups. Together with other oxidative modifications, this generates protein carbonyls, causing protein denaturation and aggregation. In turn, this overwhelms the ubiquitin/proteasome system, which can no longer eliminate these defective, damaged proteins. Aggregates of these ubiquinated proteins are a prominent pathological feature found within intracellular inclusion bodies in specific brain regions in many ‘protein conformational’ neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS and Huntington's disease. # S14.2 IMAGING NEUROINFLAMMATION IN ALCOHOLISM {#article-title-2} Cognitive deficits may impair the ability of patients' engagement in behavior change programs. Alcohol-related brain damage (ARBD) may present sub-clinically, and is a growing cause of cognitive impairment. While thiamine deficiency has been emphasized as a cause of ARBD and parenteral thiamine is an important preventative strategy, the mechanisms are probably multifactorial. The role of neuroinflammation in the pathogenesis of a wide range of neurodegenerative processes following acute and chronic insults is receiving growing attention. Pre-clinical and post-mortem evidence suggest that neuroinflammation is important in the pathogenesis of ARBD, but this has yet to be demonstrated in vivo in the human brain. The 18 kDa Translocator Protein (TSPO) is upregulated in activated microglia. PET ligands specific for the TSPO have been proposed to be useful for the quantification of neuroinflammation in human subjects in vivo . [11C]PK11195 has been used extensively for the past 20 years for this purpose, and hepatic encephalopathy, including cases precipitated by alcohol, is associated with increased [11C]PK11195 binding (Cagnin et al. , 2006). The utility of [11C]PK11195 has been limited by uncertainties in its quantification, due to a low signal-to-noise ratio in the tissue and problematic plasma quantification. Novel TSPO ligands such as [11C]PBR28 address these problems (Imaizumi et al. , 2008) and provide an exciting opportunity to probe the role of neuroinflammation in the pathogenesis of cognitive impairment related to chronic alcohol intake. Such a tracer could be used to investigate the relationship between microglial activation and indices of cognitive function. The time course of microglial activation has prognostic significance in other disorders (Ramlackhansingh et al., 2011), and may be relevant in ARBD. The relationship between neuroinflammation and neurotransmitter perturbations in alcohol dependence and withdrawal may be detectable by imaging in vivo in the human brain (Umhau et al. , 2010). Finally, TSPO ligand PET studies provide the opportunity to quantify the change in neuroinflammation produced by novel prophylactic compounds. # S14.3 CAN PERIPHERAL MARKERS INDICATE NEUROINFLAMMATION? {#article-title-3} There is increasing evidence that indicates that there is an association between the circulating concentrations of low-grade chronic inflammatory markers with cognitive symptoms of depression, Parkinson's and Alzheimer's disease. However, there have been no studies as to whether such changes occur in chronic alcohol abusers or intermittent alcohol users. Such alterations may be pertinent markers of alcohol-induced brain damage. In our recent studies, we have shown that alveolar macrophages isolated from ‘binge drinking’ rats are activated (increased IL-6 and TNFα production as well as inducible nitric oxide synthase activity), prior to and after lipopolysaccharide stimulation by comparison with control rats which were indicative of neuroinflammation in specific brain regions. Such changes were not apparent after the activation had been suppressed by administration of an NFkappaB inhibitor. These studies have been further extended in Belgian University students deemed to be ‘binge drinkers’ or not. General cognitive tests for personality, depression, anxiety, impulsivity and social cognition were assessed by validated questionnaires, and correlated with plasma cytokine content as well as the cytokine content in isolated blood monocytes before and after stimulation. The results of these studies indicate that combinations of various pro-inflammatory and anti-inflammatory cytokines may be pertinent markers of alcohol abuse and neuroinflammation in intermittent alcohol abusers. (The financial support of ERAB is gratefully acknowledged.) # S14.4 INFLAMMASOME INDUCTION REGULATES HIPPOCAMPAL NEUROGENESIS AND DEPRESSION {#article-title-4} Adult hippocampal neurogenesis is implicated in the regulation of mood and cognition. In vivo , exercise and antidepressants increase neurogenesis, whereas stress, ethanol, other addictive drugs, inflammation and aging reduce neurogenesis. Chronic ethanol self-administration in mice induces depression-like behavior (forced swim test) and decreases hippocampal neurogenesis. Antidepressant treatment reverses both depression-like behavior and loss of neurogenesis. Mechanisms were investigated using hippocampal brain slice culture neurogenesis. Similar to in vivo , ethanol treatment reduced slice neurogenesis by 50–70%. Ethanol also increased mRNA for a variety of neuroimmune genes, TNFalpha, MCP-1, IL-1beta and IL6. In mice, chronic ethanol treatment increases the levels of neuroimmune gene expression. Post-mortem human alcoholic brain shows increased levels of neuroimmune genes consistent with ethanol-induced neuroinflammation. In brain slice cultures, exogenous IL-1beta, TNFalpha and MCP1 reduce neurogenesis. Neutralizing antibodies to IL-1beta added to slice cultures increased neurogenesis and completely reversed ethanol inhibiton of neurogenesis. Exogenous IL-1 receptor antagonist, IL-1RIa, also blocked ethanol inhibition of neurogenesis, suggesting that IL-1beta mediates ethanol inhibition of neurogenesis. A number of drugs reverse ethanol inhibition of neurogenesis. Antidressants that are effective treatments of human depression reverse ethanol induction of IL1beta and stimulate neurogenesis. Drugs that blunt neuroimmune activation, block inflammasome formation or NFkappaB activation reverse ethanol inhibition of neurogenesis. These findings suggest that inflammasome induction and loss of neurogenesis contribute depression and negative affect. Antidepressants and anti-neuroinflammatory drugs reverse ethanol inhibition of neurogenesis through inhibition of IL-1beta. (This study was supported by NIH and NIAAA.)
Databáze: OpenAIRE
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