RESUMEN
AIMS: Microarray analysis of hippocampal tissue from chronic binge alcohol (CBA)-administered, simian immunodeficiency virus (SIV)-infected male macaques identified altered immune response and neurogenesis as potential mechanisms underlying cognitive deficits in macaques. This study investigated the differential brain region associations between markers of neuroinflammation and growth factor signaling with microtubule-associated protein 2 (MAP2) expression. METHODS: Adult male rhesus macaques were administered CBA (13-14 g EtOH/kg/week, n = 8) or sucrose (SUC, n = 7) beginning 3 months prior to SIV infection and continued until animals reached end-stage disease criteria (3-24 months post infection). Expression of inflammatory cytokines, growth factors, and viral loads were determined in the prefrontal cortex (PFC), caudate (CD), and hippocampus (HP). Brain-derived neurotropic factor (BDNF) expression and phosphorylation of intracellular kinases downstream of BDNF were investigated in the PFC. RESULTS: Our results show reduced MAP2 expression in the PFC of longer-surviving, CBA/SIV macaques. BDNF expression was most closely associated with MAP2 expression in the PFC. In the caudate, significant positive associations were observed between MAP2 and BDNF, time to end-stage and set-point viral load and significant negative associations for CBA. In the hippocampus, positive associations were observed between MAP2 and inflammatory cytokines, and negative associations for brain viral load and CBA. CONCLUSIONS: CBA differentially affects growth factor and inflammatory cytokine expression and viral load across brain regions. In the PFC, suppression of growth factor signaling may be an important neuropathological mechanism, while inflammatory processes may play a more important role in the CD and HP.
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Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Encéfalo/metabolismo , Mediadores de Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/metabolismo , Virus de la Inmunodeficiencia de los Simios , Animales , Consumo Excesivo de Bebidas Alcohólicas/complicaciones , Consumo Excesivo de Bebidas Alcohólicas/patología , Encéfalo/patología , Macaca mulatta , Masculino , Transducción de Señal/fisiología , Síndrome de Inmunodeficiencia Adquirida del Simio/complicaciones , Síndrome de Inmunodeficiencia Adquirida del Simio/patologíaRESUMEN
BACKGROUND: Chronic intermittent ethanol vapor (CIEV) exposure has been used extensively to produce rodent models of alcohol dependence, but unlike other models of alcohol abuse, CIEV has not been assessed as a model of end-organ damage. The purpose of this study was to characterize the effects of CIEV on peripheral organ systems affected by alcohol abuse, including the liver, lungs, and cardiovascular system. METHODS: Adult male Sprague-Dawley rats were exposed to daily CIEV for a period of 8 weeks (14HR ON/10HR OFF), producing blood alcohol levels of ~200 mg/dl. Controls were exposed to room air. After 8 weeks, echocardiography was performed to assess cardiac function. Indices of liver injury (alanine and aspartate aminotransferases [ALT and AST]; cytochrome p450 2E1 [CYP2E1]; alcohol dehydrogenase [ADH]; Oil Red O and triglyceride content; lipid peroxidation; inflammatory cytokine expression; and macrophage infiltration), and lung inflammatory cell count, proinflammatory cytokine expression, and lipid peroxidation were measured. RESULTS: Left ventricular posterior wall thickness was significantly decreased, and systolic blood pressure was significantly elevated by CIEV compared with air controls. CIEV led to a significant increase in plasma ALT and triglycerides compared with room air controls. CIEV did not affect liver triglyceride content, lipid staining or peroxidation, but increased CYP2E1 and chemokine (C-C motif) ligand 2 (CCL2) protein expression, while decreasing ADH expression. CIEV significantly increased numbers of both polymorphonuclear neutrophils and lymphocytes in the bronchoalveolar lavage fluid, indicative of pulmonary inflammation. However, CIEV did not produce significant changes in lung mass, pulmonary lipid peroxidation, inflammatory cytokine expression, or edema. CONCLUSIONS: These results show that CIEV produces hepatic, pulmonary, and cardiovascular effects in rats similar to those found in other models of chronic alcohol administration. Alcohol vapor administration is a novel method of alcohol-induced tissue injury with high potential for widespread use in alcohol toxicology research.
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Trastornos Inducidos por Alcohol/sangre , Trastornos Inducidos por Alcohol/patología , Modelos Animales de Enfermedad , Etanol/administración & dosificación , Etanol/toxicidad , Administración por Inhalación , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Densidad Ósea/efectos de los fármacos , Densidad Ósea/fisiología , Edema/sangre , Edema/inducido químicamente , Edema/patología , Hepatopatías Alcohólicas/sangre , Hepatopatías Alcohólicas/patología , Enfermedades Pulmonares/sangre , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/patología , Masculino , Ratas , Ratas Sprague-Dawley , VolatilizaciónRESUMEN
Traumatic brain injury (TBI) represents a leading cause of morbidity and mortality among young individuals. Alcohol abuse is a risk factor associated with increased TBI incidence. In addition, up to 26% of TBI patients engage in alcohol consumption after TBI. Limited preclinical studies have examined the impact of post-injury alcohol exposure on TBI recovery. The aim of this study was to determine the isolated and combined effects of TBI and alcohol on cognitive, behavioral, and physical recovery, as well as on associated neuroinflammatory changes. Male Sprague-Dawley rats (â¼300g) were subjected to a mild focal TBI by lateral fluid percussion (â¼30PSI, â¼25ms) under isoflurane anesthesia. On day 4 after TBI, animals were exposed to either sub-chronic intermittent alcohol vapor (95% ethanol 14h on/10h off; BALâ¼200mg/dL) or room air for 10days. TBI induced neurological dysfunction reflected by an increased neurological severity score (NSS) showed progressive improvement in injured animals exposed to room air (TBI/air). In contrast, TBI animals exposed to alcohol vapor (TBI/alcohol) showed impaired NSS recovery throughout the 10-day period of alcohol exposure. Open-field exploration test revealed an increased anxiety-like behavior in TBI/alcohol group compared to TBI/air group. Additionally, alcohol-exposed animals showed decreased locomotion and impaired novel object recognition. Immunofluorescence showed enhanced reactive astrocytes, microglial activation, and HMGB1 expression localized to the injured cortex of TBI/alcohol as compared to TBI/air animals. The expression of neuroinflammatory markers showed significant positive correlation with NSS. These findings indicated a close relationship between accentuated neuroinflammation and impaired neurological recovery from post-TBI alcohol exposure. The clinical implications of long-term consequences in TBI patients exposed to alcohol during recovery warrant further investigation.
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Consumo de Bebidas Alcohólicas/inmunología , Lesiones Encefálicas/inmunología , Depresores del Sistema Nervioso Central/farmacología , Corteza Cerebral/efectos de los fármacos , Etanol/farmacología , Conducta Exploratoria/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Lesiones Encefálicas/fisiopatología , Corteza Cerebral/inmunología , Corteza Cerebral/lesiones , Corteza Cerebral/patología , Ectodisplasinas/efectos de los fármacos , Ectodisplasinas/inmunología , Conducta Exploratoria/fisiología , Proteína Ácida Fibrilar de la Glía/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/inmunología , Proteína HMGB1/efectos de los fármacos , Proteína HMGB1/inmunología , Inflamación , Ratas , Ratas Sprague-Dawley , Reconocimiento en Psicología/fisiología , Índices de Gravedad del TraumaRESUMEN
OBJECTIVE: The present study examined interactions between simian immunodeficiency virus (SIV), chronic binge alcohol (CBA), and antiretroviral therapy (ART) on growth factor signaling, neuroinflammatory markers, viral loads (VL), and CD4+ cell counts. DESIGN: Adult male rhesus macaques were administered CBA (13-14âg ethanol (EtOH)/kg per week) or sucrose (SUC) 3 months prior to SIVmac251 infection until the study endpoint. At viral setpoint, a subset of CBA/SIV+ and SUC/SIV+ macaques were randomized to receive daily ART (9-[2-Phosphonyl-methoxypropyly]adenine [PMPA] 20âmg/kg, 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), 30âmg/kg). Frontal cortex (FC) and basal ganglia (BG) were collected for gene and protein expression. METHODS: Relationships between brain and plasma VL or CD4+ cell counts were determined using linear regression. Effects of SIV, CBA, and ART on markers of neuroinflammation and brain-derived neurotrophic factor (BDNF) signaling were determined by ANOVA and linear regression. RESULTS: SIV increased FC and BG neuroinflammatory and glial cell gene expression (CX3CR1, B2M), and reduced FC protein kinase B phosphorylation. CBA decreased FC and BG tropomyosin receptor kinase B (TrkB) phosphorylation, and increased full-length TrkB (TrkB-FL) and SLC1A3 expression in FC and BG, respectively. ART suppressed plasma and brain VL, reduced neuroinflammatory gene expression in FC (IBA1, CX3CR1, and GFAP), and BG (CD74 and CD11ß), and did not restore FC or BG BDNF signaling deficits. CONCLUSIONS: Results show ART-mediated reduction in VL and neuroinflammatory gene expression, irrespective of CBA administration. ART did not attenuate SIV- and CBA-mediated BDNF signaling deficits, suggesting these deficits, despite effective neuroinflammation suppression, may explain CBA- and SIV-associated neurocognitive deficits. Therapeutics targeting growth factor signaling may be important adjuvants in treating HIV-associated neurocognitive decline.
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Consumo Excesivo de Bebidas Alcohólicas , Infecciones por VIH , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Factor Neurotrófico Derivado del Encéfalo , Etanol , Macaca mulatta , Masculino , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Carga ViralRESUMEN
Alcohol use disorders (AUD) exacerbate neurocognitive dysfunction in Human Immunodeficiency Virus (HIV+) patients. We have shown that chronic binge alcohol (CBA) administration (13-14 g EtOH/kg/wk) prior to and during simian immunodeficiency virus (SIV) infection in rhesus macaques unmasks learning deficits in operant learning and memory tasks. The underlying mechanisms of neurocognitive alterations due to alcohol and SIV are not known. This exploratory study examined the CBA-induced differential expression of hippocampal genes in SIV-infected (CBA/SIV+; n = 2) macaques in contrast to those of sucrose administered, SIV-infected (SUC/SIV+; n = 2) macaques. Transcriptomes of hippocampal samples dissected from brains obtained at necropsy (16 months post-SIV inoculation) were analyzed to determine differentially expressed genes. MetaCore from Thomson Reuters revealed enrichment of genes involved in inflammation, immune responses, and neurodevelopment. Functional relevance of these alterations was examined in vitro by exposing murine neural progenitor cells (NPCs) to ethanol (EtOH) and HIV trans-activator of transcription (Tat) protein. EtOH impaired NPC differentiation as indicated by decreased ßIII tubulin expression. These findings suggest a role for neuroinflammation and neurogenesis in CBA/SIV neuropathogenesis and warrant further investigation of their potential contribution to CBA-mediated neurobehavioral deficits.
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Consumo Excesivo de Bebidas Alcohólicas/complicaciones , Perfilación de la Expresión Génica/métodos , Hipocampo/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Animales , Consumo Excesivo de Bebidas Alcohólicas/genética , Consumo Excesivo de Bebidas Alcohólicas/inmunología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Etanol/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Macaca mulatta/virología , Ratones , Neurogénesis/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunologíaRESUMEN
Alcohol consumption contributes to increased incidence and severity of traumatic injury. Compared with patients who do not consume alcohol, alcohol-consuming patients have higher rates of long-term morbidity and mortality during recovery from injury. This can be attributed in part to an impaired immune response in individuals who consume alcohol. Acute and chronic alcohol use can affect both the innate and adaptive immune defense responses within multiple organ systems; the combination of alcohol use and injury results in increased susceptibility to bacterial and viral pathogens. This review examines the major deleterious effects of alcohol on immunity following tissue damage or traumatic injury, with a focus on alcohol's influence on the ability of the immune and major organ systems to fight disease and to repair damaged tissues following injury.