Synthesis of Imidazo[4,5-d]oxazolo[3,4-a]pyridines. New Heterocyclic Analogues of Lignans

Madrigal, Blanca; Puebla, Pilar; Caballero, Esther; Peláez, Rafael; Gravalos, D. G.; Medarde, Manuel

doi:10.1002/1521-4184(200105)334:5<177::aid-ardp177>3.0.co;2-k

Cited by 4 publications

(2 citation statements)

References 9 publications

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“…2). Similarly stress increases brain NF-κB activation (Madrigal et al 2001), cytokines, prostaglandin E2 and COX-2 levels (Madrigal et al 2003) in part due to reversal of acute glucocorticoid anti-inflammatory responses to pro-inflammatory NF-κB activation in frontal cortex (Munhoz et al 2010). Stress and drug abuse cycles promote addiction and elevate glucocorticoids (Armario 2010), likely contributing to activation of brain NF-κB transcription of innate immune genes.…”

Section: Stress and Drug Abuse Promote Addiction And Nf-κb Transcriptmentioning

confidence: 99%

Induction of innate immune genes in brain create the neurobiology of addiction

Crews

Zou

Qin

2011

Brain, Behavior, and Immunity

280

244

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Addiction occurs through repeated abuse of drugs that progressively reduce behavioral control and cognitive flexibility while increasing limbic negative emotion. Recent discoveries indicate neuroimmune signaling underlies addiction and co-morbid depression. Low threshold microglia undergo progressive stages of innate immune activation involving astrocytes and neurons with repeated drug abuse, stress, and/or cell damage signals. Increased brain NF-κB transcription of proinflammatory chemokines, cytokines, oxidases, proteases, TLR and other genes create loops amplifying NF-κB transcription and innate immune target gene expression. Human post-mortem alcoholic brain has increased NF-κB and NF-κB target gene message, increased microglial markers and chemokine-MCP1. Polymorphisms of human NF-κB1 and other innate immune genes contribute to genetic risk for alcoholism. Animal transgenic and genetic studies link NF-κB innate immune gene expression to alcohol drinking. Human drug addicts show deficits in behavioral flexibility modeled pre-clinically using reversal learning. Binge alcohol, chronic cocaine, and lesions link addiction neurobiology to frontal cortex, neuroimmune signaling and loss of behavioral flexibility. Addiction also involves increasing limbic negative emotion and depression-like behavior that is reflected in hippocampal neurogenesis. Innate immune activation parallels loss of neurogenesis and increased depression-like behavior. Protection against loss of neurogenesis and negative affect by anti-oxidant, anti-inflammatory, anti-depressant, opiate antagonist and abstinence from ethanol dependence link limbic affect to changes in innate immune signaling. The hypothesis that innate immune gene induction underlies addiction and affective disorders creates new targets for therapy.

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Section: Stress and Drug Abuse Promote Addiction And Nf-κb Transcriptmentioning

confidence: 99%

Induction of innate immune genes in brain create the neurobiology of addiction

Crews

Zou

Qin

2011

Brain, Behavior, and Immunity

280

244

View full text Add to dashboard Cite

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“…Furthermore, work from our laboratory and others indicate that ethanol also increases the transcription of NF-κB target genes, including chemokine monocyte chemoattractant protein-1 (MCP-1, CCL2; He and Crews, 2008), proinflammatory cytokines [tumor necrosis factor-α (TNFα), Interleukin (IL)-1β, and IL-6], proinflammatory oxidases [iNOS (Zou and Crews, 2010), cyclooxygenase (COX; Knapp and Crews, 1999), and NOX (Qin et al, 2008)], and proteases (TACE and tPA; Zou and Crews, 2010). Similarly, stress increases the expression of NF-κB (Madrigal et al, 2001), cytokines, prostaglandin E2, and COX-2 levels (Madrigal et al, 2003) in the brain. In addition, chronic stress causes the reversal of acute glucocorticoid anti-inflammatory responses to proinflammatory NF-κB activation in the cortex (Munhoz et al, 2010).…”

Section: Drugs and Stress Induce Innate Immune Genes Through Activatimentioning

confidence: 99%

Addiction, Adolescence, and Innate Immune Gene Induction

Crews¹,

Vetreno²

2011

Front. Psychiatry

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Repeated drug use/abuse amplifies psychopathology, progressively reducing frontal lobe behavioral control, and cognitive flexibility while simultaneously increasing limbic temporal lobe negative emotionality. The period of adolescence is a neurodevelopmental stage characterized by poor behavioral control as well as strong limbic reward and thrill seeking. Repeated drug abuse and/or stress during this stage increase the risk of addiction and elevate activator innate immune signaling in the brain. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a key glial transcription factor that regulates proinflammatory chemokines, cytokines, oxidases, proteases, and other innate immune genes. Induction of innate brain immune gene expression (e.g., NF-κB) facilitates negative affect, depression-like behaviors, and inhibits hippocampal neurogenesis. In addition, innate immune gene induction alters cortical neurotransmission consistent with loss of behavioral control. Studies with anti-oxidant, anti-inflammatory, and anti-depressant drugs as well as opiate antagonists link persistent innate immune gene expression to key behavioral components of addiction, e.g., negative affect-anxiety and loss of frontal–cortical behavioral control. This review suggests that persistent and progressive changes in innate immune gene expression contribute to the development of addiction. Innate immune genes may represent a novel new target for addiction therapy.

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