Development of the Neuroimmune Modulator Ibudilast for the Treatment of Alcoholism: A Randomized, Placebo-Controlled, Human Laboratory Trial

Ray, Lara A.; Bujarski, Spencer; Shoptaw, Steven; Roche, Daniel; Heinzerling, Keith G.; Miotto, Karen

doi:10.1038/npp.2017.10

Cited by 108 publications

(88 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As such, Ibudilast may be useful as a maintenance therapy to prevent craving for a variety of drugs. Ibudilast may also decrease cue-and stress-induced reinstatement of alcohol craving, as well as decrease the subjective effects of alcohol in individuals with alcohol use disorder (Ray et al, 2017).…”

Section: Clinical Implications and Potential Therapeutic Targetsmentioning

confidence: 99%

Glial mechanisms underlying substance use disorders

Linker

Cross

Leslie

2018

Eur J of Neuroscience

View full text Add to dashboard Cite

Addiction is a devastating disorder that produces persistent maladaptive changes to the central nervous system, including glial cells. Although there is an extensive body of literature examining the neuronal mechanisms of substance use disorders, effective therapies remain elusive. Glia, particularly microglia and astrocytes, have an emerging and meaningful role in a variety of processes beyond inflammation and immune surveillance, and may represent a promising therapeutic target. Indeed, glia actively modulate neurotransmission, synaptic connectivity and neural circuit function, and are critically poised to contribute to addictive‐like brain states and behaviors. In this review, we argue that glia influence the cellular, molecular, and synaptic changes that occur in neurons following drug exposure, and that this cellular relationship is critically modified following drug exposure. We discuss direct actions of abused drugs on glial function through immune receptors, such as Toll‐like receptor 4, as well as other mechanisms. We highlight how drugs of abuse affect glia‐neural communication, and the profound effects that glial‐derived factors have on neuronal excitability, structure, and function. Recent research demonstrates that glia have brain region‐specific functions, and glia in different brain regions have distinct contributions to drug‐associated behaviors. We will also evaluate the evidence demonstrating that glial activation is essential for drug reward and drug‐induced dopamine release, and highlight clinical evidence showing that glial mechanisms contribute to drug abuse liability. In this review, we synthesize the extensive evidence that glia have a unique, pivotal, and underappreciated role in the development and maintenance of addiction.

show abstract

Section: Clinical Implications and Potential Therapeutic Targetsmentioning

confidence: 99%

Glial mechanisms underlying substance use disorders

Linker

Cross

Leslie

2018

Eur J of Neuroscience

View full text Add to dashboard Cite

show abstract

“…In a recent trial, the effects of Ibudilast (50 mg, BID) on measures of subjective response to alcohol, drug cue and stress were examined among participants (n=24) with current (i.e., within the past month) mild-to-severe alcohol use disorder (Ray et al, 2017). After 7 days of medication maintenance, participants completed an IV alcohol administration session (up to target breath alcohol contents: 0.02, 0.04, 0.06, and 0.08 g/dl), an alcohol cue session and a stress-exposure session.…”

Section: Drugs Of Abuse and Glial Cell Activitymentioning

confidence: 99%

Glial and neuroinflammatory targets for treating substance use disorders

Bachtell

Jones

Heinzerling

et al. 2017

Drug and Alcohol Dependence

View full text Add to dashboard Cite

Background The plenary session at the 2016 Behavior, Biology and Chemistry: Translational Research in Addiction Conference focused on glia as potential players in the development, persistence and treatment of substance use disorders. Glia partake in various functions that are important for healthy brain activity. Drugs of abuse alter glial cell activity producing several perturbations in brain function that are thought to contribute to behavioral changes associated with substance use disorders. Consequently, drug-induced changes in glia-driven processes in the brain represent potential targets for pharmacotherapeutics treating substance use disorders. Methods Four speakers presented preclinical and clinical research illustrating the effects that glial modulators have on abuse-related behavioral effects of psychostimulants and opioids. This review highlights some of these findings and expands its focus to include other research focused on drug-induced glia abnormalities and glia-focused treatment approaches in substance use disorders. Results Preclinical findings show that drugs of abuse induce neuroinflammatory signals and disrupt glutamate homeostasis through their interaction with microglia and astrocytes. Preclinical and clinical studies testing the effects of glial modulators show general effectiveness in reducing behaviors associated with substance use disorders. Conclusions The contribution of drug-induced glial activity continues to emerge as an intriguing target for substance use disorder treatments. Clinical investigations of glial modulators have yielded promising results on substance use measures and indicate that they are generally safe and well-tolerated. However, results have not been entirely positive and more questions remain for continued exploration in the development and testing of glial-directed treatments for substance use disorders.

show abstract

“…MIF, and more recently DDT, have been implicated in the pathogenesis of several pathologies, including immunoinflammatory and autoimmune diseases (38,(42)(43)(44) and cancer (45)(46)(47). As anticipated above, that MIF may represent an important pathogenic molecule in the pathogenesis of AUD emerges from recent studies indicating that the dual inhibitor of phosphodiesterase-4 and -10 and MIF, named IBUD, has beneficial effects of AUD both in rodent models and human patients (31,32). In particular, this trial consisted of a randomized, crossover, double-blind, placebo-controlled laboratory study of IBUD in non treatment-seeking individuals that had suffered with mild-to-severe AUD, within the last month.…”

Section: Discussionmentioning

confidence: 93%

Transcriptomic analysis reveals moderate modulation of macrophage migration inhibitory factor superfamily genes in alcohol use disorders

et al. 2020

View full text Add to dashboard Cite

Alcohol use disorder (AUD) is a primary, chronic and relapsing disease of brain reward, motivation and memory, which is associated with several comorbidities, including major depression and post-traumatic stress disorder. It has been revealed that Ibudilast (IBUD), a dual inhibitor of phosphodiesterase-4 and-10 and of macrophage migration inhibitory factor (MIF), exerts beneficial effects on AUD in rodent models and human patients. Therefore, IBUD has attracted increasing interest, with research focusing on the elucidation of the pathogenic role of MIF and its homologue, D-dopachrome tautomerase (DDT), in the pathogenesis and maintenance of AUD. By using DNA microarray analysis, the current study performed a transcriptomic expression analysis of MIF, DDT and their co-receptors, including CD74, C-X-C chemokine receptor (CXCR)2, CXCR4 and CXCR7 in patients with AUD. The results revealed that the transcriptomic levels of MIF, DDT and their receptors were superimposable in the prefrontal cortex of rodents and patients with AUD and human patients. Furthermore, peripheral blood cells from heavy drinkers exhibited a moderate increase in MIF and DDT levels, both at the baseline and following exposure to alcohol-associated cues, based on individual situations that included alcohol-related stimuli resulting in subsequent alcohol use (buying alcohol and being at a bar, watching others drink alcohol). Considering the overlapping effects of MIF and DDT, the inverse Fisher's χ 2 test was performed on unadjusted P-values to evaluate the combined effect of MIF and DDT. The results revealed a significant increase in these cytokines in heavy drinkers compared with controls (moderate drinkers). To the best of our knowledge, the present study demonstrated for the first time that MIF and DDT expression was upregulated in the blood of patients with AUD. These results therefore warrant further study to evaluate the role of MIF and DDT in the development and maintenance of AUD, to evaluate their use as biomarkers to predict the psychotherapeutic and pharmacological response of patients with AUD and for use as therapeutic targets.

show abstract

Development of the Neuroimmune Modulator Ibudilast for the Treatment of Alcoholism: A Randomized, Placebo-Controlled, Human Laboratory Trial

Cited by 108 publications

References 85 publications

Glial mechanisms underlying substance use disorders

Glial mechanisms underlying substance use disorders

Glial and neuroinflammatory targets for treating substance use disorders

Transcriptomic analysis reveals moderate modulation of macrophage migration inhibitory factor superfamily genes in alcohol use disorders

Contact Info

Product

Resources

About