Transdermal delivery of cannabidiol attenuates binge alcohol-induced neurodegeneration in a rodent model of an alcohol use disorder

Abstract

Excessive alcohol consumption, characteristic of alcohol use disorders, results in neurodegeneration and behavioral and cognitive impairments that are hypothesized to contribute to the chronic and relapsing nature of alcoholism. Therefore, the current study aimed to advance the preclinical development of transdermal delivery of cannabidiol (CBD) for the treatment of alcohol-induced neurodegeneration. In experiment 1, 1.0%, 2.5% and 5.0% CBD gels were evaluated for neuroprotection. The 5.0% CBD gel resulted in a 48.8% reduction in neurodegeneration in the entorhinal cortex assessed by Fluoro-Jade B (FJB), which trended to statistical significance (p = 0.069). Treatment with the 5.0% CBD gel resulted in day 3 CBD plasma concentrations of ~100.0 ng/mL so this level was used as a target concentration for development of an optimized gel formulation. Experiment 2 tested a next generation 2.5% CBD gel formulation, which was compared to CBD administration by intraperitoneal injection (IP; 40.0 mg/kg/d). This experiment found similar magnitudes of neuroprotection following both routes of administration; transdermal CBD decreased FJB+ cells in the entorhinal cortex by 56.1% (p < 0.05), while IP CBD resulted in a 50.6% (p < 0.05) reduction in FJB+ cells. These results demonstrate the feasibility of using CBD transdermal delivery systems for the treatment of alcohol-induced neurodegeneration.

IL-1 receptor signaling in the basolateral amygdala modulates binge-like ethanol consumption in male C57BL/6J mice

“…It is important to denote that the mechanism by which Fluoro-jade staining works is unknown, therefore it is perceivable that early stages of cellular death may not be incorporated in these cell counts (Poirier et al, 2000). However, very little FJC+ cells were expected to be induced by three cycles of DID as the BECs produced in the DID paradigm likely do not reach a level that would cause neurodegeneration (Liput et al, 2013). This is only the second paper to demonstrate that the DID paradigm does not elicit cellular damage (Sprow et al, 2015), but the first to use a marker of neurodegeneration.…”

“…This staining was performed on animals following one or three, 4-day DID cycles and were euthanized immediately following the final DID cycle (Ethanol n= 8-9/subgroup; Sucrose n=6-7/subgroup; H2O n=10). FJC processing was performed in accordance with manufacture instructions (Millipore, Billerica, MA) similar to previously published methods (Liput et al, 2013; Qin and Crews, 2012b). Briefly, every fourth section was mounted on Superfrost-Plus slides (Fisher Scientific, Pittsburgh, PA).…”

Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release

“…Despite studies suggesting that CBD modulates responses induced by diverse drugs of abuse and enhances extinction of cocaine-induced conditioned place preference (Parker et al, 2004), its effects upon cocaine toxicity as well as the underlying mechanisms have remained unclear (Liput et al, 2013;Morgan et al, 2013). CBD exerts pharmacological actions on a range of distinct biological systems and intracellular pathways (Izzo et al, 2009), including the mammalian target of rapamycin (mTOR), which has been implicated in protecting against neurotoxicity, acute epileptic seizures and epileptogenesis (Bailey et al, 2012;McDaniel and Wong, 2011;Shrivastava et al, 2011;Zhang and Wong, 2012).…”

Jobelyn® Supplement Lowered Neuronal Degeneration: Significance of Altered p53 and &#x0264;-Enolase Protein Expressions in Prefrontal Cortex of Rat Exposed to Ethanol

“…Excessive alcohol ingestion, characteristic of alcohol use disorders (AUDs), results in neurodegeneration, which is responsible for the cognitive and behavioral impairment that drives the transition to alcohol addiction [1] . Globally, about 80 million people have diagnos-able AUDs, making it a major global health concern [2] .…”

“…To date, renowned medications for the treatment of AUDs: acamprosate, disulfiram, and naltrexone, have been clinically unsatisfactory [2] . They targeted the psychoactive properties of alcohol; while the neurodegenerative effect of alcohol that drives alcohol-induced neurological dysfunction was not managed by these specific remedies [1] . The prefrontal cortex (PFC) is highly susceptible to alcohol-induced damage [3] .…”