Comparison of Cannabidiol, Antioxidants, and Diuretics in Reversing Binge Ethanol-Induced Neurotoxicity

Abstract

Binge alcohol consumption in the rat induces substantial neurodegeneration in the hippocampus and entorhinal cortex. Oxidative stress and cytotoxic edema have both been shown to be involved in such neurotoxicity, whereas N-methyl-D-aspartate (NMDA) receptor activity has been implicated in alcohol withdrawal and excitoxic injury. Because the nonpsychoactive cannabinoid cannabidiol (CBD) was previously shown in vitro to prevent glutamate toxicity through its ability to reduce oxidative stress, we evaluated CBD as a neuroprotectant in a rat binge ethanol model. When administered concurrently with binge ethanol exposure, CBD protected against hippocampal and entorhinal cortical neurodegeneration in a dose-dependent manner. Similarly, the common antioxidants butylated hydroxytoluene and ␣-tocopherol also afforded significant protection. In contrast, the NMDA receptor antagonists dizocilpine (MK-801) and memantine did not prevent cell death. Of the diuretics tested, furosemide was protective, whereas the other two anion exchanger inhibitors, L-644,711 [(R)-(ϩ)-(5,6-dichloro2,3,9,9a-tetrahydro 3-oxo-9a-propyl-1H-fluoren-7-yl)oxy acetic acid] and bumetanide, were ineffective. In vitro comparison of these diuretics indicated that furosemide is also a potent antioxidant, whereas the nonprotective diuretics are not. The lack of efficacy of L-644,711 and bumetanide suggests that the antioxidant rather than the diuretic properties of furosemide contribute most critically to its efficacy in reversing ethanol-induced neurotoxicity in vitro, in our model. This study provides the first demonstration of CBD as an in vivo neuroprotectant and shows the efficacy of lipophilic antioxidants in preventing binge ethanol-induced brain injury.

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain

“…There is much experimental evidence indicating that binge ethanol administration produces blood alcohol levels similar to or lower than those obtained in the current study causing observable neuronal cell loss and that this effect is especially prominent in the hippocampus, entorhinal and frontal cortex (Collins et al 1996;Obernier et al 2002b;Zharkovsky et al 2003;Hamelink et al 2005). Neuronal damage was visualized and quantified in the form of argyrophilic neurons with cupric-silver staining techniques (Collins et al 1996;Hamelink et al 2005), which, although methods of choice to assess irreversible neurodegeneration caused by a great variety of insults, have the disadvantage that they do not identify the nature of the damaged neuron. In this study, exposure to plasma ethanol levels of up to 450 mg/dl did not produce any long-term effect on the concentration of 5-HT or the density of 5-HT transporters in the hippocampus and cortex, which indicates an absence of neurotoxic effect on 5-HT containing neurons.…”

“…Similar binge ethanol administration was previously used to mimic a single cycle of binge drinking in humans (Collins et al 1998;Miki et al 2000;Obernier et al 2002a,b;Hamelink et al 2005). Ethanol or air was pumped into the inhalation chamber at a flow of 1 ml/min for 3 h daily during 4 consecutive days.…”

“…Episodic ethanol intoxication and withdrawal, characteristic of binge alcoholism or chronic ethanol administration, induces substantial neurodegeneration in the hippocampus and entorhinal cortex of the rat (Miki et al 2000;Zharkovsky et al 2003;Prendergast et al 2004;Baydas and Tuzcu 2005;Hamelink et al 2005). Several mechanisms were postulated to be involved in ethanol neurodegeneration, some of them also being involved in MDMA-induced neuronal damage.…”

Molecular Targets of Cannabidiol in Neurological Disorders

“…Finally, one property of CBD that has long thought to be important in its mode of action is its ability to act as an antioxidant and was originally considered to arise from its ability to directly scavenge ROS [218,219]. However, the protective effect of CBD has also been associated with an upregulation of Cu,Zn superoxide dismutase mRNA, an antioxidant enzyme [220].…”

Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage

“…CBD has also been proven to be protective against a number of druginduced adverse outcomes in animals. For example, CBD was shown to prevent cocaine-induced hepatotoxicity [52], reverse binge ethanol-induced neurotoxicity [53], and even mitigate the cardiac effects of THC [54,55]. In addition, CBD administration is known to attenuate amphetamine-induced hyperlocomotion [56].…”