Acute consumption of moderate to large amounts of ethanol(Et) activates the hypothalamic-pituitary-adrenal axis (HPAA) and chronic, excessive Et intake can lead to permanent brain damage. Activation of the HPAA or hypercortisolism accompanies both short- and long-term consumption of Et and the Et withdrawal syndrome. Since a relative state of elevated glucocorticoids (chronic continuous or chronic intermittent) can lead to neural changes and even cell death, particularly in the hippocampus, the progressive loss of cognitive capacity in many alcoholics may be due in part to hypercortisolemia and subsequent irreversible neural damage in the hippocampus and other areas of the central nervous system. Using an intragastric cannulated rodent model and short-term (4 days) intermittent or binge-type Et administration, we have demonstrated site-specific CNS neurodegeneration in the dentate gyrus of the hippocampus, the entorhinal cortex and the piriform cortex. The observed Et-induced neurodegeneration was functionally validated as noted by the decline in learning and memory capacity in the Et-treated animals in the hippocampal-dependent Morris water maze test.Ongoing efforts to define the mechanism of Et's cytotoxicity continue by us and others. Surprisingly, the coadministration of glutamate receptor subtype antagonists or calcium uptake blocking drugs with Et are not neuroprotective, which argues against a glutamate-receptor dependent excitotoxic basis for the neurodegeneration; however, evidence for a glutamate-dependent, non-receptor or metabolic mechanism of excitotoxicity exists. Furthermore, elevated glucocorticoids exacerbate the Et-induced neurodegeneration presumably through excitotoxic mechanisms. To date the most potent cytoprotective agent in the binge-type rodent model has been shown to be Furosemide(FUR), an anion transport inhibitor; however, our finding that LY-644,711, bumetanide and SITS, which are drugs with mechanisms of action similar to FUR, are not neuroprotective would argue against a primary ionic, edema-based mechanism of neurotoxicity. Finally, with the knowledge that certain cannabinoids are neuroprotective, we coadministered cannabidiol with Et and found a significant reduction of neurodegeneration. Since in vitro studies have demonstrated that cannabidiol blocked glutamate-NMDA, -AMPA or -kainate receptor-mediated toxicity, it would appear that the cannabidiol site of action is downstream of receptor activation and perhaps has a generalized metabolic or anti-oxidant mechanism of neuroprotection. To confirm that the protection with cannabidiol was due to its antioxidant properties, two other common antioxidants, Vitamin E and butylated hydroxytoluene (BHT), were tested. Both Vitamin E, a well known antioxidant, and BHT, an antioxidant commonly used as a food preservative, protected to a similar degree as cannabidiol in our binge-type animal model of alcoholism. The neuroprotection afforded by diverse antioxidant compounds in our binge-type model of alcoholism suggests that oxidative stress and the generation of reactive oxygen species are partially responsible for the brain damage associated with excessive Et consumption.
NIH ExPorter
NIH ExPorter