Excitotoxicity caused by ethanol (ETOH) withdrawal (EWD) is highly detrimental to the developing brain. Targeting this excitotoxicity has been shown to be a promising approach for improving outcome following developmental ETOH exposure. Activation of nicotinic acetylcholine receptors (nAChR), in the central nervous system can be protective against EWD. We examined the ability of DMXB-A, a α7 nAChR agonist, to reduce neurotoxicity caused by EWD in the hippocampus. To test this, an organotypic hippocampal slice culture was used. Slices were exposed to ETOH (100mM) or control medium. After 10 days, the slices were treated with DMXB-A (1, 3, or 10uM) during EWD. After 24 hours of EWD cell damage in the CA1, CA3, and dentate gyrus of the hippocampus was analyzed. The combination of EWD and NMDA produced increased toxicity compared to controls in the CA1 region, DMXB-A attenuated this effect, suggesting that DMXB-A was protective against EWD neurotoxicity in vitro. These findings are exciting because this drug is currently in clinical trials for a variety of CNS conditions and so has significant translational potential. Further research is necessary to better understand the extent of its neuroprotective properties and to determine its ability to reduce behavioral deficits following prenatal ethanol exposure.

Prenatal alcohol exposure (Fetal Alcohol Syndrome [FAS] and Fetal Alcohol Spectrum Disorders [FASD’s]) represents the leading preventable cause of intellectual disabilities in the western world, with FASDs estimated to affect approximately 2-5% of live births in the United States at an approximate annual cost of $3.6 billion (CDC, 2015; May et al., 2009). Ethanol (ETOH) exposure during development can lead to a variety of long-term behavioral impairments including problems with executive functioning, motor coordination, spatial learning, attention, and hyperactivity (Jones, 2011; Mattson & Riley, 1998). Much research has been conducted to develop pharmacological and/or environmental interventions to reduce these deficits, however, there are currently no clinically approved medications to treat the deficits related to fetal ETOH exposure. The current study used a developmental “3rd trimester” ETOH exposure model in neonatal rats to test the hypothesis that compounds targeting the nicotinic system will reduce deficits associated with ETOH exposure. Both compounds demonstrated promise in reducing some of the effects of developmental ethanol exposure, with DMXB-A treatment after ethanol exposure reducing balance deficits in females and spatial memory deficits in males. Solidago nemoralis treatment after ETOH exposure reduced learning and memory deficits in males and balance and executive functioning deficits in both sexes. With these results and previous work in this lab and others there appears to be ample evidence for their usefulness in reducing various forms of neurotoxicity. The long-term goal of this research is to evaluate the usefulness of both DMXB-A & Solidago nemoralis (SN) in treating deficits related to developmental ETOH exposure in humans and hopefully develop a treatment for these disorders.