Behavioral deficits and cellular damage following developmental ethanol exposure in rats are attenuated by CP-101,606, an NMDAR antagonist with unique NR2B specificity

Abstract

NMDAR-mediated excitotoxicity has been implicated in some of the impairments following fetal ethanol exposure. Previous studies suggest that both neuronal cell death and some of the behavioral deficits can be reduced by NMDAR antagonism during withdrawal, including antagonism of a subpopulation of receptors containing NR2B subunits. To further investigate NR2B involvement, we selected a compound, CP-101,606 (CP) which binds selectively to NR2B/2B stoichiometries, for both in vitro and in vivo analyses. For the in vitro study, hippocampal explants were exposed to ethanol for 10 days and then 24 h following removal of ethanol, cellular damage was quantified via propidium iodide fluorescence. In vitro ethanol withdrawal-associated neurotoxicity was prevented by CP (10 and 25 nM). In vivo ethanol exposure was administered on PNDs 1-7 with CP administered 21 h following cessation. Activity (PNDs 20-21), motor skills (PNDs 31-33), and maze navigation (PNDs 43-44) were all susceptible to ethanol insult; treatment with CP (15 mg/kg) rescued these deficits. Our findings show that CP-101,606, a drug that blocks the NR2B/2B receptor, can reduce some of the damaging effects of "3rd trimester" alcohol exposure in our rodent model. Further work is clearly warranted on the neuroprotective potential of this drug in the developing brain.

Choline Ameliorates Deficits in Balance Caused by Acute Neonatal Ethanol Exposure

“…Supplementation with choline prior to ethanol exposure shows improved neurite outgrowth and signaling in the presence of ethanol (30). We conducted the current study to determine if choline supplementation prior to an acute exposure to ethanol on P5 would reduce the effects of ethanol on the dowel crossing test, a test of balance and coordination that relies heavily on normal cerebellar function in mice (21). …”

Preclinical pharmacology and pharmacokinetics of CERC‐301, a GluN2B‐selective N‐methyl‐D‐aspartate receptor antagonist

“…; Lewis et al. ). Lack of a nonclinical neurotoxicity signal with GluN2B‐specific antagonists, along with the absence of ketamine‐like psychotomimetic effects in the clinical setting allows administration of these agents at higher doses to achieve higher receptor occupancies (than what has been predicted herein), should the clinical data necessitate that in the future clinical trials.…”

Alcohol and Developing Neuronal Circuits

“…Inhibition of glycogen synthase kinase 3 (lithium); inhibition of cannabinoid receptor-1 (SR141716A) (Sadrian et al, 2012) (Subbanna et al, 2013) Impaired hippocampal cholinergic transmission Choline supplementation (Monk et al, 2012) Excitotoxic damage during alcohol withdrawal Inhibition of NMDA receptors (eliprodil; CP-101,606; memantine) (Lewis et al, 2012) (Idrus et al, 2011) ↓Parallel fiber-Purkinje cell synapses in the cerebellum Motor training (Klintsova et al, 2002) ↑Oxidative stress in several brain regions Voluntary exercise; omega-3 fatty acid supplementation (Brocardo et al, 2012) (Patten et al, 2013) ↓Purkinje neuron and microglia numbers Peroxisome proliferator-activated receptor-γ agonists (15-deoxy-Δ12,15 prostaglandin J2 and pioglitazone) (Kane et al, 2011) that several laboratories have undertaken studies on regions that have received relatively little attention, such as the amygdala, striatum, visual and barrel cortex, agranular insular cortex, and prelimbic cortex (Cullen, Burne, Lavidis, & Moritz, 2013;Hamilton et al, 2010;Kelly, Leggett, & Cronise, 2009;Medina & Krahe, 2008;Middleton, Varlinskaya, & Mooney, 2012;Zhou, Wang, & Zhu, 2010;Zhou, Wang, & Zhu, 2012). Functional neuroimaging studies have begun to shed light on the deficits in network connectivity that are present in the brains of patients with FASDs (Diwadkar et al, 2013;Meintjes et al, 2010;Wozniak et al, 2013).…”

“…Studies suggest that excitotoxicity mediated by NMDA receptors during ethanol withdrawal could, in part, be responsible for the neuronal damage observed after binge-like ethanol exposure during the third-trimester equivalent. NMDAreceptor blockade during withdrawal has been shown to ameliorate ethanol-induced deficits in spatial discrimination reversal learning and spatial learning (Lewis et al, 2012;Thomas, Fleming, & Riley, 2002;Thomas, Garcia, Dominguez, & Riley, 2004). Other therapeutic interventions that have been shown to mitigate deficits in hippocampal-dependent learning or hippocampal neuronal damage in rodents exposed to ethanol during the third-trimester equivalent include voluntary exercise , nicotinamide (Ieraci & Herrera, 2006), pyruvate (Ullah et al, 2011), omega-3 fatty acids (Patten, Brocardo, & Christie, 2013), resveratrol (Tiwari & Chopra, 2011), and peptides derived from activity-dependent neuroprotective protein or activity-dependent neurotrophic factor (Incerti et al, 2010).…”