Protection of neurons and microglia against ethanol in a mouse model of fetal alcohol spectrum disorders by peroxisome proliferator-activated receptor-γ agonists

Sex Differences in Early Postnatal Microglial Colonization of the Developing Rat Hippocampus Following a Single-Day Alcohol Exposure

“…In the healthy developing brain, microglia are involved in many necessary, normal development processes including the culling of apoptotic cells, synaptic pruning, and masculinization of the brain and behavior (Dalmau et al 1998; Bessis et al 2007; Paolicelli et al 2011; Lenz et al 2013). Following identification of a pathogen, microglia respond by changing their phenotypic activation state to increase production of pro-inflammatory cytokines (Kreutzberg 1996; Hanisch 2002; Town et al 2005; Neumann et al 2008; Kane et al 2011; McClain et al 2011; Topper et al 2015; Boschen et al 2016). …”

Function of Thymosin Beta-4 in Ethanol-Induced Microglial Activation

“…We used a synthetic copy of the naturally-occurring 43-amino acid Tβ4 peptide (RegeneRx, Bethesda, MD, USA). The animal experiment was performed as described previously [17,18]. In brief, 4 g/kg/d ethanol or control was administered daily by intraesophageal gavage on postnatal days 4 through 9.…”

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).…”

“…Exposure during the first-and second-trimester equivalent has been shown to reduce numbers of not only Purkinje cells but also granule cells (Maier & West, 2001;Servais et al, 2007). Binge-like ethanol exposure during the third-trimester equivalent has been consistently demonstrated to be detrimental to Purkinje and granule cells, causing a significant reduction in their numbers via multiple mechanisms, including oxidative stress, reduction in the activity of neurotrophic factors, alterations in cell migration and axonal outgrowth, and neuroimmune deficits (Chen & Charness, 2008;Goodlett, Horn, & Zhou, 2005;Hamre & West, 1993;Heaton, Mitchell, & Paiva, 1999;Heaton, Mitchell, & Paiva, 2000;Heaton, Paiva, Mayer, & Miller, 2002;Kane, Chang, Roberson, Garg, & Han, 2008;Kane et al, 2011;Kumada et al, 2010;Light, Brown, Newton, Belcher, & Kane, 2002). In addition, exposure during the third-trimester equivalent reduces the frequency of events generated by climbing fiber activation (i.e., complex spikes), an effect that may be a consequence of a reduction in cell numbers in the inferior olive or functional alterations at climbing fiber-to-Purkinje neuron synapses (Backman, West, Mahoney, & Palmer, 1998;Pierce, Hayar, Williams, & Light, 2011).…”

“…Exposure of neonatal mice using gavage (from postnatal days 3 to 5; BAL = 0.25-0.325 g/dl) caused a decrease in Purkinje cell and microglia numbers; treatment with peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists during postnatal days two to five mitigated the effects of ethanol on these cells (Kane et al, 2011). PPAR-γ agonists (e.g., rosiglitazone) are clinically used to treat patients with type II diabetes, and it will be interesting to determine if these can be safely administered during pregnancy and be used to ameliorate the impact of ethanol exposure on the cerebellum.…”