Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

Abstract

Lithium has been shown to be neuroprotective against various insults including ethanol exposure. We previously reported that ethanol-induced apoptotic neurodegeneration in the postnatal day 7 (P7) mice is associated with decreases in phosphorylation levels of Akt, glycogen synthase kinase-3β (GSK-3β), and AMP-activated protein kinase (AMPK), and alteration in lipid profiles in the brain. Here, P7 mice were injected with ethanol and lithium, and the effects of lithium on ethanol-induced alterations in phosphorylation levels of protein kinases and lipid profiles in the brain were examined. Immunoblot and immunohistochemical analyses showed that lithium significantly blocked ethanolinduced caspase-3 activation and reduction in phosphorylation levels of Akt, GSK-3β and AMPK. Further, lithium inhibited accumulation of cholesterol ester (ChE) and Nacylphosphatidylethanolamine (NAPE) triggered by ethanol in the brain. These results suggest that Akt, GSK-3β, and AMPK are involved in ethanol-induced neurodegeneration and the neuroprotective effects of lithium by modulating both apoptotic and survival pathways.

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice

“…Our previous studies using cultured neurons ( 47 ) or P7 mice ( 15,17 ) also suggest that the elevation of these lipids is partially due to enhanced lipogenesis and de novo ceramide synthesis by ethanol treatment. While we are not able to eliminate the possibility that ethanol increases the entry of serum lipids into the brain, our previous studies showing brain region-specifi c accumulation of TG, ChE, and NAPE ( 17 ), different accumulation kinetics among these lipids ( 15 ), and the different effects of neuroprotective agents on each lipid content ( 17,48 ) suggest that the entry of serum lipids is not a major cause of the observed lipid elevation in the brain. Table 1 shows that ceramide, ChE, and NAPE also increased in KO mice treated with ethanol, although the elevation of TG did not reach a statistically signifi cant level.…”

GSK3β in Ethanol Neurotoxicity

“…Lithium also prevents ethanol-induced apoptosis and activation of caspase-3 and caspase-9 in cultured cerebellar granule neurons [140]. This is confirmed by a study using the same paradigm of lithium treatment; injection of lithium at 15 min following ethanol exposure blocks ethanol-induced caspase-3 activation as well as ethanol-mediated down-regulation of p-GSK3β(Ser9), p-Akt, and p-AMPK in the forebrain of 7-day-old mice [141]. …”

Distinct neurobehavioral dysfunction based on the timing of developmental binge-like alcohol exposure

“…This hypothesized imbalance is a mechanistic foundation for many of the neurobehavioral deficits found in FASD and related cognitive disorders (Sadrian et al, 2013). How long-term synaptic imbalance is initiated by early ethanol exposure is unclear, but is likely connected to the many well-documented effects of ethanol on brain function, such as: apoptotic neurodegeneration (Ikonomidou et al, 2000, Chakraborty et al, 2008), altered synaptic transmission in specific cell populations (Sanderson et al, 2009, Wang et al, 2013), skewed neurotransmitter profiles (Sari et al, 2010), disruption of glutamatergic receptor subunit regulation (Nixon et al, 2002), dendritic tree reduction of PV+ interneurons (De Giorgio et al, 2012), and decreased neurogenesis (Burd et al, 2012); all found immediately following insult and some shown lasting into adulthood. These effects have each been demonstrated after acute or short-term ethanol exposure and are therefore often attributed to disruption of developmental processes occurring within that period.…”