[PMC free article] [PubMed] [Google Scholar] 30

[PMC free article] [PubMed] [Google Scholar] 30. suppressed phosphorylated ERK, and lithium counteracted both the phosphorylated ERK suppressant action and neuroapoptotic action of these anesthetic drugs. Conclusion If further testing finds lithium to be safe for use in pediatric/obstetric medicine, administration of a single dose of Sorbic acid lithium prior to anesthesia induction may be a suitable means of mitigating the risk of anesthesia-induced developmental neuroapoptosis. INTRODUCTION Transient exposure of infant rodents to several classes of drugs, including N-methyl-D-aspartic acid antagonists and gamma-aminobutyric acid-A agonists, triggers widespread neurodegeneration in the developing brain.1C6 The cell death process triggered by these drugs displays all of the classical ultrastructural characteristics of apoptosis3, 7, 8 and is mediated by the Bax-dependent mitochondrial intrinsic pathway involving cytochrome-c release and activation of caspases 9 and 3.9C11 The window of vulnerability to these agents coincides with the developmental period of rapid synaptogenesis,1, 2 also known as the brain growth spurt period, which in mice and rats occurs primarily during the first 2 weeks after birth, but in humans extends from about mid-gestation to several years after birth.12 Ethanol, which has both N-methyl-D-aspartic acid antagonist and gamma-aminobutyric acid-A-mimetic properties, induces widespread neurodegeneration in the developing EGFR brain.1, 3, 6 Zhong et al. recently reported that a single dose of lithium (6 mEq/kg) co-administered with ethanol to infant mice protects against ethanol-induced neuroapoptosis.13 Further, it was hypothesized that the protective Sorbic acid effect of lithium might be mediated by action of lithium on the glycogen synthase kinase 3 signaling system; however, no evidence for an interaction between either ethanol or lithium and the glycogen synthase kinase system was found. Recent work in our laboratory has demonstrated that lithium suppresses the programmed cell death process that occurs naturally in the developing mouse brain and has confirmed the findings of Zhong et al. that lithium powerfully protects against ethanol-induced neuroapoptosis.14 To explore the mechanism of action of lithium, we focused on kinase signaling systems (extracellular signal-regulate kinase (ERK), serine/threonine-specific protein kinase (Akt), Jun N-terminal kinase (JNK)) that are believed to play a regulatory role in cell survival. We found that very rapidly (within 30 minutes) after ethanol administration, Sorbic acid there is a marked suppression of ERK phosphorylation and that lithium stimulates ERK phosphorylation and prevents ethanol from suppressing this phosphorylation process.14 Ethanol also suppressed phosphorylated Akt, but lithium did not counteract this effect. We also found that ethanol activates the JNK system; but this does not explain the neurotoxic action of ethanol, as JNK activation did not occur in the same neuronal populations that are killed by ethanol. The present study was undertaken to determine whether anesthetic drugs suppress ERK and/or Akt phosphorylation, whether lithium counteracts this suppressant action, and whether lithium protects against anesthesia-induced developmental neuroapoptosis. The anesthetic drugs focused on in this study were ketamine, an agent that interacts primarily with N-methyl-D-aspartic acid glutamate receptors, and propofol, an agent that interacts primarily with gamma-aminobutyric acid-A receptors, but also possibly interacts with N-methyl-D-aspartic acid glutamate receptors.15 Materials and Methods The first set of experiments sought to determine whether anesthetic drugs mimic ethanol in suppressing phosphorylation of ERK and Akt, and if they do, whether lithium counteracts this suppressant action. For this purpose, postnatal day 5 (P5) C57/Bl6 mouse pups were treated with vehicle, ketamine (40 mg/kg, subcutaneous), propofol (50 mg/kg, intraperitoneal), lithium (6 mEq/kg, i.p) or a combination of ketamine (40 mg/kg) or propofol (50 mg/kg) and lithium (6 mEq/kg). These anesthetic dosing regimens were used because they have been shown to induce a significant neuroapoptosis response in C57BL6 infant mice.14, 16 This dose of lithium was chosen because it was the dose Zhong et al.13 used in their original study showing that lithium protects against ethanol-induced neuroapoptosis. Pups were killed 120 minutes after administration of drug, brains collected and cytosolic extracts of caudate putamen were.