title: Lithium reduces apoptosis and autophagy after neonatal hypoxia-ischemia.
abstract: Lithium is used in the treatment of bipolar mood disorder. Reportedly, lithium can be neuroprotective in models of adult brain ischemia. The purpose of this study was to evaluate the effects of lithium in a model of neonatal hypoxic-ischemic brain injury. Nine-day-old male rats were subjected to unilateral hypoxia-ischemia (HI) and 2 mmol/kg lithium chloride was injected i.p. immediately after the insult. Additional lithium injections, 1 mmol/kg, were administered at 24-h intervals. Pups were killed 6, 24 or 72 h after HI. Lithium reduced the infarct volume from 24.7±2.9 to 13.8±3.3 mm(3) (44.1%) and total tissue loss (degeneration + lack of growth) from 67.4±4.4 to 38.4±5.9 mm(3) (43.1%) compared with vehicle at 72 h after HI. Injury was reduced in the cortex, hippocampus, thalamus and striatum. Lithium reduced the ischemia-induced dephosphorylation of glycogen synthase kinase-3β and extracellular signal-regulated kinase, the activation of calpain and caspase-3, the mitochondrial release of cytochrome c and apoptosis-inducing factor, as well as autophagy. We conclude that lithium could mitigate the brain injury after HI by inhibiting neuronal apoptosis. The lithium doses used were in the same range as those used in bipolar patients, suggesting that lithium might be safely used for the avoidance of neonatal brain injury.
authors.affiliation: Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Roughton
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.forename: K
authors.initials: K
authors.lastname: Blomgren
authors.forename: C
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008094:Lithium / Q000627:therapeutic use*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D051033:Apoptosis Inducing Factor; D018696:Neuroprotective Agents; D045304:Cytochromes c; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D002154:Calpain; D053148:Caspase 3