TY - JOUR
T1 - Lithium reduces apoptosis and autophagy after neonatal hypoxia-ischemia
AU - Li, Q.
AU - Li, H.
AU - Roughton, K.
AU - Wang, X.
AU - Kroemer, G.
AU - Blomgren, K.
AU - Zhu, C.
N1 - Funding Information:
Acknowledgements. This work was supported by the Swedish Research Council, the Swedish Childhood Cancer Foundation (Barncancerfonden), Swedish governmental grants to scientists working in health care (ALF), the National Natural Science Foundation of China (to CZ: 30870883), the Wilhelm and Martina Lundgren Foundation, the Frimurare Barnhus Foundation, the Gothenburg Medical Society, the Swedish Society of Medicine.
PY - 2010/7/1
Y1 - 2010/7/1
N2 - 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 mm3 (44.1%) and total tissue loss (degeneration + lack of growth) from 67.4±4.4 to 38.4±5.9 mm3 (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.
AB - 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 mm3 (44.1%) and total tissue loss (degeneration + lack of growth) from 67.4±4.4 to 38.4±5.9 mm3 (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.
KW - Apoptosis-inducing factor (AIF)
KW - Asphyxia
KW - Caspase
KW - ERK
KW - GSK-3
UR - http://www.scopus.com/inward/record.url?scp=79958730602&partnerID=8YFLogxK
U2 - 10.1038/cddis.2010.33
DO - 10.1038/cddis.2010.33
M3 - Article
C2 - 21364661
AN - SCOPUS:79958730602
SN - 2041-4889
VL - 1
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 7
M1 - e56
ER -