title: Lithium-mediated long-term neuroprotection in neonatal rat hypoxia-ischemia is associated with antiinflammatory effects and enhanced proliferation and survival of neural stem/progenitor cells.
abstract: The aim of this study was to evaluate the long-term effects of lithium treatment on neonatal hypoxic-ischemic brain injury, inflammation, and neural stem/progenitor cell (NSPC) proliferation and survival. Nine-day-old male rats were subjected to unilateral hypoxia-ischemia (HI) and 2 mmol/kg lithium chloride was injected intraperitoneally immediately after the insult. Additional lithium injections, 1 mmol/kg, were administered at 24-hour intervals for 7 days. Animals were killed 6, 24, 72 hours, or 7 weeks after HI. Lithium reduced total tissue loss by 69%, from 89.4±14.6 mm(3) in controls (n=15) to 27.6±6.2 mm(3) in lithium-treated animals (n=14) 7 weeks after HI (P<0.001). Microglia activation was inhibited by lithium treatment, as judged by Iba-1 and galectin-3 immunostaining, and reduced interleukin-1β and CCL2 levels. Lithium increased progenitor, rather than stem cell, proliferation in both nonischemic and ischemic brains, as judged by 5-bromo-2-deoxyuridine labeling 24 and 72 hours as well as by phospho-histone H3 and brain lipid-binding protein labeling 7 weeks after HI. Lithium treatment also promoted survival of newborn NSPCs, without altering the relative levels of neuronal and astroglial differentiation. In summary, lithium conferred impressive, morphological long-term protection against neonatal HI, at least partly by inhibiting inflammation and promoting NSPC proliferation and survival.
authors.affiliation: Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hongfu
authors.initials: H
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Du
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Sun
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wang
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
authors.forename: Changlian
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018692:Antimanic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D037502:Galectin 3 / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D018692:Antimanic Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D037502:Galectin 3; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D018021:Lithium Chloride