Therapeutic Benefits of Delayed Lithium Administration in the Neonatal Rat after Cerebral Hypoxia-Ischemia

Aim: We have previously shown that lithium treatment immediately after hypoxia-ischemia (HI) in neonatal rats affords both short-and long-term neuroprotection. The aim of this study was to evaluate possible therapeutic benefits when lithium treatment was delayed 5 days, a time point when most cell death is over. Methods: Eight-day-old male rats were subjected to unilateral HI and 2 mmol/kg lithium chloride was injected intraperitoneally 5 days after the insult. Additional lithium injections of 1 mmol/kg were administered at 24 h intervals for the next 14 days. Brain injury was evaluated 12 weeks after HI. Serum cytokine measurements and behavioral analysis were performed before sacrificing the animals. Results: Brain injury, as indicated by tissue loss, was reduced by 38.7%, from 276.5 +/- 27.4 mm(3) in the vehicle-treated group to 169.3 +/- 25.9 mm(3) in the lithium-treated group 12 weeks after HI (p<0.01). Motor hyperactivity and anxiety-like behavior after HI were normalized by lithium treatment. Lithium treatment increased neurogenesis in the dentate gyrus as indicated by doublecortin labeling. Serum cytokine levels, including IL-1 alpha, IL-1 beta, and IL-6, were still elevated as late as 5 weeks after HI, but lithium treatment normalized these cytokine levels. Conclusions: Delayed lithium treatment conferred long-term neuroprotection in neonatal rats after HI, and this opens a new avenue for future development of treatment strategies for neonatal brain injury that can be administered after the acute injury phase.