Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death.
OBJECTIVE
In vitro and in vivo studies have demonstrated neuroprotective actions of lithium. The present study investigated the effect of a low dose of lithium on infarct volume and neurological outcome as well as on apoptotic and inflammatory processes in rats exposed to focal ischemia.


METHODS
Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 minutes followed by reperfusion. Lithium (1 mmol/kg) was given subcutaneously daily for 14 days before the onset of MCAO and 2 days thereafter. Blood parameters and cerebral blood flow were assessed before, during, and after MCAO. Rats were examined for neurological deficits 24 and 48 hours after MCAO. Two days after MCAO, the brains were removed for immunohistochemical evaluation of caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), activated microglia, and the expression of AP-1 proteins (c-Fos and c-Jun). Infarct volume was assessed by cresyl violet staining.


RESULTS
Pretreatment with lithium did not alter cerebral blood flow or blood parameters. Neurological deficits were significantly decreased in rats treated with lithium at 24 and 48 hours after ischemia. Infarct volume was reduced in rats treated with lithium at 48 hours after ischemia. Lithium significantly decreased the ischemia-induced caspase-3 immunoreactivity and TUNEL staining as well as the AP-1 protein expression in the penumbra of the ischemic cortex. No changes in activated microglia were observed.


CONCLUSIONS
The present study demonstrates that chronic treatment with lithium at a low dose exhibits neuroprotection in transient focal cerebral ischemia. Antiapoptotic mechanisms are involved in the lithium-induced neuroprotective effects.
Xu
Jihong
J
Institute of Pharmacology, Christian-Albrechts University of Kiel, Germany.
Culman
Juraj
J
Blume
Annegret
A
Brecht
Stephan
S
Gohlke
Peter
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003864:Depression, Chemical; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D016651:Lithium Carbonate / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D017628:Microglia / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000032:analysis; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control; D016037:Single-Blind Method; D018808:Transcription Factor AP-1 / Q000032:analysis
D015415:Biomarkers; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D018808:Transcription Factor AP-1; D016651:Lithium Carbonate; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases