Short-term lithium treatment promotes neuronal survival and proliferation in rat striatum infused with quinolinic acid, an excitotoxic model of Huntington's disease

Mol Psychiatry. 2004 Apr;9(4):371-85. doi: 10.1038/


We assessed the ability of lithium to reduce neurodegeneration and to stimulate cell proliferation in a rat model of Huntington's disease in which quinolinic acid (QA) was unilaterally infused into the striatum. LiCl (0.5-3.0 mEq/kg) was injected subcutaneously 24 h before and 1 h after QA infusion. At 7 days after QA injection, lithium significantly diminished the loss of neurons immunostained for Neuronal Nuclei (NeuN) in the injured striatum, but failed to prevent the reduction of NADPH-diaphorase-positive striatal interneurons. Lithium also reduced the number of neurons showing DNA damage or activated caspase-3. This neuroprotection was associated with an upregulation of Bcl-2 protein levels in the striatal tissue and an increase in the number and density of Bcl-2 immunostaining in striatal neurons. Bromodeoxyuridinie (BrdU) labeling in the lithium-treated injured striatum revealed the presence of large numbers of proliferating cells near the QA-injection site, with a reduction of BrdU-labeled cells in the subventricular zone (SVZ). All BrdU-labeled cells in the SVZ and the majority of BrdU-labeled cells near the QA-injection site were negative for either NeuN or glial fibrillary acidic protein (GFAP), suggesting that they are undifferentiated progenitor cells. However, a small number of BrdU-positive cells found in the QA-injected and lithium-treated striatum site were positive for either NeuN or GFAP. Our results suggest that lithium is neuroprotective in the QA-injection model of Huntington's disease not only due to its ability to inhibit apoptosis but also because it can stimulate neuronal and astroglial progenitor proliferation in the QA-injected striatum or their migration from the SVZ.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • Corpus Striatum / cytology
  • Corpus Striatum / drug effects*
  • Corpus Striatum / enzymology
  • DNA Damage / drug effects
  • Dose-Response Relationship, Drug
  • Huntington Disease / chemically induced
  • Huntington Disease / drug therapy*
  • Huntington Disease / metabolism
  • Huntington Disease / pathology*
  • Interneurons / drug effects
  • Lithium / pharmacology*
  • Male
  • Neurons / drug effects*
  • Neurons / enzymology
  • Neuroprotective Agents / pharmacology*
  • Neurotoxins
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Quinolinic Acid
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation


  • Neuroprotective Agents
  • Neurotoxins
  • Proto-Oncogene Proteins c-bcl-2
  • Lithium
  • Quinolinic Acid