Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations

Bipolar Disord. 2016 Dec;18(8):692-695. doi: 10.1111/bdi.12449. Epub 2016 Nov 24.


Objectives: The putative neuroprotective effects of lithium treatment rely on the fact that it modulates several homeostatic mechanisms involved in the neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. The aim of this study was to evaluate the effects of subtherapeutic and therapeutic concentrations of chronic lithium treatment on brain-derived neurotrophic factor (BDNF) synthesis and secretion.

Methods: Primary cultures of cortical and hippocampal neurons were treated with different subtherapeutic (0.02 and 0.2 mM) and therapeutic (2 mM) concentrations of chronic lithium treatment in cortical and hippocampal cell culture.

Results: Lithium treatment increased the intracellular protein expression of cortical neurons (10% at 0.02 mM) and hippocampal neurons (28% and 14% at 0.02 mM and 0.2 mM, respectively). Extracellular BDNF of cortical neurons increased 30% and 428% at 0.02 and 0.2 mM, respectively and in hippocampal neurons increased 44% at 0.02 mM.

Conclusion: The present study indicates that chronic, low-dose lithium treatment up-regulates BDNF production in primary neuronal cell culture.

Keywords: BDNF; chronic lithium treatment; cortical neurons; hippocampal neurons; low-dose lithium treatment.

MeSH terms

  • Animals
  • Antimanic Agents / pharmacology
  • Bipolar Disorder* / drug therapy
  • Bipolar Disorder* / metabolism
  • Brain-Derived Neurotrophic Factor* / analysis
  • Brain-Derived Neurotrophic Factor* / metabolism
  • Cells, Cultured
  • Cerebral Cortex* / drug effects
  • Cerebral Cortex* / metabolism
  • Depressive Disorder, Major* / drug therapy
  • Depressive Disorder, Major* / metabolism
  • Disease Models, Animal
  • Hippocampus* / drug effects
  • Hippocampus* / metabolism
  • Lithium / pharmacology*
  • Long Term Adverse Effects / chemically induced
  • Long Term Adverse Effects / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / therapeutic use
  • Rats


  • Antimanic Agents
  • Brain-Derived Neurotrophic Factor
  • Neuroprotective Agents
  • Lithium