Nrf2-BDNF-TrkB pathway contributes to cortical hemorrhage-induced depression, but not sex differences

Honglei Ren, Ranran Han, Xi Liu, Limin Wang, Raymond C. Koehler, Jian Wang

Research output: Contribution to journalArticlepeer-review


Post-stroke depression, observed in 30-50% of stroke patients, negatively affects quality of life and mortality. The pathogenesis of post-stroke depression is complex, but heightened reactive oxygen species production and inflammation might be two key factors. We have reported that intracerebral hemorrhage (ICH) in cerebral cortex produces depression-like behavior in young male mice. Here, we found that mice lacking nuclear factor erythroid-derived 2-related factor 2 (Nrf2), a transcription factor that upregulates antioxidant proteins and trophic factors such as brain-derived neurotrophic factor (BDNF), had more severe depression-like behavior than wild-type mice at days 21 to 28 after cortical ICH (c-ICH). Moreover, the expression of Nrf2, heme oxygenase-1, BDNF, and TrkB were significantly decreased in wild-type mice after c-ICH. Interestingly, TP-500 (2 mg/kg), a potent Nrf2 inducer, decreased the inflammatory response and reactive oxygen species production on day 28 after c-ICH and improved depression-like behaviors. TrkB receptor antagonist ANA-12 abolished this anti-depression effect. Depression was more severe in female than in male wild-type mice after ICH, but TP-500 improved depression-like behavior in females. These results suggest that downregulation of Nrf2-BDNF-TrkB signaling contributes to development of post-stroke depression, and that Nrf2 inducer TP-500 might improve depression after c-ICH.

Original languageEnglish (US)
Pages (from-to)3288-3301
Number of pages14
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number12
StatePublished - Dec 2021


  • BDNF
  • Intracerebral hemorrhage
  • Nrf2
  • depression
  • stroke

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


Dive into the research topics of 'Nrf2-BDNF-TrkB pathway contributes to cortical hemorrhage-induced depression, but not sex differences'. Together they form a unique fingerprint.

Cite this