Anti-inflammatory and neuroprotective effects of natural cordycepin in rotenone-induced PD models through inhibiting Drp1-mediated mitochondrial fission

Neurotoxicology. 2021 May;84:1-13. doi: 10.1016/j.neuro.2021.02.002. Epub 2021 Feb 4.


Accumulating evidences suggest that inflammation-mediated neurons dysfunction participates in the initial and development of Parkinson's disease (PD), whereas mitochondria have been recently recognized as crucial regulators in NLRP3 inflammasome activation. Cordycepin, a major component of cordyceps militaris, has been shown to possess neuroprotective and anti-inflammatory activity. However, the effects of cordycepin in rotenone-induced PD models and the possible mechanisms are still not fully understood. Here, we observed that motor dysfunction and dopaminergic neurons loss induced by rotenone exposure were ameliorated by cordycepin. Cordycepin also reversed Drp1-mediated aberrant mitochondrial fragmentation through increasing AMPK phosphorylation and maintained normal mitochondrial morphology. Additionally, cordycepin effectively increased adenosine 5'-triphosphate (ATP) content, mitochondrial membrane potential (MMP), and reduced mitochondrial ROS levels, as well as inhibited complex 1 activity. More importantly, cordycepin administration inhibited the expression of NLRP3 inflammasome components and the release of pro-inflammatory cytokine in rotenone-induced rats and cultured neuronal PC12 cells. Moreover, we demonstrated that the activation of NLRP3 inflammasome within neurons could be suppressed by the mitochondrial division inhibitor (Mdivi-1). Collectively, the present study provides evidence that cordycepin exerts neuroprotective effects partially through preventing neural NLRP3 inflammasome activation induced by Drp1-dependent mitochondrial fragmentation in rotenone-injected PD models.

Keywords: Cordycepin; Drp1; Mitochondrial dynamics; NLRP3 inflammasome; Parkinson’s disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Deoxyadenosines / pharmacology
  • Deoxyadenosines / therapeutic use*
  • Dose-Response Relationship, Drug
  • Dynamins / antagonists & inhibitors*
  • Dynamins / metabolism
  • Insecticides / toxicity
  • Male
  • Mitochondrial Dynamics / drug effects*
  • Mitochondrial Dynamics / physiology
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • PC12 Cells
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Rotenone / toxicity*


  • Anti-Inflammatory Agents
  • Deoxyadenosines
  • Insecticides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neuroprotective Agents
  • Nlrp3 protein, rat
  • Rotenone
  • Dnm1l protein, rat
  • Dynamins
  • cordycepin