Mitochondria and NMDA receptor-dependent toxicity of berberine sensitizes neurons to glutamate and rotenone injury

PLoS One. 2014 Sep 5;9(9):e107129. doi: 10.1371/journal.pone.0107129. eCollection 2014.

Abstract

The global incidence of metabolic and age-related diseases, including type 2 diabetes and Alzheimer's disease, is on the rise. In addition to traditional pharmacotherapy, drug candidates from complementary and alternative medicine are actively being pursued for further drug development. Berberine, a nutraceutical traditionally used as an antibiotic, has recently been proposed to act as a multi-target protective agent against type 2 diabetes, dyslipidemias, ischemic brain injury and neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. However, the safety profile of berberine remains controversial, as isolated reports suggest risks with acute toxicity, bradycardia and exacerbation of neurodegeneration. We report that low micromolar berberine causes rapid mitochondria-dependent toxicity in primary neurons characterized by mitochondrial swelling, increased oxidative stress, decreased mitochondrial membrane potential and depletion of ATP content. Berberine does not induce caspase-3 activation and the resulting neurotoxicity remains unaffected by pan-caspase inhibitor treatment. Interestingly, inhibition of NMDA receptors by memantine and MK-801 completely blocked berberine-induced neurotoxicity. Additionally, subtoxic nanomolar concentrations of berberine were sufficient to sensitize neurons to glutamate excitotoxicity and rotenone injury. Our study highlights the need for further safety assessment of berberine, especially due to its tendency to accumulate in the CNS and the risk of potential neurotoxicity as a consequence of increasing bioavailability of berberine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Berberine / toxicity*
  • Cells, Cultured
  • Drug Interactions
  • Embryo, Mammalian
  • Glutamic Acid / pharmacology*
  • HEK293 Cells
  • Humans
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neurotoxins / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Rotenone / pharmacology*

Substances

  • Neurotoxins
  • Receptors, N-Methyl-D-Aspartate
  • Rotenone
  • Berberine
  • Glutamic Acid

Grant support

Research was funded by grants from the Academy of Finland (HJH) (grant numbers 218081 and 263762), the FGSN/Brain & Mind (KK) and GPBM/Integrative Life Science (CAB) doctoral programs and the University of Helsinki (KK, CAB, HJH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.