Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Catherine E. Creeley, David F. Wozniak, Anthony Nardi, Nuri B. Farber, John W. Olney

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


The NMDA antagonist, memantine (Namenda), and the cholinesterase inhibitor, donepezil (Aricept), are currently being used widely, either individually or in combination, for treatment of Alzheimer's disease (AD). NMDA antagonists have both neuroprotective and neurotoxic properties; the latter is augmented by drugs, such as pilocarpine, that increase cholinergic activity. Whether donepezil, by increasing cholinergic activity, might augment memantine's neurotoxic potential has not been investigated. In the present study, we determined that a dose of memantine (20 mg/kg, i.p.), considered to be in the therapeutic (neuroprotective) range for rats, causes a mild neurotoxic reaction in the adult rat brain. Co-administration of memantine (20 or 30 mg/kg) with donepezil (2.5-10 mg/kg) markedly potentiated this neurotoxic reaction, causing neuronal injury at lower doses of memantine, and causing the toxic reaction to become disseminated and lethal to neurons throughout many brain regions. These findings raise questions about using this drug combination in AD, especially in the absence of evidence that the combination is beneficial, or that either drug arrests or reverses the disease process.

Original languageEnglish
Pages (from-to)153-167
Number of pages15
JournalNeurobiology of Aging
Issue number2
StatePublished - Feb 2008


  • Cell killing
  • Cholinergic
  • Dendrotoxic
  • Donepezil
  • Excitotoxic
  • Glutamatergic
  • Memantine
  • NMDA antagonist
  • Neurotoxicity
  • Tacrine
  • Vacuoles


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