Mitochondria as a target for neurotoxins and neuroprotective agents

Ann N Y Acad Sci. 2003 May;993:334-44; discussion 345-9. doi: 10.1111/j.1749-6632.2003.tb07541.x.

Abstract

Mitochondrial permeability transition pores represent a multiprotein complex that includes components of both inner and outer membrane. The pores regulate transport of ions and peptides in and out of mitochondria, and their regulation is associated with a general mechanism for maintaining Ca(2+) homeostasis in the cell and apoptosis. Various pathologic factors may induce a pathologic activation of the permeability transition and an irreversible opening of mitochondria pores. This event is a major step in the development of neurotoxicity and neurodegeneration. This paper explores the effect of MPP(+) and beta-amyloid fragment 25-35, neurotoxins that are known to generate Parkinson's-like syndrome and Alzheimer's disease, on the regulation of the mitochondrial pores. Both neurotoxins induce opening of mitochondrial pores, which is prevented by cyclosporin A, a specific inhibitor of the permeability transition. The effect of MPP(+) and beta-amyloid may be also prevented by an endogenous precursor of melatonin, N-acetylserotonin, by an anti-Alzheimer's medication tacrine, and by dimebon, which is in development as an agent for the therapy of Alzheimer's disease and other types of dementia. The paper illustrates that the effect on mitochondrial pores is an important aspect of the mechanism of neurotoxicity. Substances that may prevent opening of mitochondrial pores induced by neurotoxins may preserve the mitochondrial function and, thus, may have potential as neuroprotective agents.

MeSH terms

  • 1-Methyl-4-phenylpyridinium / pharmacology*
  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Calcium / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Cyclosporine / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Indoles / pharmacology
  • Lipid Peroxidation
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism*
  • Neuroprotective Agents / pharmacology*
  • Nootropic Agents / pharmacology
  • Peptide Fragments / pharmacology*
  • Permeability
  • Rats
  • Rats, Wistar
  • Serotonin / analogs & derivatives*
  • Serotonin / metabolism
  • Tacrine / pharmacology

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Enzyme Inhibitors
  • Indoles
  • Neuroprotective Agents
  • Nootropic Agents
  • Peptide Fragments
  • amyloid beta-protein (25-35)
  • Serotonin
  • Tacrine
  • Cyclosporine
  • latrepirdine
  • N-acetylserotonin
  • 1-Methyl-4-phenylpyridinium
  • Calcium