GDNF protects against aluminum-induced apoptosis in rabbits by upregulating Bcl-2 and Bcl-XL and inhibiting mitochondrial Bax translocation

Neurobiol Dis. 2001 Oct;8(5):764-73. doi: 10.1006/nbdi.2001.0429.

Abstract

Direct (intracisternal) injection of aluminum complexes into rabbit brain results in a number of similarities with the neuropathological and biochemical changes observed in Alzheimer's disease and provides the opportunity to assess early events in neurodegeneration. This mode of administration induces cytochrome c release from mitochondria, a decrease in Bcl-2 in both mitochondria and endoplasmic reticulum, Bax translocation into mitochondria, activation of caspase-3, and DNA fragmentation. Coadministration of glial cell neuronal-derived factor (GDNF) inhibits these Bcl-2 and Bax changes, upregulates Bcl-XL, and abolishes the caspase-3 activity. Furthermore, treatment with GDNF dramatically inhibits apoptosis, as assessed by the TUNEL technique for detecting DNA damage. Treatment with GDNF may represent a therapeutic strategy to reverse the neuronal death associated with Alzheimer's disease and may exert its effect on apoptosis-regulatory proteins.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Animals
  • Apoptosis / drug effects*
  • Caspase 3
  • Caspases / metabolism
  • Cisterna Magna
  • Cytochrome c Group / metabolism
  • DNA Fragmentation
  • Drug Evaluation, Preclinical
  • Endoplasmic Reticulum / metabolism
  • Female
  • Gene Expression Regulation / drug effects
  • Genes, bcl-2
  • Glial Cell Line-Derived Neurotrophic Factor
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • In Situ Nick-End Labeling
  • Injections
  • Mitochondria / metabolism*
  • Nerve Growth Factors*
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / pharmacology
  • Nerve Tissue Proteins / therapeutic use*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Organometallic Compounds / administration & dosage
  • Organometallic Compounds / toxicity
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Pyrones / administration & dosage
  • Pyrones / toxicity
  • Rabbits
  • bcl-2-Associated X Protein
  • bcl-X Protein

Substances

  • Cytochrome c Group
  • Glial Cell Line-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Organometallic Compounds
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrones
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • aluminum maltolate
  • Caspase 3
  • Caspases