GDNF protects against aluminum-induced apoptosis in rabbits by upregulating Bcl-2 and Bcl-XL and inhibiting mitochondrial Bax translocation.
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.
Ghribi
O
O
Department of Pathology, University of Virginia, Charlottesville, Virginia 22908, USA.
Herman
M M
MM
Forbes
M S
MS
DeWitt
D A
DA
Savory
J
J
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002946:Cisterna Magna; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation; D004353:Drug Evaluation, Preclinical; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020287:In Situ Nick-End Labeling; D007267:Injections; D008928:Mitochondria / Q000378:metabolism*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000633:toxicity; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D011753:Pyrones / Q000008:administration & dosage / Q000633:toxicity; D011817:Rabbits; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D003574:Cytochrome c Group; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009942:Organometallic Compounds; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011753:Pyrones; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C067527:aluminum maltolate; D053148:Caspase 3; D020169:Caspases