Abstract
We describe a new molecular mechanism of cell death by excitotoxicity mediated through nuclear transcription factor κB (NFκB) in rat embryonic cultures of dopaminergic neurons. Treatment of mesencephalic cultures with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) resulted in a number of changes that occurred selectively in dopaminergic neurons, including persistent elevation in intracellular Ca2+ monitored with Fura-2, and a significant increase in intramitochondrial oxidation of dihydrorhodamine 123, probably associated with transient increase of mitochondrial permeability, cytochrome c release, nuclear translocation of NFκB, and transcriptional activation of the oncogenep53. Interruption of any of these steps by specific antagonists prevented neurite pruning and programmed cell death. In contrast, cell death was not prevented by caspase antagonists and only partly prevented by nitric-oxide synthase inhibitors. This signal transduction pathway might be a contributing mechanism in ongoing neuronal death in Parkinson disease.
Footnotes
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This work was partially supported by National Institutes of Health grants (to M.P.G. and L.L.D.) and by a Joint Junior Faculty Award of the United Parkinson Foundation and the Parkinson Disease Foundation (to G.A.d.E.).
- Abbreviations:
- PD
- Parkinson disease
- DN
- dopaminergic neuron
- TNF
- tumor necrosis factor
- NFκB
- nuclear transcription factor κB
- GluR
- glutamate receptor
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- ROS
- reactive oxygen species
- TH
- tyrosine hydroxylase
- phos-p53
- phosphoprotein p53
- MAP2
- microtubule associated protein 2
- EM
- electron microscopy
- 5,7-DHT
- 5,7-dihydroxitryptamine
- DHR123
- dihydrorhodamine 123
- DTT
- dithiothreitol
- PMSF
- phenylmethylsulfonyl fluoride
- EMSA
- electrophoretic mobility shift assay
- ELISA
- enzyme-linked immunosorbent assay
- PCR
- polymerase chain reaction
- NBQX
- 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide
- NAS
- 1-napthyl-acetyl spermine trihydrochloride
- CSA
- cyclosporin A
- DEA/NO
- sodium 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate
- PDTC
- pyrrolidine dithiocarbamate
- LTCC
- L-type Ca2+channel
- Cyt-c
- cytochrome c
- mPT
- mitochondrial permeability transition
- NO
- nitric oxide NOS, nitric-oxide synthase
- Received October 22, 2002.
- Accepted December 20, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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