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Muscarinic receptor-mediated pyridostigmine-induced neuronal apoptosis.
- Source :
-
Neurotoxicology [Neurotoxicology] 2000 Aug; Vol. 21 (4), pp. 541-52. - Publication Year :
- 2000
-
Abstract
- Pyridostigmine is a reversible cholinesterase (ChE) inhibitor that is associated with neurologic dysfunction involving both central and peripheral nervous systems. To determine the neurotoxic potential of pyridostigmine, rats were sacrificed at intervals after drug administration (0.5-1.85 mg/kg, i.p., twice daily for 4 days) and brains examined histologically. ChE inhibition was used as a biomarker of pyridostigmine activity. Using the in situ terminal deoxynucleotidyl transferase nick-end labeling of DNA fragments (TUNEL) method and electron microscopy, apoptotic brain cell death was noted in cerebral cortex over a dose range of 0.5-1.85 mg/kg and at the higher dose (1.85 mg/kg), apoptosis was also noted in striatum and hippocampus. These responses were blocked by pretreatment with atropine. Rat cortical cells in culture also underwent apoptosis when exposed to pyridostigmine (250 microM for 24 hr), indicating that the pyridostigmine can initiate apoptosis, independent of peripheral mechanisms. Pretreatment of cells with atropine (10 microM) inhibited pyridostigmine-induced apoptosis, confirming the response was mediated by muscarinic receptors. Short term treatment of rats with pyridostigmine (1.85 mg/kg twice daily for 4 days) induced a prolonged apoptotic response, which was evident in rat cortex up to 30 days after the last dose. Active apoptosis persisted, despite recovery of serum ChE activity. These in vivo and in vitro observations indicate that pyridostigmine can initiate a prolonged neurodegeneration.
- Subjects :
- Animals
Brain drug effects
Brain enzymology
Cells, Cultured
Cerebral Cortex cytology
Cerebral Cortex drug effects
Cholinesterases metabolism
DNA Fragmentation drug effects
In Situ Nick-End Labeling
Male
Microscopy, Electron
Neurons ultrastructure
Rats
Rats, Sprague-Dawley
Apoptosis drug effects
Neurons drug effects
Parasympathomimetics pharmacology
Pyridostigmine Bromide pharmacology
Receptors, Muscarinic drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0161-813X
- Volume :
- 21
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Neurotoxicology
- Publication Type :
- Academic Journal
- Accession number :
- 11022862