Subchronic effects following a single sarin exposure on blood-brain and blood-testes barrier permeability, acetylcholinesterase, and acetylcholine receptors in the central nervous system of rat: a dose-response study.
Subchronic neurotoxic effects of sarin (O-isopropyl methylphosphonofluoridate) treatment at various doses in male Sprague Dawley rats were studied. The animals were treated with a single intramuscular (im) injection of 0.01, 0.1, 0.5, or 1 x LD50 (100 microg/kg). The animals were maintained for 90 d thereafter. [3H]Hexamethonium iodide was used to monitor the changes in blood-brain barrier (BBB) permeability in cortex, brainstem, midbrain, and cerebellum. Brainstem exhibited a significant decrease (approximately 58% of control) in uptake of [3H]hexamethonium iodide at 1 x LD50 dose. No significant changes were observed in BBB permeability in cortex, midbrain, and cerebellum at any dose. Plasma butyrylcholinesterase (BChE) activity remained unchanged, reflecting recovery of the enzyme activity from the initial inhibition following single exposure of 1 x LD50 sarin. Acetylcholinesterase (AChE) activity in the cortex remained inhibited (approximately 29%), whereas in the brainstem there was an increase (approximately 20%) at 1 x LD50 dose of sarin. The m2-selective muscarinic acetylcholine receptor (m2-mAChR) ligand binding was inhibited significantly at 1 x LD50 in the cortex, whereas brainstem showed significantly increased (approximately 45%) ligand binding at 1 x LD50 dose. Nicotinic acetylcholine receptor (nAChR), on the other hand, showed a biphasic response in ligand binding in the cortex with a decrease (approximately 30%) at 0.01 x LD50 but an increase (approximately 40%) at 1 x LD5O. Brainstem did not show any significant change in nAChR ligand binding. These results suggest that single exposure of sarin could lead to changes that may play an important role in neuropathological abnormalities in the central nervous system.
Jones
K H
KH
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Dechkovskaia
A M
AM
Herrick
E A
EA
Abdel-Rahman
A A
AA
Khan
W A
WA
Abou-Donia
M B
MB
D000110:Acetylcholinesterase / Q000032:analysis / Q000187:drug effects*; D000818:Animals; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D001814:Blood-Testis Barrier / Q000187:drug effects* / Q000502:physiology; D002490:Central Nervous System / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007928:Lethal Dose 50; D008024:Ligands; D008297:Male; D010539:Permeability; D018923:Persian Gulf Syndrome / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000032:analysis / Q000187:drug effects*; D012524:Sarin / Q000493:pharmacokinetics / Q000633:toxicity*
D002619:Chemical Warfare Agents; D008024:Ligands; D011950:Receptors, Cholinergic; D012524:Sarin; D000110:Acetylcholinesterase