Differential mRNA expression of acetylcholinesterase in the central nervous system of rats with acute and chronic exposure of sarin & physostigmine.
A time-course study was carried out to measure the acetylcholinesterase (AChE) gene expression in the brain of female rats exposed to different doses of sarin and physostigmine. Short-term effects were studied with an acute single subcutaneous dose (s.c.) of 80 microg kg(-1) (0.5 x LD(50)) sarin. Cortex and cerebellum showed a significant decline in AChE mRNA expression at 2.5, 24 and 72 h. Biochemical studies showed that plasma butrylcholinesterase (BChE) and brain AChE activities were significantly decreased at 2.5 h, which came back to near control values by 24 h in both cases. For long-term chronic studies, three groups of female rats received daily doses of physostigmine (0.1 mg kg(-1) day(-1)) intramuscularly (i.m.), sarin (15 microg kg(-1) day(-1)) s.c. independently and a combined dose of physostigmine (i.m.) (0.1 mg kg(-1) day(-1)) followed by sarin (s.c.) (15 microg kg(-1) day(-1)) continuously for 30 days. Differential AChE mRNA levels in cortex and cerebellum of rat brain were observed after 30 days and after a lag period of another 30 days with no further administration. Plasma (BChE) and brain (AChE) showed irregular inhibition profile in biochemical studies at 30 days and returned to control levels after 60 days. The acute single subcutaneous administration of sarin for short-term as well as chronic long-term studies showed that AChE inhibition alone does not lead to observed changes in mRNA expression of AChE gene. These observations further suggest that route of administration as well as dose exposure regimen also contributes to the regulation of AChE mRNA expression.
Bansal
Iti
I
Defence Research and Development Establishment, Defence Research and Development Organization, Gwalior, India.
Waghmare
C K
CK
Anand
T
T
Gupta
A K
AK
Bhattacharya
B K
BK
D000110:Acetylcholinesterase / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000097:blood; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D007928:Lethal Dose 50; D010830:Physostigmine / Q000493:pharmacokinetics / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012524:Sarin / Q000493:pharmacokinetics / Q000633:toxicity*; D013997:Time Factors; D023382:Toxicity Tests, Acute; D036401:Toxicity Tests, Chronic
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D012333:RNA, Messenger; D010830:Physostigmine; D012524:Sarin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase