Lesion of central cholinergic systems by systemically administered acetylcholinesterase antibodies in newborn rats.
To determine if systemically administered antibodies could reach antigenic targets and cause immunologic lesions in brains of newborn rats, murine monoclonal antibodies against rat acetylcholinesterase were injected i.p. on the first postnatal day. As early as 24 h after injection, antibodies were detected immunocytochemically in brain parenchyma, along with punctate debris that showed intense cholinesterase activity. Total acetylcholinesterase activity in the brain dropped by 30%, and 10S activity was almost undetectable at day 3, implying true enzyme loss since the antibodies did not directly impair catalytic function. At day 7, 10S acetylcholinesterase began to recover but the activity remained only half that of controls. At day 12, total acetylcholinesterase activity was still reduced (30% in whole brain, 40% in cerebral cortex), consistent with lasting damage to cholinesterase-expressing cortical neurons. This conclusion was confirmed by histochemical experiments showing a nearly complete disappearance of acetylcholinesterase fiber-staining in cerebral cortex and basal ganglia at days 4 and 8, with residual deficits at day 12. Choline acetyltransferase activity decreased in the cerebral cortex, implying a loss of cholinergic terminals, but specifically immunoreactive perikarya remained abundant in the basal forebrain. Immunocytochemistry showed no obvious changes in three non-cholinergic markers: tyrosine hydroxylase, tryptophan hydroxylase, and glutamic acid decarboxylase. Overall, it appeared that acetylcholinesterase antibodies induced widespread but reversible damage of cholinergic fibers and terminals, while sparing cholinergic cell bodies and many other neural systems.
Rakonczay
Z
Z
Department of Pharmacology, Mayo Clinic, Rochester, MN 55905.
Hammond
P
P
Brimijoin
S
S
D000109:Acetylcholine / Q000097:blood / Q000276:immunology*; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000276:immunology*; D001835:Body Weight; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000201:enzymology; D007074:Immunoglobulin G / Q000276:immunology* / Q000494:pharmacology*; D007267:Injections; D007274:Injections, Intraperitoneal; D010275:Parasympathetic Nervous System / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis
D000906:Antibodies; D007074:Immunoglobulin G; D000109:Acetylcholine