Immunohistochemistry of advanced glycation end products in neurofilamentous axonal spheroids induced by beta-beta'-iminodipropionitrile in lower motor neurons of rat.
Chronic parenteral administration of beta-beta'-iminodipropionitrile (IDPN) in adult female rats induces large neurofilament-rich axonal spheroids (AXS) in spinal motor neurons closely resembling those AXS in early phases of amyotrophic lateral sclerosis. Immunohistochemistry of advanced glycosylation end-products (AGEs) in axonal spheroids was performed in the present study. Anti-AGE and anti-neurofilament antibodies strongly co-labeled IDPN-induced axonal spheroids, whereas motor neuron soma showed little AGE immunoreactivity. In an attempt to modify and intensify glycosylation, another group of IDPN rats was made hyperglycemic with streptozotocin after IDPN intoxication. These hyperglycemic rats showed AXS with striking AGE immunoreactivity. An additional group of rats made hyperglycemic before IDPN intoxication showed markedly diminished AXS formation, with a few small AGE-positive AXS in anterior horns. Findings suggest that AGEs are involved in neurofilament crosslinking as well as disassembly of neurofilament induced by IDPN with or without hyperglycemia. Hyperglycemia did not intensify neurofilament aggregation. Additional immunohistochemistry revealed not only aberrant phosphorylation, but also intense local production of Cu/Zn superoxide dismutase and nitrotyrosine in axonal spheroids, probably secondary to superoxide generation as a consequence of AGE production at neurofilament protein, impeding its assembly as hypothesized in motoneuron diseases.
Wang
H S
HS
Forbes Norris ALS/MDA Research Center, 2351 Clay Street, Room 412, San Francisco, CA 94115, USA. hslwang@yahoo.com
Taniguchi
A
A
Chou
S M
SM
D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D007150:Immunohistochemistry; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D016900:Neurofilament Proteins / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000378:metabolism
D017127:Glycation End Products, Advanced; D016900:Neurofilament Proteins; D009570:Nitriles; C008110:3,3'-iminodipropionitrile