Low molecular weight glycosaminoglycan C3 attenuates AF64A-stimulated, low-affinity nerve growth factor receptor-immunoreactive axonal varicosities in the rat septum.
Glycosaminoglycans (GAGs) play a pivotal role in the pathogenesis of Alzheimer's disease (AD). Although, as we have shown earlier, a low molecular weight GAG, C3, protects against ethylcholine aziridinium (AF64A)-induced cholinergic damage, and against A(beta)-induced tau-2-immunoreactivity (IR), the mechanism of the neuroprotective effect of GAGs is not yet known. Several clues exist. Previous studies in rats revealed that continuous NGF infusion (icv) after AF64A injection increases septal ChAT and AChE activities. Moreover, C3 increases axonal outgrowth in the rat hippocampus, raising the possibility of a NGF-receptor mediated neuroprotection. Furthermore, it has been reported that NGF expression is increased in the septum following AF64A administration. To study the question regarding the mechanism of neuroprotective action of GAGs, AF64A, a selective cholinotoxin, was administered stereotaxically, bilaterally, into the lateral ventricles of Fischer albino male rats (1 nmol/2 microl/side). In order to establish the effect of C3 on the expression of the NGF receptor-IR elements, C3 was administered orally (25 mg/kg, once a day), by gavage, 7 days before, and 7 days after the AF64A injection. NGF receptor immunohistochemistry revealed that AF64A induced the appearance of NGF-receptor-IR axonal varicosities in the rat medial septum. These varicose fibers were attenuated by 14 days' administration of C3. The possible explanation of our data may be that C3 increases NGF synthesis in the lateral septum. The increased level of NGF could suppress the increased, AF64A-induced NGF receptor expression in the medial septal nucleus. These results further accentuate our earlier observations that C3 may have potential as a therapeutic agent in AD and other neurodegenerative disorders.
Dudas
Bertalan
B
Lake Erie College of Osteopathic Medicine, LECOM, 1858 West Grandview Boulevard, Erie, PA 16509-1025, USA. bdudas@lecom.edu
Rose
Michael
M
Cornelli
Umberto
U
Hanin
Israel
I
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D001388:Aziridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002794:Choline / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003176:Complement C3 / Q000494:pharmacology*; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D006025:Glycosaminoglycans / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects; D009466:Neuromuscular Blocking Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D020665:Septum of Brain / Q000166:cytology* / Q000187:drug effects
D001388:Aziridines; D003176:Complement C3; D006025:Glycosaminoglycans; D009466:Neuromuscular Blocking Agents; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; C044894:ethylcholine aziridinium; D002795:Choline O-Acetyltransferase; D002794:Choline