The comparative pathology of the glycosidase inhibitors swainsonine, castanospermine, and calystegines A3, B2, and C1 in mice.
To study various polyhydroxy-alkaloid glycosidase inhibitors, 16 groups of 3 mice were dosed using osmotic minipumps with swainsonine (0, 0.1, 1, and 10 mg/kg/day), castanospermine, and calystegines A(3), B(2), and C(1) (1, 10, and 100 mg/kg/day). After 28 days, the mice were euthanized, necropsied, and examined using light and electron microscopy. The high-dose swainsonine-treated mice developed neurologic disease with neuro-visceral vacuolation typical of locoweed poisoning. Castanospermine- and calystegines-treated mice were clinically normal; however, high-dose castanospermine-treated mice had thyroid, renal, hepatic, and skeletal myocyte vacuolation. Histochemically, swainsonine- and castanospermine-induced vacuoles contained mannose-rich oligosaccharides. High-dose calystegine A(3)-treated mice had increased numbers of granulated cells in the hepatic sinusoids. Electron microscopy, lectin histochemistry, and immunohistochemistry suggest these are pit cells (specialized NK cells). Histochemically, the granules contain glycoproteins or oligosaccharides with abundant terminal N-acetylglucosamine residues. Other calystegine-treated mice were histologically normal. These findings indicate that swainsonine produced lesions similar to locoweed, castanospermine caused vacuolar changes with minor changes in glycogen metabolism, and only calystegine A(3) produced minimal hepatic changes. These also suggest that in mice calystegines and castanospermine are less toxic than swainsonine, and as rodents are relatively resistant to disease, they are poor models to study such induced storage diseases.
Stegelmeier
Bryan L
BL
USDA-ARS, Poisonous Plant Research Laboratory, Logan, Utah 84321, USA. bryan.stegelmeier@ars.usda.gov
Molyneux
Russell J
RJ
Asano
Naoki
N
Watson
Alison A
AA
Nash
Robert J
RJ
D000470:Alkaloids / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D007212:Indolizines; D027741:Ipomoea / Q000737:chemistry; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011897:Random Allocation; D017026:Swainsonine; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology*; D013997:Time Factors; D014326:Tropanes; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology*; D054836:Indolizidines
D000470:Alkaloids; D006026:Glycoside Hydrolases; D007212:Indolizines; D017026:Swainsonine; D014326:Tropanes; C055033:calystegin; C037806:castanospermine; D054836:Indolizidines