Protection by 3-aminobenzamide and nicotinamide against streptozotocin-induced beta-cell toxicity in vivo and in vitro.
To increase knowledge about the defense mechanisms of pancreatic beta-cells exposed to acute injury, the patterns of protection exerted by 3-aminobenzamide and nicotinamide against the effects of streptozotocin have been studied in vivo and in vitro. It was found that 3-aminobenzamide, a strong inhibitor of the NAD-consuming nuclear enzyme poly(ADP-ribose) synthetase, is maximally effective against streptozotocin-induced diabetes in the rat when administered 45-60 min after the beta-cytotoxic agent, unlike nicotinamide, which exerts best protection when given very close to streptozotocin. A partial protection is still afforded by 3-aminobenzamide administered as long as 120 minutes after streptozotocin. In isolated islets, each protective agent, if added to the incubation medium 20 or even 40 minutes after the exposure of the islets to streptozotocin, is able to partially prevent the effects of the damaging drug on glucose-stimulated insulin release. However, best protection in vitro is obtained when either 3-aminobenzamide or nicotinamide is added simultaneously with the toxic agent. Our results support the concept that the reversibility of streptozotocin-induced acute damage in beta-cells depends on the preservation of intracellular NAD pools during critical time intervals. This can be achieved by two different partially overwhelming mechanisms: a) early stimulation of NAD biosynthesis (prevailing effect of nicotinamide) and b) strong inhibition of poly ADP-ribosylation activity (main effect of 3-aminobenzamide).
Masiello
P
P
Istituto di Patologia Generale, University of Pisa, Italy.
Novelli
M
M
Fierabracci
V
V
Bergamini
E
E
D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects*; D008297:Male; D009536:Niacinamide / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains
D001549:Benzamides; D001786:Blood Glucose; D007328:Insulin; D009536:Niacinamide; C025160:3-aminobenzamide