Protective effect of tonapofylline (BG9928), an adenosine A1 receptor antagonist, against cisplatin-induced acute kidney injury in rats.
OBJECTIVE
Cisplatin (CIS) induces nephrotoxicity partly through renal vasoconstriction and decreased glomerular filtration effects thought to involve adenosine acting on adenosine A(1) receptors (A1Rs). We studied the effect of the orally active, A1R antagonist tonapofylline (BG9928) on biochemical measures of renal function in CIS-induced acute kidney injury (AKI) in rats.


METHODS
Tonapofylline, 1 mg/kg b.i.d., p.o., was administered on days 0-1 or 0-6 to rats treated with CIS 5.5 mg/kg i.v. Prednisolone (PRED) 5 mg/kg s.c. (day 0) served as a positive control. Serum creatinine and urea nitrogen (BUN) were measured in serial blood samples taken over the 13-day study period.


RESULTS
CIS produced significant elevations in creatinine, reduction in body weight and marked proximal tubular injury throughout the renal cortex and outer medulla. Tonapofylline, days 0-1 or 0-6 and PRED all produced sustained reductions in post-CIS serum creatinine and BUN levels compared with controls, improved body weight recovery and significant attenuation of CIS-induced kidney pathology scores.


CONCLUSIONS
These data support the involvement of A1Rs in CIS-induced AKI in rats. Tonapofylline may be useful in the clinical setting for the prevention of kidney failure induced by nephrotoxic agents such as CIS.
Gill
Alan
A
Biogen Idec, Inc., Cambridge, Mass. 02142, USA.
Wortham
Kathleen
K
Costa
Don
D
Davis
Wendell
W
Ticho
Barry
B
Whalley
Eric
E
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D007677:Kidney Function Tests; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D011239:Prednisolone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014970:Xanthines / Q000494:pharmacology*
D058916:Adenosine A1 Receptor Antagonists; D000970:Antineoplastic Agents; C505954:BG 9928; D005938:Glucocorticoids; D014970:Xanthines; D011239:Prednisolone; D003404:Creatinine; D002945:Cisplatin