Protective Effect of Tonapofylline (BG9928), an Adenosine A₁ Receptor Antagonist, against Cisplatin-Induced Acute Kidney Injury in Rats

Abstract

Background/Aims: Cisplatin (CIS) induces nephrotoxicity partly through renal vasoconstriction and decreased glomerular filtration effects thought to involve adenosine acting on adenosine A₁ 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. Conclusion: 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.

Role of losartan on the renal cortex damage induced by cisplatin in adult male albino rats

“…Also, tubules with regenerative changes were observed. These changes run parallel with the findings documented by previous researchers [24,26,27] who stated morphological changes consistent with acute nephrosis within the cortex.…”

Purinergic signalling in the kidney in health and disease

“…It has been suggested that adenosine may be involved in the haemodynamic changes in the kidney induced by cisplatin [128]. Cisplatin upregulates A 1 receptors in rat kidney [25] and A 1 receptor antagonists have a protective effect against cisplatininduced acute kidney injury in rats [107]. Adenosine antagonists have protective effects against acute renal failure [156, 253,358].…”

Adenosine A1 receptor antagonist, L-97-1, improves survival and protects the kidney in a rat model of cecal ligation and puncture induced sepsis

“…These results of these studies suggest that L-97-1 may provide protection to the kidney by increasing renal blood flow. Furthermore, adenosine A 1 receptor antagonists block cisplatin induce nephrotoxicity (Gill et al, 2009; Knight et al, 1991; Nagashima et al., 1995). In one study, the adenosine A 1 receptor antagonist, tonapofylline (BG 9928), significantly reduced elevated levels of serum BUN and creatinine and improved renal pathology scores, including reducing interstitial inflammation (Gill et al, 2009).…”

“…Furthermore, adenosine A 1 receptor antagonists block cisplatin induce nephrotoxicity (Gill et al, 2009; Knight et al, 1991; Nagashima et al., 1995). In one study, the adenosine A 1 receptor antagonist, tonapofylline (BG 9928), significantly reduced elevated levels of serum BUN and creatinine and improved renal pathology scores, including reducing interstitial inflammation (Gill et al, 2009). Thus in sepsis, by blocking activation of adenosine A 1 receptors in the lung and the kidney, an adenosine A 1 receptor antagonist may improve outcome by attenuating acute lung injury and maintaining renal blood flow and function.…”