Treatment with NZ-419 (5-Hydroxy-1-methylimidazoline-2,4-dione), a Novel Intrinsic Antioxidant, against the Progression of Chronic Kidney Disease at Stages 3 and 4 in Rats

Abstract

For rats, glomerular filtration rate (GFR) and its relative GFR (ratio to normal GFR 0 ) were estimated in order to classify their chronic kidney disease (CKD) into 5 stages like those in humans. The adenine-loaded rats, which were used to show the intrinsic antioxidant and creatinine (Cr) metabolite, NZ-419 (5-hydroxy-1-methylimidazolidine-2,4-dione), when taken orally, prevented the progression of chronic renal failure (CRF), were used as a model to reach the severest stage 5. In this report, we show that, by using both a tubular lesion and a glomerular lesion models (adenine-loaded and 5/6 nephrectomized rats, respectively), peroral NZ-419 might be a common tool to prevent the progression of CRF at CKD stages 3 and 4 under the condition that most rats in the control group still remained at stage 4 (0.15Ͻ ϽGFR/GFR 0 Ͻ Ͻ0.29) at the last. At the minimum effective dose (MED: 100 mg/kg/d) of NZ-419 in adenine-loaded rats, serum Cr and all oxidative stress markers were ameliorated. Two doses (80, 160 mg/kg/d), at around the MED, used for 5/6 nephrectomized rats with a similar CRF severity, gave significant inhibitory effects against the increases in blood urea nitrogen, decreases in renal blood flow and renal plasma flow, and nephrotic syndrome. Oxidative stress markers, the urinary methylguanidine and serum albumin level, were significantly ameliorated.

Crystal structure of 3-(2-(4-isobutylphenyl)propanoyl)-1-methylimidazolidine-2,4-dione, C17H22N2O3

“…Qviductus Ranne [3] has significant pharmacological activities, mainly in anti-oxidation, anti-inflammatory, anti-anxiety, antitussive, and anti-fatigue [4][5][6][7]. 1-Methylhydantoin, as a main effective constituent in Oviducts Ranne, has been widely used in pharmaceutical industry [8].…”

Creatinine and HMH (5-hydroxy-1-methylhydantoin, NZ-419) as intrinsic hydroxyl radical scavengers

“…Intrinsic levels of HMH increase in mammals (8,10) in DM and CKD patients and orally administered HMH has prevented the progression of CKD at stages 3-5 in rats (3,5,6,40,41). We believe that HMH could act as a 'selfdefense' substance.…”

“…As reported earlier (6), we classified the CKD of rats into 5 stages like those in humans (32,55). Table 1 shows a description of the 5 stages of CKD in human subjects and rats (6). In the case of rats, if the GFR had not been measured, we can estimate the eGFR by using our correlation equation below (y: GFR/GFR 0 = GFR/5.7; x: sCrn mg/dL) (6): y = 0.47/x − 0.035 (n = 12: R 2 = 0.97)…”

“…Intrinsic levels of HMH increase in DM and CKD patients (8,10). HMH prevents the progression of CKD at stages 3-5 in rats, if enough HMH is given orally (3,5,6,(37)(38)(39)(40)(41) instead of Crn. We believe that HMH might be a kind of 'self-defense' substance.…”

“…Creatinine (Crn) is one of the main intrinsic hydroxyl radical (•OH) scavengers (1)(2)(3)(4)(5)(6)(7)(8), but this simple fact has not yet become widely accepted. One main reason might be an incorrect old belief that Crn has been taught to be an end-metabolite in mammals.…”