Effects of N-acetyl-L-cysteine on redox status and markers of renal function in mice inoculated with Bothrops jararaca and Crotalus durissus terrificus venoms.

Renal dysfunction is an important aggravating factor in accidents caused by Crotalus durissus terrificus (Cdt) and Bothrops jararaca (Bj) bites. N-acetyl-l-cysteine (NAC) is well known as a nephroprotective antioxidant with low toxicity. The present study investigated the effects of NAC on redox status and markers of renal function in mice that received vehicle (controls) or venoms (v) of Cdt and Bj. In controls NAC promoted hypercreatinemia, hypouremia, hyperosmolality with decreased urea in urine, hyperproteinuria, decreased protein and increased dipeptidyl peptidase IV (DPPIV) in membrane-bound fraction (MF) from renal cortex (RC) and medulla (RM). NAC ameliorated or normalized altered creatinuria, proteinemia and aminopeptidase (AP) acid in MF, AP basic (APB) in soluble fraction (SF), and neutral AP in SF and MF from RC and RM in vBj envenomation. NAC ameliorated or normalized altered neutral AP in SF from RC and RM, and DPPIV and protein in MF from RC in vCdt envenomation. NAC ameliorated or restored renal redox status respectively in vCdt and vBj, and normalized uricemia in both envenomations. These data are promising perspectives that recommend the clinical evaluation of NAC as potential coadjuvant in the anti venom serotherapy for accidents with these snake's genera.

Tratamento uricostático, uricosúrico e antioxidante na insuficiência renal aguda e na letalidade induzidas pelo veneno de Crotalus durissus terrificus em camundongos / Uricostatic, uricosuric and antioxidant treatments in acute renal failure and lethality induced by Crotalus durissus terrificus venom in mice

Acute renal failure (ARF) is one of the most serious complications of envenoming by Crotalus durissus terrificus bites. The present study investigates the effects of n-acetil-Lcisteína (NAC), allopurinol and probenecid on classical parameters of renal function and renal oxidative stress, as well as the effects of NAC on renal aminopeptidase activities, in the kidney of mice inoculated with C. d. terrificus venom (vCdt). The treatment of envenomed mice with NAC ameliorates the content of protein in the membrane-bound fraction of renal cortex and the activity levels of soluble neutral aminopeptidase in the renal cortex and medulla, and of dipeptidyl peptidase IV in the membrane-bound fraction of the renal cortex. In addition, NAC mitigates the uricemia and the renal oxidative imbalance, two marked features of the nephrotoxic effect of vCdt. Increased uricemia and oxidative stress induced by this venom are also ameliorated by allopurinol and probenecid. However, among these three agents under study only the allopurinol significantly reduces the lethality of vCdt. The effectiveness of probenecid would be compromised by hypercreatinemia, hypocreatinuria and worsening of the urinary hypo-osmolality caused by this drug in envenomed mice. In turn, the highest effectiveness of allopurinol seems to be due to its high ability to decrease the intracellular levels of uric acid and/or to block xanthine oxidase-associated oxidants. Data provide consistent evidences linking uric acid, oxidative stress and ARF induced by C. d. terrificus venom, showing that this envenoming constitutes an attractive animal model suitable for studying the hyperuricemia and that the allopurinol deserves to be clinically evaluated as an approach complementary to anti-snake venom serotherapy.

A insuficiência renal aguda (IRA) é uma das complicações mais graves resultantes do envenenamento por Crotalus durissus terrificus. O presente estudo investiga os efeitos da nacetil-L-cisteína (NAC), do alopurinol e do probenecid nos parâmetros clássicos da função renal, estresse oxidativo renal e, no caso da NAC, também sobre atividades aminopeptidásicas renais, em camundongos inoculados com veneno de C. d. terrificus (vCdt). O tratamento do envenenamento por vCdt com a NAC melhora o teor de proteína da fração de membrana do córtex renal e as atividades de aminopeptidase neutra solúvel no córtex e medula renais e de dipeptidil peptidase IV da fração de membrana do córtex renal. Além disso, a NAC melhora a uricemia e o desequilíbrio oxidativo renal, duas características marcantes do efeito nefrotóxico do vCdt. O aumento da uricemia e estresse oxidativo induzido por esse veneno também é amenizado por alopurinol e probenecid. Porém, dentre esses três agentes avaliados somente o alopurinol reduz significativamente a letalidade do vCdt. A eficácia do probenecid estaria comprometida porque este fármaco também produz hipercreatinemia, hipocreatinúria e piora a hipo-osmolalidade urinária nos camundongos envenenados. Por sua vez, a maior eficácia do alopurinol parece ser consequência de sua maior capacidade em diminuir os níveis intracelulares de ácido úrico e/ou por sua habilidade de bloquear oxidantes associados à xantina oxidase. Esses dados fornecem evidências consistentes da ligação entre ácido úrico, estresse oxidativo e a IRA induzida por veneno de C. d. terrificus, mostrando que esse envenenamento constitui um interessante modelo animal para o estudo da IRA associada à hiperuricemia e que o alopurinol merece ser avaliado clinicamente como uma abordagem complementar à soroterapia anti-veneno de serpente.

Lipoic acid effects on renal function, aminopeptidase activities andoxidative stress in Crotalus durissus terrificus envenomation in mice

Crotalus durissus terrificus envenomation has been associated with direct nephrotoxicity, rhabdomyolysis, hyperuricemia, urinary hypoosmolality, alterations in aminopeptidaseactivities (AP) and oxidative stress. This study evaluated the effects of lipoic acid (LA) on renal function, lethality, AP and GSSG/GSH in mice injected with C. d. terrificus venom (vCdt). The doses and routes of administration of LA and vCdt promoted no systemic myotoxicity. LA did not alter significantly the lethality of vCdt. In nonenvenomed, LA induced hypercreatinemia, urinary hyperosmolality, decrease of urinary urea and creatinine, increase of protein in plasma and in soluble fraction (SF) and decrease in membraneboundfraction (MF) of cortex and medulla. Decreased levels of all AP (except neutral-AP in MF-medulla) were also induced by LA in nonenvenomed. LA associated with vCdt decreased plasma osmolality, hematocrit, urinary uric acid, but increased urinary and SF-medullar protein. LA mitigated the increase of protein in SF-cortex and corrected hyperuricemia, GSSG/GSH and protein in MF-cortex and MF-medulla, as well as decreased plasma neutral AP and acid AP in MF-medulla of envenomed mice. Data suggest that LA contributes to the solubilization/remotion of proteins in MF with impairment of most AP,but it could be beneficial for the treatment of the direct nephrotoxicity of vCdt.