Effects of S-Propargyl-Cysteine (SPRC) in Caerulein-Induced Acute Pancreatitis in Mice

Abstract

Hydrogen sulfide (H2S), a novel gaseous messenger, is synthesized endogenously from L-cysteine by two pyridoxal-5′-phosphate-dependent enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). S-propargyl-cysteine (SPRC) is a slow H2S releasing drug that provides cysteine, a substrate of CSE. The present study was aimed to investigate the effects of SPRC in an in vivo model of acute pancreatitis (AP) in mice. AP was induced in mice by hourly caerulein injections (50 µg/kg) for 10 hours. Mice were treated with SPRC (10 mg/kg) or vehicle (distilled water). SPRC was administered either 12 h before or 3 h before the induction of pancreatitis. Mice were sacrificed 1 h after the last caerulein injection. Blood, pancreas and lung tissues were collected and processed to measure the plasma amylase, plasma H2S, myeloperoxidase (MPO) activities and cytokine levels in pancreas and lung. The results revealed that significant reduction of inflammation, both in pancreas and lung was associated with SPRC given 3 h prior to the induction of AP. Furthermore, the beneficial effects of SPRC were associated with reduction of pancreatic and pulmonary pro-inflammatory cytokines and increase of anti-inflammatory cytokine. SPRC administered 12 h before AP induction did not cause significant improvement in pancreatic and lung inflammation. Plasma H2S concentration showed significant difference in H2S levels between control, vehicle and SPRC (administered 3 h before AP) treatment groups. In conclusion, these data provide evidence for protective effects of SPRC in AP possibly by virtue of its slow release of endogenous H2S.

Medicinal Chemistry: Insights into the Development of Novel H2S Donors

“…These findings indicated that SPRC could be another protective molecule in MI, and the effects of SPRC are probably mediated by the CSE/H 2 S pathway. Other effects of SPRC, such as anticancer and anti-inflammation, have also been reported Sidhapuriwala et al 2012). …”

H2S and Inflammation: An Overview

“…Therefore, protective actions of H 2 S-releasing compounds may be caused by an inhibition of endogenous H 2 S formation, possibly by a negative feedback mechanism caused by very low local levels of H 2 S. Another slow H 2 S-releasing drug is S-propargyl-cysteine (SPRC), a structural analog of S-allyl cysteine (SAC) with a common cysteine-containing structure. Pretreatment with SPRC has been shown to protect mice against acute pancreatitis and associated lung injury (Sidhapuriwala et al 2012). Another slow H 2 S-releasing compound is GYY4137 (morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate), which has been reported to have an anti-inflammatory action (Li et al 2009(Li et al , 2013.…”

H2S during circulatory shock: Some unresolved questions

“…For example: lethal hypoxia [3], ischemia/reperfusion (I/R)-injury [4–30], cardiac arrest [31–36], hemorrhage and resuscitation [37–45], acute lung injury resulting from blunt chest trauma [46,47] and/or injurious mechanical ventilation [48–50], as well as systemic inflammation resulting from endotoxin injection [51–59], acute pancreatitis [60–63], polymicrobial sepsis [64–70], and/or burn injury [71–73]. While the beneficial effect of exogenous H 2 S supplementation and maintaining endogenous H 2 S production, respectively, are well-established in I/R injury, equivocal results were reported after cardiac arrest, hemorrhage and resuscitation, and, in particular, in sepsis: inhaling gaseous H 2 S [33,44,48,50,53,54,65], the injection of the sulfide-containing salts NaSH [31,39,49,51,59,63,64,66–71,120] and Na 2 S [32,34–38,41,42,44,47,48,72,73] or the slow-releasing H 2 S donor GYY4137 [55] as well as of inhibitors of H 2 S production [43,45,58–60,62,63,67–71,120] were associated with attenuation of shock-related organ dysfunction. Consequently, knowledge about vascular sulfide concentrations may assume major importance, in particular in the context of “ acute on chronic disease ”, i.e., during circulatory shock in animals with pre-existing chronic disease, which per se may markedly alter endogenous H 2 S production, e.g., atherosclerosis [74], arterial hypertension [75,76], chronic kidney disease [77,78], and/or chronic obstructive pulmonary disease (COPD) [79–81].…”