Acetazolamide Protects Steatotic Liver Grafts against Cold Ischemia Reperfusion Injury

Abstract

Ischemia reperfusion injury (IRI) is a primary concern in liver transplantation, especially when steatosis is present. Acetazolamide (AZ), a specific carbonic anhydrase (CA) inhibitor, has been suggested to protect against hypoxia. Here, we hypothesized that AZ administration could be efficient to protect fatty livers against cold IRI. Obese Zucker rat livers were preserved in Institut Georges Lopez-1 storage solution for 24 hours at 4°C and ex vivo perfused for 2 hours at 37°C. Alternatively, rats were also treated with intravenous injection of AZ (30 mg/kg) before liver recovery. Liver injury, hepatic function, and vascular resistance were determined. CA II protein levels and CA hydratase activity were assessed as well as other parameters involved in IRI (endothelial nitric oxide synthase, mitogen activated protein kinase family, hypoxic inducible factor 1 alpha, and erythropoietin). We demonstrated that AZ administration efficiently protects the steatotic liver against cold IRI. AZ protection was associated with better function, decreased vascular resistance, and activation of endothelial nitric oxide synthase. This was consistent with an effective mitogen activated protein kinase inactivation. Finally, no effect on the hypoxic inductible factor 1 alpha/erythropoietin pathway was observed. The present study demonstrated that AZ administration is a suitable pharmacological strategy for preserving fatty liver grafts against cold IRI.

How many carbonic anhydrase inhibition mechanisms exist?

“…A particular feature of the new classes of CAIs discovered in the last years is that they show a much higher isoform-selectivity profile compared to most sulfonamides and sulfamates (of which 1-19 are the typical representatives, see Figure 1). Thus, there is enthusiasm and optimism that the new generations of CAIs will show less side effects and more efficacy for the treatment of the classical pathologies associated with these enzymes but also to newer ones such as neuropathic pain 171 , cerebral ischemia 172,173 , and obviously tumors (with SLC-0111 20 in clinical trials, as mentioned earlier 2,19,54 ). Despite the problem of the fabricated data and similar scientific misconduct issues described in paragraph 7, I will conclude this article in an optimistic manner 174 .…”

Carbonic anhydrase inhibitor attenuates ischemia-reperfusion induced acute lung injury

“…There were a few studies on AZA in IR in other organs. Bejaoui et al found that AZA protected liver grafts against IR injury[17]; Lin and colleagues suggested that AZA decreased infarct size in cardiac IR[18]; An et al demonstrated that AZA exerted a reno-protective role against I/R-induced acute renal injury[19]. In another study, researchers investigated the role of AZA in intracerebral hemorrhage(ICH)-induced brain injury in rats[20].…”

“…Prior studies have addressed the anti-inflammatory effects of AZA[17, 27]. Wang et al found that AZA could decrease pro-inflammatory cytokines, such as monocyte chemoattractant protein-1, IL-1β, TNF-α and Interferon gamma in rat lung injury of acute mountain sickness[27].…”

“…Elevated mitogen activated protein kinases (MAPKs) are found in lung injury[28]. It has been reported that treatment with AZA may cause decreased expression of MAPKs[17]. …”

Synthesis and carbonic anhydrase I, II, IV and XII inhibitory properties of N-protected amino acid – sulfonamide conjugates

“…), most anions, dithiocarbamates and their isosteres, carboxylates and hydroxamates binding in this way [1][2][3]5,13 ; (ii) the inhibitors that anchor to the zinc-coordinated water molecule/hydroxide ion, represented by the phenols, some carboxylates, the polyamines, 2-thioxocoumarins, and sulfocoumarins [1][2][3]13,14 ; (iii) the inhibitors which occlude the entrance to the active site cavity (coumarins and their isosteres), this binding site coinciding with that where CA activators bind [13][14][15][16][17][18][19][20] ; (iv) the compounds which bind out of the active site cavity (a carboxylic acid derivative was seen to inhibit CA in this manner) 21 , and (v) compounds for which the inhibition mechanism is not known, among which the secondary/tertiary sulfonamides as well as imatinib/nilotinib are the most investigated examples 13,[22][23][24][25][26] . The sulfonamides however remain the main class of CAIs with many clinically used drugs as antiglaucoma agents [27][28][29] , diuretics 30 , antiobesity drugs [31][32][33] , antiepilpetics 34 , and more recently agents for the management of hypoxic tumors [35][36][37][38] , neuropathic pain 39 and ischaemia 40,41 . Continuing our interest in designing biolog...…”