An Overview of the Potential Therapeutic Applications of CO-Releasing Molecules

Table 1

A summary of the potential therapeutic applications of CORMs.

	CORM	Effect	Ref.
Bacteria:
E. coli	CORM-2	Decreased viability of uropathogenic isolates and reduced colonization of human bladder epithelial cells	[17]
		Suppressed cell membrane respiration in the EC598 strain
	PhotoCORM		[18]
	TryptoCORM	Reduces cell viability by > 99.9%	[19]
N. gonorrhoeae	TryptoCORM	Reduces cell viability by > 99%	[20]
H. pylori	CORM-2	Reduced cell viability via inhibition of Ni-containing urease	[21]
	CORM-3
S. typhimurium	CORM-3	Reduced growth and viability	[22]
P. aeruginosa	CORM-2	CORM-2, -3, and -371 reduced bacterial O2 consumption and displayed bactericidal properties	[23]
	CORM-3
	CORM-371	CORM-A1 slowed bacterial growth (bacteriostatic)
	CORM-A1
	[MnBr2(CO)4]	Varied reduction of cellular growth for a variety of strains	[24]
Neurodifferentiation and neuroprotection:
Neurodifferentiation	CORM-A1	Improved neuronal differentiation and yield in NT2 cell line by promoting oxidative metabolism	[25]
Neuroprotection	CORM-2	Increased viability of neural stem cells and reduced number of apoptotic cells	[26]
		Lessened mitochondrial damage and improved neurological function of mice after induced cardiac arrest	[27]
	ALF186	Prevented apoptosis in nerve cells simulating ischemic respiratory arrest by increasing cellular cGMP levels	[28]
	ALF492	Protected mice against cerebral malaria	[29]
Cochlear inflammation	CORM-2	Inhibited MCP-1/CCL2 upregulation, reducing oxidative stress and protecting against cochlear inflammation	[30]
Neuroinflammation	CORM-3	Reduced inflammatory response in BV-2 microglial cells by reducing NO production	[31]
		Suppresses interleukin-1β-induced inflammatory responses	[32]
Nociception and diabetes:
Neuropathic pain	CORM-2	Attenuated mechanical allodynia, thermal hyperalgesia, and thermal allodynia when used in combination with the antinociceptive JWH-015	[33]
		Reduced sciatic nerve injury-induced mechanical and thermal hypersensitivity by attenuating spinal microglial activation and expression of NOS1/2 and CD11b/c proteins	[34]
Diabetes	CORM-A1	Facilitated beta cell regeneration by reducing T-helper cell counts and TGF-β and Ki-67 expression	[35]
Inflammatory disease:
Colitis	CORM-2	Reduced cell survival of colitis-inducing cells	[36]
	CO-HbV	Reduced tissue damage and prolonged survival of mice with induced colitis	[37]
Bacterial LPS-induced inflammation	CORM-2	Prevented LPS-mediated inflammation by reducing TLR4/MD2 expression on dendritic cell surfaces and protected mice against increased neutrophil counts associated with septic inflammation	[38]
Tumour necrosis factor α-induced inflammation	CORM-2	Induced p65 glutathionylation which protects cysteinyl residues from irreversible oxidation	[39]
Inflammatory disease (cont.):
Inflammation-induced blood clotting	CORM-2	Decreased blood clotting in human umbilical vein endothelial cells by suppressing MAPK and NF-κB signaling pathways	[40]
Uveitis	CORM-A1	Improved retina morphology and expression of IFNgamma and IL-17A was lowered and IL-10 raised in uveitis-induced mice	[41]
Chronic inflammatory pain	CORM-2	Reduced mechanical allodynia and thermal hyperalgesia in mice and diminished upregulation of NOS1 expression	[42]
Intestinal barrier function	CORM-2	Improved barrier function of intestinal epithelial cells by suppressing phosphorylation of the myosin light chain	[43]
Periodontal disease	CORM-3	Inhibited nuclear translocation of NF-κB and reduced DNA binding of p65/p50 subunits	[44]
Vascular inflammation	CORM-3	Inhibited neutrophilic myeloperoxidase activity	[45]
Sepsis and associated conditions:
Oxidative stress	CORM-2	Reduced oxidative stress during sepsis by increasing HO-1 expression	[46]
NO-induced lipid peroxidation	CORM-2	Attenuated inducible NO synthase and NO production	[46]
CLP-induced sepsis	CORM-2	Improved morphology of intestinal mucosa during sepsis, protecting against LPS-induced intestinal damage	[47]
		Reduced mortality of mice with sepsis-induced acute kidney injury by reducing biomarkers	[48]
Septic lung injury	CORM-3	Restored downregulated annexin A2 levels to normal in LPS-induced lung sepsis	[49]
Myocardial dysfunction	CORM-3	Improved myocardial function in cardiac fibroblasts of septic mice by inhibiting activation of the NLRP3 inflammasome	[50]
Abnormal platelet coagulation	CORM-2	Abnormal platelet activation was reduced by inhibition of glycoprotein-mediated HS1 phosphorylation	[51]
Hyperglycemia	CORM-2	Suppression of hepatic glucose metabolism in mice	[52]
Recruitment of PMN leukocytes	CORM-3	Reduced leukocyte infiltration and attenuated several (but not all) proteins expressed during sepsis	[53]
Obesity:
Dietary-induced	CORM-A1	Reduced weight gain, aided weight loss, and increased lean body mass in mice receiving a high-fat diet	[54]
	CORM-2	Reduced leptin resistance and led to lower body weight of animals fed high-fat diet	[55]
Hyperglycemia	CORM-A1	Decreased hyperglycemia and reduced plasma insulin levels	[54]
Angiogenesis, aggregation, and cancer:
Angiogenesis	CORM-2	Prevented endothelial cell migration and proliferation induced by vascular endothelial growth factor and suppressed phosphorylation of retinoblastoma protein, halting extreme cell replication	[56]
Cancer	CORM-401	Promoted vasorelaxation of precontracted aortic rings	[57]
	CORM-2	Increased survival of mice with A20 lymphoma tumours when encapsulated by folic acid-tagged protein nanoemulsions	[58]
		Prevented global protein synthesis in pancreatic stellate cells	[59]
	PhotoCORM	Reduced cell biomass upon irradiation at 365 nm	[60]
Cell aggregation	CORM-2	Decreased binding affinity of a integrin-specific ligand and lead to reduced cellular aggregation	[61]
Hemorrhagic shock and postresuscitation injuries:
Hemorrhagic shock	CORM-A1	Maintained levels of fenestrations, cells, and adherent leukocytes by reducing expression of cytokines	[62]
	CORM-3	Increased frequency of live human umbilical vein endothelial cells; reduced apoptosis and decreased mitochondrial transmembrane potential and reduced tissue necrosis	[63]
Postresuscitation myocardial injury	CORM-2	Reduced myocytolysis and damage from myocardial fibers and decreased cardiac mitochondrial ROS	[64]
Hypoxia reoxygenation	CORM-3	Conserved cell viability	[65]
Cardiac transplantation	CORM-3	Prolonged survival of rats after heart transplantation	[65]
		Improved coronary flow in mice following heart transplantation	[66]
Kidney transplantation	CORM-2	Pretreating donor rats improved renal histology and function in recipients and long term treatment, however, produced excess lymphocyte accumulation and glomerulus atrophy	[67]
	CORM-3
Gastric, intestinal, kidney, and liver disorders:
Gastric disorder	CORM-2	Reduced formation of mucosal lesions caused by alendronate (osteoclast inhibitor) in rats stressed by water immersion	[68]
Liver injury	CORM-A1	Reduced hepatocyte cell death by decreasing CK18 cleavage products and lowering RIP3 expression	[69]
Hepatitis	CORM-A1	Significantly reduced deaths in a murine model of autoimmune hepatitis	[70]
Nephrotoxicity	CORM-3	Reduced cell damage induced by cisplatin in renal epithelial cells by suppressing caspase-3 activity and prevented apoptosis and kidney mass loss	[71]
Renoprotection	CORM-3	Increased viability of normal and cancerous human renal cells that were subjected to cisplatin-induced toxicity and ischemia-reperfusion injury	[72]
Intestinal disorder	CORM-3	Partially restored intestinal contractility in mice presenting postoperative ileus and reduced oxidative stress levels	[73]
Lungs:
Pulmonary hypertension	CORM-3	Prevented ventricular hypertrophy and distal pulmonary artery muscularization in hypoxia-induced mice	[74]
		Resulted in irreversible pulmonary vasoconstriction in an in vitro hypoxic pulmonary vasoconstriction model	[75]
Ocular system:
Intraocular pressure	CORM-3	Lowered intraocular pressure in rabbits	[76]
Cardiovascular effects:
Cardioprotection/toxicity	CORM-2	Decreased oxidative stress and apoptosis induced by DXR (antitumor agent) in a narrow therapeutic window	[77]
		Attenuated angiotensin II-induced aortic smooth muscle cell migration by inhibiting matrix metalloproteinase-9 expression and ROS/interleukin-6 generation	[78]
	CORM-3	Improved recovery of cardiac structure and function following myocardial infarction in rats	[79]
Pro- and anticoagulant effects:
Procoagulation	CORM-2	Increased strength and velocity of clot formation	[80–82]
		Attenuates snake venom with fibrinogenolytic and thrombin-like activity	[83–86]
Anticoagulation	CORM-2	Reduced platelet aggregation in aortic allograft recipient mice	[87]
	CORM-3	Decreased arterial thrombus formation	[88]
	CORM-A1