Table 1 Pathophysiological effects and mechanisms of vitamin C in sepsis and ischemia reperfusion: animal studies
From: Vitamin C revisited
Model; dose and timing of ascorbate [study] | Pathophysiological effect | Mechanisms |
|---|---|---|
Ischemia reperfusion | ||
Cardiac arrest (VF-ES) in rats; 50 and 100 mg/kg i.v. at start of CPR [33] | Increases successful resuscitation after cardiac arrest rates and 72-hour survival (100 mg/kg better than 50 mg/kg) | Preservation of histology |
Reduced mitochondrial swelling | ||
Preserves mitochondrial respiration (complex I and IV) | ||
Inhibits MDA ↑ | ||
LAD coronary artery ischemia ± ischemic preconditioning in pigs; 2 g i.v. + 25 mg/minute before IPC or before ischemia [42] | Does not affect infarct size | |
Attenuates the beneficial effect of ischemic preconditioning indicating free oxygen radicals are involved in ischemic preconditioning | ||
Middle cerebral artery clamping in mice; DHA 40, 250 and 500 mg/kg, AA 250 and 500 mg/kg, before, 15 minutes and 3 hours after [81] | DHA gives dose-dependent: | DHA passes blood–brain barrier, ascorbate does not |
● Reperfusion blood flow ↑ | No beneficial effect of ascorbate | |
● Infarct size ↓ | ||
● Neurological deficit ↓ | ||
● Mortality ↓ (if given before ischemia) | ||
Abdominal aortic clamping in rats; 100 mg/kg i.v. before [37] | Attenuates lung injury | MDA in blood and lung ↓ |
Renal ischemia in rabbits; 15 mg/kg 24 hours and 1 hour before and 0.83 mg/minute during [34] | Ameliorates renal structure and function | PAF and PAF-like lipids ↓ |
Myeloperoxidase activity ↓ | ||
Hepatic ischemia (clamping HA–PV) rats; 30, 100, 300, and 1,000 mg/kg 5 minutes before [38] | Bile flow and cholate secretion ↑ | 30 and 100 mg/kg: |
Extremely high dose is prooxidant | ● AST and lipid peroxidation ↓ | |
● Prevents ↓ of cytochrome P450 1,000 mg/kg | ||
● Injury and loss of function ↑ | ||
IPC + hepatic ischemia (clamping left HA and PV) in rats; 100 mg/kg i.v. after IPC before clamping [41] | Ascorbate or IPC plus ascorbate after IPC reduce mitochondrial damage and dysfunction | Prevents mitochondrial: |
● Swelling | ||
● Peroxide ↑, MDA ↑ | ||
● GSH and GSH/GSSG ↓ | ||
● Glutamate dehydrogenase ↓ | ||
● ATP ↓ (ascorbate plus IPC) | ||
Liver ischemia in rats; 100 mg/kg i.v. 1 hour before [40] | Attenuates reperfusion liver injury | Attenuation of O2 – and NO release |
Liver ischemia (clamping HA and PV) in rats; oral vitamin C for 5 days [39] | Attenuates myocardial injury and protects cardiac function after liver ischemia | Systemic hydroxyl radical ↓ |
Myocardial MDA | ||
Skeletal muscle ischemia in rats; oral vitamin C for 5 days [35] | Preserves muscle function | Muscle myeloperoxidase ↓ |
Reduces edema | Neutrophil infiltration ↓ | |
Respiratory burst ↓ | ||
Skeletal muscle tourniquet in rats; 50 mg/kg i.v. before ischemia, before reperfusion, or both [36] | Preserves muscle function | Blood malondialdehyde↓ |
Reduces edema | Muscle malondialdehyde = | |
Neutrophil influx | ||
Sepsis | ||
Systemic and microcirculation | ||
CLP in rats; 76 mg/kg i.v. directly after [32] | Restores blood pressure and density of perfused capillaries | |
CLP in mice; 200 mg/kg 30 minutes before [6] | Improves microvascular constriction and arterial pressure responses to norepinephrine | iNOS expression ↓ |
iNOS mRNA ↓ | ||
ROS production ↓ | ||
CLP in mice; baseline and 23 hours after 200 mg/kg [48] | Restores arteriolar conducted vasoconstriction | Reduces increased: |
● nNOS activity | ||
● Nitrite/nitrate | ||
CLP in rats; 76 mg/kg after 1 hour, 6 hours and 2 hours [44] | Prevents maldistributed blood flow and low arterial blood pressure | Blood flow impairment: |
● Requires NADPH oxidase | ||
● Reversal by ascorbate or BH4 | ||
● eNOS dependent | ||
FIP in mice; 10 or 200 mg/kg i.v. 6 hours after [47] | Prevents/reverses septic impairment of capillary blood flow for 18 hours and improves survival | Blood flow impairment depends on the NADPH oxidase subunit gp91phox |
Ascorbate effects are eNOS dependent | ||
Ascorbate suppresses iNOS ↑ activity | ||
FIP in mice; 10 mg/kg i.v. prophylactic or delayed [46] | Prevention or reversal of septic platelet adhesion and/or flow stoppage | Capillary flow stoppage |
● eNOS dependent | ||
● Platelet adhesion predicts 90 % | ||
CLP in mice; 200 mg/kg i.v. at baseline and 3 hours after [50] | Prevents vascular leakage | Inhibits production of: |
● O2 – and NO by NADPH oxidase, iNOS and nNOS | ||
● Peroxynitrite | ||
● 3-Nitrotyrosine-positive proteins ↓ | ||
● Inhibits PP2A activation | ||
Preserves endothelial occludin phosphorylation | ||
Organ injury and function | ||
Intraperitoneal LPS in guinea pigs; low vs. high vitamin C diet [51] | Dietary vitamin C | Hepatic lipid peroxidation ↓ |
Increases hepatic vitamin C and vitamin E content | Hepatic protein carbonyls ↓ | |
Reduces oxidative damage to lipids and proteins | Hepatic GSH and GSH/GSSG ↑ (vitamin C + vitamin E) | |
CLP in rats; 100 mg/kg directly after [53] | Decreases hepatic injury | Suppresses AST and ALT ↑ |
Improves drug-metabolizing function | Prevents GSH and GSH/GSSG ↓ | |
Prevents CYP1A1 and CYP2E1 mRNA, and CYP1A2 activity | ||
FIP or LPS in mice; 200 mg/kg i.p. after LPS [54] | Attenuates sepsis-induced acute lung injury and improves 72-h survival | Preserves lung architecture and barrier |
Proinflammatory chemokine expression ↓ microvascular thrombosis ↓ | ||
Nuclear factor-kappaB activation ↓ | ||
Normalizes coagulation | ||
Immune defense against infection | ||
Klebsiella pneumonia in mice; ascorbate deficient vs. ascorbate supplemented for 25 days [56] | Ascorbate deficiency increases death from infection | No effect on: |
● Cellular response | ||
● Amino acid and lipid peroxidation | ||
Higher concentration of bacteria in ascorbate deficiency |