Among the identifiable causes, the male factor stands out in about half of infertile couples, representing a growing problem. Accordingly, there has been a decline in both global fertility rates and sperm counts in recent years.

Among the mechanisms likely plausible to account for idiopathic cases, oxidative stress OS has currently been increasingly recognized as a key factor in MI, through phenomena such as mitochondrial dysfunction, lipid peroxidation, DNA damage and fragmentation and finally, sperm apoptosis.

In addition, elevated reactive oxygen species ROS levels in semen are associated with worse reproductive outcomes. However, despite an increasing understanding on the role of OS in the pathophysiology of MI, therapeutic interventions based on antioxidants have not yet provided a consistent benefit for MI, and there is currently no clear consensus on the optimal antioxidant constituents or regimen.

Therefore, there is currently no applicable antioxidant treatment against this problem. This technique allows for real-time biochemical monitoring of markers of ischemia and neuronal injury, and is being increasingly used in highly advanced neurocritical care units. It certainly holds promise as a tool to improve our understanding of OS and its management in the neurocritical care setting, and for future use as a means for direct administration of potential antioxidant therapy.

Imaging techniques hold promise as useful tools for assessment of OS in vivo , although the clinical utility of these techniques remains limited. Nuclear magnetic resonance spectroscopy, such as the Nuclear Overhauser effect enhanced magnetic resonance imaging MRI , electron spin resonance spectroscopy, and 31 P-nuclear magnetic resonance spectroscopy can create images of free radical distributions in animals [ 14 , 15 ].

Brain damage attributed to OS may be detected on MRI. For example, the relaxivity of the pro-oxidant ferric form of hemoglobin on T1-weighted imaging is higher than its ferrous counterparts [ 16 ]. Oxidative modifications of DNA, protein, and lipids by ROS play an important role in neuronal injury and its severity following cerebral ischemia.

In a prospective study of 45 patients with acute ischemic stroke, the activities of the scavenger enzymes, SOD, and catalase were lower in stroke patients than controls, and the study showed a gradual increase in time for as many as 15 days poststroke, which correlated with the degree of neurological deficits [ 17 ].

In another study, plasma concentrations of α- and β-carotene were lower in patients with acute ischemic stroke than healthy controls, and were negatively associated with high sensitivity C-reactive protein level and the National Institute of Health Stroke Scale NIHSS score after adjustment for age and sex [ 18 ].

Similarly, in a study of 70 patients with acute ischemic stroke and 70 controls with similar risk factors, serum levels of NO, malondialdehyde, and glutathione were significantly elevated in stroke patients, and the levels of NO and malondialdehyde correlated with the Canadian Neurological Scale score [ 19 ].

Taffi et al. They found that mean plasma levels of peroxynitrite were significantly higher in stroke patients and that NO levels were associated with worsening evolution of NIHSS score from admission to day 30, suggesting that changes in NO metabolism may be a marker of brain injury following ischemic stroke.

However, the role of NO following ischemia is complex. Other reports have linked greater NO production to improved vascular reactivity and anti-inflammatory responses following ischemia [ 21 , 22 ]. Overall, the previously described studies implicate a pathophysiological role for OS in ischemic stroke and suggest deleterious effects of OS on stroke severity and clinical outcome.

Few clinical studies examined the use of antioxidants in ischemic stroke. The ability of the free radical-trapping agent NXY to reduce functional disability after ischemic stroke was previously investigated.

Despite encouraging results in early phase II testing, the subsequent definitive phase III trial did not show beneficial effects [ 23 , 24 ]. Several reasons have been proposed for the failure of NXY [ 25 ].

Future studies investigating the role of OS on long-term poststroke recovery are needed. Reperfusion injury plays an important role in the pathophysiology of neuronal injury following cerebral ischemia via several deleterious pathways including: cytochrome-c release, expression of matrix metalloproteinase MMP , caspase induction, and reduction of DNA repair enzymes [ 26 ].

In a case control study of ischemic stroke patients presenting within 8 hours of stroke onset, F2-isoprostanes were elevated in stroke cases compared with controls early on, but not at later time points, and they correlated with MMP-9, indicating that OS is also implicated in activation MMP-9 and blood-brain barrier injury after ischemia reperfusion [ 27 ].

Additionally, the antioxidant enzyme SOD blocks these pathways, thereby preventing apoptosis following cerebral ischemia [ 28 ], suggesting that antioxidant therapy could be a potential therapeutic strategy to prevent reperfusion injury following reperfusion therapy, such as thrombolysis.

After intracerebral hemorrhage ICH , large numbers of hemoglobin-containing red blood cells are released into the brain parenchyma. Iron has been implicated in neuronal injury and delayed brain edema formation after ICH via several mechanisms including activation of lipid peroxidation, exacerbation of excitotoxicity, and inhibition of sodium-potassium pump activity [ 29 — 31 ].

Increased hydroxyl radical formation leads to OS and subsequent cell death. A large number of experimental studies show that iron is neurotoxic after ICH. Goldstein et al. Studies in rat models of ICH also confirm the role of iron toxicity that it is mediated via OS mechanisms.

Huang et al. In similar studies, Nakamura et al. These findings suggest that iron-mediated OS contributes to DNA damage and brain injury after ICH and that limiting iron-mediated oxidative injury in the brain is a potential therapeutic target in ICH.

Emerging evidence also links iron to neuronal injury in ICH patients. Serum ferritin on admission correlates with the relative perihematoma edema PHE on day 3, which coincides with the timing for hemoglobin hemolysis [ 35 ] and functional outcome at 3 months [ 36 ], and the iron content within the hematoma, estimated by MRI, correlates with PHE volume [ 37 ].

The role of OS in patients with ICH has been investigated in a small study of 13 patients with spontaneous ICH and 15 patients with traumatic ICH, compared to 40 healthy controls [ 38 ]. ICH patients had significantly lower plasma levels of vitamin C and vitamin C levels inversely correlated with the severity of neurological impairment, as assessed by Glasgow Coma Scale and the NIHSS, and the diameter of the hematoma.

These findings suggest depletion of antioxidants following ICH, and also suggest that its severity, which presumably reflects the severity of OS, correlates with indices of injury-related clinical impairments. The Cerebral Hematoma and NXY Treatment Trial CHANT investigated the use of the free radical-trapping agent NXY in ICH; treatment initiated within 6 hours of ICH onset and continued for 72 hours showed no difference in mortality or the distribution of modified Rankin Scale scores at 90 days between NXY- and placebo-treated patients [ 39 ].

Clinical studies in ICH patients also have identified genome-wide associations between Apolipoprotein-E variants APOE ε2 and ε4 and lobar ICH; The APOE ε4 allele amplifies the inflammatory responses, increases cerebral edema, and is associated with worse outcome after ICH [ 40 , 41 ].

In mouse models, treatment with APOE analogue, COG , resulted in reduced functional deficit, decreased brain concentrations of inflammatory proteins, and less cerebral edema [ 42 ].

Clearly, more clinical studies are needed to assess the role of APOE and OS in ICH patients. In rodent models of subarachnoid hemorrhage SAH , there is evidence of increased superoxide anion and nicotinamide adenine dinucleotide phosphate NADPH oxidase, both powerful oxidizing agents [ 43 , 44 ].

In addition, treatment with alpha-lipoic acid, a dithiol antioxidant, improves neurological outcome and decreases brain edema and free radical generation [ 44 ]. In another study of rat model of aneurysm genesis, ROS were related to aneurysm formation [ 43 ].

In this study, rats were fed a high salt diet for 3 months in addition to a lysyl-oxidase inhibitor, an enzyme involved in catalyzing the cross-linking between collagen and elastin.

Upregulation of ROS-producing genes, suppression of ROS-eliminating genes, and many highly oxidative species, such as heme-oxygenase, NOS, MMP-2, and a 47 kDa portion of NADPH oxidase were detected within the spontaneous aneurysms that formed, using reverse transcriptase PCR analysis, Western blot, and immunohistochemistry [ 43 ].

Pre-treatment with edavarone, a free-radical scavenger, decreased size of the aneurysm and the production of the previously mentioned oxidizing agents within the aneurysm, and also within infiltrating macrophages and smooth muscle cells [ 43 ].

These effects were more profound when studying these phenomena in a p47 NADPH oxidase knockout mouse, suggesting that this may be one of the key oxidizing agents required for initiating the aneurysm signaling cascade.

The prognostic value of OS has been investigated in postsurgical aneurysmal SAH patients; cerebrospinal fluid levels of malondialdehyde emerged as significant predictors of poor outcome at 6 months [ 45 ]. A Japanese proof-of-concept study investigated the use rectal indomethicin and selective brain cooling in patients with aneurysmal SAH and ICH, and found reduced cerebrospinal fluid expression of inflammatory cytokines and ROS [ 46 ].

No outcome data were presented. Few randomized, controlled clinical trials have examined the use of radical scavengers in SAH patients, but the results have been disappointing [ 47 , 48 ].

The synthetic aminosteroid, tirilazad mesylate, which inhibits lipid peroxidation, has been extensively studied in SAH with variable results [ 49 — 51 ]. Overall, there was no difference in long-term outcome or symptomatic vasospasm between active treatment and placebo.

Reactive oxygen species play a role in the pathogenesis of traumatic brain injury TBI. Cats subjected to fluid-driven piston percussion model to induce TBI have significantly more superoxide anion production after TBI compared to controls [ 52 ].

They also have persistent cerebral arteriolar dilation and reduced responsiveness to hypocapnic vasosconstriction after TBI, and the arteriolar dilation is reduced by treatment with SOD and catalase [ 53 ].

In rat models of TBI, administration of progesterone before the insult reduced levels of isoprostane and improved neurological recovery [ 54 ]. In an attempt to translate this into the clinical setting, the Progesterone for Traumatic Brain Injury: Experimental Clinical Treatment ProTECT III , a phase III clinical study is currently enrolling patients to determine whether or not progesterone will be the first experimentally vetted treatment for TBI.

Similar to ICH, APOE is another possible target for ameliorating neurological injury after TBI. APOE has been shown to reduce ROS and other inflammatory markers after many different kinds of insults [ 55 ].

When APOE or its analogues are given to rats before TBI, they not only have improved neurological outcome, but the size of the contusion is reduced compared to controls [ 56 ].

Conversely, the APOE ε4 allele, which codes for a form of APOE that is the least effective in reducing the cerebral inflammatory response, predisposes to worse outcomes after neurological injury, including TBI [ 57 , 58 ].

It remains to be seen whether APOE or its analogues have a place in the treatment of TBI. Despite the large number of antioxidants tried in MODS, few had a significant effect on morbidity or mortality [ 60 , 61 ].

One explanation is that the antioxidants tested were not targeted to mitochondria. Injection of MitoQ in a sepsis model reduced radical production and lowered markers of hepatic and renal injury [ 62 ].

In addition, some systemic antioxidants have been tried for sepsis: N-acetylcysteine and deferoxamine [ 63 — 65 ]. Individually, these drugs have failed to improve outcome in human trials, although the combination of these drugs has shown some promise in a cecal ligation mouse model of sepsis [ 66 , 67 ].

It has been theorized that this may be due to a much more oxidative environment in sepsis that results in all of the N-acetylcysteine being oxidized by free iron released from cytochome-c and hemolysis.

Subcutaneous injection of N-acetylcysteine and deferoxamine 3 hours after cecal ligation resulted in decreased cytochrome-c release, radical formation, and liver necrosis [ 66 ].

These results suggest that the complex pathway of OS-mediated injury in critically ill patients may necessitate a multimodal poly-therapeutic approach, as opposed to single therapeutic strategies. There has been some success in the treatment of sepsis with antioxidants, namely, omega fatty acids and selenium.

A German group randomized 10 septic patients requiring parenteral nutrition to receive either a standard omega 6-based lipid infusion or a fish-derived omega 3 lipid infusion [ 68 ]. The neutrophils derived from the omega 3 group were better able to metabolize free fatty acids, which are potent oxidants, and responded to ex vivo stimulation more briskly.

The study was too small to demonstrate any improved outcome, but the results are promising and should be investigated further.

Selenium has been tested in severe sepsis, with patients who had APACHE III scores greater than 70 who were randomized to receive intravenous selenium for 14 days or placebo [ 69 ]. The selenium group had a significant improvement in day mortality. Furthermore, the mortality benefit was accentuated in the most critically ill patients with APACHE scores greater than , more than three organ failures, and those with disseminated intravascular coagulation.

The investigators also measured glutathione peroxidases-3 activity and found much higher activity in the treatment group. Both omega-3 fatty acids and selenium are relatively simple measures that could be instituted in intensive care units across the country, however, further investigation and larger studies are required before antioxidants will see their roles elevated to the standard of care for MODS.

Another type of organ failure that neurointensivists commonly deal with is cardiac arrest. Oxidative stress plays an important role in brain injury following cardiac arrest. In rats subjected to 7. In humans, exposure of human umbilical vein endothelial cells to the plasma of out of hospital-cardiac arrest patients increased the production of ROS and decreased production of anti-oxidants, such as SOD, glutathione, and glutathione peroxidase in the cells exposed to cardiac arrest patients vs.

normal controls [ 71 ]. The protective effects of therapeutic hypothermia in cardiac arrest patients on mortality and neurological outcomes is well established [ 72 ]. Animal studies show that hypothermia decreases the production of ROS, stabilizes mitochondrial membrane potentials, phosphorlyates a survival kinase called Akt, and decreases cell death compared to normothermia in murine cardiac myocytes exposed to conditions simulating ischemia and reperfusion [ 73 ].

In rats, hypothermia reduces malondialdehyde levels in the brain during reperfusion following hypoxic ischemia compared with normothermia [ 74 ].

Acute lung injury ALI and adult respiratory distress syndrome ARDS are common problems in neurocritical patients. The inciting events are defined by either direct injury to the lung, such as aspiration or pneumonia versus indirect injury to the lung, such as sepsis [ 75 ].

Reactive species in ARDS come from a variety of sources including high inspired fraction of oxygen, depletion of endogenous anti-oxidants, and intra- and extra-pulmonary inflammation [ 76 , 77 ].

A study measuring oxidized products of xanthine oxidase in ARDS patients correlated strongly with outcome, supporting the role for ROS in the pathophysiology of ARDS [ 77 ]. Similar to shock studies, several anti-oxidants have been investigated for ARDS in the clinical setting; N-acetylcysteine replenished levels of neutrophilic glutathione, but had no effect on oxidant or elastase production [ 77 ].

Another study using intravenous liposomal delivery of prostaglandin E1 to ARDS patients in order to decrease the production of exhaled hydrogen peroxide and ROS production found no effect at all on reducing oxidants or improving outcome [ 78 ].

The biochemical changes of OS suggest that antioxidant therapy may be theoretically achieved by the following strategies: 1 restoring endogenous antioxidants and nutrients and supplementation with exogenous trace elements, vitamins, and nutrients with antioxidant properties; or 2 administering drugs that reduce OS, such as statins, iron-modifying agents such as deferoxamine, or minocycline.

We discuss below the potential utility of these strategies and present data regarding their use in the critical care setting. It is intuitive that any of these strategies would probably be more efficacious if implemented before a massive OS takes place, i.

Therefore, these candidate antioxidant strategies can potentially be used for preventive or therapeutic purposes. There is a rationale to support exogenous supply of antioxidant trace elements, vitamins, and nutrients during critical illness.

The levels of nutrients with antioxidant properties are decreased in critical illness. For example, patients with ICH have lower plasma levels of vitamin C compared with healthy volunteers [ 38 ].

Other studies have shown a reduction in muscle glutamine and glutathione and muscle protein synthesis in intensive care patients [ 81 ]. There is also evidence that low endogenous stores on antioxidant nutrients are associated with increased free radical generation, augmentation of the systemic inflammatory response, subsequent cell injury and death, and even higher morbidity and mortality in critically ill patients [ 6 , 7 ].

In addition, proof-of-concept studies have shown that supplementation with trace elements and vitamins, such as selenium, and vitamins A, C, and E, improve antioxidant capacity by increasing the activity of glutathione peroxidase, or reducing plasma TBARS, and isoprostanes [ 82 ].

Vitamins C and E may also reduce infectious complications by restoring neutrophil function and cell-mediated immunity, and selenium improves phagocytosis and immunoglobulin synthesis. Although results from some of these trials were encouraging, the benefit of this therapy has not been clearly established.

Several reasons have been proposed: 1 the vast majority of these studies were performed in small and heterogeneous populations of critically ill patients, and were largely underpowered; and 2 uncertainties regarding the correct dose to use, appropriate time to start immune nutrition, and the appropriate route of administration; the enteral versus parenteral.

In a meta-analysis of 11 studies selected from 44 studies based on strict criteria of early immune nutrition using antioxidant trace elements and vitamins in well-defined intensive care patient populations, Heyland et al. They also found that none of the trials using immune nutrition reported deleterious effects from using exogenous micronutrients, and they concluded that supplementation with antioxidant trace elements and vitamins in intensive care patients is safe and possibly beneficial.

They argued that immune nutrition must be started very early after admission to the intensive care unit and that high-dose parenteral nutrition appears to have a stronger impact on outcome.

Crimi et al. Recently, Casaer et al. It is noteworthy, however, that Casaer et al. Given the previously described, the use of immune nutrition therapy in neurocritical care might be a rationale and promising strategy.

However, more definitive evidence from large-scale, randomized, placebo-controlled, and well-designed trials in this specific patient population is still required. Vitamin B12 has glutathione-sparing antioxidant properties via stimulation of methionine synthase activity and reaction with ROS and NOS.

It also inhibits NOS and NO production, and decreases NF-κB activation. N-acetylcysteine has multiple putative antioxidant properties by decreasing NF-κB activation and cytokines production, regenerating NO as a sulfhydryl donor, and replenishing glutathione, and scavenging ROS as a precursor of glutathione.

N-acetylcysteine has been extensively studied in critically ill patients with acute respiratory distress syndrome, organ failure, and septic shock. These studies have produced inconsistent results [ 83 , 89 , 90 ]. We found no studies of N-acetylcysteine in neurocritical care, to date.

Albumin has antioxidant effects, largely mediated by its thiol sulfhydryl group portion, which attaches to ROS and NOS. It also decreases copper-mediated lipid peroxidation, and modulates nitric oxide-mediated vascular dilatation. Hypoalbuminemia is common in critically ill patients, including those with TBI and various neurological conditions, and is associated with increased morbidity and mortality [ 91 ].

Studies of albumin supplementation in surgical and medical critically ill patients had inconsistent results.

The Saline versus Albumin Fluid Evaluation SAFE study of found no advantage for albumin in comparison with saline [ 92 ], and a subsequent post-hoc subgroup analysis of patients with TBI suggested that resuscitation with albumin was associated with increased odds ratio for death [ 93 ].

A Cochrane meta-analysis found no benefit in a heterogenous group of previously published studies [ 94 ]. Powner [ 95 ] recently argued that it is important to separate data from studies regarding albumin infusions intended to restore or maintain intravascular pressure or volume goals from the potential benefit of preventing hypoalbuminemia during neurocritical care.

The use of albumin in TBI, and hypertensive and traumatic ICH has been investigated in small studies [ 96 — 98 ]. Although the clinical results were encouraging, these studies were too small and most were nonrandomized and single arm to derive definite conclusions.

Preliminary results from the Treatment of Subarachnoid Hemorrhage with Human Albumin ALISAH study indicate that doses up to 1. Although recruitment in ALIAS part 1 was halted due to safety concerns, preliminary efficacy data from this cohort suggests a trend toward a favorable outcome among albumin-treated subjects [ 99 ].

Statins can modulate endogenous pro-oxidative and anti-oxidative systems. For example, statins dose dependently inhibit platelet-mediated low-density lipoprotein oxidation and isoprostane formation, reduce malondialdehyde, and increase SOD and glutathione peroxidase activities in erythrocytes.

In a recent two-center, two-arm, randomized, open-label, controlled study of pravastatin, in intensive care patients, Makris et al. Statin therapy has also been investigated in patients with ALI; it was shown to be safe and associated with a significant decrease in bronchoalveolar lavage interleukin-8, but had no other effects compared to placebo [ ].

Although preclinical studies have shown benefits from statins in models of TBI and related disease processes, including cerebral ischemia, ICH, and subarachnoid hemorrhage, clinical studies have been shortcoming [ ]. The use of statins in patients with aneurysmal subarachnoid hemorrhage has been investigated in several small clinical trials.

A meta-analysis of four randomized controlled trials involving patients revealed no significant effects on vasospasm, detected by transcranial Doppler, delayed cerebral ischemia, poor outcome, or mortality [ ]. The ongoing phase III Simvastatin in Aneurysmal Subarachnoid Hemorrhage STASH multi-center randomized controlled phase III trial should help to further clarify the role of statins in these patients.

Retrospective studies suggest that antecedent use of statins is associated with improved outcome and reduced mortality in patients with acute ischemic stroke and ICH [ , ]. Future studies examining the role of statins as an acute treatment in PHE reduction in ICH and resultant effect on mortality and functional outcome after ischemic and hemorrhagic stroke are warranted.

Studies using iron-modifying agents in animal models of cerebral ischemia and ICH provide evidence for a potential therapeutic benefit.

Tirilazad mesylate, a potent inhibitor of iron-dependent lipid peroxidation, attenuates neuronal necrosis and improve the neurological status in several animal models of cerebral ischemia [ ].

Treatment with bipyridyl, an iron-chelating agent, significantly attenuates the development of brain edema 24 hours after the induction of ischemia [ ]. Similarly, treatment with deferoxamine, another iron chelator, has been shown to reduce infarct size and improve the neurological status in rats subjected to transient middle cerebral artery occlusion [ ].

Deferoxamine may also alleviate reperfusion-induced injury following ischemia. In one study, treatment with deferoxamine attenuated death rate and hemorrhagic transformation in a rat model of transient focal ischemia [ ]. Treatment with deferoxamine also attenuates the production of ROS, blocks hemoglobin-mediated potentiation of glutamate neurotoxicity, reduces brain malondialdehyde content and induces recovery of sodium-potassium pump activity, and exerts diverse protective effects after experimental ICH [ 29 , 33 , — ].

Emerging evidence also supports a potential therapeutic role for deferoxamine following intraventricular and subarachnoid hemorrhages [ , ]. Deferoxamine decreases the availability of free iron for the production of hydroxyl radicals by forming a stable complex with ferric iron.

However, the potential beneficial effects of deferoxamine may be only partly related to its iron chelating abilities. Very few clinical studies have investigated the use of iron-modifying agents in stroke patients. Two multi-center trials examined the use of tirilazad in acute ischemic stroke [ , ].

The Randomized Trial of High Dose Tirilazad in Acute Stroke RANTTAS II investigated a higher dose The use of tirilazad mesylate in patients with subarachnoid hemorrhage was also investigated in several randomized, placebo-controlled, trials.

Although it reduced the incidence of symptomatic vasospasm, it had no effect on the overall long-term clinical outcome [ ]. Clinical investigations of deferoxamine in stroke have gained attention in recent years. In ICH, a small, open-label, phase-I, safety and dose-finding study of deferoxamine in patients with spontaneous ICH safety and tolerability of deferoxamine in acute cerebral hemorrhage — deferoxamine mesylate in ICH was recently completed [ ].

This study enrolled 20 subjects into 5 dose tiers of deferoxamine, which was given as a continuous intravenous infusion for 3 consecutive days starting within 16 h of ICH symptoms onset. Repeated daily infusions of deferoxamine were well tolerated and did not cause excessive serious adverse events or mortality.

Interestingly, deferoxamine also seemed to exert a modest blood pressure-lowering effect. Similarly, a phase I-II, double-blind, randomized, placebo-controlled, dose-finding study to evaluate the safety and pharmacokinetics of deferoxamine in patients with acute ischemic stroke who are treated with intravenous recombinant tissue plasminogen activator rt-PA within 3 hours of stroke onset, and to explore the effects of treatment on clinical outcomes, infarct volumes, hemorrhagic transformation, and brain edema development The Thrombolysis and Deferoxamine in Middle Cerebral Artery Occlusion — TANDEM-1 is currently underway.

Minocycline has anti-inflammatory and anti-apoptotic properties, inhibits polysdenosine diphosphate ribose polymerase-1 and matrix metalloproteinases, and is an effective antioxidant and radical scavenger. Minocycline has neuroprotective effects in vivo against cerebral ischemia and in vitro against glutamate-induced cell death, an inhibition of OS by minocycline may be partly responsible for these effects [ ].

Minocycline also chelates iron, and prevents the neuronal death induced by ferrous sulfate [ ] and attenuated brain edema and neurological deficits in rat models of ICH [ ]. An open-label, dose-escalation, safety and dose-finding study of minocycline, administered intravenously within 6 h of symptom onset, in patients with acute ischemic stroke was recently completed Minocycline to Improve Neurologic Outcome in Stroke [MINOS] [ ], and plans for a phase III study are currently underway.

Interestingly, lower plasma levels of MMP-9 was seen among rt-PA treated subjects in the MINOS trial, suggesting that combining minocycline with rt-PA might prevent the adverse consequences of thrombolysis [ ]. Overwhelming pre-clinical and clinical evidence supports the presence of OS in several neurocritical conditions.

Although dietary supplementation with antioxidant vitamins and the use of pharmacological agents targeting OS and its downstream cascade seems to be rational, the benefits of various attempted antioxidant strategies to date have not been clearly demonstrated. Several reasons have been advocated, including the wide variability in the nature and severity of illness in intensive care patients.

Future studies should consider these issues to avoid past mistakes. Several studies of antioxidant drugs, such as statins, minocycline, and deferoxamine in specified populations of neurological patients are currently underway, and its results could have important implications in neurocritical care.

Although the role of antioxidant strategies in neurocritical care is slowly evolving, it is likely to be an integral component of the overall strategy for neurological critical care in the future.

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Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol ;— Poirier J. Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. Trends Neurosci ;— Hoane MR, Holland MA, Birky ND, Dang T, et al.

The novel apolipoprotein E-based peptide COG improves sensorimotor performance and reduces injury magnitude following cortical contusion injury. Smith C, Graham DI, Murray LS, Stewart J, et al. Association of APOE e4 and cerebrovascular pathology in traumatic brain injury.

J Neurol Neurosurg Psychiatry ;— Ariza M, Pueyo R, Matarín Mdel M, et al. Influence of APOE polymorphism on cognitive and behavioural outcome in moderate and severe traumatic brain injury. Fink MP. Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis.

Crit Care Clin ;— Berger MM, Chiolero RL. Antioxidant supplementation in sepsis and systemic inflammatory response syndrome. Crit Care Med ;ss Biesalski HK, McGregor GP. Antioxidant therapy in critical care—is the microcirculation the primary target? Lowes DA, Webster NR, Murphy MP, et al.

The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis. Rank N, Haertel C, Lenhart A, Welte M, et al.

N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: results of a prospective, randomized, double-blind study.

Crit Care Med ;—

You should seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

The Nutrition Source does not recommend or endorse any products. Skip to content The Nutrition Source. The Nutrition Source Menu. Search for:. Home Nutrition News What Should I Eat? In , a rating tool called the Oxygen Radical Absorbance Capacity ORAC was created by scientists from the National Institute on Aging and the United States Department of Agriculture USDA.

It was used to measure the antioxidant capacity of foods. The USDA provided an ORAC database on its website highlighting foods with high ORAC scores, including cocoa, berries, spices, and legumes. Blueberries and other foods topping the list were heavily promoted in the popular press as disease-fighters even if the science was weak, from cancer to brain health to heart disease.

However, 20 years later the USDA retracted the information and removed the database after determining that antioxidants have many functions, not all of which are related to free radical activity. Although this was not a primary endpoint for the trial, it nevertheless represents an important outcome.

In the Heart Outcomes Prevention Evaluation HOPE trial, the rates of major cardiovascular events were essentially the same in the vitamin E A recent trial of vitamin E in Israel, for example, showed a marked reduction in coronary heart disease among people with type 2 diabetes who have a common genetic predisposition for greater oxidative stress.

In the Supplementation en Vitamines et Mineraux Antioxydants SU. MAX study, 13, French men and women took a single daily capsule that contained mg vitamin C, 30 mg vitamin E, 6 mg beta-carotene, mcg selenium, and 20 mg zinc, or a placebo, for seven and a half years.

The vitamins had no effect on overall rates of cardiovascular disease. Lung disease A study from the Journal of Respiratory Research found that different isoforms of vitamin E called tocopherols had opposing effects on lung function.

Cancer When it comes to cancer prevention, the picture remains inconclusive for antioxidant supplements. MAX randomized placebo-controlled trial showed a reduction in cancer risk and all-cause mortality among men taking an antioxidant cocktail low doses of vitamins C and E, beta-carotene, selenium, and zinc but no apparent effect in women, possibly because men tended to have low blood levels of beta-carotene and other vitamins at the beginning of the study.

Age-related eye disease A six-year trial, the Age-Related Eye Disease Study AREDS , found that a combination of vitamin C, vitamin E, beta-carotene, and zinc offered some protection against the development of advanced age-related macular degeneration, but not cataracts, in people who were at high risk of the disease.

However, relatively short trials of lutein supplementation for age-related macular degeneration have yielded conflicting findings. The study found that people taking the vitamins were less likely to progress to late-stage AMD and vision loss.

However, the study authors noted that taking lutein and zeaxanthin alone or vitamin E alone did not have a beneficial effect on these eye conditions. The Selenium and Vitamin E Cancer Prevention Trial SELECT Eye Endpoints Study, which followed 11, men for a mean of five years, did not find that vitamin E and selenium supplements, in combination or alone, protected from age-related cataracts.

It did not find that antioxidant supplements of vitamin E or selenium, alone or in combination, protected against dementia compared with a placebo. Early death A meta-analysis of 68 antioxidant supplement trials found that taking beta-carotene and vitamin A and E supplements increased the risk of dying.

It was also difficult to compare interventions because the types of supplements, the dosages taken, and the length of time they were taken varied widely. The same authors conducted another systematic review of 78 randomized clinical trials on antioxidant supplements including beta-carotene, vitamin A, vitamin C, vitamin E, and selenium alone or in combination.

The study found that both people who were healthy and those with diseases taking beta-carotene and vitamin E supplements had a higher rate of death. The duration of the studies varied widely from one month to 12 years, with varying dosages.

The first inkling came in a large trial of beta-carotene conducted among men in Finland who were heavy smokers, and therefore at high risk for developing lung cancer.

The trial was stopped early when researchers saw a significant increase in lung cancer among those taking the supplement compared to those taking the placebo. Again, an increase in lung cancer was seen in the supplement group.

MAX trial, rates of skin cancer were higher in women who were assigned to take vitamin C, vitamin E, beta-carotene, selenium, and zinc. These results came from the Selenium and Vitamin E Cancer Prevention Trial SELECT that followed 35, men for up to 12 years.

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Stroke ;—5. Download references. Disclosure forms provided by the authors are available with the online version of this article. Department of Neurology, Divisions of Neurocritical Care, Beth Israel Deaconess Medical Center, Boston, MA, , USA.

Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, Brookline Avenue — Palmer , Boston, MA, , USA. You can also search for this author in PubMed Google Scholar.

Correspondence to Magdy H. Reprints and permissions. Hanafy, K. Antioxidant Strategies in Neurocritical Care. Neurotherapeutics 9 , 44—55 Download citation. Published : 02 December Issue Date : January Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Download PDF. Abstract An increase in oxidative stress and overproduction of oxidizing reactive species plays an important role in the pathophysiology of several conditions encountered in the neurocritical care setting including: ischemic and hemorrhagic strokes, traumatic brain injury, acute respiratory distress syndrome, sepsis, and organ failure.

Novel Therapeutic Strategies for Traumatic Brain Injury: Acute Antioxidant Reinforcement Article 15 February Vitamin C revisited Article Open access 06 August Oxidative Damage Mechanisms in Traumatic Brain Injury and Antioxidant Neuroprotective Approaches Chapter © Use our pre-submission checklist Avoid common mistakes on your manuscript.

Introduction Increased production of oxidizing free radical species with subsequent oxidative stress OS plays an important role in critically ill neurological patients and is central to the pathophysiology of many conditions, such as ischemic and hemorrhagic strokes, traumatic brain injury, subarachnoid hemorrhage, sepsis, acute respiratory distress syndrome, and organ failure.

The Basic Mechanisms and Molecular Biology of Oxidative Stress Normal physiological processes, such as cellular respiration, generate small amounts of oxidizing reactive oxygen species ROS and reactive nitrogen species RNS.

Full size image. Monitoring Oxidative Stress In Vivo The currently available methods to assess OS in vivo include: direct quantification by electron spin resonance; or indirect determination of total radical-trapping antioxidant capacity, measurement of DNA damage using chromatography, or detection of oxidized biological markers of OS.

Role of Oxidative Stress in Various Neurological Conditions Ischemic Stroke Oxidative modifications of DNA, protein, and lipids by ROS play an important role in neuronal injury and its severity following cerebral ischemia.

Intracerebral Hemorrhage After intracerebral hemorrhage ICH , large numbers of hemoglobin-containing red blood cells are released into the brain parenchyma. Subarachnoid Hemorrhage In rodent models of subarachnoid hemorrhage SAH , there is evidence of increased superoxide anion and nicotinamide adenine dinucleotide phosphate NADPH oxidase, both powerful oxidizing agents [ 43 , 44 ].

Traumatic Brain Injury Reactive oxygen species play a role in the pathogenesis of traumatic brain injury TBI. Acute Lung Injury Acute lung injury ALI and adult respiratory distress syndrome ARDS are common problems in neurocritical patients.

Potential Antioxidant Strategies The biochemical changes of OS suggest that antioxidant therapy may be theoretically achieved by the following strategies: 1 restoring endogenous antioxidants and nutrients and supplementation with exogenous trace elements, vitamins, and nutrients with antioxidant properties; or 2 administering drugs that reduce OS, such as statins, iron-modifying agents such as deferoxamine, or minocycline.

Antioxidant Nutrients in Neurocritical Care There is a rationale to support exogenous supply of antioxidant trace elements, vitamins, and nutrients during critical illness.

Pharmacological Antioxidant Therapy N-Acetylcysteine N-acetylcysteine has multiple putative antioxidant properties by decreasing NF-κB activation and cytokines production, regenerating NO as a sulfhydryl donor, and replenishing glutathione, and scavenging ROS as a precursor of glutathione.

Albumin Albumin has antioxidant effects, largely mediated by its thiol sulfhydryl group portion, which attaches to ROS and NOS. Statins Statins can modulate endogenous pro-oxidative and anti-oxidative systems. Iron-Modifying Agents Studies using iron-modifying agents in animal models of cerebral ischemia and ICH provide evidence for a potential therapeutic benefit.

Minocycline Minocycline has anti-inflammatory and anti-apoptotic properties, inhibits polysdenosine diphosphate ribose polymerase-1 and matrix metalloproteinases, and is an effective antioxidant and radical scavenger.

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These compounds endowed several properties in the mitigation of various animal stresses, starting from physiology to molecular level. This chapter elucidates oxidative stress, natural and synthetic antioxidants, and particular focus are emphasized that how antioxidant supplementation can help to improve animal fertility and productivity.

Moreover, the mechanism by which antioxidants produce fruitful effects will also be highlighted. Oxidative stress is the condition in which the overproduction of free radicals is produced and the antioxidant system unable to neutralize them [ 1 ].

Limited quality of free radicals is compulsory to maintain physiological function, and accelerated production may lead to damage lipids, DNA, and proteins [ 2 ]. The efficacy of oxidative metabolites in female reproduction depends upon the site, amount and exposing levels to oxidant molecules [ 3 ].

In livestock, the appearance of the disease causes a reduction in the antioxidant status of the animals [ 4 ]. Oxidative stress is observed in several pathological conditions that influence animal health, welfare, and productive performance [ 5 ].

Indeed, in some productive phases, animals experience physiological alteration, such as farrowing and lactation, weaning, high temperature, and different stresses, that may decline antioxidant status [ 6 , 7 , 8 ].

Oxidative stress may influence physiological function of various reproductive events which thus involved in problems associated with pregnancy [ 9 ].

The purpose of this chapter is to exploit the beneficial effect of antioxidant compounds various aspects of female reproduction and also discuss how antioxidant approaches improve animal productive performance and well-being.

Reactive oxygen species ROS encompasses of superoxide anion, hydrogen peroxide and hydroxyl radical. Their production is possible due to natural oxygen leakage [ 11 ]. Other origin of ROS production are metabolic reactions that are sustainable for life, the exogenous sources include X-rays, ozone, cigarette smoking, air pollutants, certain drugs and pesticides, and industrial chemicals [ 12 ].

Interestingly, the reactions of consists of enzymatic and nonenzymatic reactions within the body also produce free radicals.

Many enzymatic reactions prevail in the respiratory chain, phagocytosis, prostaglandin synthesis, and cytochrome P system [ 14 ], although nonenzymatic reactions are based on oxygen with organic compounds and ionizing reactions also generate free radicals [ 15 ]. ROS are comprised of oxygen ions, free radicals and peroxides.

High level of ROS or reduce concentration of antioxidants induce oxidative stress that trigger cellular damage of macromolecules utilizing different ways. It has responsible for causing chronic diseases by interacting with molecular signaling pathways which alters gene expression [ 16 ].

The interaction between chemicals and signaling molecules are necessary to understand the involvement of ROS role in pathogenesis. Redox interaction with various proteins residues and ROS is the key component of inter-processes.

Further reaction yields to produce reactive sulfenic acid and sulfonamide. Oxidation of these molecules leads to cause ultra-structural changes or functional alteration [ 17 ].

Thus, for this purpose more oxygen is required which in turn causes the overproduction of ROS. So, it is very crucial to maintain the balance between oxidative stress and the antioxidant system for perfect functioning of the body [ 18 ].

Antioxidants are substances that overcome adverse effect of oxidative damages. They are available as natural and synthetic compounds. Natural antioxidants are derived from natural sources like food, cosmetics, and pharmaceutical industries. While the synthetic one is created artificially through chemical reactions [ 19 ].

The antioxidant system consists of enzymatic and non-enzymatic. The first one is also referred as natural antioxidants. They consist of superoxide dismutase SOD catalase and glutathione peroxidase GSH-Px. Antioxidant enzymes are endowed to protect living cells against oxidant products.

The SOD is an enzyme district superoxide anion radical into hydrogen peroxide. Another enzyme called catalase is in charge of catalysing the breakdown of hydrogen peroxide into water and oxygen. GSH-Px employs glutathione as a co-substrate and is composed of selenium. An enzyme found in the cytoplasm, it excludes hydrogen peroxide.

However, in comparison with catalase, it has various ranges of substrates comprising lipid peroxides. The prime function of the Glutathione peroxidase is to decontaminate low levels of hydrogen peroxide in the cell. Non-enzymatic antioxidants include dietary supplements or synthetic antioxidants.

The complex nature of the body antioxidant system is impaired by consumption of dietary antioxidant such as vitamins and minerals [ 20 ]. Vitamin C, vitamin E, plant polyphenol, carotenoids, and glutathione are non-enzymatic antioxidants, they causes inhibition of free radicals reactions.

Antioxidants can be classified as water-soluble or lipid-soluble depending on how potent they are. A water-soluble vitamin called vitamin C is found in cellular fluids such the cytosol and cytoplasmic matrix.

Antioxidants can be divided into small-molecule and large-molecule antioxidants depending on their size. The small one neutralizes ROS through scavenging process.

The example includes Vitamin C, vitamin E, carotenoids, and glutathione GSH. A large size of the molecule antioxidants comprises SOD, CAT, and GPx and albumin that captivate ROS and the attack form essential proteins.

The mechanism by which antioxidants are utilized which offer protection against inhibition of free radical formation, scavenging free radicals, involved in repair-damage via free radicals, help to establish an environment that is conducive for the antioxidants to function effectively [ 21 ].

Synthetic antioxidants are phenolic compounds responsible for eliminating free radicals and suppressing chain-reaction. They consist of butylated hydroxyl anisole BHA , butylated hydroxyltoluene BHT , propyl gallate PG , metal chelating agent EDTA , tertiary butyl hydroquinone TBHQ , and nordihydroguaiaretic acid NDGA [ 21 ].

In commercial dairy and beef farming, various stresses influence economic benefit that is linked with declined productive and reproductive performance in cattle.

It has been observed that diverse endogenous and exogenous sources of ROS lead to stresses that cause over generation of free radicals and eventually result in oxidative stress [ 22 , 23 ]. It is well recognized that the consequences of oxidative stress have deleterious effects on immune system reproductive function, animal growth, development, and on general health [ 24 , 25 ].

Hence, the antioxidant network is responsible for the preservation and maintenance of animal redox status in cells and tissues and is thus responsible for neglecting the harmful effect of stresses. Considering this mechanism, selenium has its own importance [ 26 , 27 ]. It is noted that 25 selenoproteins have been identified in animal tissues; most of them are contributed in the conservation of body redox balance and antioxidant defense [ 27 ].

It is well-recognized in some animal species that the bioavailability of the Se relies on the dietary source of Se provided [ 28 , 29 , 30 ].

The Se integration relies on the rumen environment, which gradually declines depending upon the particular source of Se [ 31 ]. Selenium is present in two forms, inorganic and organic [ 32 ].

These forms may be a vital source of selenium [ 33 ]. It has been known that Se supplementation enhances female fertility but the exact mechanism is still not unknown. The progesterone hormone derived from the corpus luteum is a dominant hormone of pregnancy.

This hormone is synthesized from cholesterol via several enzymatic reactions in which molecular oxygen is utilized for its reactions.

These reactions generate oxygen radicals and different peroxides which are detrimental to cells [ 34 ]. In in vivo study, indicated that the inclusion of luteinizing hormone in luteal cells culture concurrently enhanced progesterone level in the medium and also the lipid peroxides in cells [ 35 ].

For luteal regression, the accretion of H 2 O 2 [ 36 ] or lipid peroxides [ 37 ] in the corpus luteum has been documented.

These findings show that corpus luteum requires antioxidant defense toward peroxides to stabilize normal functions. The significance of the corpus luteum has also been projected by Ref. Moreover, the inclusion of Se in luteal cells reduced the concentration of lipid peroxides in a cell [ 35 ].

Se as the part of glutathione peroxidase may destroy peroxides, in connection with superoxide dismutase, vitamin E, and beta-carotene.

Pregnancy is a normal mechanism in which overburden metabolic rate disrupts antioxidant status and energy balance. Once the zona pellucida is separated from the embryo, it enhances the production of ROS [ 40 ]. The nutritional requirement during early pregnancy is increased to maintain animal health and pregnancy, which is in turn generation of oxidative stress [ 42 ].

Although, malnutrition is also common around the globe in small ruminants because of the high price of the feed, especially in developing countries. Hence, small ruminants are easy to keep due to several reasons [ 43 ].

Malnutrition during pregnancy has deleterious effect on the conception rate and on fetus development [ 44 ]. Animal supplementation in a diet with plant source have sufficient nutrition and has been assumed to be the potential source of antioxidants to attenuate early pregnancy stress in goats [ 45 , 46 ].

The plant compounds exert diverse nutrition comprises of rich source of antioxidants and immune-modulatory properties, which act as a potential feed supplement for ruminants [ 47 , 48 ].

Moringa oleifera MO is a multifaceted medicinal tree with high nutritional values [ 49 ]. Its leaves are rich sources of several nutritious compounds, such as proteins, amino acids, minerals, and vitamins [ 50 ]. Apart of that, MO is also a rich source of antioxidant compounds, such as phenolic acids, vitamin E, vitamin C, selenium, zinc, and β carotene.

These compounds have more robust antioxidant potential than synthetic ones [ 51 ]. The basal diet supplemented with 3. It also promoted progesterone profile, improved conception rate, and attenuated ROS production in early pregnancy of goats.

In another study, by Ref. The supplementation profoundly enhanced number of live-born piglets, total litter weight, and reducing the chance of low-weight piglets.

Moreover, supplementation declined MDA levels in sows and piglets. The mothers who had supplementation showed a higher trend of weaning weight. The results conclude from pregnancies that offering maternal supplementation with herbal antioxidants in pregnancy profoundly enhanced reproductive efficiency, litter traits, and piglet performance.

Reproductive performance is a main indicator related to maternal nutrition. The periparturient period causes reduced feed intake, and endocrine and metabolic alterations which disrupt energy balance and antioxidant index [ 22 , 53 ].

In this period, increased nutritional requirements, such as digestion rate, mammary development, and fetus growth have been reported [ 54 ].

Pasture grazing and feeding on crop residues have a diverse nutritional profile and feeding on such sources is not adequate to meet the energy requirement of lactating animals [ 55 ]. In this scenario, pregnant animals are vulnerable to oxidative stress [ 56 ], which threatens to biomolecules and eventually affect productive and reproductive parameters [ 57 ].

Colostrum is the composition of immunoglobulins, minerals and other biological substances which transfer form colostrum to the young ones [ 58 ].

The quality of the colostrum depends upon maternal nutrition [ 59 , 60 ]. The diet supplemented with phytobiotics has been assumed to be the main source of managing nutrition-induced oxidative stress in pregnancy and lactation in livestock [ 45 , 46 , 61 ]. In a recent study by Ali et al.

oleifera leaf powder MOLP during periparturient period. He reported the increased biochemical and antioxidant indices of colostrum and milk.

The milk yield, weight gain of the kids, and reproductive performance were enhanced with 2 and 3. Further, the findings suggested that the diet supplemented with 3. The in vitro embryo production IVEP technique is employed to combat infertility-related problems in mammalian species [ 62 ].

This tool has been known to be utilized for the production of large scale offspring from elite animals. The IVM prognosis relies on diverse factors consisting of oocyte quality and culture conditions [ 63 ]. The source of antioxidants from female organs has been reported to reduce ROS production [ 64 ].

The main hurdle which decides the fate of oocyte success during IVM is oxidative stress [ 64 ]. Accelerated ROS production might result in oocyte death and embryonic loss [ 65 , 66 ].

An antioxidant approach during IVM has been proposed to govern oocytes from the deleterious effect of oxidative stress by maintaining a basal level of ROS [ 67 , 68 ].

Presently, different antioxidants are utilized during IVM to confirm balanced intracellular redox status, resulting in good-quality of oocytes [ 69 , 70 ].

The inclusion of antioxidants, such as thiols, polyphenols, melatonin, carotenoids, resveratrol, and vitamins C and E, to the IVM medium has been verified in different studies to increase oocyte quality and attenuate exceeding ROS damage [ 71 , 72 ].

Previous evidence has reported that the balance amount of antioxidants and ROS in IVEP media which may be favorable for embryonic development [ 73 , 74 ].

At present, the widely employed antioxidant in IVEP is cysteamine; its efficiency is mostly associated with the stage of IVM. It has been found to stimulate the embryonic process and secreting of glutathione GSH , which is prevalent in male and female gametes from harmful effect of ROS [ 75 ].

Moreover, cysteine and glutathione have been implied in IVEP protocols with good results [ 73 , 76 ]. The positive effect of antioxidants is illustrated in Table 1.

Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Edited by Paz Otero. Open access peer-reviewed chapter Antioxidant Strategies to Improve Female Reproduction Written By Tarique Hussain.

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Chapter metrics overview 59 Chapter Downloads View Full Metrics. Impact of this chapter. Abstract Animals are only productive once their reproductive cycle is continuously flown. Keywords reactive oxygen species oxidative stress animal fertility productivity antioxidants.

Introduction Oxidative stress is the condition in which the overproduction of free radicals is produced and the antioxidant system unable to neutralize them [ 1 ]. Antioxidants Dose Animal species Maturation vs.

control rate References Melatonin 10— 9 M 10— 7 M 10— 6 M Bovine Sheep Mouse Table 1. The beneficial effect of antioxidant supplementation in different animal species. References 1. Sies H, Berndt C, Jones DP. Oxidative stress. Annual Review of Biochemistry.

Rahal A, Kumar A, Singh V, Yadav B, Tiwari R, Chakraborty S, et al. Oxidative stress, prooxidants, and antioxidants: The interplay. BioMed Research International.

Article ID 3. Aruoma OI, Halliwell B. Superoxide-dependent and ascorbate-dependent formation of hydroxyl radicals from hydrogen peroxide in the presence of iron. Are lactoferrin and transferrin promoters of hydroxyl-radical generation?

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Effects of age and weaning conditions on blood indicators of oxidative status in pigs. PLoS One. Rossi R, Pastorelli G, Cannata S, Corino C. Effect of weaning on total antiradical activity in piglets.

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In: Antioxidants-Benefits, Sources, Mechanisms of Action. The levels of nutrients with antioxidant properties are decreased in critical illness.

For example, patients with ICH have lower plasma levels of vitamin C compared with healthy volunteers [ 38 ]. Other studies have shown a reduction in muscle glutamine and glutathione and muscle protein synthesis in intensive care patients [ 81 ].

There is also evidence that low endogenous stores on antioxidant nutrients are associated with increased free radical generation, augmentation of the systemic inflammatory response, subsequent cell injury and death, and even higher morbidity and mortality in critically ill patients [ 6 , 7 ].

In addition, proof-of-concept studies have shown that supplementation with trace elements and vitamins, such as selenium, and vitamins A, C, and E, improve antioxidant capacity by increasing the activity of glutathione peroxidase, or reducing plasma TBARS, and isoprostanes [ 82 ].

Vitamins C and E may also reduce infectious complications by restoring neutrophil function and cell-mediated immunity, and selenium improves phagocytosis and immunoglobulin synthesis. Although results from some of these trials were encouraging, the benefit of this therapy has not been clearly established.

Several reasons have been proposed: 1 the vast majority of these studies were performed in small and heterogeneous populations of critically ill patients, and were largely underpowered; and 2 uncertainties regarding the correct dose to use, appropriate time to start immune nutrition, and the appropriate route of administration; the enteral versus parenteral.

In a meta-analysis of 11 studies selected from 44 studies based on strict criteria of early immune nutrition using antioxidant trace elements and vitamins in well-defined intensive care patient populations, Heyland et al. They also found that none of the trials using immune nutrition reported deleterious effects from using exogenous micronutrients, and they concluded that supplementation with antioxidant trace elements and vitamins in intensive care patients is safe and possibly beneficial.

They argued that immune nutrition must be started very early after admission to the intensive care unit and that high-dose parenteral nutrition appears to have a stronger impact on outcome. Crimi et al. Recently, Casaer et al. It is noteworthy, however, that Casaer et al. Given the previously described, the use of immune nutrition therapy in neurocritical care might be a rationale and promising strategy.

However, more definitive evidence from large-scale, randomized, placebo-controlled, and well-designed trials in this specific patient population is still required.

Vitamin B12 has glutathione-sparing antioxidant properties via stimulation of methionine synthase activity and reaction with ROS and NOS. It also inhibits NOS and NO production, and decreases NF-κB activation.

N-acetylcysteine has multiple putative antioxidant properties by decreasing NF-κB activation and cytokines production, regenerating NO as a sulfhydryl donor, and replenishing glutathione, and scavenging ROS as a precursor of glutathione.

N-acetylcysteine has been extensively studied in critically ill patients with acute respiratory distress syndrome, organ failure, and septic shock. These studies have produced inconsistent results [ 83 , 89 , 90 ]. We found no studies of N-acetylcysteine in neurocritical care, to date. Albumin has antioxidant effects, largely mediated by its thiol sulfhydryl group portion, which attaches to ROS and NOS.

It also decreases copper-mediated lipid peroxidation, and modulates nitric oxide-mediated vascular dilatation.

Hypoalbuminemia is common in critically ill patients, including those with TBI and various neurological conditions, and is associated with increased morbidity and mortality [ 91 ]. Studies of albumin supplementation in surgical and medical critically ill patients had inconsistent results.

The Saline versus Albumin Fluid Evaluation SAFE study of found no advantage for albumin in comparison with saline [ 92 ], and a subsequent post-hoc subgroup analysis of patients with TBI suggested that resuscitation with albumin was associated with increased odds ratio for death [ 93 ].

A Cochrane meta-analysis found no benefit in a heterogenous group of previously published studies [ 94 ]. Powner [ 95 ] recently argued that it is important to separate data from studies regarding albumin infusions intended to restore or maintain intravascular pressure or volume goals from the potential benefit of preventing hypoalbuminemia during neurocritical care.

The use of albumin in TBI, and hypertensive and traumatic ICH has been investigated in small studies [ 96 — 98 ]. Although the clinical results were encouraging, these studies were too small and most were nonrandomized and single arm to derive definite conclusions. Preliminary results from the Treatment of Subarachnoid Hemorrhage with Human Albumin ALISAH study indicate that doses up to 1.

Although recruitment in ALIAS part 1 was halted due to safety concerns, preliminary efficacy data from this cohort suggests a trend toward a favorable outcome among albumin-treated subjects [ 99 ]. Statins can modulate endogenous pro-oxidative and anti-oxidative systems.

For example, statins dose dependently inhibit platelet-mediated low-density lipoprotein oxidation and isoprostane formation, reduce malondialdehyde, and increase SOD and glutathione peroxidase activities in erythrocytes.

In a recent two-center, two-arm, randomized, open-label, controlled study of pravastatin, in intensive care patients, Makris et al. Statin therapy has also been investigated in patients with ALI; it was shown to be safe and associated with a significant decrease in bronchoalveolar lavage interleukin-8, but had no other effects compared to placebo [ ].

Although preclinical studies have shown benefits from statins in models of TBI and related disease processes, including cerebral ischemia, ICH, and subarachnoid hemorrhage, clinical studies have been shortcoming [ ]. The use of statins in patients with aneurysmal subarachnoid hemorrhage has been investigated in several small clinical trials.

A meta-analysis of four randomized controlled trials involving patients revealed no significant effects on vasospasm, detected by transcranial Doppler, delayed cerebral ischemia, poor outcome, or mortality [ ]. The ongoing phase III Simvastatin in Aneurysmal Subarachnoid Hemorrhage STASH multi-center randomized controlled phase III trial should help to further clarify the role of statins in these patients.

Retrospective studies suggest that antecedent use of statins is associated with improved outcome and reduced mortality in patients with acute ischemic stroke and ICH [ , ]. Future studies examining the role of statins as an acute treatment in PHE reduction in ICH and resultant effect on mortality and functional outcome after ischemic and hemorrhagic stroke are warranted.

Studies using iron-modifying agents in animal models of cerebral ischemia and ICH provide evidence for a potential therapeutic benefit. Tirilazad mesylate, a potent inhibitor of iron-dependent lipid peroxidation, attenuates neuronal necrosis and improve the neurological status in several animal models of cerebral ischemia [ ].

Treatment with bipyridyl, an iron-chelating agent, significantly attenuates the development of brain edema 24 hours after the induction of ischemia [ ].

Similarly, treatment with deferoxamine, another iron chelator, has been shown to reduce infarct size and improve the neurological status in rats subjected to transient middle cerebral artery occlusion [ ].

Deferoxamine may also alleviate reperfusion-induced injury following ischemia. In one study, treatment with deferoxamine attenuated death rate and hemorrhagic transformation in a rat model of transient focal ischemia [ ]. Treatment with deferoxamine also attenuates the production of ROS, blocks hemoglobin-mediated potentiation of glutamate neurotoxicity, reduces brain malondialdehyde content and induces recovery of sodium-potassium pump activity, and exerts diverse protective effects after experimental ICH [ 29 , 33 , — ].

Emerging evidence also supports a potential therapeutic role for deferoxamine following intraventricular and subarachnoid hemorrhages [ , ]. Deferoxamine decreases the availability of free iron for the production of hydroxyl radicals by forming a stable complex with ferric iron.

However, the potential beneficial effects of deferoxamine may be only partly related to its iron chelating abilities.

Very few clinical studies have investigated the use of iron-modifying agents in stroke patients. Two multi-center trials examined the use of tirilazad in acute ischemic stroke [ , ]. The Randomized Trial of High Dose Tirilazad in Acute Stroke RANTTAS II investigated a higher dose The use of tirilazad mesylate in patients with subarachnoid hemorrhage was also investigated in several randomized, placebo-controlled, trials.

Although it reduced the incidence of symptomatic vasospasm, it had no effect on the overall long-term clinical outcome [ ]. Clinical investigations of deferoxamine in stroke have gained attention in recent years. In ICH, a small, open-label, phase-I, safety and dose-finding study of deferoxamine in patients with spontaneous ICH safety and tolerability of deferoxamine in acute cerebral hemorrhage — deferoxamine mesylate in ICH was recently completed [ ].

This study enrolled 20 subjects into 5 dose tiers of deferoxamine, which was given as a continuous intravenous infusion for 3 consecutive days starting within 16 h of ICH symptoms onset. Repeated daily infusions of deferoxamine were well tolerated and did not cause excessive serious adverse events or mortality.

Interestingly, deferoxamine also seemed to exert a modest blood pressure-lowering effect. Similarly, a phase I-II, double-blind, randomized, placebo-controlled, dose-finding study to evaluate the safety and pharmacokinetics of deferoxamine in patients with acute ischemic stroke who are treated with intravenous recombinant tissue plasminogen activator rt-PA within 3 hours of stroke onset, and to explore the effects of treatment on clinical outcomes, infarct volumes, hemorrhagic transformation, and brain edema development The Thrombolysis and Deferoxamine in Middle Cerebral Artery Occlusion — TANDEM-1 is currently underway.

Minocycline has anti-inflammatory and anti-apoptotic properties, inhibits polysdenosine diphosphate ribose polymerase-1 and matrix metalloproteinases, and is an effective antioxidant and radical scavenger. Minocycline has neuroprotective effects in vivo against cerebral ischemia and in vitro against glutamate-induced cell death, an inhibition of OS by minocycline may be partly responsible for these effects [ ].

Minocycline also chelates iron, and prevents the neuronal death induced by ferrous sulfate [ ] and attenuated brain edema and neurological deficits in rat models of ICH [ ].

An open-label, dose-escalation, safety and dose-finding study of minocycline, administered intravenously within 6 h of symptom onset, in patients with acute ischemic stroke was recently completed Minocycline to Improve Neurologic Outcome in Stroke [MINOS] [ ], and plans for a phase III study are currently underway.

Interestingly, lower plasma levels of MMP-9 was seen among rt-PA treated subjects in the MINOS trial, suggesting that combining minocycline with rt-PA might prevent the adverse consequences of thrombolysis [ ].

Overwhelming pre-clinical and clinical evidence supports the presence of OS in several neurocritical conditions. Although dietary supplementation with antioxidant vitamins and the use of pharmacological agents targeting OS and its downstream cascade seems to be rational, the benefits of various attempted antioxidant strategies to date have not been clearly demonstrated.

Several reasons have been advocated, including the wide variability in the nature and severity of illness in intensive care patients. Future studies should consider these issues to avoid past mistakes. Several studies of antioxidant drugs, such as statins, minocycline, and deferoxamine in specified populations of neurological patients are currently underway, and its results could have important implications in neurocritical care.

Although the role of antioxidant strategies in neurocritical care is slowly evolving, it is likely to be an integral component of the overall strategy for neurological critical care in the future. Collier BR, Giladi A, Dossett LA, Dyer L, Fleming SB, Cotton BA.

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