Wednesday, March 19, 2014

A Possible Strategy for Dealing with Stroke Damage

Interestingly despite the hype and fear attributed to cancer, stroke is the second leading cause of death in the developed world behind only heart disease and responsible for approximately 10% of deaths worldwide.1,2 There are two major types of stroke: ischemic and hemorrhagic. An ischemic stroke is due to a lack of blood flow largely born from a blockage (arterial embolism, thrombosis, etc.). A hemorrhagic stroke is due to a hemorrhage in the brain resulting in abnormal blood flow creating significant losses in most areas of the brain and overflows in others. Not surprisingly limiting blood flow to the brain can rapidly facilitate the loss of brain function due to cellular malfunction and death resulting in difficulty moving one or more parts of the body, trouble talking and hearing, visual difficulty, as well as other motor and cognitive breakdowns eventually leading to death.

Ischemic strokes are more common than hemorrhagic (approximately 80% to 20%) and have four major causes: 1) Thrombosis; 2) Venous thrombosis; 3) Embolism; 4) Systemic hypoperfusion.1,3 Thrombosis involves the obstruction of a blood vessel due to clot formation in the local region. Embolisms are obstructions, typically clots, fat globules or gas bubbles, that form elsewhere in the body that result in blocked blood flow in some other region away from the location of the obstruction. Systemic hypoperfusion is a general decrease in blood supply born from a psychological condition like shock. Due to the fatal outcomes associated with a stroke numerous methods have been developed to recognize its onset, occurrence and aftermath. The onset of most strokes involve face weakness, arm drift and abnormal speech as early symptoms.4

These symptoms only describe overt strokes; another type of stroke is covert where symptoms are relatively absent. Fortunately covert strokes typically result in less brain damage than overt strokes. However, despite the reduced permanent damage, covert strokes are much more common (5x more probable) and can result in significant mental problems like dementia and depression.5 Unfortunately the ongoing problem with strokes is that despite continuing advances in treatment and rehabilitation a vast majority of people who suffer from a stroke will have a permanent cognitive and/or motor impairment.

Some prevention methodologies have been proposed to reduce the probability of a stroke or reduce the damage that occurs during a stroke. Not surprisingly there is significant support for routine physical activity as a means to reduce the probability of an ischemic stroke.6-8 In fact meta-analysis suggests that the benefits of exercise are indiscriminate with regards to sex and that the most active individuals have a 25% reduced rate of stroke versus those who are least active.7

One rationality for why consistent exercise is able to achieve this result is the improvement of vascular function, which increases blood flow efficiency, reduces hypertension and limits infarct size.9,10 Another possibility may simply be that those who exercise the most have healthier lifestyles on a whole then those who do not exercise a lot; however, this rationality foregoes the general health benefits exercise brings. Unfortunately due to the nature of a stroke there is little one can do from a preventative standpoint beyond live a reasonably healthy life of no smoking, no to very moderate drinking, exercise and proper diet.

Some could argue that one should take anti-coagulants like warfarin or blood thinners like aspirin, but these pharmaceutical agents are more reactionary treatments intended to prevent repeat strokes or secondary short-term strokes (similar to aftershocks) versus reducing damage derived from principle strokes. Aspirin is especially used by individuals who have previously suffered myocardial infarctions or with high cardiovascular risk factors like atherosclerosis.5 Some also support the use of clopidogrel and dipyridamole to increase the probability of platelet flow to avoid platelet aggregation, which can lead to clot formation.5 However, there are some concerns that improper timing in treatment with anti-coagulation agents could create a net physiological detriment.11 After the event ischemic strokes are commonly treated with thrombolysis (i.e. clot busting drugs) or intra-arterial fibrinolysis (site injection through a catheter) whereas hemorrhagic strokes typically require neurosurgery due to the excessive bleeding.5

However, these reactionary methods are active methods for reducing damage born from a stroke, which are largely dependent on the existence of secondary available parties because the suffering individual is frequently rendered incapable of assisting him/herself. The development of a passive method to reduce damage without the need to take drugs would go a long way to increasing the probability for reducing damage from strokes, reducing long-term healthcare costs and increasing qualify of life. One possibility for a more passive “damage prevention” therapy revolves around neutralization of reactive oxygen species (ROS).

In the 80s it was theorized that oxidative stress induced damage from ROS was prevalent in the reperfusion stage of post-ischemic strokes and accounted for a significant amount of damage, especially because cells have a reduced capacity to neutralize ROS in ischemic stroke conditions.12-16 The origin of ROS in cerebral ischemia is derived from the events that occur during reoxygenation after spontaneous or thrombolytic reperfusion. The abnormally large and rapid influx of oxygen after the depravation of oxygen leads to accelerated enzymatic reactions, especially in the electron transport chain facilitating the creation of larger than normal concentrations of ROS.

In addition there is a slower build-up of natural antioxidants due to transcription and translation delays due to the lack of oxygen and other signaling molecules. Unfortunately there are still questions regarding the exact mechanisms of this injury, i.e. if it differs from oxidative damage born from ROS in other parts of the body, but the presence of peroxynitrite (ONOO-) and hydroxyl radicals (OH-) are considered important for significant ischemic damage due to their aggressive and indiscriminate damage potentials.17,18

If the ROS damage theory is correct then an obvious prevention strategy would be to increase antioxidant concentrations. However, increasing these concentrations on a dietary or pharmaceutical level has an immediate problem in that both types of antioxidants have difficulties passing the blood brain barrier, if they can at all. Another problem is that there are questions to the general effectiveness of significant antioxidant concentrations derived from pharmaceutical origins where consumption may actually endanger health rather than improve it due to restraints on the ability of cells to absorb these antioxidants.

Another concern with an antioxidant strategy is that while ROS are cytotoxic at large concentrations most also have important roles as signaling molecules that regulate various processes like cellular differentiation, proliferation and apoptosis or even protect against bacterial infections.19-21 Thus there is the possibility that increasing antioxidant concentration too much can neutralize these signaling operations and create negative biological outcomes. Therefore, an alternative strategy is required if antioxidants are going to be utilized to reduce ROS damage in strokes.

The best strategy seems to be providing a natural reactant molecule that will allow the body to facilitate increased natural antioxidant protection. One option for achieving this “on-site limited neutralization” strategy may be increasing gaseous biological hydrogen. Previous research has demonstrated that hydrogen can selectively reduce ONOO- and OH- and have a protective effect on cerebral, hepatic, intestinal, lung and myocardium I/R injury along with neonatal hypoxia ischemia and cerebral ischemia.22-27 This protective effect seems to depend on hydrogen concentrations of approximately 25 umol/L.22

The antioxidant effect of hydrogen also has various secondary advantages: 1) its high natural permeability allows it to penetrate biomembranes and diffuse into the cytosol, mitochondria and nucleus; 2) it appears to have a specific selectivity which targets highly reactive ROS leaving less active ROS to perform their necessary secondary messenger signaling functions; 3) a toxicity threshold that is so high that hydrogen is basically non-toxic at any realistic concentration.22

There are two major methods for increasing gaseous hydrogen concentration in the body. First, direct consumption typically achieved by consuming hydrogen-doped water or inhaling hydrogen gas. Hydrogen water is commonly created through electrolysis increasing free hydrogen concentration to anywhere from 0.6 mM to 0.8 mM whereas inhalation of hydrogen gas typically occurs in a 2% by volume hydrogen mixture.28 Basically the feed is designed to replace nitrogen with hydrogen maintaining oxygen concentration.

The second method for increasing biological hydrogen concentration utilizes bacteria in the intestinal system. Bacteria are able to produce excess amounts of hydrogen as a byproduct of fermentation. In most situations there is little to no biological influence from this hydrogen production due to the typical level of normal hydrogen concentrations.29 However, if an individual consumes certain foods fermentation levels can be increased dramatically producing a biologically relevant effect.

One of these key “hydrogen producing” foods is lactulose. Lactulose is a synthetic sugar comprised of one fructose and one galactose molecule and is commonly used in the treatment of constipation.30 The principle reasons for the hydrogen capacity of lactulose is its complex nature and it cannot be digested by the human digestive infrastructure. 20 grams of lactulose can increase exhaled hydrogen to a similar level as 300 ml hydrogen saline with a longer resident time in the body.2,30 While lactulose is relatively non-toxic from a direct consumption perspective there are some concerns that excessive and routine consumption can result in an increased probability for small intestinal bacterial overgrowth.

What is the methodology behind how hydrogen is able to neutralize ROS? Past research supports increasing hydrogen concentrations leading to increases in HO-1, CAT and SOD all agents that are able to neutralize various ROS.31,32 However, after more detailed analysis hydrogen also seems to increase the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2).16 Nrf2 is viewed as one of the principle pathways that governs the expression of molecules which act to neutralize oxidative stressors. Some believe that this activation is based on a form of hormesis where H2 is able to mitigate the effects of more toxic ROS species allowing overexpression of less toxic ROS, which leads to the activation of Nrf2 eventually neutralizing the lesser ROS species.22 In scenarios that lack sufficient H2 concentrations there is a higher probability of the more toxic ROS trigger cell damage and apoptosis limiting the future activation of the Nrf2 pathway leading to a cascade damage effect.

This hormesis process is thought to occur as followed. Under normal conditions Nrf2 is stored in the cytoplasm by Kelch like-ECH-associated protein (Keap1) and is tagged by Cullin 3 for ubiquitination resulting in a typical half-life of only 20 minutes. Under oxidative stress conditions it is thought that cysteine residues in Keap1 are disrupted dramatically reducing the probability of Cullin 3 tagging both through reducing binding efficiency and increasing Nrf2 mobility as disruption of Keap1 allows Nrf2 to translocate into the nucleus. Presence in the nucleus allows Nrf2 to form a heterodimer with small Maf protein and bind antioxidant response element (ARE) that activates numerous anti-oxidative genes initiating their transcription and translation.

However, hormesis is a somewhat controversial idea biologically. So others believe that hydrogen directly activates Nrf2-dependent genes like HO-1 and it is Nrf2 activation that results in the neutralization of ROS. This belief is supported by research where the protective effects of hydrogen were lost in Nrf2-deficient mice.31 While there exists the possibility that hydrogen can directly scavenge ROS the activation of Nrf2 appears to be the dominant method behind the correlation between increased hydrogen concentration and reduced ROS damage. However, the exact relationship between hydrogen, ROS neutralization and Nrf2 activation remains unclear. Despite the lack of specific details in this relationship, both the consumption of hydrogen doped saline/water and the consumption of lactulose increase hydrogen concentrations in vivo and also has neuroprotective effects with regards to strokes.27

Another possible mechanism for hydrogen-induced protection could involve not hydrogen directly, but the conversion of hydrogen to hydrogen sulfide (H2S). There is some evidence to suggest that H2S is a cytoprotective against oxidative stress in similar context to Nrf2,33-36 especially with regards to peroxynitrite (ONOOH/ONOO-) or hypochlorite (HOCL).37,38 While some believe that this antioxidant ability is derived from direct scavenging of oxidants due to its comparable reactivity to cysteine and glutathione,33,38,39 this belief does not seem accurate because the reaction between H2S and ROS is too slow41 and the H2S concentration is too low in vivo40,42 even despite the possibility of metallic catalyst availability.43 Therefore, H2S may interact with Nrf2 increasing expression rates and thereby increasing its protective effects against ROS. Of course one of the problems with theorizing about the role of H2S as an antioxidant is the lack of reliable methods to specifically measure H2S in vivo to tie H2S concentration increases to Nrf2 concentration increases.44,45

There is remaining uncertainty corresponding to increasing gaseous hydrogen concentration in the blood and its role in managing stroke damage, but studies in mice have demonstrated encouraging results regarding stroke induced damage reduction that should drive further study in humans.2,27 In fact some preliminary studies with lactulose has demonstrated reduced symptoms in Parkinson disease patients.27 With the general cost of lactulose or hydrogen doped water being very cheap if this method is applicable to reducing damage from strokes in a passive manner (just drink x amount of hydrogen doped water a day) millions of dollars can be saved in healthcare expenses as well as increasing the quality of life for numerous people. Overall while this hydrogen preventative theory is in its early stages of development, it would be in the best interest of official organizations like the American Stroke Association to investigate human applications of increasing hydrogen concentrations to reduce stroke damage.

Citations –

1. Donnan, G, et Al. “Stroke.” Lancet. 2008. 371:1612-1623.

2. Chen, X, et Al. “Lactulose: an effective preventive and therapeutic option for ischemic stroke by production of hydrogen.” Medical Gas Research. 2012. 2:3-7.

3. Sims, N, and Muyderman, H. “Mitochondria oxidative metabolism and cell death in stroke.” Biochim. Biophys. Acta. 2010. 1802:80-91.

4. Wikipedia Entry – Stroke.

5. Vermeer, S, Longstreth Jr., W, and Koudstall, P. “Silent brain infarcts: a systematic review.” Lancet Neurology. 2007. 6:611-619.

5. Goldstein, L, et Al. “Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2006. 113:e873–e923.

6. Reimers, C, Knapp, G, and Reimers, A. “Exercise as stroke prophylaxis.” Deutsches Arzteblatt International. 2009. 106:715-721.

7. Middleton, L, et Al. “Physical activity in the prevention of ischemic stroke and improvement of outcome: a narrative review.” Neuroscience and Biobehavioral Reviews. 2013. 37:133-137.

8. Leung, F, et Al. “Exercise, vascular wall and cardiovascular diseases: an update (part 1). Sports Medicine. 2012. 38:1009-1024.

9. Yung, L, et Al. “Exercise, vascular wall and cardiovascular diseases: an update (part 2). Sports Medicine. 2009. 39:45-63.

10. Paciaroni, M, et Al. “Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials.” Stroke. 2007. 38:423-30.

11. Flamm, E, et Al. “Free radicals in cerebral ischemia.” Stroke. 1978. 9:445-447.

12. Chan, P. “Oxygen radicals in focal cerebral ischemia.” Brain Pathol. 1994. 4:59-65.

13. Ozkul, A, et Al. “Oxidative stress in acute ischemic stroke.” J. Clin. Neurosci. 2007. 14:1062-1066.

14. Nanetti, L, et Al. “Oxidative stress in ischaemic stroke. Eur. J. Clin. Invest. 2011. 41:1318-1322.

15. Shi, D, et Al. “Lactulose ameliorates cerebral ischemia-reperfusion injury in rats by inducing hydrogen by activating Nrf2 expression.” Free Radical Biology and Medicine. 2013. 65:731-741.

16. Chen, H, et Al. “Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection.” Antioxid. Redox Signaling. 2011. 14:1505–1517.

17. Chan, P.H. “Oxygen radicals in focal cerebral ischemia.” BrainPathol. 1994. 4:59–65.

18. Sauer, H, Wartenberg, M, and Hescheler, J. “Reactive oxygen species as intracellular
messengers during cell growth and differentiation.” Cell. Physiol. Biochem. 2001. 11:173–186.

19. Liu, H, et Al. “Redox-dependent transcriptional regulation.” Circ. Res. 2005. 97:967–974.

20. Winterbourn, C. “Biological reactivity and biomarkers of the neutrophil oxidant,
hypochlorous acid.” Toxicology. 2007. 181:223–227.

21. Ohsawa, I, et Al. “Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.” Nature Medicine. 2007. 13(6):688-707.

22. Fukuda, K, et Al. “Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress.” Biochem. Biophys. Res. Commun. 2007. 361:670–674.

23. Zheng, X, et Al. “Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats.” Free Radic.Res. 2009. 43:478–484.

24. Zheng, J, et Al. “Saturated hydrogen saline protects the lung against oxygen toxicity.” Undersea Hyperbaric Med. 2010. 37:185–192.

25. Sun, Q, et Al. Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp. Biol.Med. 2009. 234:1212–1219.

26. Cai, J, et Al. “Neuroprotective effects of hydrogen saline in neo-natal hypoxia–ischemia rat model.” Brain Res. 2009. 1256:129–137.

27. Ito, M, et Al. “Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats.” Medical Gas Research. 2012. 2:15-22.

27. Levitt, M. “Production and excretion of hydrogen gas in man.” New England Journal of Medicine. 1969. 281:122-127.

28. Voskuijl, W, et Al. “PEG 3350 (Transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomised, controlled, multicentre trial.” Gut. 2004. 53:1590-1594.

29. Kawamura, T, et Al. “Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo.” Am. J. Physiol. Lung Cell Mol. Physiol.” 2013. 304:L646–L656.

30. Li, J, et Al. “Protective effects of hydrogen-rich saline in a rat model of permanent focal cerebral ischemia via reducing oxidative stress and inflammatory cytokines.” Brain Res. 2012. 1486:103–111.

31. Li, Qian, and Lancaster Jr, J. “Chemical foundations of hydrogen sulfide biology.” Nitric Oxide. 2013. 35:21-34.

32. Fu, Z, et Al. “Hydrogen sulfide protects rat lung from ischemia-reperfusion injury.” Life Sci. 2008. 82:1196-1202.

33. Jha, S, et Al. “Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and anti-apoptotic signaling.” Am. J. Physiol. Heart Circ. Physiol. 2008. 295:H801-H806.

34. Kimura, Y, Goto, Y, and Kimura, H. “Hydrogen sulfide increase glutathione production and suppresses oxidative stress in mitochondria.” Antioxid. Redox. Signal. 2010. 12:1-13.

35. Whiteman, M, et Al. “The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite scavenger?” J. Neurochem. 2004. 90:765-768.

36. Whiteman, M, et Al. “Hydrogen sulphide: a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain?” Biochem. Biophys. Res. Commun. 2005. 326:794-798.

37. Tapley, D, Buettner, G, and Shick, J. “Free radicals and chemiluminescence as products of the spontaneous oxidation of sulfide in seawater, and their biological implications.” Biol. Bull. 1999. 196:52-56.

38. Carballal, S, et Al. “Reactivity of hydrogen sulfide with peroxxynitrite and other oxidants of biological interest.” Free Radic. Biol. Med. 2011. 50:196-205.

39. Chen, K, and Morris, J. “Kinetics of oxidation of aqueous sulfide by O2.” Environ. Sci. Technol. 1972. 6:529-537.

40. Nagy, P, and Winterbourn, C. “Rapid reaction of hydrogen sulfide with the neutrophil oxidant hypochlorous acid to generate polysulfides.” Chem. Res. Toxicol. 2010. 23:1541-1543.

41. Baxter, C, and Van, R. “The oxidation of sulfide to thiosulfate by metalloprotein complexes and by ferritin.” Biochim. Biophys. Acta. 1958. 28:573-578.

42. Olson, K. “A practical look at the chemistry and biology of hydrogen sulfide.” Antioxid. Redox. Signal. 2012. 17:32-44.

43. Whiteman, M, et Al. “Emerging role of hydrogen sulfide in health and disease: critical appraisal of biomarkers and pharmacological tools.” Clin. Sci. (Lond). 2011. 121:459-488.

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