Acute cerebral infarction treated with hydrogen and edaravoneScientific Research
Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study
Medical Gas Research volume 1
Abstract
Background
In the acute phase of cerebral infarction, MRI indices (rDWI and rADC) worsened in the first 3-7 days after onset, and then gradually returned to normal in about 10 days (pseudo-normalization time), even after the tissue had infarcted. Since effective treatment can significantly improve these indicators and within the natural pseudo-normalization time, a comprehensive analysis of these changes provides an opportunity to objectively assess the effectiveness of different treatments for cerebral infarction. Hydroxyl free radicals are very destructive to tissues and will aggravate cerebral infarction. We treated patients with acute-phase brainstem infarction by intravenous administration of hydroxyl scavengers (edaravone and hydrogen gas) and assessed treatment efficacy by serial observation and analysis of these MRI markers.Treatment effects were assessed and compared in two groups (edaravone alone and edaravone and hydrogen combined) to assess the beneficial effects of hydrogen addition.
Methods
The patients were divided into edaravone alone group (group E, 26 cases) and edaravone combined with hydrogenated saline group (group EH, 8 cases). The initial hump amplitude in rDWI, the initial fall in rADC, and the pseudo-normalized time were measured continuously in each patient, and the mean of these data was compared between the two groups and with natural histories in the literature.
Results
The rDWI initial hump of the E group reached 2.0, which was better than the natural history of 2.5, but not as good as the 1.5 of the EH group. The initial decline in rADC in the E group was 0.6, which was close to the natural history, but lower than the 0.8 in the EH group.The pseudo-normalization time for rDWI and rADC was 9 days only in the EH group and longer in the other groups. Adding hydrogen does not cause any side effects.
Conclusion
The use of hydroxyl radical scavengers in the acute phase of brainstem infarction improves MRI indices in the natural history. The effect of the EH group was more obvious and significant. These findings may imply the need for more frequent daily administration of hydroxyl scavengers or possibly additional hydrogen effects on scavenger mechanisms.
References
Yang Q, Brian M, Tress BM, Barber PA, Desmond PM, Darby DG, Gerraty RP, Li T, Davis SM: Study of apparent diffusion coefficient and anisotropy in patients with Acute Stroke. Stroke. 1999, 30: 2382-2390. 10.1161/01.STR.30.11.2382.
Schwamm LH, Koroshetz WJ, Sorensen GA, Wang B, Copen WA, Rordorf G, Buonanno FS, Schaefer PW, Gonzalez GR: Serial Diffusion-and Hemodynamic-Weighted Magnetic Resonance Imaging. Stroke. 1998, 29: 2268-2276. 10.1161/01.STR.29.11.2268.
Huang IJ, Chen CY, Chung HW, Chang DC, Lee CC, Chin SC, Liou M: Time Course of Cerebral Infarction in the Middle Cerebral Arterial Territory: Deep Watershed versus Territorial Subtypes on Diffusion-weighted MR Images. Radiology. 2001, 221: 35-42. 10.1148/radiol.2211001412.
Fiebach JB, Schellinger JO, Sartor HW: Serial analysis of the apparent diffusion coefficient time course in human stroke. Neuroradiology. 2002, 44: 294-298. 10.1007/s00234-001-0720-8.
Liu S, Karonen JO, Liu Y, Vanninen Ft, Partanen K, Cinbnen MK, Vainio P, Aronen HJ: Serial Measurements of the Apparent Diffusion Coefficient in Human Stroke on Five Time Points over Three Months. Proc Intl Sot Mag Reson Med. 2000, 8: 1203-
Huang L, Wong XH, Li G: The application of DWI and ADC map in cerebral infarction. Proc Intl Soc Mag Reson Med. 2001, 9: 1446-
Marks MP, Tong DC, Beaulieu C, Albers GW, deCrespigny A, Moseley MR: Evaluation of early reperfusion and i.v. tPA therapy using diffusion-and perfusion-weighted MRI. Neurology. 1999, 52: 1792-1798.
Schaefer POW, Hassankhani A, Putman C, Sorensen GA, Schwamm L, Koroshez W, Gonzalez GR: Characterization and evolution of diffusion MNRE imaging abnormalities in Stroke patients undergoing intra-arterial thrombolysis. ANJR. 2004, 25: 951-957.
Tanaka M: Pharmacological and clinical profile of the free radical scavenger edaravone as a neuroprotective agent. Folia Pharmacol Jpn. 2002, 119: 301-308. 10.1254/fpj.119.301.
Kageyama M, Toriyama S, Tsubosita A, Muraki S, Yamada T, Ishibashi A: A post-marketing drug use survey of a neuroprotecive drug Radicut injection 30 mg(non-proprietary name: edaravone) for acute ischemic stroke. J New Rem Clin. 2009, 58: 1212-1226.
Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S: Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007, 13: 688-694. 10.1038/nm1577.
Takagi M: Concept of branch atheromatous disease. Neurol Med. 2008, 69: 542-549.
Burdett JH, Elster AD, Ricci PE: Acute Cerebral Infarction: Quantification of Spin-Density and T2 Shine-through Phenomena on Diffusion-weighted MR Images. Radiology. 1999, 212: 333-339.
Edaravone Acute Infarction Study Group: Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis. 2003, 15: 222-229.
Yamamoto Y, Kuwahara T, Watanabe K, Watanabe K: Antioxidant activity of 3-methyl-1-phenyl-2-pyrazolin-5-one. Redox Report. 1996, 2: 333-338.
Zhang N, Komine-Kobayashi M, Tanaka R, Liu M, Mizuno Y, Urabe T: Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke. 2005, 36: 2220-2225. 10.1161/01.STR.0000182241.07096.06.
Kawai H, Nakai H, Suga M, Yuki S, Watanabe T, Saito KI: Effects of a novel free radical scavenger, MCl-186, on ischemic brain damage in the rat distal middle cerebral artery occlusion model. J Pharmacol Exp Ther. 1997, 281: 921-927.
Yoshida H, Metoki N, Ishikawa A, Imaizumi T, Matsumiya T, Tanji K, Ota K, Ohyama C, Satoh K: Edaravone improves the expression of nerve growth factor in human astrocytes subjected to hypoxia/reoxygenation. Neurosci Res. 2010, 66: 284-289. 10.1016/j.neures.2009.11.011.
Zhang W, Sato K, Hayashi T, Omori N, Nagano I, Kato S, Horiuchi S, Abe K: Extension of ischemic therapeutic time window by a free radical scavenger, Edaravone, reperfused with tPA in rat brain. Neurol Res. 2004, 26: 342-348. 10.1179/016164104225014058.
Watanabe T, Tahara M, Todo S: The Novel Antioxidant Edaravone: From Bench to Bedside. Cardiovascular Therapeutics. 2008, 26: 101-114. 10.1111/j.1527-3466.2008.00041.x.
Lapchak PA: A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy?. Expert Opinion on Pharmacotherapy. 2010, 11: 1753-1763. 10.1517/14656566.2010.493558.
Nakao A, Sugimoto R, Billiar TR, McCurry KR: Therapeutic antioxidant medical gas. J Clin Biochem Nutr. 2009, 44: 1-13. 10.3164/jcbn.08-193R.
Kajiyama S, Hasegawa G, Asano M, Hosoda H, Fukui M, Nsksmura N, Kitawaki J, Imai S, Nakano K, Ohta M, Adachi T, Obayashi H, Yoshikawa T: Supplementation of hydrogen-rich water improves lipid andd glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nur Res. 2008, 28: 137-143.
Buchholz BM, Kaczorowski DJ, Sugimoto R, Yang R, Wang Y, Billiar TR, McCurry KR, Bauer AJ, Nakao A: Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am I transplant. 2008, 8: 2015-2024.
Saitoh Y, Okayasu H, Xiao L, Harata Y, Miwa N: Neutral pH hydrogen-enriched electrolyzed water achieves tumor-preferential clonal growth inhibition over normal cells and tumor invasion inhibition concurrently with intracellular oxidant repression. Oncol Res. 2008, 17: 247-255. 10.3727/096504008786991620.
Cardinal JS, Zhan J, Wang Y, Sugimoto R, Tsung A, McCurry KR, Billar R, Nakao A: Oral administration of hydrogen water prevents chronic allograft nephropathy in rat renal transplantation. Kidney Int. 2010, 77: 101-109. 10.1038/ki.2009.421.
Nakao A, Kaczorowski DJ, Wang Y, Cardinal JS, Buchholz BM, Sugimoto R, Tobita K, Lee S, Toyoda Y, Billar TR, McCurry KR: Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both. J Heart Lung Transplant. 2010, 29: 544-553. 10.1016/j.healun.2009.10.011.
Xie K, Yu Y, Pei Y, Hou L, Chen S, Xiong L, Wang G: Protective effects of hydrogen gas on murine polymicrobial sepsis via reducing oxidative stress and HMGB1 release. Shock. 2010, 34: 90-97.
Liu Q, Shen WF, Sun HY, Fan DF, Nakao A, Cai JM, Yan G, Zhou WP, Shen RX, Yang JM, Sun XJ: Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice. Liver Int. 2010, 30: 958-968. 10.1111/j.1478-3231.2010.02254.x.
Nakayama M, Nakao H, Hamada H, Itami N, Nakazawa R, Ito S: A novel bioactive hemodialysis system using dissolved dihydrogen(H2) produced by water electrolysis: a clinical trial. Nephrol Dial Transplant. 2010, 25: 3026-3033. 10.1093/ndt/gfq196.
Chen CW, Chen QB, Mao YF, Xu SM, Xia CY, Shi XY, Zang ZH, Yuan HB, Sun XJ: Hydrogen-rich saline protects against spinal cord injury in rats. Neurochem Res. 2010, 35: 1111-1118. 10.1007/s11064-010-0162-y.
Fujita K, Seike T, Yutsudo N, Ohno M, Yamada H, Yamaguchi H, Sakumi K, Yamakawa Y, Kido M, Takaki A, Katafuchi T, Tanaka Y, Nakabeppu y, Noda M: Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. PloS One. 2009, 30: 1-10. e7247
Li J, Wang C, Zhang JH, Cai JM, Cao YP, Sun XJ: Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer’s disease by reduction of oxidative stress. Brain Res. 2010, 1328: 152-161.
Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N: Effectiveness of Hydrogen Rich Water on Antioxidant Status of Subjects with Potential Metabolic Syndrome–An Open Label Pilot Study. J Clin Biochem Nutr. 2010, 46: 140-149. 10.3164/jcbn.09-100.
Higashi Y, Jitsuiki D, Chayama K, Yoshizumi M: Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, for treatment of cardiovascular disease. Recent Patents on Cardiovascular Drug Discovery. 2006, 1: 85-93. 10.2174/157489006775244191.
DOI: 10.1186
Published on: 20110706
Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study
Medical Gas Research volume 1
Abstract
Background
In the acute phase of cerebral infarction, MRI indices (rDWI and rADC) worsened in the first 3-7 days after onset, and then gradually returned to normal in about 10 days (pseudo-normalization time), even after the tissue had infarcted. Since effective treatment can significantly improve these indicators and within the natural pseudo-normalization time, a comprehensive analysis of these changes provides an opportunity to objectively assess the effectiveness of different treatments for cerebral infarction. Hydroxyl free radicals are very destructive to tissues and will aggravate cerebral infarction. We treated patients with acute-phase brainstem infarction by intravenous administration of hydroxyl scavengers (edaravone and hydrogen gas) and assessed treatment efficacy by serial observation and analysis of these MRI markers.Treatment effects were assessed and compared in two groups (edaravone alone and edaravone and hydrogen combined) to assess the beneficial effects of hydrogen addition.
Methods
The patients were divided into edaravone alone group (group E, 26 cases) and edaravone combined with hydrogenated saline group (group EH, 8 cases). The initial hump amplitude in rDWI, the initial fall in rADC, and the pseudo-normalized time were measured continuously in each patient, and the mean of these data was compared between the two groups and with natural histories in the literature.
Results
The rDWI initial hump of the E group reached 2.0, which was better than the natural history of 2.5, but not as good as the 1.5 of the EH group. The initial decline in rADC in the E group was 0.6, which was close to the natural history, but lower than the 0.8 in the EH group.The pseudo-normalization time for rDWI and rADC was 9 days only in the EH group and longer in the other groups. Adding hydrogen does not cause any side effects.
Conclusion
The use of hydroxyl radical scavengers in the acute phase of brainstem infarction improves MRI indices in the natural history. The effect of the EH group was more obvious and significant. These findings may imply the need for more frequent daily administration of hydroxyl scavengers or possibly additional hydrogen effects on scavenger mechanisms.
References
Yang Q, Brian M, Tress BM, Barber PA, Desmond PM, Darby DG, Gerraty RP, Li T, Davis SM: Study of apparent diffusion coefficient and anisotropy in patients with Acute Stroke. Stroke. 1999, 30: 2382-2390. 10.1161/01.STR.30.11.2382.
Schwamm LH, Koroshetz WJ, Sorensen GA, Wang B, Copen WA, Rordorf G, Buonanno FS, Schaefer PW, Gonzalez GR: Serial Diffusion-and Hemodynamic-Weighted Magnetic Resonance Imaging. Stroke. 1998, 29: 2268-2276. 10.1161/01.STR.29.11.2268.
Huang IJ, Chen CY, Chung HW, Chang DC, Lee CC, Chin SC, Liou M: Time Course of Cerebral Infarction in the Middle Cerebral Arterial Territory: Deep Watershed versus Territorial Subtypes on Diffusion-weighted MR Images. Radiology. 2001, 221: 35-42. 10.1148/radiol.2211001412.
Fiebach JB, Schellinger JO, Sartor HW: Serial analysis of the apparent diffusion coefficient time course in human stroke. Neuroradiology. 2002, 44: 294-298. 10.1007/s00234-001-0720-8.
Liu S, Karonen JO, Liu Y, Vanninen Ft, Partanen K, Cinbnen MK, Vainio P, Aronen HJ: Serial Measurements of the Apparent Diffusion Coefficient in Human Stroke on Five Time Points over Three Months. Proc Intl Sot Mag Reson Med. 2000, 8: 1203-
Huang L, Wong XH, Li G: The application of DWI and ADC map in cerebral infarction. Proc Intl Soc Mag Reson Med. 2001, 9: 1446-
Marks MP, Tong DC, Beaulieu C, Albers GW, deCrespigny A, Moseley MR: Evaluation of early reperfusion and i.v. tPA therapy using diffusion-and perfusion-weighted MRI. Neurology. 1999, 52: 1792-1798.
Schaefer POW, Hassankhani A, Putman C, Sorensen GA, Schwamm L, Koroshez W, Gonzalez GR: Characterization and evolution of diffusion MNRE imaging abnormalities in Stroke patients undergoing intra-arterial thrombolysis. ANJR. 2004, 25: 951-957.
Tanaka M: Pharmacological and clinical profile of the free radical scavenger edaravone as a neuroprotective agent. Folia Pharmacol Jpn. 2002, 119: 301-308. 10.1254/fpj.119.301.
Kageyama M, Toriyama S, Tsubosita A, Muraki S, Yamada T, Ishibashi A: A post-marketing drug use survey of a neuroprotecive drug Radicut injection 30 mg(non-proprietary name: edaravone) for acute ischemic stroke. J New Rem Clin. 2009, 58: 1212-1226.
Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S: Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007, 13: 688-694. 10.1038/nm1577.
Takagi M: Concept of branch atheromatous disease. Neurol Med. 2008, 69: 542-549.
Burdett JH, Elster AD, Ricci PE: Acute Cerebral Infarction: Quantification of Spin-Density and T2 Shine-through Phenomena on Diffusion-weighted MR Images. Radiology. 1999, 212: 333-339.
Edaravone Acute Infarction Study Group: Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis. 2003, 15: 222-229.
Yamamoto Y, Kuwahara T, Watanabe K, Watanabe K: Antioxidant activity of 3-methyl-1-phenyl-2-pyrazolin-5-one. Redox Report. 1996, 2: 333-338.
Zhang N, Komine-Kobayashi M, Tanaka R, Liu M, Mizuno Y, Urabe T: Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke. 2005, 36: 2220-2225. 10.1161/01.STR.0000182241.07096.06.
Kawai H, Nakai H, Suga M, Yuki S, Watanabe T, Saito KI: Effects of a novel free radical scavenger, MCl-186, on ischemic brain damage in the rat distal middle cerebral artery occlusion model. J Pharmacol Exp Ther. 1997, 281: 921-927.
Yoshida H, Metoki N, Ishikawa A, Imaizumi T, Matsumiya T, Tanji K, Ota K, Ohyama C, Satoh K: Edaravone improves the expression of nerve growth factor in human astrocytes subjected to hypoxia/reoxygenation. Neurosci Res. 2010, 66: 284-289. 10.1016/j.neures.2009.11.011.
Zhang W, Sato K, Hayashi T, Omori N, Nagano I, Kato S, Horiuchi S, Abe K: Extension of ischemic therapeutic time window by a free radical scavenger, Edaravone, reperfused with tPA in rat brain. Neurol Res. 2004, 26: 342-348. 10.1179/016164104225014058.
Watanabe T, Tahara M, Todo S: The Novel Antioxidant Edaravone: From Bench to Bedside. Cardiovascular Therapeutics. 2008, 26: 101-114. 10.1111/j.1527-3466.2008.00041.x.
Lapchak PA: A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy?. Expert Opinion on Pharmacotherapy. 2010, 11: 1753-1763. 10.1517/14656566.2010.493558.
Nakao A, Sugimoto R, Billiar TR, McCurry KR: Therapeutic antioxidant medical gas. J Clin Biochem Nutr. 2009, 44: 1-13. 10.3164/jcbn.08-193R.
Kajiyama S, Hasegawa G, Asano M, Hosoda H, Fukui M, Nsksmura N, Kitawaki J, Imai S, Nakano K, Ohta M, Adachi T, Obayashi H, Yoshikawa T: Supplementation of hydrogen-rich water improves lipid andd glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nur Res. 2008, 28: 137-143.
Buchholz BM, Kaczorowski DJ, Sugimoto R, Yang R, Wang Y, Billiar TR, McCurry KR, Bauer AJ, Nakao A: Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am I transplant. 2008, 8: 2015-2024.
Saitoh Y, Okayasu H, Xiao L, Harata Y, Miwa N: Neutral pH hydrogen-enriched electrolyzed water achieves tumor-preferential clonal growth inhibition over normal cells and tumor invasion inhibition concurrently with intracellular oxidant repression. Oncol Res. 2008, 17: 247-255. 10.3727/096504008786991620.
Cardinal JS, Zhan J, Wang Y, Sugimoto R, Tsung A, McCurry KR, Billar R, Nakao A: Oral administration of hydrogen water prevents chronic allograft nephropathy in rat renal transplantation. Kidney Int. 2010, 77: 101-109. 10.1038/ki.2009.421.
Nakao A, Kaczorowski DJ, Wang Y, Cardinal JS, Buchholz BM, Sugimoto R, Tobita K, Lee S, Toyoda Y, Billar TR, McCurry KR: Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both. J Heart Lung Transplant. 2010, 29: 544-553. 10.1016/j.healun.2009.10.011.
Xie K, Yu Y, Pei Y, Hou L, Chen S, Xiong L, Wang G: Protective effects of hydrogen gas on murine polymicrobial sepsis via reducing oxidative stress and HMGB1 release. Shock. 2010, 34: 90-97.
Liu Q, Shen WF, Sun HY, Fan DF, Nakao A, Cai JM, Yan G, Zhou WP, Shen RX, Yang JM, Sun XJ: Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice. Liver Int. 2010, 30: 958-968. 10.1111/j.1478-3231.2010.02254.x.
Nakayama M, Nakao H, Hamada H, Itami N, Nakazawa R, Ito S: A novel bioactive hemodialysis system using dissolved dihydrogen(H2) produced by water electrolysis: a clinical trial. Nephrol Dial Transplant. 2010, 25: 3026-3033. 10.1093/ndt/gfq196.
Chen CW, Chen QB, Mao YF, Xu SM, Xia CY, Shi XY, Zang ZH, Yuan HB, Sun XJ: Hydrogen-rich saline protects against spinal cord injury in rats. Neurochem Res. 2010, 35: 1111-1118. 10.1007/s11064-010-0162-y.
Fujita K, Seike T, Yutsudo N, Ohno M, Yamada H, Yamaguchi H, Sakumi K, Yamakawa Y, Kido M, Takaki A, Katafuchi T, Tanaka Y, Nakabeppu y, Noda M: Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. PloS One. 2009, 30: 1-10. e7247
Li J, Wang C, Zhang JH, Cai JM, Cao YP, Sun XJ: Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer’s disease by reduction of oxidative stress. Brain Res. 2010, 1328: 152-161.
Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N: Effectiveness of Hydrogen Rich Water on Antioxidant Status of Subjects with Potential Metabolic Syndrome–An Open Label Pilot Study. J Clin Biochem Nutr. 2010, 46: 140-149. 10.3164/jcbn.09-100.
Higashi Y, Jitsuiki D, Chayama K, Yoshizumi M: Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, for treatment of cardiovascular disease. Recent Patents on Cardiovascular Drug Discovery. 2006, 1: 85-93. 10.2174/157489006775244191.
