Potential of edaravone for neuroprotection in neurologic diseases that do not involve cerebral infarction (Review)

  • Authors:
    • Kiyoshi Kikuchi
    • Ko-ichi Kawahara
    • Hisaaki Uchikado
    • Naohisa Miyagi
    • Terukazu Kuramoto
    • Tomoya Miyagi
    • Yoko Morimoto
    • Takashi Ito
    • Salunya Tancharoen
    • Naoki Miura
    • Kazunori Takenouchi
    • Yoko Oyama
    • Binita Shrestha
    • Fumiyo Matsuda
    • Yoshihiro Yoshida
    • Shinihiro Arimura
    • Kentaro Mera
    • Ko-ichi Tada
    • Narimasa Yoshinaga
    • Ryuichi Maenosono
    • Yoshiko Ohno
    • Teruto Hashiguchi
    • Ikuro Maruyama
    • Minoru Shigemori
  • View Affiliations

  • Published online on: June 7, 2011     https://doi.org/10.3892/etm.2011.281
  • Pages: 771-775
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Edaravone was originally developed as a potent free radical scavenger and has been widely used to treat cerebral infarction in Japan since 2001. Several free radical scavengers have been developed and some of them have progressed to clinical trials for the treatment of cerebral infarction. One such scavenger, edaravone, has been approved by the regulatory authority in Japan for the treatment of patients with cerebral infarction. Of particular interest is the ability of edaravone to diffuse into the central nervous system in various neurologic diseases. Aside from its hydroxyl radical scavenging effect, edaravone has been found to have beneficial effects on inflammation, matrix metalloproteinases, nitric oxide production and apoptotic cell death. Concordantly, edaravone has been found to have neuroprotective effects in a number of animal models of disease, including stroke, spinal cord injury, traumatic brain injury, neurodegenerative diseases and brain tumors. The proven safety of edaravone following 9 years of use as a free radical scavenger suggests that it may have potential for development into an effective treatment of multiple neurologic conditions in humans.

Contents

Introduction

Effects of edaravone on various neurologic diseases that do not involve cerebral infarction

Current and future developments

Introduction

Edaravone (Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan) was the first neuroprotective drug to be introduced worldwide and, since 2001, has been used to treat numerous patients with cerebral infarction in Japan. Edaravone has also been introduced in the US for the early management of adults with ischemic stroke (13). The anti-oxidant actions of edaravone are believed to enhance prostacyclin production, inhibit lipoxygenase metabolism of arachidonic acid by trapping hydroxyl radicals, inhibit alloxan-induced lipid peroxidation and quench active oxygen. These effects lead to the protection of various cell types, such as endothelial and myocardial cells, against damage by reactive oxygen species (ROS) (4). Although many compounds have been evaluated, few drugs have been found to be successful in studies conducted in Western countries. By contrast, trials conducted by Japanese researchers have been more successful (5). Several free radical scavengers have been developed and certain of these, including ebselen, tirilazad and NXY-059, have progressed to clinical trials (6). However, trials of ebselen and tirilazad in patients with cerebral infarction were terminated because of inadequate therapeutic effects (7,8). Meanwhile, in the Stroke-Acute Ischemic NXY Treatment II trials, NXY-059 was found to be ineffective for the treatment of cerebral infarction when administered within 6 h after the onset of symptoms (9).

Recently, edaravone has been found to have other properties unrelated to its anti-oxidant actions that may be useful for the treatment of a number of other diseases (Table I). Of particular interest is the potential for the use of edaravone in neurologic conditions, such as subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), spinal cord injury (SCI), traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To the best of our knowledge, no reports have reviewed a role for edaravone in various neurologic diseases that do not involve cerebral infarction to date. The purpose of this review is to examine the properties of edaravone that may lead to neuroprotection and to summarize the current state of research on the use of edaravone in a number of animal models of neurologic disease.

Table I.

Beneficial effects of edaravone in models of neurologic disease.

Table I.

Beneficial effects of edaravone in models of neurologic disease.

ModelEffect of edaravoneSubjectsRefs.
Cerebral aneurysm Anti-inflammatoryMice19
Cerebral vasospasmScavenges hydroxyl radicalsCells23
Intracerebral hemorrhageReduces iron- and thrombin-induced brain injuryRats24
Spinal cord injury
Decreases nNOSRabbits32
Increases eNOSRabbits32
Increases Cu/Zn SODRabbits32
Increases DNA repair functionRabbits33
Traumatic brain injury
Anti-apoptoticRats39
Increase neural stem cellsRats40
Decreases alkoxyl radicalsPatients, rats41,42
Amyotrophic lateral sclerosis
Decreases SOD1 depositionMice46
Anti-oxidantPatients49
Parkinson’s disease
Anti-apoptoticRats52
Anti-oxidantRats52
Anti-inflammatoryRats52
Multiple sclerosisDecreases iNOSMice55
Radiation injuryAnti-apoptoticCells, mice56,60

[i] nNOS, neuronal nitric oxide synthase; eNOS, endothelial nitric oxide synthase; SOD, superoxide dismutase.

One clinical trial found that the administration of edaravone alone within 72 h of cerebral infarction onset significantly reduced infarct volume and produced sustained benefits during a 3-month follow-up period (10,11). Recently, Unno et al reported that the total amount of edaravone used was associated with its efficacy in terms of rehabilitation gain (12). Meanwhile, the administration of edaravone within 24 h of the onset of cerebral infarction was used for patients with lacunae, large-artery atherosclerosis and cardioembolism cerebral infarctions (2). Several lines of evidence have shown that edaravone has neuroprotective effects following brain injury after cerebral infarction. For example, cerebral infarction is associated with enhanced expression of aquaporin-4 (AQP4), which causes acute edema, metalloproteinase-9 (MMP-9) and the release of high-mobility group box-1 (HMGB-1) from affected tissue, worsening the clinical outcomes (2,3,5,13,14). Edaravone is a low-molecular-weight agent that readily crosses the blood-brain barrier and its activity is not limited to the vascular compartment (4,15). Furthermore, edaravone was found to inhibit MMP-9-related brain hemorrhage in rats treated with recombinant tissue plasminogen activator (14) and attenuate cerebral ischemic injury by suppressing AQP-4 (3). Moreover, edaravone was found to rescue rats from cerebral infarction by attenuating the release of HMGB-1 in neuronal cells (2). Taken together, these findings suggest that edaravone may be used to treat patients with cerebral infarction by targeting and inhibiting the deleterious molecular events associated with brain injury.

Effects of edaravone on various neurologic diseases that do not involve cerebral infarction

Subarachnoid hemorrhage

A SAH caused by rupture of a saccular cerebral aneurysm (CA) is a life-threatening disease with a 30-day mortality rate of 45% and mild-to-severe morbidity rate of 30% (16,17). CA is a relatively common disease with a prevalence ranging from 1 to 5% as found in a large autopsy series (18). Despite its clinical and public significance, the detailed mechanisms of the initiation, progression and rupture of CAs remain to be elucidated, resulting in the absence of effective medical treatment for patients with ruptured and unruptured CAs (19). Yet, edaravone has been found to effectively inhibit CA formation by suppressing inflammation-related gene expression in aneurysmal walls in mice (19).

Cerebral vasospasm is one of the major causes of mortality and morbidity in patients with SAH (20). The detailed pathogenesis of cerebral vasospasm remains unclear and, in spite of intense and extensive investigations over the past four decades, no optimal treatment has been established (21). Recently, Munakata et al reported a trend toward a lesser incidence of delayed ischemic neurological deficits and a lesser incidence of poor outcome caused by cerebral vasospasm in edaravone-treated patients (22). Edaravone was found to exhibit a clear and selective inhibitory effect against hydroxyl radical-induced vasocontraction in the canine basilar artery in vitro (23).

Intracerebral hemorrhage

ICH is an often-fatal stroke subtype (24) and accounts for 8–15% of all strokes in Western populations and 20–30% in Asian populations (25). ICH frequently produces severe neurologic deficits due to secondary brain edema (24). Edaravone was found to attenuate ICH-induced brain edema, neurologic deficits and oxidative injury in rats. In addition, edaravone was found to reduce iron- and thrombin-induced brain injury (24).

Ischemic spinal cord injury

One of the most serious clinical diseases is SCI, the incidence of which has been increasing yearly (26). Spinal cord repair is a problem that has long puzzled neuroscientists (27,28). The repair of the injured human spinal cord with resultant functional recovery is one of the major challenges of contemporary neuroscience (29). Although the mortality rate of SCI has dropped to <5%, the disability rate associated with SCI remains high (26). Edaravone has a protective effect on spinal cord neurons, both neurologically and histologically, by suppressing the level of free radical species in rabbits (30,31). Edaravone prevents spinal cord damage and affects the enzyme levels of nitric oxide synthase and Cu/Zn superoxide dismutase (SOD) after transient ischemia in rabbits (32). Furthermore, edaravone was demonstrated to reduce oxidative cellular damage and to increase DNA repair function in the rabbit spinal cord after transient ischemia (33). Moreover, evaluation of the effect of edaravone on lipid peroxide formation and downstream of the cascade of ROS production by measuring malonyldialdehyde in injured spinal cord homogenates found that edaravone significantly attenuated lipid peroxide formation by >45% in the acute stage of SCI (34).

Traumatic brain injury

TBI presents a major worldwide social, economic and health problem (35). In the US, the mortality rate is estimated to be 21% 30 days after TBI (36). TBI occurs as a result of a direct mechanical insult to the brain and induces central nervous system degeneration and neuronal cell death (37,38). Edaravone administration following TBI was found to inhibit free radical-induced neuronal degeneration and apoptotic cell death around the damaged area, and to improve cerebral dysfunction following TBI in rats (39). Furthermore, edaravone increased neural stem cell numbers around the area of damage following rat TBI (40). Moreover, edaravone scavenges alkoxyl radicals in both patients and rats with TBI (41,42).

Amyotrophic lateral sclerosis

ALS is one of the most common neuromuscular diseases with a worldwide incidence of 8 cases per 100,000 individuals per year (43). ALS is a devastating neurodegenerative disorder characterized by progressive and relatively selective degeneration of upper and lower motor neurons (44). Patients suffer from atrophy and paralysis of systemic voluntary muscles, including respiratory muscles, leading to respiratory failure and subsequent death 3–5 years after disease onset (44). An effective therapy for ALS that is capable of ameliorating its clinical course remains unknown (44). Twenty percent of familial ALS is caused by mutations in the Cu/Zn-dependent SOD1 gene, which was first reported in 1993 (45). The deposition of abnormal SOD1 in the anterior horns was found to be reduced by edaravone administration (46). Since the administration of edaravone was found to result in a marked decrease in the 3-nitrotyrosine/tyrosine ratio, a marker of oxidative stress, the suppression of oxidative stress is likely to be upstream of the inhibition of aggregate formation (4648). Furthermore, edaravone was found to effectively slow symptom progression and motor neuron degeneration in a mouse model of ALS (46). The beneficial effects of edaravone on Wobbler mice with ALS-like symptoms have also been reported (49). Moreover, a small-sized open trial with edaravone suggested that the drug is safe and may delay the progression of functional motor disturbances in ALS patients (49). Yoshino and Kimura reported that the concentration of 3-nitrotyrosine in the cerebrospinal fluid from ALS patients was reduced following intravenous administration of edaravone (49). Thus, edaravone is a promising therapeutic agent for human motor neuron diseases, including ALS (50). However, evidence for the beneficial effects of edaravone on human ALS patients awaits the publication of the results of a phase III clinical trial of ALS currently ongoing in Japan (50).

Parkinson’s disease

PD is the most common neurodegenerative disorder after Alzheimer’s disease (51). The prevalence is estimated at 0.3% in the entire population in industrialized countries, rising to 1% in those over 60 years of age and to 4% of the population over 80 (51). Studies regarding its incidence report that it is between 8 and 18 per 100,000 individuals per year (51). Edaravone was found to exert neuroprotective effects on PD models both in vivo (52) and in vitro (52,53). The underlying mechanisms may involve anti-apoptotic, anti-oxidative and/or the anti-inflammatory effects of edaravone (52,53). Edaravone may be a potential therapeutic agent for PD, although the high therapeutic dosage required is a problem for clinical applications (52,53).

Multiple sclerosis

Multiple sclerosis (MS) has a prevalence that ranges between 2 and 150 per 100,000 individuals depending on the country or specific population (54). Research directions regarding MS treatments include investigations aimed to better understand its pathogenesis and heterogeneity; research of more effective, convenient or tolerable new treatments; creation of therapies for progressive subtypes; neuroprotection strategies and the search for effective symptomatic treatments (55).

Brain tumors

Cranial radiation therapy is widely used to treat primary and metastatic brain tumors and head and neck cancers (56). Patients who receive radiotherapy involving the brain frequently experience progressive cognitive decline (57,58). White matter necrosis and vasculopathy are overt pathologies caused by radiation-induced injury (59). Edaravone was found to protect human neural stem cells from radiation-induced apoptosis (60). In mouse models, edaravone protected neurons from apoptosis after irradiation and protected spatial memory retention deficits (56).

Current and future developments

In this review, we report the possible beneficial effects of edaravone, not only on brain injury following ischemia and reperfusion in patients with cerebral infarction, but also on various neurologic diseases. Recently, it has been reported that edaravone is effective in various models of neurologic disease (Table I). Due to the lack of clinical studies using edaravone, it remains unclear whether edaravone treatment is beneficial for patients who have excess oxidative stress and whether edaravone reduces the mortality rate of these patients. Controlled studies using a large population of patients are required to determine the effects of edaravone on various diseases. It is expected that edaravone may be useful for the treatment of various diseases in which oxidative stress may be involved in the pathogenesis.

References

1. 

Adams HP Jr, del Zoppo G, Alberts MJ, et al: Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 38:1655–1711. 2007.

2. 

Kikuchi K, Kawahara K, Tancharoen S, et al: The free radical scavenger edaravone rescues rats from cerebral infarction by attenuating the release of high-mobility group box-1 in neuronal cells. J Pharmacol Exp Ther. 329:865–874. 2009. View Article : Google Scholar : PubMed/NCBI

3. 

Kikuchi K, Tancharoen S, Matsuda F, et al: Edaravone attenuates cerebral ischemic injury by suppressing aquaporin-4. Biochem Biophys Res Commun. 390:1121–1125. 2009. View Article : Google Scholar : PubMed/NCBI

4. 

Higashi Y, Jitsuiki D, Chayama K and Yoshizumi M: Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger for treatment of cardiovascular diseases. Recent Pat Cardiovasc Drug Discov. 1:85–93. 2006. View Article : Google Scholar : PubMed/NCBI

5. 

Lapchak PA and Zivin JA: The lipophilic multifunctional antioxidant edaravone (Radicut) improves behavior following embolic strokes in rabbits: a combination therapy study with tissue plasminogen activator. Exp Neurol. 215:95–100. 2009. View Article : Google Scholar

6. 

Wang CX and Shuaib A: Neuroprotective effects of free radical scavengers in stroke. Drugs Aging. 24:537–546. 2007. View Article : Google Scholar : PubMed/NCBI

7. 

Green AR and Shuaib A: Therapeutic strategies for the treatment of stroke. Drug Discov Today. 11:681–693. 2006. View Article : Google Scholar : PubMed/NCBI

8. 

Van der Worp HB, Kappelle LJ, Algra A, et al: The effect of tirilazad mesylate on infarct volume of patients with acute ischemic stroke. Neurology. 58:133–135. 2002.PubMed/NCBI

9. 

Shuaib A, Lees KR, Lyden P, et al: NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 357:562–571. 2007. View Article : Google Scholar : PubMed/NCBI

10. 

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. 15:222–229. 2003. View Article : Google Scholar

11. 

Zhang N, Komine-Kobayashi M, Tanaka R, Liu M, Mizuno Y and Urabe T: Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke. 36:2220–2225. 2005. View Article : Google Scholar

12. 

Unno Y, Katayama M and Shimizu H: Does functional outcome in acute ischaemic stroke patients correlate with the amount of free-radical scavenger treatment? A retrospective study of edaravone therapy. Clin Drug Investig. 30:143–155. 2010. View Article : Google Scholar

13. 

Papadopoulos MC, Krishna S and Verkman AS: Aquaporin water channels and brain edema. Mt Sinai J Med. 69:242–248. 2002.PubMed/NCBI

14. 

Yagi K, Kitazato KT, Uno M, et al: Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator. Stroke. 40:626–631. 2009. View Article : Google Scholar : PubMed/NCBI

15. 

Yoshida H, Yanai H, Namiki Y, Fukatsu-Sasaki K, Furutani N and Tada N: Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury. CNS Drug Rev. 12:9–20. 2006. View Article : Google Scholar : PubMed/NCBI

16. 

Feigin VL and Findlay M: Advances in subarachnoid hemorrhage. Stroke. 37:305–308. 2006. View Article : Google Scholar : PubMed/NCBI

17. 

Van Gijn J, Kerr RS and Rinkel GJ: Subarachnoid haemorrhage. Lancet. 369:306–318. 2007.

18. 

Wiebers DO, Whisnant JP, Huston J III, et al: Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 362:103–110. 2003. View Article : Google Scholar : PubMed/NCBI

19. 

Aoki T, Nishimura M, Kataoka H, Ishibashi R, Nozaki K and Hashimoto N: Reactive oxygen species modulate growth of cerebral aneurysms: a study using the free radical scavenger edaravone and p47phox(−/−) mice. Lab Invest. 89:730–741. 2009.PubMed/NCBI

20. 

Dorsch NW and King MT: A review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage Part I: incidence and effects. J Clin Neurosci. 1:19–26. 1994. View Article : Google Scholar : PubMed/NCBI

21. 

Nakagomi T, Yamakawa K, Sasaki T, Saito I and Takakura K: Effect of edaravone on cerebral vasospasm following experimental subarachnoid hemorrhage. J Stroke Cerebrovasc Dis. 12:17–21. 2003. View Article : Google Scholar : PubMed/NCBI

22. 

Munakata A, Ohkuma H, Nakano T, Shimamura N, Asano K and Naraoka M: Effect of a free radical scavenger, edaravone, in the treatment of patients with aneurysmal subarachnoid hemorrhage. Neurosurgery. 64:423–429. 2009. View Article : Google Scholar : PubMed/NCBI

23. 

Tosaka M, Hashiba Y, Saito N, Imai H, Shimizu T and Sasaki T: Contractile responses to reactive oxygen species in the canine basilar artery in vitro: selective inhibitory effect of MCI-186, a new hydroxyl radical scavenger. Acta Neurochir. 144:1305–1310. 2002. View Article : Google Scholar

24. 

Nakamura T, Kuroda Y, Yamashita S, et al: Edaravone attenuates brain edema and neurologic deficits in a rat model of acute intracerebral hemorrhage. Stroke. 39:463–469. 2008. View Article : Google Scholar : PubMed/NCBI

25. 

Fayad PB and Awad IA: Surgery for intracerebral hemorrhage. Neurology. 51:S69–S73. 1998. View Article : Google Scholar

26. 

McDonald JW and Sadowsky C: Spinal-cord injury. Lancet. 359:417–425. 2002. View Article : Google Scholar

27. 

Andersson U, Wang H, Palmblad K, et al: High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med. 192:565–570. 2000. View Article : Google Scholar : PubMed/NCBI

28. 

Ao Q, Wang AJ, Chen GQ, Wang SJ, Zuo HC and Zhang XF: Combined transplantation of neural stem cells and olfactory ensheathing cells for the repair of spinal cord injuries. Med Hypotheses. 69:1234–1237. 2007. View Article : Google Scholar : PubMed/NCBI

29. 

Rosenfeld JV, Bandopadhayay P, Goldschlager T and Brown DJ: The ethics of the treatment of spinal cord injury: stem cell transplants, motor neuroprosthetics, and social equity. Top Spinal Cord Inj Rehabil. 14:76–88. 2008. View Article : Google Scholar : PubMed/NCBI

30. 

Aoyama T, Hida K, Kuroda S, et al: Edaravone (MCI-186) scavenges reactive oxygen species and ameliorates tissue damage in the murine spinal cord injury model. Neurol Med Chir. 48:539–545. 2008. View Article : Google Scholar : PubMed/NCBI

31. 

Suzuki K, Kazui T, Terada H, et al: Experimental study on the protective effects of edaravone against ischemic spinal cord injury. J Thorac Cardiovasc Surg. 130:1586–1592. 2005. View Article : Google Scholar : PubMed/NCBI

32. 

Takahashi G, Sakurai M, Abe K, Itoyama Y and Tabayashi K: MCI-186 prevents spinal cord damage and affects enzyme levels of nitric oxide synthase and Cu/Zn superoxide dismutase after transient ischemia in rabbits. J Thorac Cardiovasc Surg. 126:1461–1466. 2003. View Article : Google Scholar : PubMed/NCBI

33. 

Takahashi G, Sakurai M, Abe K, Itoyama Y and Tabayashi K: MCI-186 reduces oxidative cellular damage and increases DNA repair function in the rabbit spinal cord after transient ischemia. Ann Thorac Surg. 78:602–607. 2004. View Article : Google Scholar : PubMed/NCBI

34. 

Ohta S, Iwashita Y, Takada H, Kuno S and Nakamura T: Neuroprotection and enhanced recovery with edaravone after acute spinal cord injury in rats. Spine. 30:1154–1158. 2005. View Article : Google Scholar : PubMed/NCBI

35. 

Maas AI, Stocchetti N and Bullock R: Moderate and severe traumatic brain injury in adults. Lancet Neurol. 7:728–741. 2008. View Article : Google Scholar : PubMed/NCBI

36. 

Greenwald BD, Burnett DM and Miller MA: Congenital and acquired brain injury. 1 Brain injury: epidemiology and pathophysiology. Arch Phys Med Rehabil. 84:S3–S7. 2003. View Article : Google Scholar : PubMed/NCBI

37. 

Chirumamilla S, Sun D, Bullock MR and Colello RJ: Traumatic brain injury induced cell proliferation in the adult mammalian central nervous system. J Neurotrauma. 19:693–703. 2002. View Article : Google Scholar : PubMed/NCBI

38. 

Rice AC, Khaldi A, Harvey HB, et al: Proliferation and neuronal differentiation of mitotically active cells following traumatic brain injury. Exp Neurol. 183:406–417. 2003. View Article : Google Scholar : PubMed/NCBI

39. 

Itoh T, Satou T, Nishida S, et al: Edaravone protects against apoptotic neuronal cell death and improves cerebral function after traumatic brain injury in rats. Neurochem Res. 35:348–355. 2009. View Article : Google Scholar : PubMed/NCBI

40. 

Itoh T, Satou T, Nishida S, Tsubaki M, Hashimoto S and Ito H: The novel free radical scavenger, edaravone, increases neural stem cell number around the area of damage following rat traumatic brain injury. Neurotox Res. 16:378–389. 2009. View Article : Google Scholar : PubMed/NCBI

41. 

Dohi K, Satoh K, Mihara Y, et al: Alkoxyl radical-scavenging activity of edaravone in patients with traumatic brain injury. J Neurotrauma. 23:1591–1599. 2006. View Article : Google Scholar : PubMed/NCBI

42. 

Dohi K, Satoh K, Nakamachi T, et al: Does edaravone (MCI-186) act as an antioxidant and a neuroprotector in experimental traumatic brain injury? Antioxid Redox Signal. 9:281–287. 2007. View Article : Google Scholar : PubMed/NCBI

43. 

Raibon E, Todd LM and Moller T: Glial cells in ALS: the missing link? Phys Med Rehabil Clin N Am. 19:441–459. 2008. View Article : Google Scholar : PubMed/NCBI

44. 

Mitchell JD and Borasio GD: Amyotrophic lateral sclerosis. Lancet. 369:2031–2041. 2007. View Article : Google Scholar : PubMed/NCBI

45. 

Rosen DR, Siddique T, Patterson D, et al: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 362:59–62. 1993. View Article : Google Scholar

46. 

Ito H, Wate R, Zhang J, et al: Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp Neurol. 213:448–455. 2008. View Article : Google Scholar : PubMed/NCBI

47. 

Kabashi E and Durham HD: Failure of protein quality control in amyotrophic lateral sclerosis. Biochim Biophys Acta. 1762:1038–1050. 2006. View Article : Google Scholar : PubMed/NCBI

48. 

Valentine JS and Hart PJ: Misfolded CuZnSOD and amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 100:3617–3622. 2003. View Article : Google Scholar : PubMed/NCBI

49. 

Yoshino H and Kimura A: Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study). Amyotroph Lateral Scler. 7:241–245. 2006. View Article : Google Scholar : PubMed/NCBI

50. 

Takahashi R: Edaravone in ALS. Exp Neurol. 217:235–236. 2009. View Article : Google Scholar : PubMed/NCBI

51. 

De Lau LM and Breteler MM: Epidemiology of Parkinson’s disease. Lancet Neurol. 5:525–535. 2006.

52. 

Yuan WJ, Yasuhara T, Shingo T, et al: Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons. BMC Neurosci. 9:752008. View Article : Google Scholar : PubMed/NCBI

53. 

Ma L, Cao TT, Kandpal G, et al: Genome-wide microarray analysis of the differential neuroprotective effects of antioxidants in neuroblastoma cells overexpressing the familial Parkinson’s disease alpha-synuclein A53T mutation. Neurochem Res. 35:130–142. 2010.PubMed/NCBI

54. 

Rosati G: The prevalence of multiple sclerosis in the world: an update. Neurol Sci. 22:117–139. 2001. View Article : Google Scholar : PubMed/NCBI

55. 

Cohen JA: Emerging therapies for relapsing multiple sclerosis. Arch Neurol. 66:821–828. 2009. View Article : Google Scholar

56. 

Motomura K, Ogura M, Natsume A, Yokoyama H and Wakabayashi T: A free-radical scavenger protects the neural progenitor cells in the dentate subgranular zone of the hippocampus from cell death after X-irradiation. Neurosci Lett. 485:65–70. 2010. View Article : Google Scholar : PubMed/NCBI

57. 

Anderson VA, Godber T, Smibert E, Weiskop S and Ekert H: Cognitive and academic outcome following cranial irradiation and chemotherapy in children: a longitudinal study. Br J Cancer. 82:255–262. 2000.PubMed/NCBI

58. 

Crossen JR, Garwood D, Glatstein E and Neuwelt EA: Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol. 12:627–642. 1994.PubMed/NCBI

59. 

Monje ML and Palmer T: Radiation injury and neurogenesis. Curr Opin Neurol. 16:129–134. 2003. View Article : Google Scholar : PubMed/NCBI

60. 

Ishii J, Natsume A, Wakabayashi T, et al: The free-radical scavenger edaravone restores the differentiation of human neural precursor cells after radiation-induced oxidative stress. Neurosci Lett. 423:225–230. 2007. View Article : Google Scholar

Related Articles

Journal Cover

September-October 2011
Volume 2 Issue 5

Print ISSN: 1792-0981
Online ISSN:1792-1015

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Kikuchi K, Kawahara K, Uchikado H, Miyagi N, Kuramoto T, Miyagi T, Morimoto Y, Ito T, Tancharoen S, Miura N, Miura N, et al: Potential of edaravone for neuroprotection in neurologic diseases that do not involve cerebral infarction (Review). Exp Ther Med 2: 771-775, 2011
APA
Kikuchi, K., Kawahara, K., Uchikado, H., Miyagi, N., Kuramoto, T., Miyagi, T. ... Shigemori, M. (2011). Potential of edaravone for neuroprotection in neurologic diseases that do not involve cerebral infarction (Review). Experimental and Therapeutic Medicine, 2, 771-775. https://doi.org/10.3892/etm.2011.281
MLA
Kikuchi, K., Kawahara, K., Uchikado, H., Miyagi, N., Kuramoto, T., Miyagi, T., Morimoto, Y., Ito, T., Tancharoen, S., Miura, N., Takenouchi, K., Oyama, Y., Shrestha, B., Matsuda, F., Yoshida, Y., Arimura, S., Mera, K., Tada, K., Yoshinaga, N., Maenosono, R., Ohno, Y., Hashiguchi, T., Maruyama, I., Shigemori, M."Potential of edaravone for neuroprotection in neurologic diseases that do not involve cerebral infarction (Review)". Experimental and Therapeutic Medicine 2.5 (2011): 771-775.
Chicago
Kikuchi, K., Kawahara, K., Uchikado, H., Miyagi, N., Kuramoto, T., Miyagi, T., Morimoto, Y., Ito, T., Tancharoen, S., Miura, N., Takenouchi, K., Oyama, Y., Shrestha, B., Matsuda, F., Yoshida, Y., Arimura, S., Mera, K., Tada, K., Yoshinaga, N., Maenosono, R., Ohno, Y., Hashiguchi, T., Maruyama, I., Shigemori, M."Potential of edaravone for neuroprotection in neurologic diseases that do not involve cerebral infarction (Review)". Experimental and Therapeutic Medicine 2, no. 5 (2011): 771-775. https://doi.org/10.3892/etm.2011.281