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            -Arginine improves the symptoms of strokelike episodes in MELAS

Koga, Yasutoshi; Akita, Yukihiro; Nishioka, Junko; Yatsuga, Shuichi; Povalko, Nataliya; Tanabe, Yuzo; Fujimoto, Shinji; Matsuishi, Toyojiro

doi:10.1212/01.wnl.0000151976.60624.01

Cited by 288 publications

(235 citation statements)

References 11 publications

(7 reference statements)

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“…Fifteen to 22 patients were included in the various outcomes. The results of these studies showed improved clinical recovery and neuroimaging (statistical parametric mapping-single proton emission computed tomography, SPM-SPECT) in a few patients who received arginine-HCl, as well as significantly increased plasma NO, citrulline, and cyclic guanosine monophosphate [12]. Separate acute studies showed that MELAS patients had lower diameter brachial arteries compared with control patients at baseline, which improved after administration of intravenous arginine-HCl, but not to the full extent of controls [13].…”

Section: Argininementioning

confidence: 97%

“…MELAS is associated with recurrent "metabolic strokes", attributed to possible vasoconstriction. This concept has been supported by a series of uncontrolled, open-label, chronic clinical trials of oral arginine administration, and also short-term controlled trials of acute administration of arginine-hydrogen chloride (HCl) during clinical exacerbations, originating from Karume University in collaboration with other medical centers in Japan [12][13][14][15][16]. Although arginine has been used widely for clinical purposes, including treatment of urea cycle disorders, it may be associated with adverse effects, particularly in the soluble arginineHCl form, which is administered parenterally [17].…”

Section: Argininementioning

confidence: 99%

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Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Kerr

2013

Neurotherapeutics

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Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q 10 (CoQ 10 ; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ 10 ), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ 10 ), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, openlabel/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinicallyrelevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.

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Section: Argininementioning

confidence: 97%

Section: Argininementioning

confidence: 99%

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Kerr

2013

Neurotherapeutics

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“…Some have studied the benefits of administering L-arginine, a precursor to the vasodilator NO in patients with MELAS stroke-like episodes Fig. 2 (a, b) (Koga et al 2002(Koga et al , 2005(Koga et al , 2007. It has been found that intravenously administered L-arginine improved acute stroke-like symptoms in MELAS patients (Koga et al 2005).…”

Section: Similarity To Stroke In Melasmentioning

confidence: 99%

“…2 (a, b) (Koga et al 2002(Koga et al , 2005(Koga et al , 2007. It has been found that intravenously administered L-arginine improved acute stroke-like symptoms in MELAS patients (Koga et al 2005). Furthermore, long-term supplementation of oral L-arginine has been shown to improve endothelial dysfunction and potentially play a role in the prevention of stroke-like episodes in MELAS (Koga et al 2006).…”

Section: Similarity To Stroke In Melasmentioning

confidence: 99%

Stroke and Stroke-Like Symptoms in Patients with Mutations in the POLG1 Gene

et al. 2011

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Introduction/Methods Mutations in POLG1, the gene encoding mitochondrial polymerase gamma (Polg), have been associated with a number of well-characterized phenotypes. In this study, we report two cases of patients with biallelic POLG1 mutations and stroke. We also performed a review of the literature and report on all clinical studies of patients with POLG1 mutations in which stroke was described in the phenotype. For each patient, genotype and phenotype are reported.Results Including our two patients, a total of 22 patients have been reported with POLG1 mutations and stroke. The average age of onset of stroke in these patients was 9 years with a range of 1-23 years. In cases where localization was reported, the occipital lobes were the primary location of the infarct. Mutations in the linker-linker or linker-polymerase domains were the most frequent genotype observed. Seizures (16/22) and hepatic dysfunction/failure (8/22) were the most commonly reported symptoms in the stroke cohort.Conclusion This article raises an underrecognized point that patients with POLG1 mutations may suffer a cerebrovascular accident at a young age. The most common location of the infarction is in the occipital lobe. The presentation may be similar to MELAS and can be misdiagnosed as a migrainous stroke.

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“…In several screened patients, there is evidence of deregulation of components involved in the ureacycle control, particularly the Arginase enzyme (12). L-arginine, the substrate for Arginase, has been successfully used in clinical pharmacotherapy where it significantly increases the utrophin level in dystrophic muscle (21) and improves cerebral ischemia in MELAS patients during the acute phase of stroke (22). These findings point to a possible role of amino acid metabolism in the pathogenesis of mitochondrial disease suggesting that: (i) the urea cycle may be crucial in disease progression, and (ii) steps in the arginine metabolic pathway are promising targets for novel therapeutic approaches.…”

Section: 'Metabolic Genes' Including Genes Involved In the Lipid Permentioning

confidence: 99%

Molecular research technologies in mitochondrial diseases: The microarray approach

Crimi

O’Hearn

Wallace

et al. 2005

IUBMB Life (International Union of Biochemistry and Molecular B

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SummaryMitochondria are ubiquitous in eukaryotic cells where they generate much of the cellular energy by the process of oxidative phosphorylation (OXPHOS). The approximately 1500 genes of the mitochondrial genome are distributed between the cytoplasmic, maternally-inherited, mitochondrial DNA (mtDNA) which encodes 37 genes and the nuclear DNA (nDNA) which encompasses the remaining mitochondrial genes. The interplay between the mtDNA and nDNA encoded mitochondrial genes and their role in mitochondrial disorders is still largely unclear. One approach for elucidating the pathophysiology of mitochondrial diseases has been to look at changes in the expression of mtDNA and nDNA-encoded genes in response to specific mitochondrial genetic defects. Initial studies of gene expression changes in response to mtDNA defect employed blot technologies to analyze changes in the expression of individual genes one at a time. While Southern/Northern blot experiments confirmed the importance of nDNA -mtDNA interactions in the pathophysiology of mitochondrial myopathy, the methodology used limited the number of genes that could be analyzed from each patient. This barrier has been overcome, in part by the advent of DNA microarray technology. In DNA microarrays gene sequences or oligonucleotides homologous to gene sequences are arrayed on a solid support. The RNA from the subject is then isolated, the mRNA converted to cDNA and the cDNA labeled with a fluorescent probe. The labeled cDNA is hybridized on the microarray and the fluorescence bound to each array is then quantified. Recently, these technologies have been applied to mitochondrial disease patient tissues and the presence of coordinate changes in mitochondrial gene expression confirmed. IUBMB Life, 57: 811-818, 2005

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l -Arginine improves the symptoms of strokelike episodes in MELAS

Cited by 288 publications

References 11 publications

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Stroke and Stroke-Like Symptoms in Patients with Mutations in the POLG1 Gene

Molecular research technologies in mitochondrial diseases: The microarray approach

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