Methylene blue and the neurotoxic mechanisms of ifosfamide encephalopathy

Küpfer, A; Aeschlimann, Christian; Cerny, Thomas

doi:10.1007/s002280050102

Cited by 97 publications

(65 citation statements)

References 31 publications

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“…The metabolic enhancing effects of MB are not necessarily limited to one brain region or function; rather MB may help meet ongoing metabolic demands for any region engaged in a particular function, such as memory retention in the postextinction phase. MB is an Food and Drug Administration-approved drug that is readily available and that has already been used clinically for many years as an antidote for certain metabolic poisons (Kupfer et al 1996) and as an inhibitor of oxygen free radical generation in reperfusion injury to the brain (Kelner et al 1988;Salaris et al 1991). Our results suggest that MB administered in conjunction with extinction behavioral therapy in humans may be a useful therapeutic agent to facilitate retention of extinction of conditioned fear or other traumatic memories.…”

Section: Prefrontal Cortex Was More Activated By the Postextinction Mmentioning

confidence: 75%

Extinction Memory Improvement by the Metabolic Enhancer Methylene Blue

González-Lima¹,

Bruchey²

2004

Learn. Mem.

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We investigated whether postextinction administration of methylene blue (MB) could enhance retention of an extinguished conditioned response. MB is a redox compound that at low doses elevates cytochrome oxidase activity, thereby improving brain energy production. Saline or MB (4 mg/kg intraperitoneally) were administered to rats for 5 d following extinction training of tone-footshock conditioning. Postextinction freezing was lower in rats receiving MB compared with saline, suggesting that MB improved retention of the extinction memory. The MB effect was specific to tone-evoked freezing because there were no differences in pretone freezing. Control subjects similarly injected with MB showed no evidence of nonspecific effects on measures of motor activity and fearfulness. MB-treated rats exhibited both greater retention of extinction and greater overall brain metabolic activity. Rats with higher retention of extinction also showed a relative increase in cytochrome oxidase activity in prefrontal cortical regions, especially anterior infralimbic cortex, dorsal and medial frontal cortex, and lateral orbital cortex. These regional metabolic increases were also correlated to the behavioral freezing index used to assess retention of extinction. It was concluded that MB administered postextinction could enhance retention of extinction memory through an increase in brain cytochrome oxidase activity.

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Section: Prefrontal Cortex Was More Activated By the Postextinction Mmentioning

confidence: 75%

Extinction Memory Improvement by the Metabolic Enhancer Methylene Blue

González-Lima¹,

Bruchey²

2004

Learn. Mem.

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“…[26][27][28] Moreover, it also known to be neurotoxic when administered either intraventricularly or intrathecally to humans. [29][30][31][32][33][34][35][36] Reported complications from these routes of administration include nausea, stupor, headache, weakness or numbness in the arms or legs, pain, facial paresis, optic neuropathy, spinal cord necrosis, and even death.…”

Section: November (2 Of 2) 2003 Neurology 61 1333mentioning

confidence: 99%

The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis [RETIRED]

et al. 2003

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Abstract-Mitoxantrone is the first drug approved for the treatment of secondary progressive multiple sclerosis (SPMS) in the United States. This assessment considers use of mitoxantrone in the treatment of MS. Mitoxantrone probably reduces the clinical attack rate and reduces attack-related MRI outcomes in patients with relapsing MS (Type B recommendation). Also, mitoxantrone may have a beneficial effect on disease progression in patients with MS whose clinical condition is worsening (Type B recommendation). The potential for serious toxicity of mitoxantrone, however, must be taken into account when considering this therapy in individual patients. Moreover, because the potential clinical benefits on disease progression appear to be only modest, the results of the single phase III trial should be replicated in another (and hopefully much larger) clinical study before this agent is widely recommended for the treatment of patients with MS. NEUROLOGY 2003;61:1332-1338 Mitoxantrone hydrochloride (Novantrone) is an anthracenedione that has been used as an antineoplastic agent to treat hormone-refractory prostate cancer and acute nonlymphocytic leukemia in adults. It exerts its antineoplastic action by intercalating into DNA and producing both DNA strand-breaks and interstrand cross-links; it also interferes with RNA synthesis and markedly inhibits the enzyme topoisomerase II, which aids in the DNA repair process. [1][2][3][4] In the treatment of MS, mitoxantrone represents the latest in a long line of general immunosuppressive agents studied in this disease. Previously, most such agents have not shown clear-cut benefits in this condition. [5][6][7][8][9][10] On the basis of a phase III clinical trial in Europe, 11,12 and an earlier phase II study, 13 mitoxantrone recently received an expanded indication from the Food and Drug Administration (FDA) for use in secondary progressive MS (SPMS), in progressiverelapsing MS, and for patients with worsening relapsing-remitting (RR) MS. This last category is defined as patients whose neurologic status remains significantly abnormal between MS attacks.Mitoxantrone is the first drug approved for these indications in the United States, and it is the purpose of this assessment to consider both the evidence leading to the recent FDA approval as well as the appropriate clinical role of this agent in the management of patients with MS.Description of the analytic process. Articles for this review were searched in Medline under the keywords mitoxantrone and MS. Forty-one articles were identified by this search. The abstracts of these articles were reviewed and the original articles were selected for inclusion in the analysis only if they were either controlled trials or case series using mitoxantrone in the treatment of MS. Five such articles were identified, in addition to the phase III trial. 11,12 In addition, the reference lists of the articles found in this manner were also reviewed to identify articles or abstracts not found by the computer search.Analysis of the evidence. Followi...

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“…We choose methylene blue (MB) as antioxidant that inhibits the generation of oxygen free radicals in ‘in vitro’ models of ischemia and reoxygenation by inhibiting xanthine oxidase [19]. MB is used in patients having refractory septic shock [20]or some neurological diseases [21, 22]and in experimental studies [23]. In refractory septic shock, intravenous infusion of MB increases arterial blood pressure and systemic vascular resistance without modifying cardiac output, oxygen delivery, or oxygen consumption [20].…”

Section: Introductionmentioning

confidence: 99%

Does Methylene Blue Protect the Kidney Tissues from Damage Induced by Ciclosporin A Treatment?

Rezzani

Rodella²,

Corsetti³

et al. 2001

Nephron

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Ciclosporin A (CsA) is the first-choice immunosuppressant universally used in allotransplantation and autoimmune diseases. However, it has been demonstrated that this drug produces negative side effects in several organs and in particular in the lymphoid organs and in the kidney. It has been suggested that the CsA causes deleterious effects because it increases the oxygen free radical production. Here we wanted to test whether antioxidants protect the kidney parenchyma from the toxicity induced by CsA. We used methylene blue (MB), because it inhibits the formation of oxygen free radicals. The study was carried out in four groups of Wistar rats. Group I animals were intraperitoneally injected with MB (1 mg/kg/day) for 21 days; group II animals were subcutaneously injected with CsA (15 mg/kg/day) for 21 days; group III animals were treated with CsA combined with MB at the same doses and for the same periods as groups I and II, and group IV animals were injected subcutaneously with olive oil for 21 days as controls. The kidneys and the thymuses were subsequently removed and examined by conventional morphological staining (hematoxylin-eosin and Masson’s trichrome) and enzymatic (NADPH-diaphorase, cytochrome, c oxidase, and superoxide anion production) and immunoenzymatic (inducible nitric oxide synthase – iNOS, endothelial nitric oxide synthase – eNOS) techniques. The thymuses were used to check the persistence of CsA-immunsuppressive effects during MB administration. Group I, III, and IV animals showed a normal kidney architecture and low levels of NADPH-diaphorase and of superoxide anion in all structures studied (proximal and distal tubules, glomeruli and the Henle loops). The cytochrome c oxidase showed a strong activity in proximal tubules, a moderate activity in distal tubules, and a weak activity in glomeruli and in the Henle loops. The expression of iNOS was weak in the proximal tubular epithelial cells and negative in the glomeruli, while eNOS was found to be moderately positive in the glomeruli and in the interstitial arteries, but not in the tubules and in the Henle loops. Degenerative changes with tubulointerstitial injury in the cortex of CsA-treated kidneys (group II) and increases of NADPH-diaphorase levels, iNOS activity, and superoxide staining were found in all structures. The expression of eNOS did not change in group I, III and IV animals. MB combined with CsA prevented the degenerative changes caused by CsA, preserving the structural, enzymatic, and immunoenzymatic integrity of the renal parenchyma. The mechanism by which MB exerts its protective action is not yet clear, but it seems to be due to its ability to inhibit xanthine oxidase and to quench nitric oxide production. Moreover, these data have been also supported by the following: (1) the superoxide anion levels were very high after CsA treatment and reduced after CsA-MB treatment, and (2) the iNOS levels increased in CsA-treated rats and showed normal levels after CsA-MB treatment. Moreover we demonstrated that MB administration did no co...

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Methylene blue and the neurotoxic mechanisms of ifosfamide encephalopathy

Cited by 97 publications

References 31 publications

Extinction Memory Improvement by the Metabolic Enhancer Methylene Blue

Extinction Memory Improvement by the Metabolic Enhancer Methylene Blue

The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis [RETIRED]

Does Methylene Blue Protect the Kidney Tissues from Damage Induced by Ciclosporin A Treatment?

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