Ascorbic acid glucoside reduces neurotoxicity and glutathione depletion in mouse brain induced by nitrotriazole radiosensitazer

Чердынцева, Н. В.; Иванова, А. С.; Иванов, В. В.; Cherdyntsev, Evgeny; Nair, Cherupally Krishnan Krishnan; Kagiya, Tsutomu

doi:10.4103/0973-1482.119303

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…Note: these mice were 8 weeks of age vs 4 weeks for the previous comparison). These values are comparable to published ascorbic acid levels obtained through different quantitative methods and appear to be internally consistent, but do not approach the fourfold change observed in spinal cord ( Cherdyntseva et al, 2013 ; Furusawa et al, 2008 ; Li et al, 2008 ). Thus, changes in serum ascorbate do not provide a reliable indicator of ascorbate levels in the spinal cord, suggesting that the changes observed by mass spec in spinal cord are not systemic.…”

Section: Resultssupporting

confidence: 76%

Metabolite profile of a mouse model of Charcot–Marie–Tooth type 2D neuropathy: implications for disease mechanisms and interventions

et al. 2016

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Charcot-Marie-Tooth disease encompasses a genetically heterogeneous class of heritable polyneuropathies that result in axonal degeneration in the peripheral nervous system. CharcotMarie-Tooth type 2D neuropathy (CMT2D) is caused by dominant mutations in glycyl tRNA synthetase (GARS). Mutations in the mouse Gars gene result in a genetically and phenotypically valid animal model of CMT2D. How mutations in GARS lead to peripheral neuropathy remains controversial. To identify putative disease mechanisms, we compared metabolites isolated from the spinal cord of Gars mutant mice and their littermate controls. A profile of altered metabolites that distinguish the affected and unaffected tissue was determined. Ascorbic acid was decreased fourfold in the spinal cord of CMT2D mice, but was not altered in serum. Carnitine and its derivatives were also significantly reduced in spinal cord tissue of mutant mice, whereas glycine was elevated. Dietary supplementation with acetyl-L-carnitine improved gross motor performance of CMT2D mice, but neither acetyl-L-carnitine nor glycine supplementation altered the parameters directly assessing neuropathy. Other metabolite changes suggestive of liver and kidney dysfunction in the CMT2D mice were validated using clinical blood chemistry. These effects were not secondary to the neuromuscular phenotype, as determined by comparison with another, genetically unrelated mouse strain with similar neuromuscular dysfunction. However, these changes do not seem to be causative or consistent metabolites of CMT2D, because they were not observed in a second mouse Gars allele or in serum samples from CMT2D patients. Therefore, the metabolite 'fingerprint' we have identified for CMT2D improves our understanding of cellular biochemical changes associated with GARS mutations, but identification of efficacious treatment strategies and elucidation of the disease mechanism will require additional studies.

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Section: Resultssupporting

confidence: 76%

Metabolite profile of a mouse model of Charcot–Marie–Tooth type 2D neuropathy: implications for disease mechanisms and interventions

et al. 2016

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“…Whether these experiments are at all relevant to likely effects in aerobic tissue in vivo is unclear: in fact, administration of ascorbic acid glucoside (but not ascorbic acid) did reduce neurotoxicity of the 3-nitrotriazole, sanazole (Figure 1) (12) in a mouse model. 136 Interestingly, the 5-nitrofuran nifurtimox, widely used in humans against Chagas' disease (American trypanosomiasis), is a substrate for aldehyde dehydrogenase 2; inhibitors of this enzyme protect against toxicity in a zebrafish model, 137 with significant implications for the use of nitrofurans in man since low-cost inhibitors of this enzyme are available. 138 Nifurtimox is currently under Phase 2 clinical trial in chemotherapy of neuroblastoma.…”

Section: Problem 3: Ascorbatementioning

confidence: 99%

Nitroimidazoles as hypoxic cell radiosensitizers and hypoxia probes: misonidazole, myths and mistakes

Wardman

2018

The British Journal of Radiology

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Nitroimidazoles have been extensively explored as hypoxic cell radiosensitizers but have had limited clinical success, with efficacy restricted by toxicity. However, they have proven clinically useful as probes for tumour hypoxia. Both applications, and probably much of the dose-limiting toxicities, reflect the dominant chemical property of electron affinity or ease of reduction, associated with the nitro substituent in an aromatic structure. This single dominant property affords unusual, indeed extraordinary flexibility in drug or probe design, suggesting further development is possible in spite of earlier limitations, in particular building on the benefit of hindsight and an appreciation of errors made in earlier studies. The most notable errors were: the delay in viewing cellular thiol depletion as a likely common artefact in testing in vitro; slow recognition of pH-driven concentration gradients when compounds were weak acids and bases; and a failure to explore the possible involvement of pH and ascorbate in influencing hypoxia probe binding. The experience points to the need to involve a wider range of expertise than that historically involved in many laboratories when studying the effects of chemicals on radiation response or using diagnostic probes.

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“…Ìàêñèìàëüíàÿ ãåíåðàöèÿ 6,9 ìêM H 2 O 2 ïðîèñõîäèò ïðè êîíöåíòðàöèè öèñòàìèíà â êëåòêàõ 0,6 ìM [1]. Ìåõàíèçì àíòèòîêñè÷åñêîãî äåéñòâèÿ àñêîðáèíîâîé êèñëîòû, êàê è äðóãèõ ïðèðîäíûõ àíòèîêñèäàíòîâ, ñâÿçàí ñ ñóáñòðàòíîé ïîääåðaeêîé àíòèîêñèäàíòíîãî ïîòåíöèàëà êëåòîê çà ñ÷åò âîññòàíîâëåíèÿ ýíäîãåííîãî óðîâíÿ âîññòàíîâëåííîãî ãëóòàòèîíà, êîòîðûé ñíèaeàåòñÿ ïðè èíòåíñèâíûõ ïåðåêèñíûõ ïðîöåññàõ âî âðåìÿ ðåàëèçàöèè ìåòàáîëè÷åñêîé ôàçû îòðàâëåíèÿ [5]. Ðàíåå îòìå÷àëîñü, ÷òî òîêñè÷íîñòü àìèíîòèîëîâ ìîaeíî ñíèçèòü ïðè ñòèìóëÿöèè àíòèîêñèäàíòíîé ñèñòåìû îðãàíèçìà, à òàêaeå ïðè ïðèìåíåíèè áèîôëàâîíîèäîâ è òèîëîâûõ àíòèäîòîâ ïðè ñîõðàíåíèè ïðîòèâîëó÷åâûõ ñâîéñòâ ðàäèîïðîòåêòîðà [1,2].…”

Section: ðåçóëüòàòû è èõ îáñóAeäåíèåunclassified

Влияние Аскорбиновой Кислоты На Острую Токсичность И Противолучевые Свойства Цистамина В Опытах На Мелких И Крупных Животных

Ушаков¹

2018

Эксп. и клин. фармакол.

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Опыты проведены на 510 беспородных белых мышах и 101 собаке. Животных облучали гамма-квантами 60Со в смертельных дозах и определяли противолучевые свойства цистамина в комбинации с аскорбиновой кислотой. Отдельно оценивали влияние аскорбиновой кислоты на острую токсичность цистамина. Выявлено, что в опытах на мышах аскорбиновая кислота в дозах 100 – 500 мг/кг снижает токсичность цистамина — смещение ЛД50 около 20 %. Аскорбиновая кислота в дозе 200 мг/кг в опытах на собаках также снижала токсичность цистамина со смещением ЛД50 препарата с 74,5 (65,4 – 84,5) до 111,0 (105,2 – 117,1) мг/кг. Цистамин в опытах на мышах и собаках обладал выраженной противолучевой активностью, обеспечивая выживаемость 56 – 63 % животных при 100 % смертности в контрольной группе на облучение. При применении цистамина в сочетании с аскорбиновой кислотой полностью сохранялись его противолучевые свойства.

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Ascorbic acid glucoside reduces neurotoxicity and glutathione depletion in mouse brain induced by nitrotriazole radiosensitazer

Abstract: Administration of ascorbic acid glucoside, but not ascorbic acid, before sanazole administration protected from sanazole-induced neurotoxicity by preventing the decrease in the brain reduced glutathione level and providing high level of ascorbic acid in plasma.

Cited by 4 publications

References 33 publications

Metabolite profile of a mouse model of Charcot–Marie–Tooth type 2D neuropathy: implications for disease mechanisms and interventions

Metabolite profile of a mouse model of Charcot–Marie–Tooth type 2D neuropathy: implications for disease mechanisms and interventions

Nitroimidazoles as hypoxic cell radiosensitizers and hypoxia probes: misonidazole, myths and mistakes

Влияние Аскорбиновой Кислоты На Острую Токсичность И Противолучевые Свойства Цистамина В Опытах На Мелких И Крупных Животных

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