High hopes at high altitudes: pharmacotherapy for acute mountain sickness and high-altitude cerebral and pulmonary oedema

Wright, A. D.; Brearey, SP; Imray, C.

doi:10.1517/14656566.9.1.119

Cited by 44 publications

(26 citation statements)

References 82 publications

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“…Their use in these neurological disorders as well as in epilepsy (Aggarwal et al., 2013) confirms the ability of these drugs to reach the brain at effective concentrations. Due to the long‐term use of MTZ and ATZ in chronic conditions, the efficacy and the safety of their systemic administration have been widely assessed (Wright, Brearey & Imray, 2008), making clinical trials for CAIs in AD a concrete possibility. Our novel findings on the mitochondrial effects of MTZ and ATZ against neuronal and vascular amyloid toxicity justify the selection of these drugs as a therapeutic strategy for AD and CAA.…”

Section: Introductionmentioning

confidence: 99%

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

et al. 2018

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SummaryMounting evidence suggests that mitochondrial dysfunction plays a causal role in the etiology and progression of Alzheimer's disease (AD). We recently showed that the carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) prevents amyloid β (Aβ)‐mediated onset of apoptosis in the mouse brain. In this study, we used MTZ and, for the first time, the analog CAI acetazolamide (ATZ) in neuronal and cerebral vascular cells challenged with Aβ, to clarify their protective effects and mitochondrial molecular mechanism of action. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Aβ, without affecting metabolic function. ATZ was effective at concentrations 10 times lower than MTZ. Both MTZ and ATZ prevented mitochondrial membrane depolarization and H2O2 generation, with no effects on intracellular pH or ATP production. Importantly, the drugs did not primarily affect calcium homeostasis. This work suggests a new role for carbonic anhydrases (CAs) in the Aβ‐induced mitochondrial toxicity associated with AD and cerebral amyloid angiopathy (CAA), and paves the way to AD clinical trials for CAIs, FDA‐approved drugs with a well‐known profile of brain delivery.

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Section: Introductionmentioning

confidence: 99%

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

et al. 2018

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“…GCs are widely used as anti-inflammatory agents for treating pathological conditions where hypoxia plays a role in disease progression such as rheumatoid arthritis and chronic obstructive pulmonary disease. GCs and hypoxia pathways have a close interplay in physiology and disease (1)(2)(3); however, recent studies report conflicting results on the cross-talk between GC action and hypoxia (4,5). Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcriptional complexes constituted by α-and β-subunits that activate diverse pathways regulating cellular glucose and lipid metabolism and proliferation (6,7).…”

mentioning

confidence: 99%

Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

Vettori

Greenald

Wilson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoid (GC) and hypoxic transcriptional responses play a central role in tissue homeostasis and regulate the cellular response to stress and inflammation, highlighting the potential for cross-talk between these two signaling pathways. We present results from an unbiased in vivo chemical screen in zebrafish that identifies GCs as activators of hypoxia-inducible factors (HIFs) in the liver. GCs activated consensus hypoxia response element (HRE) reporters in a glucocorticoid receptor (GR)-dependent manner. Importantly, GCs activated HIF transcriptional responses in a zebrafish mutant line harboring a point mutation in the GR DNA-binding domain, suggesting a nontranscriptional route for GR to activate HIF signaling. We noted that GCs increase the transcription of several key regulators of glucose metabolism that contain HREs, suggesting a role for GC/HIF cross-talk in regulating glucose homeostasis. Importantly, we show that GCs stabilize HIF protein in intact human liver tissue and isolated hepatocytes. We find that GCs limit the expression of Von Hippel Lindau protein (pVHL), a negative regulator of HIF, and that treatment with the c-src inhibitor PP2 rescued this effect, suggesting a role for GCs in promoting c-src-mediated proteosomal degradation of pVHL. Our data support a model for GCs to stabilize HIF through activation of c-src and subsequent destabilization of pVHL.hypoxia-inducible factor | glucocorticoid signaling | Von Hippel Lindau | metabolism | liver G lucocorticoids (GCs) are steroid hormones secreted from the adrenal glands that regulate carbohydrate, lipid, and protein metabolism. GCs are widely used as anti-inflammatory agents for treating pathological conditions where hypoxia plays a role in disease progression such as rheumatoid arthritis and chronic obstructive pulmonary disease. GCs and hypoxia pathways have a close interplay in physiology and disease (1-3); however, recent studies report conflicting results on the cross-talk between GC action and hypoxia (4, 5). Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcriptional complexes constituted by α-and β-subunits that activate diverse pathways regulating cellular glucose and lipid metabolism and proliferation (6, 7). Under normoxic conditions, the HIF-1α transcriptional subunit is recognized by prolyl hydroxylases and targeted for degradation via the Von Hippel Lindau (VHL)-mediated ubiquitin proteasome pathway; however, under hypoxic conditions HIF-1α is stabilized and translocates to the nucleus to exert its transcriptional activity. HIFs play a central role in many disease processes and provide a therapeutic target for treating pathological conditions including cancer, ischemia, stroke, inflammation, and chronic anemia (8-11). Screens to identify agents that stabilize HIFs have identified numerous agents, with the majority acting either via iron chelation or as 2-oxyglutarate analogs (12). In vitro HIFreporter screening methods, although extremely valuable, do not provide physiological information and may overlook tissue-s...

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“…HACE is considered to be the end stage of severe AMS and has been suggested to be an osmotic cell swelling and vasogenic edema, raising the possibility that acute hypoxia may increase blood-brain barrier (BBB) permeability (Roach and Hackett 2001). Prevention for adaptation to high-altitude environment includes slow ascent, appropriate descent, and drug therapy (Wright et al 2008;Tissot van Patot et al 2009). Among them, drug therapy is considered to be the main prevention measure.…”

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confidence: 99%

The protective role of 5-hydroxymethyl-2-furfural (5-HMF) against acute hypobaric hypoxia

Wu²,

Zhao³

et al. 2011

Cell Stress and Chaperones

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Our previous study showed that pretreatment with 5-hydroxymethyl-2-furfural (5-HMF) led to protection against hypoxic injury via a p-ERK-mediated pathway in vitro. Whether the protection of 5-HMF against hypoxia is effective in vivo is unknown. The present study is aimed to verify the role of 5-HMF in acute hypobaric hypoxia using Kunming mice as an in vivo model and further investigate the underlying mechanisms. Mice pretreated with or without 5-HMF for 1 h were exposed to acute hypobaric hypoxic condition for 6 h and then the survival time, the survival rate, the permeability of blood-brain barrier (BBB), the histological analysis in hippocampus and cortex, and the phosphorylation level of mitogen-activated protein kinases (ERK, JNK, and p38) were investigated. The results showed that 5-HMF significantly increased the survival time and the survival rate of mice. Accordingly, pretreatment with 5-HMF markedly attenuated acute hypobaric hypoxia-induced permeability of BBB (P < 0.01). In addition, the cellular damage extent of the hippocampus and the cortex induced by hypoxia for 6 h was also attenuated by pretreatment with 5-HMF, especially in the hippocampus CA1 region. Furthermore, the activation of ERK rather than JNK and p38 was involved in the protection of 5-HMF against acute hypobaric hypoxia. In summary, 5-HMF enhanced the survival capability of mice and decreased acute hypoxic damage to the brain, which may be associated with the effects on BBB and p-ERK.

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High hopes at high altitudes: pharmacotherapy for acute mountain sickness and high-altitude cerebral and pulmonary oedema

Cited by 44 publications

References 82 publications

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

The protective role of 5-hydroxymethyl-2-furfural (5-HMF) against acute hypobaric hypoxia

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