Methazolamide in high-altitude illnesses

Lu, Hui; Zhang, Huaqun; Jiang, Yuanying

doi:10.1016/j.ejps.2020.105326

Cited by 26 publications

(11 citation statements)

References 54 publications

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“…Regarding antioxidant treatment, a recent study with mice demonstrated that pretreatment with 5,6,7,8-tetrahydroxyflavone (5,6,7,8-THF), which has antioxidant properties, increased the activity levels of SOD, CAT, and GSH-Px and decreased the H 2 O 2 and MDA contents in the brain and heart, indicating that the use of this flavone as an excellent antioxidant enhancer, lipid peroxidation inhibitor, and general anti-hypoxia agent for preventing AMS merits further exploration [ 35 ]. On the other hand, methazolamide, a lipophilic analog of acetazolamide with multiple advantages over acetazolamide that also functions as a carbonic anhydrase inhibitor to abolish AMS and HACE, has been considered an antioxidative stress drug [ 44 ] since a previous study showed that methazolamide can protect cultured neurocytes against H 2 O 2 -induced oxidative damage [ 45 ].…”

Section: Oxidative Stress and High-altitude Diseasesmentioning

confidence: 99%

Oxidative Stress and Diseases Associated with High-Altitude Exposure

2022

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Several diseases associated with high-altitude exposure affect unacclimated individuals. These diseases include acute mountain sickness (AMS), high-altitude cerebral edema (HACE), high-altitude pulmonary edema (HAPE), chronic mountain sickness (CMS), and, notably, high-altitude pulmonary hypertension (HAPH), which can eventually lead to right ventricle hypertrophy and heart failure. The development of these pathologies involves different molecules and molecular pathways that might be related to oxidative stress. Studies have shown that acute, intermittent, and chronic exposure to hypobaric hypoxia induce oxidative stress, causing alterations to molecular pathways and cellular components (lipids, proteins, and DNA). Therefore, the aim of this review is to discuss the oxidative molecules and pathways involved in the development of high-altitude diseases. In summary, all high-altitude pathologies are related to oxidative stress, as indicated by increases in the malondialdehyde (MDA) biomarker and decreases in superoxide dismutase (SOD) and glutathione peroxidase (GPx) antioxidant activity. In addition, in CMS, the levels of 8-iso-PGF2α and H2O2 are increased, and evidence strongly indicates an increase in Nox4 activity in HAPH. Therefore, antioxidant treatments seem to be a promising approach to mitigating high-altitude pathologies.

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Section: Oxidative Stress and High-altitude Diseasesmentioning

confidence: 99%

Oxidative Stress and Diseases Associated with High-Altitude Exposure

2022

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“…Moreover, both ATZ and MTZ inhibited caspase-9 activation caused by Aβ in cerebrovascular EC, and the resulting apoptosis ( Solesio et al, 2018 ). MTZ has been also observed to increase the activation of nuclear factor-related factor 2 (Nrf2), in models of high-altitude sickness and more interestingly, in human neuroblastoma cells and primary cortical neurons challenged with Aβ in vitro ( Lu et al, 2020 ; Sotolongo et al, 2020 ). Nrf2-activation by MTZ increased the activity of antioxidant enzymes, such as superoxide dismutase-1 and heme-oxygenase-1, pointing to the potential downstream effects of MTZ ( Sotolongo et al, 2020 ).…”

Section: Carbonic Anhydrasesmentioning

confidence: 99%

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Lemon

Canepa

Ilies

et al. 2021

Front. Aging Neurosci.

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The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology. Stroke and AD share common risk factors such as cardiovascular disease, and also share similarities at a molecular level. In both diseases, disruption of metabolic support, mitochondrial dysfunction, increase in oxidative stress, release of inflammatory signaling molecules, and blood brain barrier disruption result in NVU dysfunction, leading to cell death and neurodegeneration. Improved therapeutic strategies for both AD and stroke are needed. Carbonic anhydrases (CAs) are well-known targets for other diseases and are being recently investigated for their function in the development of cerebrovascular pathology. CAs catalyze the hydration of CO2 to produce bicarbonate and a proton. This reaction is important for pH homeostasis, overturn of cerebrospinal fluid, regulation of CBF, and other physiological functions. Humans express 15 CA isoforms with different distribution patterns. Recent studies provide evidence that CA inhibition is protective to NVU cells in vitro and in vivo, in models of stroke and AD pathology. CA inhibitors are FDA-approved for treatment of glaucoma, high-altitude sickness, and other indications. Most FDA-approved CA inhibitors are pan-CA inhibitors; however, specific CA isoforms are likely to modulate the NVU function. This review will summarize the literature regarding the use of pan-CA and specific CA inhibitors along with genetic manipulation of specific CA isoforms in stroke and AD models, to bring light into the functions of CAs in the NVU. Although pan-CA inhibitors are protective and safe, we hypothesize that targeting specific CA isoforms will increase the efficacy of CA inhibition and reduce side effects. More studies to further determine specific CA isoforms functions and changes in disease states are essential to the development of novel therapies for cerebrovascular pathology, occurring in both stroke and AD.

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“…Next, the cells were washed twice with PBS after the removal of the growth medium (10% FBS). New culture media containing the studied compounds at a concentration (5,10,25,25 ) μM were added to the cells followed by incubation for24, 48, and 72 h.…”

Section: Mtt Assaymentioning

confidence: 99%

“…The researchers try to nd new ways to design and synthesize new derivatives of heterocyclic compounds [7]. Sulfur-containing substances such as 1,3,4-thiadiazolines and thaiazolidinone have received great attention from medicinal chemists due to their biological activities and remarkable pharmacological properties and there are commercial drugs such as methazolamide acetazolamide and etozoline [8][9][10]. 1,3,4-thiadiazole and thaiazolidinone are the best heterocyclic compounds that have a wide spectrum of biological activity.…”

Section: Introductionmentioning

confidence: 99%

Anticancer, Antioxidant Activities and Molecular Docking Study of Thiazolidine -4-one and Thiadiazol Derivatives

Alsalim

Nasir

El‐Arabey

et al. 2022

Preprint

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Liver cancer accounts for a major portion of the global cancer burden. In many nations, the prevalence of this condition has risen in recent decades. New series of thaiazolidinones and thaiadiazolidine have been designed, synthesized, and evaluated for potential antioxidant and antihepatocarcinogenic activity. The antioxidant activity of synthesized compounds was evaluated using a DPPH assay. Furthermore, we examined the compounds against HepG2 cells using MTT assay, flow cytometry analysis through the cell cycle, reactive oxygen species, and apoptosis. The result showed that compound 6b has the highest antioxidant activity with IC50 =60.614±0.739 µM. The anticancer activity showed that compounds 5 and 6b have significant toxicity against liver cancer cells HepG2, IC50 values (9.082 and 4.712) µM, respectively. Flow cytometry experiments revealed that compound 5 arrested HepG2 cells in the S process, while compound 6b arrested HepG2 cells in the G1. Compound 6b had a greater reduction in reactive oxygen species and late apoptosis than compound 5. Substantially, compound 5 had affinity energies of -7.6 and -8.5 for Akt and CDK4 proteins, respectively, but compound 6b had affinity energies of -7.8 and -10.1 for Akt1 and CDK4 proteins, respectively. Consequently, compound 6b had lower binding energies than compound 5. In this work, we used multiple bioinformatics methods to shed light on the prospective therapeutic use of these series as novel candidates to target immune cells in the tumor microenvironment of hepatocellular carcinomas such as CD8+ T cells, endothelial cells, and hematopoietic stem cells. The results of antioxidant, anticancer, molecular docking studies, and bioinformatic analysis showed that compound 6b has a potential impact and could be developed for drug discovery with further research.

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Methazolamide in high-altitude illnesses

Cited by 26 publications

References 54 publications

Oxidative Stress and Diseases Associated with High-Altitude Exposure

Oxidative Stress and Diseases Associated with High-Altitude Exposure

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Anticancer, Antioxidant Activities and Molecular Docking Study of Thiazolidine -4-one and Thiadiazol Derivatives

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