Review of the mechanism underlying mefloquine-induced neurotoxicity

Martins, Airton C.; Paoliello, Mônica Maria Bastos; Docea, Anca Oana; Santamarı́a, Abel; Tinkov, Alexey A.; Skalny, Anatoly V.; Aschner, Michael

doi:10.1080/10408444.2021.1901258

Cited by 13 publications

(9 citation statements)

References 62 publications

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“…Interestingly, molecular mechanisms of MQ‐associated calcium dysregulation and ER‐directed toxicity have been explored before in the context of MQ‐induced neurotoxic symptoms observed in malaria patients, representing a well‐documented adverse effect of this antimalarial intervention 44,45,50–52 . This adverse drug action has been attributed to specific molecular interactions including: (i) noncompetitive acetylcholine esterase inhibition, (ii) interaction with voltage‐dependent channels, and (iii) ER‐associated Ca‐ATPase (SERCA) antagonism (mimicking activity of the SERCA‐antagonist thapsigargin), all of which might be causing cytosolic overload and dysregulation of calcium homeostasis 44,52–54 . Indeed, ER stress and calcium dysregulation have been identified as critical factors in signal transduction and determination of cancer cell fate, connecting ER, mitochondrial, and lysosomal stress signaling with therapeutic efficacy, a topic with emerging relevance to melanomagenesis and therapy 55–60 .…”

Section: Discussionmentioning

confidence: 99%

Mefloquine induces ER stress and apoptosis in BRAFi‐resistant A375‐BRAF^V600E/NRAS^Q61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model

Jandova

Park

Corenblum

et al. 2022

Molecular Carcinogenesis

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Molecularly targeted therapeutics have revolutionized the treatment of BRAFV600E‐driven malignant melanoma, but the rapid development of resistance to BRAF kinase inhibitors (BRAFi) presents a significant obstacle. The use of clinical antimalarials for the investigational treatment of malignant melanoma has shown only moderate promise, attributed mostly to inhibition of lysosomal‐autophagic adaptations of cancer cells, but identification of specific antimalarials displaying single‐agent antimelanoma activity has remained elusive. Here, we have screened a focused library of clinically used artemisinin‐combination therapeutic (ACT) antimalarials for the apoptotic elimination of cultured malignant melanoma cell lines, also examining feasibility of overcoming BRAFi‐resistance comparing isogenic melanoma cells that differ only by NRAS mutational status (BRAFi‐sensitive A375‐BRAFV600E/NRASQ61 vs. BRAFi‐resistant A375‐BRAFV600E/NRASQ61K). Among ACT antimalarials tested, mefloquine (MQ) was the only apoptogenic agent causing melanoma cell death at low micromolar concentrations. Comparative gene expression‐array analysis (A375‐BRAFV600E/NRASQ61 vs. A375‐BRAFV600E/NRASQ61K) revealed that MQ is a dual inducer of endoplasmic reticulum (ER) and redox stress responses that precede MQ‐induced loss of viability. ER‐trackerTM DPX fluorescence imaging and electron microscopy indicated ER swelling, accompanied by rapid induction of ER stress signaling (phospho‐eIF2α, XBP‐1s, ATF4). Fluo‐4 AM‐fluorescence indicated the occurrence of cytosolic calcium overload observable within seconds of MQ exposure. In a bioluminescent murine model employing intracranial injection of A375‐Luc2 (BRAFV600E/NRASQ61K) cells, an oral MQ regimen efficiently antagonized brain tumor growth. Taken together, these data suggest that the clinical antimalarial MQ may be a valid candidate for drug repurposing aiming at chemotherapeutic elimination of malignant melanoma cells, even if metastasized to the brain and BRAFi‐resistant.

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Section: Discussionmentioning

confidence: 99%

Mefloquine induces ER stress and apoptosis in BRAFi‐resistant A375‐BRAF^V600E/NRAS^Q61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model

Jandova

Park

Corenblum

et al. 2022

Molecular Carcinogenesis

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“…The mechanism behind these neurological and psychiatric effects is not completely known but the mechanisms implicated include: cholinesterases inhibition, non-receptor tyrosine kinase 2 (Pyk2 and/or interaction with adenosine A (2A) receptors ( Lee et al., 2017 ). Some studies have also shown mefloquine to cause GABAergic interneuron dysfunction, inhibition of cellular transport and depression of cortical activity ( Martins et al., 2021 ).…”

Section: Possible Mechanisms Of Neurotoxicitymentioning

confidence: 99%

Mefloquine as a prophylaxis for malaria needs to be revisited

Ahmad¹,

Rahi²,

Ranjan³

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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According to WHO, 2019 witnessed 229 million cases of malaria globally, of which Africa accounted for 94% of cases. Early diagnosis and treatment are the basis of malaria management, and the need for good chemoprophylaxis especially for people travelling to endemic areas is vital. There are a number of drug options available for the prophylaxis of malaria, mefloquine being one of the drugs used. Mefloquine has been around from the 1970s, and was developed in the United States keeping in mind the soldiers that were being deployed to areas where chloroquine resistant strains of Plasmodium were discovered. Mefloquine was preferred for its once a week dosage. Within a decade of its introduction, reports of the side effects associated with its long-term use surfaced. Mefloquine is now reported to cause a myriad of neuropsychiatric side effects including anxiety, sleep disturbance, depression, dizziness and frank psychosis, especially in patients with pre-existing psychiatric disorders. Many countries like the United States and the United Kingdom have updated their drug boxes to include the warning of these potential neuropsychiatric effects. This paper reviews the side effects of mefloquine and why there is a need to revisit its use in Indian drug policy.

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“…Interestingly, small molecules such as MFQ, fatty acids like arachidonic acid, carbenoxolone, and n-alkanol were known to block Cx36 GJC 1,18,19 . Among them, MFQ, an FDA-approved antimalarial compound, is used for the prevention or treatment of mild and moderate malaria 20 , with neuropsychiatric side effects 14,18,21 . Later, it was discovered that MFQ specifically blocks Cx36 GJC, contributing to these side effects, such as spreading depression, NMDAR-mediated neuronal death, tremor, motor deficits, convulsant, stage IV seizures, cell death upon oxygenglucose deprivation, and hypersensitivity to pain [22][23][24][25][26][27][28][29] .…”

Section: Introductionmentioning

confidence: 99%

Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer

Cho,

Lee

2023

Preprint

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Connexin 36 (Cx36) forms interneuronal gap junctions, establishing electrical synapses for rapid synaptic transmission. In disease conditions, inhibiting Cx36 gap junction channels (GJCs) is beneficial, as it prevents abnormal synchronous neuronal firing and apoptotic signal propagation, mitigating seizures and progressive cell death. Here, we present cryo-electron microscopy structures of human Cx36 GJC in complex with known channel inhibitors, such as mefloquine, arachidonic acid, and 1-hexanol. Notably, these inhibitors competitively bind to the binding pocket of the N-terminal helices (NTH), inducing a conformational shift from the pore-lining NTH (PLN) state to the flexible NTH (FN) state. This leads to the obstruction of the channel pore by flat double-layer densities of lipids. These studies elucidate the molecular mechanisms of how Cx36 GJC can be modulated by inhibitors, providing valuable insights into potential therapeutic applications.

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Review of the mechanism underlying mefloquine-induced neurotoxicity

Cited by 13 publications

References 62 publications

Mefloquine induces ER stress and apoptosis in BRAFi‐resistant A375‐BRAF^V600E/NRAS^Q61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model

Mefloquine induces ER stress and apoptosis in BRAFi‐resistant A375‐BRAF^V600E/NRAS^Q61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model

Mefloquine as a prophylaxis for malaria needs to be revisited

Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer

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Review of the mechanism underlying mefloquine-induced neurotoxicity

Cited by 13 publications

References 62 publications

Mefloquine induces ER stress and apoptosis in BRAFi‐resistant A375‐BRAFV600E/NRASQ61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model

Mefloquine induces ER stress and apoptosis in BRAFi‐resistant A375‐BRAFV600E/NRASQ61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model

Mefloquine as a prophylaxis for malaria needs to be revisited

Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer

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Mefloquine induces ER stress and apoptosis in BRAFi‐resistant A375‐BRAF^V600E/NRAS^Q61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model

Mefloquine induces ER stress and apoptosis in BRAFi‐resistant A375‐BRAF^V600E/NRAS^Q61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model