New anticonvulsant candidates prevent P-glycoprotein (P-gp) overexpression in a pharmacoresistant seizure model in mice

Enrique, Andrea; Ianni, Mauricio E. Di; Goicoechea, Sofía; Lazarowski, Alberto; Valle-Dorado, María Guadalupe; Costa, Juan José López; Rocha, Luísa; Girardi, Elena; Talevi, Alan

doi:10.1016/j.yebeh.2019.106451

Cited by 19 publications

(21 citation statements)

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“…Among numerous cellular functions that are likely influenced by the presence of Al or Hg are transport and function of intra‐, extra‐cellular charged proteins, amino acids and cationic‐anionic trace elements across membranes [eg, ATP/ADP/AMP, Na + /K + exchanger, Na + /H + exchanger, water channels, active/passive transport of solutes, osmolytes or nutrients (eg, myo‐inositol, pyridoxal phosphate, ascorbic acid)]. Overview and integration of fragmented data on vaccine‐related topics, vaccine injuries and inflammatory/immune disorders suggest that presence of non‐functional metals in vaccines create mini‐electronic shocks or ‘molecular sink holes’ and induce biological defects in mitochondria, membranes and chromosoms, damaging the regulations of biological activities in tissues including alterations of gut microbiome profiles and neuronal behaviors (Figures 1, 3–5) 1,5,14,36,59–67,87–193 (manuscript in preparation)] , .…”

Section: Vaccine Toxicities: Retardation Of Mitochondria and Immune Rmentioning

confidence: 99%

“…Under incomplete mitochondrial development and hypoxic conditions of placenta, organogenesis and angiogenesis of embryo‐fetus require proper architectural organization and functioning of trophoblast epithelium for providing and consuming appropriate and sufficient growth factors/hormones, nutrients, enzymes, trace elements (metals) and respective constituent or induced receptor molecules. Exposure of the embryo‐fetus to flu shot and incipient, could pose serious threats to survival and health of both mother and fetus including altered nutrients in organogenesis, transition of myoblasts to myotube development, ratios of constituent/induced receptors, as potential contributors in growth retardation or growth promotion, fetus abortion or impaired health of newborn, infant, toddler, that also influence immunity during adulthood and aging process 1,5,8,20,24,27‐85,87‐125,129,192 (manuscript in preparation)] (Figures 1, 3 and 4).…”

Section: Vaccine Toxicities: Retardation Of Mitochondria and Immune Response Profiles Seeds Of Immune Destruction And Induction Of Mild Mmentioning

confidence: 99%

“…Integration of the scattered data on epidemiological, environmental, clinical and basic research on developmental biology, inflammatory diseases, cancer and vaccine sciences, treatment options are outlined below 1‐14,17,24,50,71,82,86,93,119,120,128,136,150‐153,155,156,176,177,182‐185,203‐207,209‐218,220 , , , :…”

Section: Twentieth Century Medicine: Shifting Disease Categories To Increase Induced Diseases In Young and Old: Wealth Transfer From The mentioning

confidence: 99%

“…As shown below, pathogen‐specific vaccines (eg, polio, swine flu, hepatitis a, b, c, MMRs, meningitis, shingles, anthrax, pertussis, HPV, SARS, Ebola, Zika, or ‘covid‐19’) and incipient weaken/destroy the complex electrobiology of immunity and Not Promote It ! 1,5,8,11,17,20,27–178 …”

Section: Author's Summary Of Accidental Discoveries‐multistep Immune Dysfunction: Setting Stage For Vaccine‐induced Injuriesmentioning

confidence: 99%

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Retracted: Deceptology in cancer and vaccine sciences: Seeds of immune destruction‐mini electric shocks in mitochondria: Neuroplasticity‐electrobiology of response profiles and increased induced diseases in four generations – A hypothesis

Khatami

2020

Clinical & Translational Med

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Schematic representation of cause, exacerbation and consequence of vaccinesinduced diverse immune disorders in immune-responsive or immune-privileged tissues. It depicts that vaccination of the unborn, alter biology of trophoblastembryo-fetus-placenta and orderly growth and development affecting epithelialmesenchymal transition, proper expression of constituent-inducible receptor molecules; consequently influence immunity of newborn, infant, children and adults. Vaccine-induced impaired organ development and immunity include impaired mitochondrial function (mitophagy), tissue bioenergetics, loss of balance in Yin (tumoricidal) and Yang (tumorigenic) pathways and altered metabolic-neuronal-hormonal activities as bases for increased induced diseases in young and old.

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Section: Vaccine Toxicities: Retardation Of Mitochondria and Immune Rmentioning

confidence: 99%

Section: Vaccine Toxicities: Retardation Of Mitochondria and Immune Response Profiles Seeds Of Immune Destruction And Induction Of Mild Mmentioning

confidence: 99%

Section: Twentieth Century Medicine: Shifting Disease Categories To Increase Induced Diseases In Young and Old: Wealth Transfer From The mentioning

confidence: 99%

Section: Author's Summary Of Accidental Discoveries‐multistep Immune Dysfunction: Setting Stage For Vaccine‐induced Injuriesmentioning

confidence: 99%

See 2 more Smart Citations

Retracted: Deceptology in cancer and vaccine sciences: Seeds of immune destruction‐mini electric shocks in mitochondria: Neuroplasticity‐electrobiology of response profiles and increased induced diseases in four generations – A hypothesis

Khatami

2020

Clinical & Translational Med

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“…Enrique et al, 2019). La inhibición de la Pgp puede realizarse de manera directa o bien, vía modulación del receptor de NMDA y mediante la acción de la ciclooxigenasa 2 (COX-2) (Kambli et al, 2017).Además de los anteriores, existen otros cuantos mecanismos implicados en el origen de las crisis y su progresión a la epilepsia, que podrían explorarse aún con mayor detalle con el propósito de descubrir nuevos agentes terapéuticos.…”

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Tamizado virtual aplicado a la búsqueda de nuevos fármacos antiepilépticos activos en el modelo de 6 Hz

Goicoechea¹

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La Epilepsia es uno de los desórdenes neurológicos más comunes, afectando a alrededor de 50 millones de personas en todo el mundo sin distinguir raza, sexo, edad y/o clase social. Esta enfermedad está caracterizada por crisis recurrentes y espontáneas provocadas por una actividad neuronal excesiva. Pese a los múltiples esfuerzos por encontrar nuevos tratamientos para esta patología existe un 30% de pacientes que no logra controlar las convulsiones con la farmacoterapia disponible, lo cual se conoce como epilepsia refractaria o intratable. Esta proporción de pacientes refractarios no se ha modificado a pesar de la considerable introducción en el mercado farmacéutico de numerosos fármacos antiepilépticos (FAEs) de última generación. Con el propósito de buscar nuevos candidatos a fármacos que demuestren protección frente a distintos tipos de crisis epilépticas, el Instituto Nacional de Salud de los Estados Unidos (National Institute of Health, NIH) ha modificado en los últimos tiempos el Programa de Screening de Fármacos Anticonvulsivos, reincorporando al modelo animal de crisis epiléptica de 6 Hz para ser utilizado en el screening primario de nuevos FAEs. A través de este modelo animal se ha identificado al fármaco de uso clínico levetiracetam, el cual está asociado a un mecanismo de acción novedoso. En el presente trabajo de tesis se propone realizar una búsqueda racional mediante tamizado virtual de nuevos compuestos activos frente al modelo de 6 Hz en ratones. Se ha realizado una campaña de tamizado virtual a partir del desarrollo de modelos computacionales basados en el ligando con capacidad de identificar compuestos candidatos con actividad anticonvulsiva frente el modelo animal en cuestión. Los modelos clasificatorios individuales han sido combinados y aplicados sobre las bases de datos DrugBank y SweetLead, revelando 57 fármacos que podrían poseer la actividad deseada. A partir de ello, se han adquirido 3 compuestos para ser evaluados durante la validación experimental frente al modelo de crisis epiléptica de 6 Hz. Como resultado, uno de los candidatos demostró poseer actividad anticonvulsiva, mientras que un segundo candidato demostró una leve tendencia a proteger frente a las crisis provocadas en el modelo animal. Los resultados obtenidos demuestran que las estrategias computacionales basadas en el ligando y aplicadas durante este trabajo de tesis, como el cribado virtual y el reposicionamiento de fármacos asistido por computadoras, han sido particularmente útiles para abordar de manera sistemática la búsqueda de nuevos usos terapéuticos de fármacos ya existentes. Asimismo, se ha destacado la importancia de aplicar estas metodologías escasamente exploradas y explotadas en el campo de la epilepsia.

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Transporter hypothesis in pharmacoresistant epilepsies. Is it at the central or peripheral level?

2021

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The multidrug-resistance (MDR) phenotype is typically observed in patients with refractory epilepsy (RE) whose seizures are not controlled despite receiving several combinations of more than two antiseizure medications (ASMs) directed against different ion channels or neurotransmitter receptors. Since the use of bromide in 1860, more than 20 ASMs have been developed; however, historically ~30% of cases of RE with MDR phenotype remains unchanged. Irrespective of metabolic biotransformation, the biodistribution of ASMs and their metabolites depends on the functional expression of some ATP-binding cassette transporters (ABC-t) in different organs, such as the blood-brain barrier (BBB), bowel, liver, and kidney, among others. ABC-t, such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP-1), and breast cancer-resistance protein (BCRP), are mainly expressed in excretory organs and play a critical role in the pharmacokinetics (PK) of all drugs. The transporter hypothesis can explain pharmacoresistance to a broad spectrum of ASMs, even when administered simultaneously. Since ABC-t expression can be induced by hypoxia, inflammation, or seizures, a high frequency of uncontrolled seizures increases the risk of RE.These stimuli can induce ABC-t expression in excretory organs and in previously non-expressing (electrically responsive) cells, such as neurons or cardiomyocytes. In this regard, an alternative mechanism to the classical pumping function of P-gp indicates that P-gp activity can also produce a significant reduction in resting membrane potential (ΔΨ0 = −60 to −10 mV). P-gp expression in neurons and cardiomyocytes can produce membrane depolarization and participate in epileptogenesis, heart failure, and sudden unexpected death in epilepsy. On this basis, ABC-t play a peripheral role in controlling the PK of ASMs and their access to the brain and act at a central level, favoring neuronal depolarization by mechanisms independent of ion channels or neurotransmitters that current ASMs cannot control.

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New anticonvulsant candidates prevent P-glycoprotein (P-gp) overexpression in a pharmacoresistant seizure model in mice

Cited by 19 publications

References 51 publications

Retracted: Deceptology in cancer and vaccine sciences: Seeds of immune destruction‐mini electric shocks in mitochondria: Neuroplasticity‐electrobiology of response profiles and increased induced diseases in four generations – A hypothesis

Retracted: Deceptology in cancer and vaccine sciences: Seeds of immune destruction‐mini electric shocks in mitochondria: Neuroplasticity‐electrobiology of response profiles and increased induced diseases in four generations – A hypothesis

Tamizado virtual aplicado a la búsqueda de nuevos fármacos antiepilépticos activos en el modelo de 6 Hz

Transporter hypothesis in pharmacoresistant epilepsies. Is it at the central or peripheral level?

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