P-Glycoprotein—a Clinical Target in Drug-Refractory Epilepsy?

Robey, Robert W.; Lazarowski, Alberto; Bates, Susan E.

doi:10.1124/mol.108.046680

Cited by 53 publications

(29 citation statements)

References 38 publications

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“…1). As a consequence of this continuous and late remaining HIF-1a activation, with an overexpression of MDR-1, we speculate that MDR-1 overexpression could be an impairment factor for the access of neuroprotective drugs to their targets as previously was suggested (Lazarowski et al 2007a, b;Robey et al 2008).…”

Section: Discussionmentioning

confidence: 75%

Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl2 in Rats

Merelli

Caltana

Girimonti³

et al. 2010

Neurotox Res

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Stroke is a major human health problem inducing long-term disability without any efficient therapeutic option being currently available. Under hypoxia, hypoxia-inducible factor-1α (HIF-1α) activates several genes as erythropoietin receptor (Epo-R) related with O(2) supply, and the multidrug-resistance gene (MDR-1) related with drug-refractory phenotype. Brain cortical injection of CoCl(2) produces focal hypoxia-like lesion with neuronal and glial alterations, as well as HIF-1α stabilization and MDR-1 overexpression. Intranasal (IN) drug delivery can by-pass blood-brain barrier (BBB) where MDR-1 is normally expressed. We evaluated the effects of IN-rHu-Epo administration on spontaneous motor activity (SMA) and the brain pattern expression of HIF-1α, MDR-1, and Epo-R in our cobalt-induced hypoxia model. Adult male Wistar rats were injected by stereotaxic surgery in frontoparietal cortex, with CoCl(2) (2 μl-50 mM; n = 20) or saline (controls; n = 20). Ten rats of each group were treated with IN-rHu-Epo 24 U or IN-saline. In addition, erythropoietic stimulation was evaluated by reticulocytes (Ret) account during three consecutive days, after intraperitoneal (i.p.)-recombinant-human Epo (rHu-Epo) (950 U; n = 6) or IN-rHu-Epo (24 U; n = 6) administration. SMA was evaluated by open field and rotarod tests, before and after surgical procedures during five consecutive days. Histological and immunostaining studies of HIF-1α, MDR-1, and Epo-R were performed on brain slides. A significant difference in SMA was observed in the hypoxic rats of IN-rHu-Epo-administered group as compared with Co-Saline-treated subjects and controls (p < 0.001). HIF-1α, EPO-R, and MDR-1 were overexpressed in the hypoxic cortex areas, while in contralateral hemisphere or controls, they were negatives. Reticulocytes were only increased in intraperitoneal (i.p.)-rHu-Epo-administered group. In spite of MDR-1 overexpression being detected in neurons, the coexpression of Epo-R could explain the positive effects observed on SMA of IN-rHu-Epo-administered group.

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Section: Discussionmentioning

confidence: 75%

Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl2 in Rats

Merelli

Caltana

Girimonti³

et al. 2010

Neurotox Res

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“…For example, changes have been observed in sodium channels and voltage-dependent calcium channels, as well as Gamma-aminobutyric acid-A (GABA-A) receptors, leading to reduced efficacy of various antiepileptic drugs. These alterations in the structure and/or functionality of the drug target of antiepileptic drugs in the brain can be intrinsic (genetic) and acquired (disease-related) [82,88,92,95]. …”

Section: Role Of Oxidative Stress In Refractory Epilepsymentioning

confidence: 99%

Role of Oxidative Stress in Refractory Epilepsy: Evidence in Patients and Experimental Models

Cárdenas-Rodríguez¹,

Huerta-Gertrudis²,

Rivera-Espinosa

et al. 2013

IJMS

124

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Oxidative stress, a state of imbalance in the production of reactive oxygen species and nitrogen, is induced by a wide variety of factors. This biochemical state is associated with systemic diseases, and diseases affecting the central nervous system. Epilepsy is a chronic neurological disorder with refractoriness to drug therapy at about 30%. Currently, experimental evidence supports the involvement of oxidative stress in seizures, in the process of their generation, and in the mechanisms associated with refractoriness to drug therapy. Hence, the aim of this review is to present information in order to facilitate the handling of this evidence and determine the therapeutic impact of the biochemical status for this pathology.

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“…However, these drugs may induce significant side effects that restrict their clinical application . Experimental evidence also supports that a better control of drug‐resistant epilepsy could be obtained if antiseizure drugs are associated with P‐glycoprotein inhibitors …”

Section: Cannabidiol May Act On Unconventional Central and Peripheralmentioning

confidence: 99%

“…P‐glycoprotein overexpression in cells of the BBB can also result from chronic oxidative stress or prolonged neuroinflammation . According to several experimental evidence, the administration of inhibitors of P‐glycoprotein function or expression represents a potential therapeutic strategy to control drug‐resistant epilepsy . Concerning this issue, the use of celecoxib, a specific COX‐2 inhibitor, reverts the P‐glycoprotein overexpression and facilitates brain delivery of antiseizure drugs in animals with epilepsy .…”

Section: Cannabidiol May Act On Unconventional Central and Peripheralmentioning

confidence: 99%

Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

Rocha¹,

Frías‐Soria²,

Ortíz

et al. 2020

Epilepsia Open

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Cannabis has been considered as a therapeutic strategy to control intractable epilepsy. Several cannabis components, especially cannabidiol (CBD), induce antiseizure effects. However, additional information is necessary to identify the types of epilepsies that can be controlled by these components and the mechanisms involved in these effects. This review presents a summary of the discussion carried out during the 2nd Latin American Workshop on Neurobiology of Epilepsy entitled “Cannabinoid and epilepsy: myths and realities.” This event was carried out during the 10th Latin American Epilepsy Congress in San José de Costa Rica (September 28, 2018). The review focuses to discuss the use of CBD as a new therapeutic strategy to control drug‐resistant epilepsy. It also indicates the necessity to consider the evaluation of unconventional targets such as P‐glycoprotein, to explain the effects of CBD in drug‐resistant epilepsy.

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P-Glycoprotein—a Clinical Target in Drug-Refractory Epilepsy?

Abstract: ABSTRACT

Cited by 53 publications

References 38 publications

Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl2 in Rats

Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl2 in Rats

Role of Oxidative Stress in Refractory Epilepsy: Evidence in Patients and Experimental Models

Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

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