Drug resistance in brain diseases and the role of drug efflux transporters

Löscher, Wolfgang; Potschka, Heidrun

doi:10.1038/nrn1728

Cited by 787 publications

(651 citation statements)

References 137 publications

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“…This divergence might be related to the P-glycoprotein, a drug efflux transporter located in the blood-brain barrier (BBB). P-glycoprotein was shown to reduce the concentration of PB in the brain, hence leading to loss of efficacy (Loscher and Potschka, 2005) and its expression is 3 folds higher in the rat brain as compared to marmosets and humans (Hoshi et al, 2013). The comparable BBB permeability between humans and marmosets (Hoshi et al, 2013) seems to consist another advantage to accurately forecast the efficacy of AEDs in humans when using these animals for testing.…”

Section: Discussionmentioning

confidence: 99%

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment

et al. 2016

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a b s t r a c tThe efficiency of most of the new antiepileptic drugs (AEDs) on clinical trials still falls short the success reported in pre-clinical studies, possibly because the validity of the animal models is insufficient to fully represent the human pathology. To improve the translational value for testing AEDs, we propose the use of non-human primates. Here, we suggest that triggering limbic seizures with low doses of PTZ in pilocarpine-treated marmosets might provide a more effective basis for the development of AED. Marmosets with epileptic background were more susceptible to seizures induced by PTZ, which were at least 3 times longer and more severe (about 6 times greater frequency of generalized seizures) in comparison to naïve peers. Accordingly, PTZ-induced seizures were remarkably less attenuated by AEDs in epileptic than naïve marmosets. While phenobarbital (40 mg/kg) virtually abolished seizures regardless of the animal's background, carbamazepine (120 mg/kg) and valproic acid (400 mg/kg) could not prevent PTZinduced seizures in epileptic animals with the same efficiency as observed in naïve peers. VPA was less effective regarding the duration of individual seizures in epileptic animals, as assessed in ECoG (p = 0.05). Similarly following CBZ treatment, the behavioral manifestation of generalized seizures lasted longer in epileptic (p < 0.05), which were also more frequent than in the naïve group (p < 0.05). As expected, epileptic marmosets experiencing stronger seizures showed more NPY-and FosB-immunostained neurons in a number of brain areas associated with the generation and spread of limbic seizures. Our results suggest that PTZ induced seizures over an already existing epileptic background constitutes a reliable and controllable mean for the screening of new AEDs.

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Section: Discussionmentioning

confidence: 99%

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment

et al. 2016

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“…Tight regulation of the BBB is required to allow nutrient and oxygen passage, while preventing access to circulating toxins, ions, amino acids and xenobiotics. The BBB endothelial cells are characterized by a lack of fenestrations, decreased pinocytosis and the presence of tight junctional proteins, multiple transport systems and enzymatic detoxification enzymes Loscher and Potschka, 2005). Each of these characteristics serves to maintain the homeostatic environment of the CNS, as well as limit the entry of many therapeutic substances into the brain (Pardridge, 1997).…”

Section: Introductionmentioning

confidence: 99%

Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain

et al. 2006

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The blood-brain barrier (BBB) is a dynamic system which maintains brain homeostasis and limits CNS penetration via interactions of transmembrane and intracellular proteins. Inflammatory pain (IP) is a condition underlying several diseases with known BBB perturbations, including stroke, Parkinson's, multiple sclerosis and Alzheimer's. Exploring the underlying pathology of chronic IP, we demonstrated alterations in BBB paracellular permeability with correlating changes in tight junction (TJ) proteins: occludin and claudin-5. The present study examines the IP-induced molecular changes leading to a loss in functional BBB integrity. IP was induced by injection of Complete Freund's Adjuvant (CFA) into the plantar surface of the right hindpaw of female Sprague-Dawley rats. Inflammation and hyperalgesia were confirmed, and BBB paracellular permeability was assessed by in situ brain perfusion of [ 14 C]sucrose (paracellular diffusion marker). The permeability of the BBB was significantly increased at 24 and 72 h post-CFA. Analysis of the TJ proteins, which control the paracellular pathway, demonstrated decreased claudin-5 expression at 24 h, and an increase at 48 and 72 h post-injection. Occludin expression was significantly decreased 72 h post-CFA. Expression of junction adhesion molecule-1 (JAM-1) increased 48 h and decreased by 72 h post-CFA. Confocal microscopy demonstrated continuous expression of both occludin and JAM-1, each co-localizing with ZO-1. The increased claudin-5 expression was not limited to the junction. These results provide evidence that chronic IP causes dramatic alterations in specific cytoarchitectural proteins and demonstrate alterations in molecular properties during CFA, resulting in significant changes in BBB paracellular permeability.

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“…It has been suggested that P-gp overexpression at the BBB lead to therapeutic failure of AEDs by several studies using rodent epilepsy models and human epileptic tissue [96, 97]. Adding a P-gp inhibitor to the anti-epileptic treatment regimens has been shown to reverse the drug-resistant phenotype [98].…”

Section: Roles Of Immune and Inflammation In Drementioning

confidence: 99%

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

Líu²,

Qin³

2013

Current Neuropharmacology

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Until recently, epilepsy medical therapy is usually limited to anti-epileptic drugs (AEDs). However, approximately 1/3 of epilepsy patients, described as drug-resistant epilepsy (DRE) patients, still suffer from continuous frequent seizures despite receiving adequate AEDs treatment of sufficient duration. More recently, with the remarkable progress of immunology, immunity and inflammation are considered to be key elements of the pathobiology of epilepsy. Activation of inflammatory processes in brain tissue has been observed in both experimental seizure animal models and epilepsy patients. Anti-inflammatory and immunotherapies also showed significant anticonvulsant properties both in clinical and in experimental settings. The above emerging evidence indicates that modulation of immunity and inflammatory processes could serve as novel specific targets to achieve potential anticonvulsant effects for the patients with epilepsy, especially DRE. Herein we review the recent evidence supporting the role of inflammation in the development and perpetuation of seizures, and also discuss the recent achievements in modulation of inflammation and immunotherapy applied to the treatment of epilepsy. Apart from medical therapy, we also discuss the influences of surgery, ketogenic diet, and electroconvulsive therapy on immunity and inflammation in DRE patients. Taken together, a promising perspective is suggested for future immunomodulatory therapies in the treatment of patients with DRE.

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Drug resistance in brain diseases and the role of drug efflux transporters

Cited by 787 publications

References 137 publications

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment

Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

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