Altered P-Glycoprotein Expression in AIDS Patients with HIV Encephalitis

Langford, Dianne; Grigorian, Aline; Rosemary, Hurford; Adame, Anthony; Ellis, Ronald J.; Hansen, Lawrence A.; Masliah, Eliezer

doi:10.1093/jnen/63.10.1038

Cited by 87 publications

(81 citation statements)

References 54 publications

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“…However, a comparison of cell systems and membrane assays have been recently described and as far as these studies are concerned it results that all compounds positive in the ATPase membrane assay are also potential substrates (Adachi et al, 2001;Polli et al, 2001). It has been proposed that the expression pattern of P-gp has a key role in the pathogenesis of brain diseases such as Alzheimer's disease (Vogelgesang et al, 2002), Parkinson's disease (Kortekaas et al, 2005) and brain HIV infection (Langford et al, 2004). ALS would seem to be no exception, although a more detailed analysis on the expression of P-gp and other drug efflux transporters in ALS mice and in human specimens would need to be undertaken.…”

Section: Discussionmentioning

confidence: 99%

Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: Therapeutic implications for amyotrophic lateral sclerosis

Boston-Howes¹,

Williams²,

Bogush³

et al. 2008

Experimental Neurology

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Synaptic accumulation of glutamate causes neuronal death in many neurodegenerative pathologies such as amyotrophic lateral sclerosis. Drugs capable of increasing glutamate uptake could therefore be therapeutically effective. We screened in a cell-based assay a library of 1040 FDA-approved drugs and nutrients for compounds that could enhance glutamate uptake. Nordihydroguaiaretic acid (NDGA), an anti-inflammatory drug that inhibits lipoxygensases, potently enhanced glutamate uptake in MN-1 cells. Given subcutaneously at 1 mg/day for 30 days in mice, NDGA increased glutamate uptake in spinal cord synaptosomes persistently throughout the treatment. However, when administered following the same regimen to the SOD1-G93A transgenic mouse model of ALS at disease onset, NDGA did not extend survival of these mice. We found that NDGA failed to sustain increased glutamate uptake in the SOD1-G93A mice despite an initial upregulation measured during the first 10 days of treatment. SOD1-G93A mice displayed a progressive increase in spinal cord expression levels of the efflux transporter P-glycoprotein beginning at disease onset. This increase was not a specific consequence of the NDGA treatment as we have measured it in untreated SOD1-G93A mice. Because P-glycoproteins control the extrusion of a broad range of toxins and xenobiotics and are responsible for drug resistance in many diseases including cancer and brain diseases such as epilepsy, we propose that the failure of NDGA in maintaining glutamate uptake upregulated in SOD1-G93A mice and its therapeutic inefficacy are due to acquired pharmacoresistance mediated by the increased expression of P-glycoprotein.

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Section: Discussionmentioning

confidence: 99%

Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: Therapeutic implications for amyotrophic lateral sclerosis

Boston-Howes¹,

Williams²,

Bogush³

et al. 2008

Experimental Neurology

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“…Decreased expression or transport function for BBB MDR1 was reported for AD [71], Creutzfeldt-Jakob disease [72], PD [73], HIV infection [74] and aging. In addition, reports suggest that glial cells also contribute to an altered distribution of therapeutic compounds in the CNS by acting as a 'secondary barrier' contributing to the drug resistance phenomenon [74][75][76].…”

Section: Relevance Of P450 and Mdt To Other Cns Disordersmentioning

confidence: 96%

“…In addition, reports suggest that glial cells also contribute to an altered distribution of therapeutic compounds in the CNS by acting as a 'secondary barrier' contributing to the drug resistance phenomenon [74][75][76]. It has been proposed that a cascade of neurovascular events alters BBB function and fuels dis ease progression in AD [77].…”

Section: Relevance Of P450 and Mdt To Other Cns Disordersmentioning

confidence: 99%

Blood-Brain Barrier P450 Enzymes and Multidrug Transporters in Drug Resistance: A Synergistic Role in Neurological Diseases

Ghosh¹

2011

CDM

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Drug penetration into the central nervous system (CNS) is controlled by the blood-brain barrier (BBB). Even though a number of strategies to circumvent the BBB and to improve drug access have been developed, drug resistance in CNS diseases remains an unmet clinical problem. We here review the mechanisms by which a healthy or pathological BBB influences drug distribution in the brain, with emphasis on the role of P450 metabolic enzymes and multi-drug transporter (MDT) proteins. In addition to the classic hepatic and gut biotransformation pathways, CNS expression of P450 enzymes may bear pharmacokinetic and pharmacodynamic significance exerting a metabolic activity and transforming parent drugs into specific products. We propose these mechanisms to play a major role in CNS drug resistant pathologies including refractory forms of epilepsy.Changes in the cerebrovascular hemodynamic conditions can affect expression of P450 enzymes and MDT proteins. This should be taken into account when developing in vitro experimental approaches to reproduce the physiological or pathological properties of the BBB. Finally, a link between P450 and MDT expression in the diseased brain and cell survival is discussed. KeywordsBlood-brain barrier; drug resistant epilepsy; multidrug transporters proteins (MDT); P450 enzymes THE BLOOD-BRAIN BARRIER: A BRIEF OVERVIEWThe brain microvascular endothelial cells that constitute the blood-brain barrier (BBB) are responsible for the passage of xenobiotics and nutrients from the blood into the brain parenchyma, and vice versa. At the cellular level, the BBB consists of endothelial cells HHS Public Access DRUG RESISTANCE IN CNS DISEASESDrug resistance in brain diseases is an unsolved clinical problem. For example, drug resistant epilepsy affects approximately 20-25% of epileptics. According to the recent consensus of the International League Against Epilepsy (ILAE), "drug resistant epilepsy is defined with the failure of adequate trials of two appropriately chosen antiepileptic drugs, whether as monotherapies or in combination, to achieve sustained seizure freedom" [7]. In the past two decades, new antiepileptic drugs (AEDs) have been developed but no major reduction in the percentage of drug-resistant patients has been achieved [8,9]. The complexity of the drug resistant epileptic phenotype reflects the nature of the pathophysiological process, its possible evolution over time and individual sensitivity to drugs. In order to explain the mechanisms underlying the drug resistant condition, a pharmacokinetic and a pharmacodynamic hypothesis were proposed more than a decade ago. AED therapeutic failure may thus be due to a modification of neuronal targets (pharmacodynamic hypothesis) [10][11][12][13] or to inadequate AED brain levels (pharmacokinetic hypothesis). Overexpression of multidrug transporter (MDTs) proteins at the BBB was considered to be a mechanism responsible for the possible AED brain misdistribution [11,[14][15][16][17][18]: overexpression of multi-drug transporters at the BBB...

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“…Different tissues in the central nervous system (CNS) can harbor distinct viral populations (1,8,20,27,32,35,38,41,42,46,51,54,57,61,62,63,64,68,69,70). Samples of viral populations are collected either by examining brain tissue from infected individuals post mortem or by drawing samples from the cerebrospinal fluid (CSF) in HIV-positive patients.…”

mentioning

confidence: 99%

Comparative Study of Methods for Detecting Sequence Compartmentalization in Human Immunodeficiency Virus Type 1

Zárate

Pond

Shapshak

et al. 2007

J Virol

119

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Human immunodeficiency virus (HIV) infects different organs and tissues. During these infection events, subpopulations of HIV type 1 (HIV-1) develop and, if viral trafficking is restricted between subpopulations, the viruses can follow independent evolutionary histories, i.e., become compartmentalized. This phenomenon is usually detected via comparative sequence analysis and has been reported for viruses isolated from the central nervous system (CNS) and the genital tract. Several approaches have been proposed to study the compartmentalization of HIV sequences, but to date, no rigorous comparison of the most commonly employed methods has been made. In this study, we systematically compared inferences made by six different methods for detecting compartmentalization based on three data sets: (i) a sample of 45 patients with sequences gathered from the CNS, (ii) sequences from the female genital tract of 18 patients, and (iii) a set of simulated sequences. We found that different methods often reached contradictory conclusions. Methods based on the topology of a phylogenetic tree derived from clonal sequences were generally more sensitive in detecting compartmentalization than those that relied solely upon pairwise genetic distances between sequences. However, as the branching structure in a phylogenetic tree is often uncertain, especially for short, low-diversity, or recombinant sequences, tree-based approaches may need to be modified to take phylogenetic uncertainty into account. Given the frequently discordant predictions of different methods and the strengths and weaknesses of each particular methodology, we recommend that a suite of several approaches be used for reliable inference of compartmentalized population structure.

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Altered P-Glycoprotein Expression in AIDS Patients with HIV Encephalitis

Cited by 87 publications

References 54 publications

Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: Therapeutic implications for amyotrophic lateral sclerosis

Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: Therapeutic implications for amyotrophic lateral sclerosis

Blood-Brain Barrier P450 Enzymes and Multidrug Transporters in Drug Resistance: A Synergistic Role in Neurological Diseases

Comparative Study of Methods for Detecting Sequence Compartmentalization in Human Immunodeficiency Virus Type 1

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