scholarly journals Cell- and tIssue-specific effects of corticosteroids in relation to glucocorticoid resistance: examples from the brain

2003 ◽  
Vol 178 (1) ◽  
pp. 13-18 ◽  
Author(s):  
OC Meijer ◽  
AM Karssen ◽  
ER de Kloet
Keyword(s):  
Tissue Specificity ◽  
Glucocorticoid Resistance ◽  
Target Tissue ◽  
Efflux Transporter ◽  
Biological Mechanisms ◽  
Specific Effects ◽  
P Glycoprotein ◽  
Multiple Levels ◽  
The Brain ◽  
Response Specificity

The biological mechanisms that determine cell-specific responses to glucocorticoid hormones may overlap with those that are associated with acquired glucocorticoid resistance. Cell and tIssue specificity can be brought about in many different ways. Studies on the brain, an important glucocorticoid target tIssue, may provide examples of regulatory mechanisms underlying response specificity at multiple levels. In this commentary a number of such mechanisms are discussed, with emphasis on regulation of glucocorticoid bio-availability by the efflux transporter P-glycoprotein and on the variable presence of nuclear proteins which modulate or interfere with gluco- and mineralocorticoid receptor-mediated transcription.

Consciousness

2018 ◽  
Author(s):  
Anil K. Seth
Keyword(s):  
Conscious Experience ◽  
Real Problem ◽  
Active Inference ◽  
Biological Mechanisms ◽  
Specific Content ◽  
Brain Responses ◽  
Biomimetic Approach ◽  
Multiple Levels ◽  
In Virtue Of ◽  
The Brain

Consciousness is perhaps the most familiar aspect of our existence, yet we still do not know its biological basis. This chapter outlines a biomimetic approach to consciousness science, identifying three principles linking properties of conscious experience to potential biological mechanisms. First, conscious experiences generate large quantities of information in virtue of being simultaneously integrated and differentiated. Second, the brain continuously generates predictions about the world and self, which account for the specific content of conscious scenes. Third, the conscious self depends on active inference of self-related signals at multiple levels. Research following these principles helps move from establishing correlations between brain responses and consciousness towards explanations which account for phenomenological properties—addressing what can be called the “real problem” of consciousness. The picture that emerges is one in which consciousness, mind, and life, are tightly bound together—with implications for any possible future “conscious machines.”

scholarly journals PPAR-α, a lipid-sensing transcription factor, regulates blood–brain barrier efflux transporter expression

2016 ◽  
Vol 37 (4) ◽  
pp. 1199-1212 ◽  
Author(s):  
Vijay R More ◽  
Christopher R Campos ◽  
Rebecca A Evans ◽  
Keith D Oliver ◽  
Gary NY Chan ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Drug Efflux ◽  
Efflux Transporter ◽  
Transport Activity ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha ◽  
P Glycoprotein ◽  
Blood Brain ◽  
The Brain ◽  
Transporter Expression

Lipid sensor peroxisome proliferator-activated receptor alpha (PPAR- α) is the master regulator of lipid metabolism. Dietary release of endogenous free fatty acids, fibrates, and certain persistent environmental pollutants, e.g. perfluoroalkyl fire-fighting foam components, are peroxisome proliferator-activated receptor alpha ligands. Here, we define a role for peroxisome proliferator-activated receptor alpha in regulating the expression of three ATP-driven drug efflux transporters at the rat and mouse blood–brain barriers: P-glycoprotein (Abcb1), breast cancer resistance protein (Bcrp/Abcg2), and multidrug resistance-associated protein 2 (Mrp2/Abcc2). Exposing isolated rat brain capillaries to linoleic acid, clofibrate, or PKAs increased the transport activity and protein expression of the three ABC transporters. These effects were blocked by the PPAR- α antagonist, GW6471. Dosing rats with 20 mg/kg or 200 mg/kg of clofibrate decreased the brain accumulation of the P-glycoprotein substrate, verapamil, by 50% (in situ brain perfusion; effects blocked by GW6471) and increased P-glycoprotein expression and activity in capillaries ex vivo. Fasting C57Bl/6 wild-type mice for 24 h increased both serum lipids and brain capillary P-glycoprotein transport activity. Fasting did not alter P-glycoprotein activity in PPAR- α knockout mice. These results indicate that hyperlipidemia, lipid-lowering fibrates and exposure to certain fire-fighting foam components activate blood–brain barrier peroxisome proliferator-activated receptor alpha, increase drug efflux transporter expression and reduce drug delivery to the brain.

scholarly journals Frizzled Fissure to Improve Central Nervous System Drug Delivery?

2014 ◽  
Vol 34 (8) ◽  
pp. 1257-1257 ◽  
Author(s):  
Lester R Drewes
Keyword(s):  
Drug Delivery ◽  
Wnt Signaling ◽  
Drug Transport ◽  
Efflux Transporter ◽  
Neurologic Diseases ◽  
P Glycoprotein ◽  
Potential Strategy ◽  
And Function ◽  
Canonical Wnt ◽  
The Brain

Delivery of therapeutics to the brain is challenging because of efflux pumps located in the vascular endothelium. A detailed analysis of Wnt signaling in a human brain endothelial cell line indicates that expression and function of P-glycoprotein, a major efflux transporter, is controlled by non-canonical Wnt signaling. Inhibition of this pathway leads to downregulation of P-glycoprotein and increased transcellular drug transport and reveals a potential strategy for improving drug delivery for treatment of neurologic diseases.

THE ROLE OF THE POLYMORPHIC EFFLUX TRANSPORTER P-GLYCOPROTEIN ON THE BRAIN ACCUMULATION OF d-METHYLPHENIDATE AND d-AMPHETAMINE

2006 ◽  
Vol 34 (7) ◽  
pp. 1116-1121 ◽  
Author(s):  
Hao-Jie Zhu ◽  
Jun-Sheng Wang ◽  
C. Lindsay DeVane ◽  
Robin L. Williard ◽  
Jennifer L. Donovan ◽  
...  
Keyword(s):  
Efflux Transporter ◽  
P Glycoprotein ◽  
The Brain

scholarly journals The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone

2002 ◽  
Vol 175 (1) ◽  
pp. 251-260 ◽  
Author(s):  
AM Karssen ◽  
OC Meijer ◽  
IC van der Sandt ◽  
AG De Boer ◽  
EC De Lange ◽  
...  
Keyword(s):  
Efflux Transporter ◽  
Wild Type ◽  
Corticosteroid Receptors ◽  
P Glycoprotein ◽  
Human Mdr1 ◽  
The Brain ◽  
Synthetic Glucocorticoid

In the present study, we have investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in hampering the access of the synthetic glucocorticoid, prednisolone. In vivo, a tracer dose of [(3)H]prednisolone poorly penetrated the brain of adrenalectomised wild-type mice, but the uptake was more than threefold enhanced in the absence of Pgp expression in mdr1a (-/-) mice. In vitro, in stably transfected LLC-PK1 monolayers the human MDR1 P-glycoprotein was able to transport prednisolone present at a micromolar concentration. A specific Pgp blocker, LY 335979, could block this polar transport of [(3)H]prednisolone. Human Pgp does not transport all steroids, as cortexolone was not transported at all and aldosterone was only weakly transported. The ability of Pgp to export the synthetic glucocorticoid, prednisolone, suggests that uptake of prednisolone in the human brain is impaired, leading to a discrepancy between central and peripheral actions. Furthermore, the ensuing imbalance in activation of the two types of brain corticosteroid receptors may have consequences for cognitive performance and mood.

Evaluation of the Impact of P-Glycoprotein (P-gp) Drug Efflux Transporter Blockade on the Systemic and Ocular Disposition of P-gp Substrate

2008 ◽  
Vol 24 (3) ◽  
pp. 290-300 ◽  
Author(s):  
Srinivasan Senthilkumari ◽  
Thirumurthy Velpandian ◽  
Nihar R. Biswas ◽  
Narayanan Sonali ◽  
Supriyo Ghose
Keyword(s):  
Drug Efflux ◽  
Efflux Transporter ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
The Impact

scholarly journals P-Glycoprotein and Breast Cancer Resistance Protein Restrict Apical-to-Basolateral Permeability of Human Brain Endothelium to Amyloid-β

2009 ◽  
Vol 29 (6) ◽  
pp. 1079-1083 ◽  
Author(s):  
Leon M Tai ◽  
A Jane Loughlin ◽  
David K Male ◽  
Ignacio A Romero
Keyword(s):  
Breast Cancer ◽  
Human Brain ◽  
Breast Cancer Resistance Protein ◽  
Amyloid Β ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
The Brain

The clearance of amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease. Conflicting data exist regarding the contribution of adenosine triphosphatebinding cassette transporters to the clearance of Aβ through the blood-brain barrier. Therefore, we investigated whether Aβ could be a substrate for P-glycoprotein (P-gp) and/or for breast cancer resistance protein (BCRP) using a human brain endothelial cell line, hCMEC/D3. Inhibition of P-gp and BCRP increased apical-to-basolateral, but not basolateral-to-apical, permeability of hCMEC/D3 cells to 125l Aβ 1–40. Our in vitro data suggest that P-gp and BCRP might act to prevent the blood-borne Aβ 1–40 from entering the brain.

Depression and Inflammatory Markers in Veterans With Multiple Sclerosis

2021 ◽  
pp. 109980042110500
Author(s):  
Pamela Newland ◽  
Yelyzaveta Basan ◽  
Ling Chen ◽  
Gregory Wu
Keyword(s):  
Multiple Sclerosis ◽  
Inflammatory Markers ◽  
Pearson Correlation ◽  
Correlation Coefficients ◽  
The United States ◽  
Biological Mechanisms ◽  
The Central Nervous System ◽  
Brain And Spinal Cord ◽  
The Brain

Multiple sclerosis (MS), an inflammatory neurodegenerative disease of the central nervous system (CNS), afflicts over one per thousand people in the United States. The pathology of MS typically involves lesions in several regions, including the brain and spinal cord. The manifestation of MS is variable and carries great potential to negatively impact quality of life (QOL). Evidence that inflammatory markers are related to depression in MS is accumulating. However, there are barriers in precisely identifying the biological mechanisms underlying depression and inflammation. Analysis of cytokines provides one promising approach for understanding the mechanisms that may contribute to MS symptoms. Methods: In this pilot study, we measured salivary levels of interleukin (IL)-6, IL-1beta (β), and IL-10 in 24 veterans with MS. Descriptive statistics were reported and Pearson correlation coefficients were obtained between cytokines and depression. Results: The anti-inflammatory cytokine IL-10 was significantly negatively associated with depression in veterans with MS (r = −0.47, p = .024). Conclusion: Cytokines may be useful for elucidating biological mechanisms associated with the depression and a measure for nurses caring for veterans with MS.

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