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Environmental Factor, November 2012

Intramural papers of the month

By Nisha Cavanaugh, Anshul Pandya, and Darshini Trivedi

New treatment allows medicines to cross blood-brain barrier

A new study by NIEHS researchers has identified a signaling pathway that reduces the transport activity of P-glycoprotein, an ATP-driven drug efflux pump in rat brain capillaries known to be a major obstacle to delivering medicines to the brain. The work may lead to new treatments for brain and spinal cord injury, brain cancer, and epilepsy in humans.

The research team used a confocal microscopy-based assay to identify a signaling pathway that abolished P-glycoprotein transport activity without changing transporter protein expression. In brain capillaries, this pathway uses sphingosine-1-phosphate (S1P) and its receptor, sphingosine-1-phosphate receptor 1 (S1PR1), to rapidly and reversibly reduce P-glycoprotein activity. The investigators used fingolimod, a drug used clinically to treat multiple sclerosis, to stimulate the S1PR1 signaling pathway in the blood-brain barrier, which turned off P-glycoprotein.

These findings were validated in vivo and led the researchers to conclude that signaling through S1PR1 can reduce P-glycoprotein activity and allow small molecule pharmaceuticals to safely cross the blood-brain barrier. (AP)

CitationCannon RE, Peart JC, Hawkins BT, Campos CR, Miller DS. (http://www.ncbi.nlm.nih.gov/pubmed/22949658)  2012. Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. Proc Natl Acad Sci U S A 109(39):15930-15935.

Neuromodulators may affect learning and memory

Scientists at NIEHS may have found a novel mechanism by which neuromodulators, such as acetylcholine (ACh), could enhance synaptic plasticity. Synaptic plasticity is the strengthening or weakening of synapses, and is a fundamental neurological mechanism that is thought to underlie learning and memory. This work helps scientists better understand how the brain processes and integrates higher brain functions.

Previous studies by the research group demonstrated that stimulation of the alpha7 nicotinic ACh receptors (nAChRs) can induce two forms of synaptic plasticity, long-term potentiation (LTP) and short-term depression (STD). In the current study, team members utilized a novel coculture, system comprised of septal tissue and hippocampus, to specifically express alpha7 nAChRs to either presynaptic or postsynaptic sites, or both, in alpha7 nAChR-deficient tissue, and dissect out the different roles of the alpha7 nAChRs in inducing LTP and STD.

The investigators found that coordination between both presynaptic and postsynaptic activities is required for the induction of alpha7 nAChR-dependent synaptic plasticity. Furthermore, the use of dual-colored genetically encoded calcium indicators indicated that the time course of presynaptic and postsynaptic changes during LTP or STD were different, suggesting that there are independent presynaptic and postsynaptic modulations during plasticity. (DT)

CitationGu Z, Lamb PW, Yakel JL. (http://www.ncbi.nlm.nih.gov/pubmed/22956824)  2012. Cholinergic coordination of presynaptic and postsynaptic activity induces timing-dependent hippocampal synaptic plasticity. J Neurosci 32(36):12337-12348.

Inverse relationship between allergy and heart attack

In a recently published article, NIEHS researchers reported that people who have allergies, also known as atopy, are less likely to have experienced a heart attack. The study was based on laboratory data and questionnaires from the National Health and Nutrition Examination Survey (NHANES) 2005-2006, a cross-sectional analysis of the U.S. population. It is the first analysis of the relation between atopy, as indicated by serum allergen-specific IgE (sIgE) antibody, and previous myocardial infarction (MI).

Previous work in mice found that those born with a Th1-biased immune program developed atherosclerosis and other inflammatory diseases, while mice displaying a Th2 bias generally developed allergies and were protected from atherosclerosis. To determine what was happening in humans, the researchers measured sIgEs that were specific to 19 allergens, and found that individuals with a history of MI also had lower sIgE antibody levels and were less likely to have a positive sIgE test or hay fever. Detailed statistical analysis found that house dust mite was the only allergen for which sIgE was associated with a reduced chance of suffering an MI. These results, if confirmed in prospective studies, may have important clinical implications for how allergen sensitization affects people’s risk for heart attack. (AP)

CitationJaramillo R, Cohn RD, Crockett PW, Gowdy KM, Zeldin DC, Fessler MB. (http://www.ncbi.nlm.nih.gov/pubmed/22921873)  2012. Relation between objective measures of atopy and myocardial infarction in the United States. J Allergy Clin Immunol; doi:10.1016/j.jaci.2012.06.033 [Online 23 August 2012].

Low-level p53 expression reveals supertransactivating response element sequences

Published in a recent issue of Proceedings of the National Academy of Sciences, NIEHS researchers provide a new understanding of how the transcription factor p53, a highly relevant tumor suppressor, interacts with its target sequences over a wide range of cellular p53 levels. In addition, they reveal new supertransactivating DNA sequences that are highly responsive at very low amounts of p53.

The researchers employed their previously developed yeast-based model system to examine cellular transcriptional activation from various target sequences in a constant chromatin environment in response to level of p53. These features were then compared to in vitro characteristics and interactions with p53. Transactivation at higher levels of p53 follows thermodynamic binding properties. However, transactivation at low levels correlates with the torsional flexibility of the targets.

Surprisingly, they identified two supertransactivating sequences, Con-A and GGG, that supported high transactivation at very low p53 expression. These had the kinetic properties of high flexibility and also low off rate for p53. They found that Con-A could potentially serve as a diagnostic tool for functionality of p53 mutations, including those associated with breast cancer that they identified in an earlier study. (NC)

CitationJordan JJ, Menendez D, Sharav J, Bono I, Rosenthal K, Resnick MA, Haran TE. (http://www.ncbi.nlm.nih.gov/pubmed/22908277)  2012. Low-level p53 expression changes transactivation rules and reveals superactivating sequences. Proc Natl Acad Sci U S A 109(36):14387-14392.

(Nisha Cavanaugh, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Structural Biology. Anshul Pandya, Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Laboratory of Neurobiology. Darshini Trivedi, Ph.D., is an IRTA fellow in the NIEHS Laboratory of Toxicology and Pharmacology.)



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