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JCI online early table of contents: April 18, 2011

Move over Prozac: new drug offers hope for depression

An estimated 19 million Americans suffer from depression, and though the symptoms might be recognizable, the brain chemistry that underlies them is incompletely understood. Research suggests that aberrant signaling by a chemical called Brain-Derived Neurotrophic Factor (BDNF) through its receptor TrkB, may contribute to anxiety and depression, and inhibiting this pathway in mice can reduce anxiety and depression-related behaviors. However, translating these findings to clinical studies will require the development of small molecule inhibitors of the BDNF/TrkB pathway that could be used pharmacologically. In this paper, researchers led by Maxime Cazorla, of Columbia University in New York, and Didier Rognan, of the Universit de Strasbourg in France, describe a screen for stable small molecules that could specifically inhibit TrkB action. They identified one they dubbed ANA-12, which had potent behavioral effects when administered to mice that suggest it will have antidepressant and anti-anxiety activity in humans. The researchers are hopeful that this new compound could be used to develop a new class of psychiatric drugs.

Identification of a lowmolecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice

Maxime Cazorla
Columbia University College of Physicians and Surgeons, New York, NY, USA
Phone: 1-212-342-3114; Fax: ; E-mail:
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Why the immune system attacks beta cells in type 1 diabetes

Type 1 diabetes (T1D) most often results from an autoimmune attack on the insulin-producing beta cells of the pancreatic islets. In searching for a genetic cause of the disease, scientists have identified multiple areas in the genome that confer susceptibility. One of these is linked to the gene Prss16, which encodes a protease called TSSP expressed in the thymus, where the T cells of the immune system mature. In this paper, Sylvie Guerder and colleagues, at the INSERM in Toulouse, France, investigated the role of TSSP in diabetes by crossing mice that do not make the protein to a T1D mouse model. They found that the loss of TSSP protected mice from developing diabetes, in part because immune cells were no longer processed in a way that made them recognize pancreatic islets. Thus TSSP is likely required for the selection of T cells that target islets. The researchers believe that this work helps explain what goes wrong in the immune system of some T1D patients, and may lead to new therapeutic strategies.

Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice

Centre de Physiopathologie de Toulouse Purpan- INSERM U563, TOULOUSE, FRANCE
Phone: 33-(0)562748376; Fax: ; E-mail:
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Understanding atherosclerotic plaque regression

Atherosclerosis is a disease marked by the buildup of fatty plaques in the blood vessel walls; the recruitment of monocytes into these plaques is thought to contribute to the progression of this chronic inflammatory condition. Medical and dietary strategies that lower plasma lipid content can cause plaques to regress, and this regression is associated with decreased monocyte infiltration. It is not clear how plaques become more stable in patients taking cholesterol-lowering drugs; if the mechanisms were better understood, scientists might be able to identify therapeutics that enhance these natural processes and improve clinical outcome.

In new research, Gwendalyn J. Randolph and colleagues, of the Mount Sinai School of Medicine in New York, New York, examined the action of macrophages in regressing plaques using a mouse model in which they could rapidly reduce cholesterol levels. They found that falling cholesterol led to plaque regression and a reduction in plaque macrophage content. Surprisingly, the decrease in plaque macrophages was related to decreased infiltration of these cells, rather than an active exit of them. The researchers believe that these findings suggest that therapies that prevent macrophage recruitment into plaques could augment the efficacy of lipid-lowering medications.

Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe/ mice during disease regression

Gwendalyn Randolph
Mt Sinai Med Ctr, New York, NY, USA
Phone: 212 659-8262; Fax: 212 803 6740; E-mail:
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Could a liver cell transplant cure lung disease?

An enzyme produced by the liver, α anti-trypsin (AAT), is a critical inactivator of proteins that can degrade lung tissue. Mutations in the gene that encodes AAT can result in a defective form of the protein called AATZ; all individuals who inherit this mutation develop emphysema, and some also suffer from liver disease. One therapeutic strategy is to supply patients with normal AAT protein, but this is prohibitively expensive, and notably does not ameliorate the liver damage associated with the disease.

In new research, a team led by Jayanta Roy-Chowdhury, of Albert Einstein College of Medicine, in the Bronx, New York, and Ira Fox, of the University of Pittsburgh Medical Center, in Pittsburgh, Pennsylvania, aimed to treat AAT deficiency in mice by transplanting liver cells (hepatocytes) that generated normal AAT protein into the livers of mice that expressed AATZ. They found that the transplanted hepatocytes grew well in the livers of AATZ mice, and caused some of the liver cells in the host mice to die. The researchers believe that this method is promising for the treatment of humans with AAT deficiency.

Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes

Jayanta Roy-Chowdhury
Albert Einstein College Of Medicine, Bronx, NY, USA
Phone: 718-430-2265; Fax: ; E-mail:
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Ion channel involved in epileptic seizures identified

Epilepsy is a seizure disorder caused by the generation of aberrant electrical activity within the brain. In animal models of the disease, seizures can be induced by the administration of drugs that activate the M1 muscarinic acetylcholine receptors, however, how this process is dysregulated in epileptic patients is not completely understood. Pannexin 1 (Panx1) is a membrane channel that allows the passage of ions and other molecules between the cytoplasm and extracellular space. Panx1 can be opened at resting membrane potential via a receptor called P2X7. The opening of Panx1 has been linked to neuronal cell death and aberrant firing, and thus could be a therapeutic target in the treatment of neurological disorders including epilepsy.

In this paper, Ji-Eun Kim and Tae-Cheon Kang of Hallym University, in Chunchon, South Korea, found that mice lacking the P2X7 receptor had increased susceptibility to seizures induced by an M1 agonist. The researchers believe that this is important evidence that P2X7-Panx1 complex plays an important role in vivo in negatively regulating M1-mediated seizures.

The P2X7 receptorpannexin-1 complex decreases muscarinic acetylcholine receptormediated seizure susceptibility in mice

Tae-Cheon Kang
Dept. of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon, KOREA
Phone: 82-33-248-2524; Fax: ; E-mail:
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Uncovering a role for the heart covering

Heart attacks, or myocardial infarctions (MIs), are a major cause of morbidity and mortality, and occur when the blood vessels that supply the heart are blocked. During an MI, the muscle cells of the heart (cardiomyocytes) are injured and die in response to the lack of blood supply. Although these cells are capable of regeneration, the damage that occurs with MI is often too severe for this response to be adequate. Substantial research is therefore aimed at identifying methods to improve the regeneration response of cardiomyocytes.

In this paper, a team led by William Pu, at Children's Hospital in Boston, Massachusetts, studied whether the epicardium, the layer of epithelial cells that lies over the heart, could affect the regeneration response. They found that epicardial cells proliferated after MI, though they did not turn into cardiomyocytes. Importantly, they also found that epicardial cells release molecules that reduce the damage and improve heart function in a mouse model of MI. The researchers hope that identifying these molecules could lead to new therapeutic strategies for MI patients.

Adult mouse epicardium modulates myocardial injury by secreting paracrine factors

William Pu
Children's Hospital, Boston, MA, USA
Phone: 617-919-2091; Fax: ; E-mail:
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Therapy for ischemic retinopathy could take a new direction

Ischemic retinopathy, which is a degeneration of the retina due to loss of blood flow, is one of the leading causes of blindness. In this condition, the lack of oxygen that follows the ischemia drives an overgrowth of blood vessels, but these do not alleviate the lack of oxygen and can cause hemorrhaging or retinal detachment. Treatment strategies for ischemic retinopathy include pharmacological inhibition of vessel growth, but an alternative might be to direct and control growth in a way that would restore normal blood supply to the retina.

In this paper, Akiyoshi Uemura and colleagues, of Kobe University Graduate School of Medicine in Kobe, Japan, hypothesized that the signals that direct normal vascular development in the retina might help counteract the disordered growth that occurs after ischemic injury. They found that during development of the retina in mouse, a neuron-derived protein called Sema3E signals through a receptor called PlexinD1 to direct normal blood vessel organization, and injecting Sema3E into the eyes of adult mice improved revascularization of eyes after injury. The researchers are hopeful that these findings will be useful in the development of new therapies for this common disorder.

Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice

Akiyoshi Uemura
RIKEN Center for Developmental Biology, Kobe, JAPAN
Phone: 81-78-306-1924; Fax: 81-78-306-1895; E-mail:
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Contact: Kathryn Claiborn
Journal of Clinical Investigation

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