Abstract-Embryonic stem (ES) cells have been established as permanent lines of undifferentiated pluripotent cells fromearly mouse embryos. ES cells provide a unique system for the genetic manipulation and the creation of knockout strains of mice through gene targeting. By cultivation in vitro as 3D aggregates called embryoid bodies, ES cells can differentiate into derivatives of all 3 primary germ layers, including cardiomyocytes. Protocols for the in vitro differentiation of ES cells into cardiomyocytes representing all specialized cell types of the heart, such as atrial-like, ventricular-like, sinus nodal-like, and Purkinje-like cells, have been established. During differentiation, cardiac-specific genes as well as proteins, receptors, and ion channels are expressed in a developmental continuum, which closely recapitulates the developmental pattern of early cardiogenesis. Exploitation of ES cell-derived cardiomyocytes has facilitated the analysis of early cardiac development and has permitted in vitro "gain-of-function" or "loss-of-function" genetic studies. Recently, human ES cell lines have been established that can be used to investigate cardiac development and the function of human heart cells and to determine the basic strategies of regenerative cell therapy. This review summarizes the current state of ES cell-derived cardiogenesis and provides an overview of how genomic strategies coupled with this in vitro differentiation system can be applied to cardiac research. Key Words: embryonic stem Ⅲ embryonic carcinoma Ⅲ embryonic germ Ⅲ in vitro differentiation Ⅲ cardiomyocytes S tem cell biology has been the subject of much recent discussion, but only the totipotent fertilized oocyte and blastomere cells of embryos at the 2-to 8-cell stage are capable of generating a fully viable organism. Stem cells from the embryo are derived from the inner cell mass (ICM), embryonic ectoderm, and primordial germ cells of the fetal genital ridge and represent pluripotent undifferentiated cells capable of proliferation, self-renewal, and the generation of large numbers of differentiated cell progeny; however, embryonic stem (ES) cells do not normally generate tissues of the trophoblast, precluding normal generation of a viable entity. 1 As development proceeds and a stem cell becomes committed to a specific lineage or decreases its proliferative potential, it is usually described as a progenitor cell. Progen-

Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic peptide secreted from the gastrointestinal tract in response to food intake. It enhances pancreatic islet ␤-cell proliferation and glucosedependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus (T2DM). diabetes ͉ exendin-4 ͉ neurodegeneration ͉ neuroprotection ͉ stroke

Type 2 (T2) diabetes mellitus (DM) has been associated with an increased incidence of neurodegenerative disorders, including Alzheimer's disease (AD). Several pathological features are shared between diabetes and AD, including dysfunctional insulin signaling and a dysregulation of glucose metabolism. It has therefore been suggested that not only may the two conditions share specific molecular mechanisms but also that agents with proven efficacy in one may be useful against the other. Hence, the present study characterized the effects of a clinically approved long-acting analogue, exendin-4 (Ex-4), of the endogenous insulin releasing incretin, glucagon-like peptide-1 (GLP-1), on stress-induced toxicity in neuronal cultures and on amyloid-beta protein (Abeta) and tau levels in triple transgenic AD (3xTg-AD) mice with and without streptozocin (STZ)-induced diabetes. Ex-4 ameliorated the toxicity of Abeta and oxidative challenge in primary neuronal cultures and human SH-SY5Y cells in a concentration-dependent manner. When 11 to 12.5 month old female 3xTg AD mice were challenged with STZ or saline, and thereafter treated with a continuous subcutaneous infusion of Ex-4 or vehicle, Ex-4 ameliorated the diabetic effects of STZ in 3xTg-AD mice, elevating plasma insulin and lowering both plasma glucose and hemoglobin A1c (HbA1c) levels. Furthermore, brain levels of Abeta protein precursor and Abeta, which were elevated in STZ 3xTg-AD mice, were significantly reduced in Ex-4 treated mice. Brain tau levels were unaffected following STZ challenge, but showed a trend toward elevation that was absent following Ex-4 treatment. Together, these results suggest a potential value of Ex-4 in AD, particularly when associated with T2DM or glucose intolerance.

Like type-2 diabetes mellitus (T2DM), neurodegenerative disorders and stroke are an ever increasing, health, social and economic burden for developed Westernized countries. Age is an important risk factor in all of these; due to the rapidly increasing rise in the elderly population T2DM and neurodegenerative disorders, both represent a looming threat to healthcare systems. Whereas several efficacious drugs are currently available to ameliorate T2DM, effective treatments to counteract pathogenic processes of neurodegenerative disorders are lacking and represent a major scientific and pharmaceutical challenge. Epidemiological data indicate an association between T2DM and most major neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Likewise, there is an association between T2DM and stroke incidence. Studies have revealed that common pathophysiological features, including oxidative stress, insulin resistance, abnormal protein processing and cognitive decline, occur across these. Based on the presence of shared mechanisms and signalling pathways in these seemingly distinct diseases, one could hypothesize that an effective treatment for one disorder could prove beneficial in the others. Glucagon-like peptide-1 (GLP-1)-based anti-diabetic drugs have drawn particular attention as an effective new strategy to not only regulate blood glucose but also to reduce apoptotic cell death of pancreatic beta cells in T2DM. Evidence supports a neurotrophic and neuroprotective role of GLP-1 receptor (R) stimulation in an increasing array of cellular and animal neurodegeneration models as well as in neurogenesis. Herein, we review the physiological role of GLP-1 in the nervous system, focused towards the potential benefit of GLP-1R stimulation as an immediately translatable treatment strategy for acute and chronic neurological disorders. AbbreviationsAb, amyloid-b; AD, Alzheimer's disease; APP, amyloid-b precursor protein; ALS, amyotrophic lateral sclerosis; BDNF, brain-derived neurotrophic factor; BrdU, bromodeoxyuridine; CNTF, ciliary neurotrophic factor; DCX, doublecortin; DOPAC, 3,4-dihydroxyphenylacetic acid; DPP-IV, dipedylpeptidase-IV; ERG, electroretinogram; Ex-4, exendin-4; GIP, gastric inhibitor peptide; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; HVA; homovanillic acid; HD, Huntington's disease; LTP, long term potentiation; MCAo, middle cerebral artery occlusion; MPTP, 1-methyl-4-phenyl-1,2,3,4,6-tetrahydroxypyridine; MPP + , 1-methyl-4-phenylpyridinum ion; NGF, nerve growth factor; 6-OHDA, 6-hydroxydopamine; PD, Parkinson's disease; RA, retinoic acid; VMAT2, vesicle monoamine transporter 2 BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2012 1586 British Journal of Pharmacology (2012) 166 1586-1599Published 2012. This article is a U.S. Government work and is in the public domain in the USA. IntroductionNeurodegenerative and cerebrovascular disorders are an ever increasing, health, social and economic burden for developed Westernized count...