ABSTRACT
We investigated the effects of exendin-4 on neural stem/progenitor cells in the subventricular zone of the adult rodent brain and its functional effects in an animal model of Parkinson's disease. Our results showed expression of GLP-1 receptor mRNA or protein in the subventricular zone and cultured neural stem/progenitor cells isolated from this region. In vitro, exendin-4 increased the number of neural stem/progenitor cells, and the number of cells expressing the neuronal markers microtubule-associated protein 2, beta-III-tubulin, and neuron-specific enolase. When exendin-4 was given intraperitoneally to naïve rodents together with bromodeoxyuridine, a marker for DNA synthesis, both the number of bromodeoxyuridine-positive cells and the number of neuronal precursor cells expressing doublecortin were increased. Exendin-4 was tested in the 6-hydroxydopamine model of Parkinson's disease to investigate its possible functional effects in an animal model with neuronal loss. After unilateral lesion and a 5-week stabilization period, the rats were treated for 3 weeks with exendin-4. We found a reduction of amphetamine-induced rotations in animals receiving exendin-4 that persisted for several weeks after drug administration had been terminated. Histological analysis showed that exendin-4 significantly increased the number of both tyrosine hydroxylase- and vesicular monoamine transporter 2-positive neurons in the substantia nigra. In conclusion, our results show that exendin-4 is able to promote adult neurogenesis in vitro and in vivo, normalize dopamine imbalance, and increase the number of cells positive for markers of dopaminergic neurons in the substantia nigra in a model of Parkinson's disease.
Subject(s)
Hypoglycemic Agents/pharmacology , Neurons/drug effects , Parkinsonian Disorders/drug therapy , Peptides/pharmacology , Recovery of Function/drug effects , Venoms/pharmacology , Animals , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Doublecortin Protein , Exenatide , Glucagon-Like Peptide-1 Receptor , Immunohistochemistry , Mice , Motor Activity/drug effects , Neurons/cytology , Neurons/metabolism , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/pathology , Rats , Receptors, Glucagon/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Stem Cells/cytology , Stem Cells/drug effects , Stem Cells/metabolism , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Substantia Nigra/pathologyABSTRACT
In recent years, it has become evident that neural stem cells in the adult mammalian brain continuously generate new neurons, mainly in the hippocampus and olfactory bulb. Although different growth factors have been shown to stimulate neurogenesis in the adult brain, very little is known about the role of neuropeptides in this process. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with pleiotropic effects acting through three receptors to which it has high affinity, namely, PACAP receptor 1 (PAC1), vasoactive intestinal peptide (VIP) receptor 1, and VIP receptor 2. We show that PAC1 is expressed in the neurogenic regions of the adult mouse brain, namely the ventricular zone of the lateral ventricle and the hippocampal dentate gyrus. Cultured neural stem cells isolated from the lateral ventricle wall of adult mice express PAC1 and proliferate in vitro in response to two PAC1 agonists, PACAP and Maxadilan, but not VIP at physiologic concentrations, indicating PAC1 as a mediator of neural stem cell proliferation. Pharmacologic and biochemical characterization of PACAP-induced neural stem cell proliferation revealed the protein kinase C pathway as the principal signaling pathway, whereas addition of epidermal growth factor synergistically enhanced the proliferating effect of PACAP. Further in vitro characterization of the effect of PACAP on neural stem cells showed PACAP capable of stimulating ex novo in vitro formation of multipotent neurospheres with the capacity to generate both neuronal and glial cells. Finally, intracerebroventricular infusion of PACAP increases cell proliferation in the ventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. We conclude that PACAP, through PAC1, is a potent mediator of adult neural stem cell proliferation.
Subject(s)
Brain/physiology , Cell Differentiation/drug effects , Neurons/drug effects , Neuropeptides/pharmacology , Stem Cells/drug effects , Adenosine Triphosphate/metabolism , Animals , Brain/cytology , Bromodeoxyuridine/metabolism , Cells, Cultured , Dose-Response Relationship, Drug , Drug Interactions , Enzyme Inhibitors/pharmacology , Epidermal Growth Factor/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Immunohistochemistry/methods , In Situ Hybridization/methods , In Vitro Techniques , Insect Proteins/pharmacology , Intracellular Space/drug effects , Intracellular Space/metabolism , Lactate Dehydrogenases/metabolism , Lateral Ventricles/cytology , Lateral Ventricles/drug effects , Lateral Ventricles/metabolism , Mice , Neurons/physiology , Pituitary Adenylate Cyclase-Activating Polypeptide , RNA, Messenger/biosynthesis , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide , Receptors, Pituitary Hormone/genetics , Receptors, Pituitary Hormone/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , Stem Cells/cytology , Thymidine/metabolism , Vasoactive Intestinal Peptide/pharmacologyABSTRACT
A series of 5-substituted 2-benzoylaminobenzoic acids has been synthesized and assayed for PPARalpha/gamma activity. Both dual activators and selective PPARgamma agonists have been identified. This class of compounds was shown to activate the PPARgamma receptor through interaction with a novel binding site.
