BRAIN GALANIN RECEPTORS AND EPILEPSY
Principal Investigator: Andrey M Mazarati
Abstract: DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the mechanisms involved in inhibition of seizure activity by the neuropeptide galanin. Our lab was the first to show that seizures alter galanin in the hippocampus and that galanin has a profound seizure-protective effect in status epilepticus. The project has three goals. First, we will develop a novel approach to down-regulate galanin receptors in naive animals, in order to study the role of galanin receptors in seizures. This will be achieved by developing and optimizing peptide nucleic acid (PNA) antisense targeted against galanin receptor subtypes 1 and 2. The effects of PNA on galanin receptors will be examined by studying galanin receptor binding, immunocytochemistry, and Western blot in galanin receptor-transfected cell lines and primary neuronal cultures. Second we will test the hypothesis that down-regulation of galanin receptor subtypes in the brain selectively increases animals' predisposition to seizures, and increases seizure-related neuronal injury. We will examine the differences between naive and galanin receptor PNA-treated rats in the initiation and maintenance of seizure activity during self-sustaining status epilepticus, and will compare the degree of neuronal injury between control and PNA-treated rats. Third, we will study putative mechanisms that underlie seizure-protective effects of galanin receptor stimulation. Specifically, we will study how galanin receptor PNA treatment affects second messenger systems (cyclic adenosine monophosphate, phosphoinisitide turnover, mitogen-activated protein kinase activity, excitatory amino acid glutamate release) and will correlate these effects with the effects of PNA on status epilepicus. The proposed project will yield important data for understanding brain mechanisms that participate in endogenous suppression of seizures, and will justify the use of active ligands of galanin receptors as a new approach for the treatment of epilepsy.
Funding Period: 2002-12-01 - 2007-11-30
more information: NIH RePORT
- Galanin and epilepsyJ T Lerner
Department of Pediatrics, Neurology Division, D Geffen School of Medicine, University of California, Box 951752, 22 474 MDCC, Los Angeles, CA 90095 1752, USA
EXS 102:183-94. 2010....
- Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetineAndrey Mazarati
Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1752, USA
Brain 131:2071-83. 2008..The finding that behavioural equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways...
- Galanin and epilepsyJ T Lerner
Dept of Pediatrics, Neurology Division, D Geffen School of Medicine at the University of California, Los Angeles, Box 951752, 22 474 MDCC, Los Angeles, California 90095 1752, USA
Cell Mol Life Sci 65:1864-71. 2008....
- Inflammation modifies status epilepticus-induced hippocampal injury during developmentRaman Sankar
Department of Pediatrics, David Geffen School of Medicine and Mattel Children s Hospital at UCLA, Los Angeles, California 90095 1752, USA
Epilepsia 48:16-8. 2007
- Kindling epileptogenesis in immature rats leads to persistent depressive behaviorAndrey Mazarati
Department of Pediatrics, David Geffen School of Medicine at UCLA, Room 22 474 MDCC, Los Angeles, CA 90095 1752, USA
Epilepsy Behav 10:377-83. 2007..We conclude that neuronal plastic changes associated with the kindling state are accompanied by the development of depressive behavior...
- Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors: The effects of subtype-selective agonists and the role of G-protein-mediated signalingAndrey Mazarati
Department of Pediatrics, Division of Pediatric Neurology, D Geffen School of Medicine at UCLA, Box 951752, 22 474 MDCC, Los Angeles, CA 90095 1752, USA
J Pharmacol Exp Ther 318:700-8. 2006..The data are important for understanding endogenous mechanisms regulating epileptogenesis and for the development of novel antiepileptogenic drugs...
- Multiple interaction sites of galnon trigger its biological effectsAnders Floren
Department of Neurochemistry, Stockholm University, Sweden
Neuropeptides 39:547-58. 2005..We conclude that galnon has multiple sites of interaction within the GPCR signaling cascade which mediate its physiological effects...
- Homodimerization and internalization of galanin type 1 receptor in living CHO cellsSebastian A Wirz
Department of Neuropharmacology, Harold L Dorris Neurological Research Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Neuropeptides 39:535-46. 2005..Internalization and dimerization of GalR1 is shown, contributing to the regulation of galanergic signaling...
- In vivo interaction between serotonin and galanin receptors types 1 and 2 in the dorsal raphe: implication for limbic seizuresAndrey M Mazarati
Department of Pediatrics, Division of Pediatric Neurology, D Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
J Neurochem 95:1495-503. 2005....
- Regulation of limbic status epilepticus by hippocampal galanin type 1 and type 2 receptorsAndrey Mazarati
West Los Angeles VA Medical Center, Research 151, Los Angeles, CA 90073, USA
Neuropeptides 39:277-80. 2005..GalR1 and GalR2 exhibit differential effects on the initiation and the maintenance phases of SE. Activation of both galanin receptor subtypes exerts neuroprotective effects under conditions of excitotoxic injury...
- Distribution and differential regulation of galanin receptor subtypes in rat brain: effects of seizure activityXiaoying Lu
Department of Neuropharmacology, The Harold L Dorris Neurological Research Center, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Neuropeptides 39:147-52. 2005....
- Role of galanin receptor 1 and galanin receptor 2 activation in synaptic plasticity associated with 3',5'-cyclic AMP response element-binding protein phosphorylation in the dentate gyrus: studies with a galanin receptor 2 agonist and galanin receptor 1 knH Badie-Mahdavi
The Scripps Research Institute, Department of Neuropharmacology, The Harold L Dorris Neurological Research Center, La Jolla, CA 92037, USA
Neuroscience 133:591-604. 2005....