EXCEED THE SPACE PROVIDED. 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 targtered 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. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS043409-04
Application #
7074456
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Stewart, Randall R
Project Start
2002-12-01
Project End
2006-11-30
Budget Start
2005-07-01
Budget End
2005-11-30
Support Year
4
Fiscal Year
2005
Total Cost
$165,793
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Mazarati, Andrey; Siddarth, Prabha; Baldwin, Roger A et al. (2008) Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine. Brain 131:2071-83
Lerner, J T; Sankar, R; Mazarati, A M (2008) Galanin and epilepsy. Cell Mol Life Sci 65:1864-71
Mazarati, Andrey; Shin, Don; Auvin, Stephane et al. (2007) Kindling epileptogenesis in immature rats leads to persistent depressive behavior. Epilepsy Behav 10:377-83
Sankar, Raman; Auvin, Stephane; Shin, Don et al. (2007) Inflammation modifies status epilepticus-induced hippocampal injury during development. Epilepsia 48 Suppl 8:16-8
Mazarati, Andrey; Lundstrom, Linda; Sollenberg, Ulla et al. (2006) 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 signaling. J Pharmacol Exp Ther 318:700-8
Mazarati, Andrey; Lu, Xiaoying (2005) Regulation of limbic status epilepticus by hippocampal galanin type 1 and type 2 receptors. Neuropeptides 39:277-80
Wirz, Sebastian A; Davis, Christopher N; Lu, Xiaoying et al. (2005) Homodimerization and internalization of galanin type 1 receptor in living CHO cells. Neuropeptides 39:535-46
Mazarati, Andrey M; Baldwin, Roger A; Shinmei, Steve et al. (2005) In vivo interaction between serotonin and galanin receptors types 1 and 2 in the dorsal raphe: implication for limbic seizures. J Neurochem 95:1495-503
Badie-Mahdavi, H; Lu, X; Behrens, M M et al. (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 kn Neuroscience 133:591-604

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