Signaling Via the ERK Cascade in the Kainate Model of Limbic Epilepsy
Abstract number :
2.060
Submission category :
Year :
2001
Submission ID :
2839
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
A.E. Anderson, MD, Pediatrics, Baylor College of Medicine, Houston, TX; A.W. Varga, Neuroscience, Baylor of Medicine, Houston, TX; L.A. Schrader, Ph.D., Neuroscience, Baylor of Medicine, Houston, TX; J.P. Adams, Ph.D., Neuroscience, Baylor of Medicine, Ho
RATIONALE: We recently demonstrated ERK activation and ERK phosphorylation of the dendritic K+ channel, Kv4.2, in the kainate model of epilepsy. In this model we have shown that inhibition of ERK activation leads to a blockade of motor seizures and ERK activation and Kv4.2 phosphorylation. The current studies further characterize ERK activation and Kv4.2 phosphorylation in the kainate model.
METHODS: Seizures were induced in adult rats by kainate (KA)(15 mg/kg IP). Experimental and control animals received the MEK inhibitor, SL327 (100 or 400 mg/kg IP), or vehicle 30 min prior to KA. Seizure activity was scored using the Racine scale. After 1 hr of motor seizures (or 3 hr after KA) the animals were sacrificed and brain tissue was prepared for immunoblotting and immunohistochemistry.
RESULTS: Kainate-induced seizures elicited a significant increase in ERK activation (p[lt]0.001) and Kv4.2 phosphorylation by ERK (CA1 and CA3 p[lt]0.0001, den p[lt]0.001). SL327 significantly attenuated these biochemical effects and blocked motor seizures in a dose-dependent manner. Time course studies revealed significant ERK activation within 15-30 min after kainate, prior to onset of motor seizures, that persisted during the development of seizures. Significantly increased Kv4.2 phosphorylation was not seen until the seizures were evident. Immunohistochemistry demonstrated increased phospho-ERK and phospho-Kv4.2 in selective input regions within hippocampus. Confocal imaging is being used to evaluate co-localization of these phospho-isoforms. Preliminary biochemistry and immunohistochemistry studies revealed significantly increased ERK activation and Kv4.2 phosphorylation by ERK in the amygdala following kainate seizures.
CONCLUSIONS: Our results demonstrate significant ERK activation and Kv4.2 phosphorylation in several limbic structures known to be involved in the kainate model of epilepsy. Furthermore our data suggest that ERK signaling is essential for the expression of seizures in the kainate model of limbic epilepsy and one mechanism could be increased Kv4.2 phosphorylation and resultant altered membrane excitability.
Support: NIH.
Disclosure: Salary - James Tzraskos is employed by Dupont Pharmaceuticals from which one of the pharmaceutical compounds utilized in the current study was obtained.