Elucidating the role of Glygocen synthase kinase-3 in epilepsy.
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1
Vrije Universiteit Brussel, Depart. of Pharmaceutical Chemistry and Drug Analysis, Belgium
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2
Katholieke Universiteit Leuven, Laboratory for Pharmaceutical Biology, Belgium
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3
Katholieke Universiteit Leuven, Experimental Genetics Group - LEGTEGG, Belgium
Glycogen synthase kinase-3 (GSK-3) was initially discovered as controlling enzyme of glycogen metabolism. Today, GSK-3 is widely recognized as a key component in a surprisingly large number of cellular processes. Overactivity of GSK-3 has been implicated in the origin or development of human diseases such as diabetes, Alzheimer's disease, Parkinson's disease and bipolar disorders. Within the field of epilepsy, the effect on seizures and on epileptic symptoms of directly targeting GSK-3 has not been studied so far. In the present study we used the corneal 6-Hz mouse model to investigate the effect of BIO-acetoxime and TCS2002, two selective and potent GSK-3 inhibitors on electrically induced seizures. Our results showed that both compounds exert potent anticonvulsant effects in the acute 6-Hz mouse model. Secondly, we showed that BIO-acetoxime, the most potent inhibitor, significantly reduced the seizure severity of 6-Hz corneally kindled mice in a dose dependent manner. Finally, by using the same 6-Hz kindling model, we compared the differences in seizure susceptibility of mice with GSK-3 neuron-specific overexpression (GSK-3 OE) relative to wildtype mice (WT). Our results showed that, although GSK-3 OE mice were more rapidly kindled, they exhibited less severe seizures, i.e. seizures with a maximal score, compared to WT mice.
Combined, we provide the first evidence for anticonvulsant actions of selective GSK-3 inhibitors and conclude that these compounds serve as potential new leads for therapy in epilepsy.
Keywords:
GSK-3,
Epilepsy,
kindling,
overexpression,
GSK-3 inhibitors
Conference:
11th National Congress of the Belgian Society for Neuroscience, Mons, Belgium, 22 May - 22 May, 2015.
Presentation Type:
Poster presentation
Topic:
Neuroscience
Citation:
Najat
A,
Walrave
L,
Esguerra
C,
De Witte
P,
Van Leuven
F,
Crawford
A and
Smolders
IJ
(2015). Elucidating the role of Glygocen synthase kinase-3 in epilepsy..
Front. Neurosci.
Conference Abstract:
11th National Congress of the Belgian Society for Neuroscience.
doi: 10.3389/conf.fnins.2015.89.00034
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Received:
24 Apr 2015;
Published Online:
05 May 2015.
*
Correspondence:
PhD. Aourz Najat, Vrije Universiteit Brussel, Depart. of Pharmaceutical Chemistry and Drug Analysis, Brussels, Belgium, 1090, Belgium, najataourz@hotmail.com