June 20, 2013 Temporal lobe epilepsy, the most common form of epilepsy, is characterized by recurrent seizures throughout life and often behavioral abnormalities, with devastating impacts on patients and their families. Unfortunately, the condition is often not responsive to anticonvulsants. Now scientists report online June 20 in the Cell Press journal Neuron that targeting a particular signaling pathway in mice can prevent the development of temporal lobe epilepsy with just two weeks of treatment, offering hope that researchers will be able to develop effective drugs to mitigate recurrent seizures and the development of epilepsy.
Many patients with temporal lobe epilepsy experience an initial episode of prolonged seizures, known as status epilepticus, which is often followed by a period of seizure-free recovery before individuals develop recurring seizures. Research in animals suggests that the prolonged seizures in status epilepticus cause or contribute to the development of epilepsy.
"An important goal of this field has been to identify the molecular mechanism by which status epilepticus transforms a brain from normal to epileptic," says Dr. James McNamara, of the Duke University Medical Center in Durham. "Understanding that mechanism in molecular terms would provide a target with which one could intervene pharmacologically, perhaps to prevent an individual from becoming epileptic."
In a mouse model of temporal lobe epilepsy that develops after status epilepticus, Dr. McNamara and his colleagues found that inhibiting the BDNF receptor, TrkB,using genetic modification of the animal to make it susceptible to chemical disruption of TrkB action at a specific time prevents the development of epilepsy as well as associated anxiety behaviors and loss of neurons. Remarkably, a two-week treatment to block TrkB activity after the initial seizure was capable of exerting long-term protective effects.
"This demonstrated that it is possible to intervene following status epilepticus and prevent the animal from becoming epileptic," says Dr. McNamara. The findings also indicate that targeting TrkB for only a limited period of time is capable of achieving successful treatment of epilepsy without the need for lifelong therapy. This highlights TrkB as a promising target for the design of drugs to prevent epilepsy development.
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- Gumei Liu, Bin Gu, Xiao-Ping He, Rasesh B. Joshi, Harold D. Wackerle, Ramona Marie Rodriguiz, William C. Wetsel, James O. McNamara. Transient Inhibition of TrkB Kinase after Status Epilepticus Prevents Development of Temporal Lobe Epilepsy. Neuron, 2013; DOI: 10.1016/j.neuron.2013.04.027
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