Importantly, the short half-life of 1NMPP1 (less than 1 hr) (Wang et al., 2003), together with direct biochemical evidence excluding persistent inhibition (G.L., unpublished data), establishes the transient nature of the kinase inhibition. The virtual elimination of spontaneous recurrent seizures and associated anxiety-like behavior were evident long after discontinuation
of TrkB kinase inhibition, demonstrating a truly preventive effect of this intervention. That SE induces loss of hippocampal neurons is evident from both histological and MRI studies of humans with severe TLE (Cascino, 1998 and Mathern et al., 1998). The control animals undergoing SE in the present study exhibited neuronal loss predominantly in the hippocampal CA3 region ipsilateral to the KA injection, as well as increased GFAP immunoreactivity typical of reactive gliosis, resembling the
pathology in humans and Selleckchem GSK2656157 confirming previous reports (Mouri et al., 2008). This pathology was significantly attenuated, but not eliminated, by transient inhibition of TrkB kinase commencing after SE. Because activation of TrkB signaling would be expected to protect neurons from HIF inhibitor death (Huang and Reichardt, 2003), the reduction in neuronal death after inhibition of TrkB kinase is surprising. One possibility is that the loss of hippocampal neurons in animals undergoing SE followed by inhibition of TrkB kinase is due to injury sustained during SE itself. If so, the greater loss of hippocampal neurons in the control groups may be due both to SE and to the many isolated seizures that ensued over a couple of months prior to death. The fact
that many isolated seizures result in destruction of hippocampal neurons (Kotloski et al., 2002) supports this idea. A diversity of behavioral disorders has been identified in patients with epilepsy with a greater frequency than in other chronic diseases, impairing the quality of life (Torta and Keller, 1999). Anxiety disorders are the most common behavioral conditions Sodium butyrate found in patients with epilepsy (Beyenburg et al., 2005). Animals undergoing SE in the current study exhibited a striking reluctance to enter the lighted compartment in the light-dark emergence test. Based on the innate aversion of rodents to brightly illuminated areas and on the spontaneous exploratory behavior of rodents in response to mild stressors (novel environment and light), the reluctance of mice undergoing SE to enter the lighted compartment is a response thought to reflect anxiety. Notably, this reluctance was eliminated in animals undergoing TrkB kinase inhibition. Thus, enhanced TrkB kinase signaling induced by SE not only results in recurrent seizures, but it also renders the subject vulnerable to expressing anxiety-like behavior.