## Results: 5

1.

Plasma (square) and brain (triangle) concentrations of LY293558 after i.m. injection of 15 mg/kg. For plasma samples:

*n*= 6 at time points 0.25, 0.5 and 1 hour;*n*= 3 at time point 1.5 hours and later. For brain samples:*n*= 3 for all time points, except at 1 hour, where*n*= 6. Data points represent the mean and standard deviation.2.

Time-course of behavioral seizure suppression by LY293558 (15 mg/kg) administered intramuscularly at 20 minutes after soman injection, along with atropine and HI-6. Data points are the group means ± S.E.M. (SOMAN,

*n*= 18; SOMAN+LY293558,*n*= 18) of the maximum Racine scale scores, in blocks of 10 minutes. Vertical arrows indicate the time points of drug administration.^{#}*P*< 0.05 in comparison with the SOMAN group (ANOVA, Bonferroni post-hoc test).3.

Administration of LY293558 (i.m.) protects against neuronal degeneration, 7 days after soman-induced SE. (A and B) Panoramic photomicrographs of Nissl-stained sections showing the brain regions from where the Fluoro-Jade C (FJC) photomicrographs shown in (C) were taken. (C) Representative photomicrographs of FJC-stained sections from the brain regions where neuronal degeneration was evaluated, for the SOMAN and the SOMAN+LY293558-treated groups. Total magnification is 100× . Scale bar is 50

*μ*m. (D) Bar graph showing the median neuropathology score and interquartile range (*n*= 18 for the SOMAN group and*n*= 18 for the SOMAN+LY293558 group) for the amygdala (Amy), piriform cortex (Pir), entorhinal cortex (Ent), the CA1 and CA3 subfields of the ventral hippocampus, hilus, and neocortex (neo-Ctx). **P*< 0.05, ***P*< 0.01, and ****P*< 0.001 in comparison with the SOMAN group (Mann-Whitney*U*test).4.

Administration of LY293558 (i.m.) stops soman-induced generalized seizures and reduces the total duration of status epilepticus (SE) in the 24-hour period after soman exposure. (A) Administration of 15 mg/kg LY293558 at 20 minutes after soman exposure completely blocked electrographic seizure activity within 40 minutes (bottom set of traces). (B) An example of seizures persisting in rats that did not receive LY293558. The numbers 1, 2, 3, and 4, in (A) and (B), refer to the electrodes/sites from where electrical activity was sampled, as shown diagrammatically in (C) (1, left frontal; 2, right frontal; 3, left parietal; 4, right parietal; 5, cerebellar reference electrode). (D) Left bar graph shows the duration of the initial SE (the SE that started within 10 minutes after soman exposure and was terminated by 15 mg/kg LY293558 in the SOMAN+LY293558 group, or spontaneously in the SOMAN group). Right bar graph shows the duration of SE throughout the 24-hour period after soman exposure. Sample size

*n*= 5 for the SOMAN group, and*n*= 8 for the SOMAN+LY293558 group. ***P*< 0.01, ****P*< 0.001 (unequal variance*t*test).5.

Administration of LY293558 (i.m.) protects against neuronal loss in the basolateral amygdala (BLA) and the CA1 hippocampal area, 7 days after soman-induced SE. (A) Panoramic photomicrographs of Nissl-stained sections of half hemispheres, outlining the amygdalar nucleus and the ventral hippocampal subfield where stereologic analysis was performed (red highlight). (B) Representative photomicrographs of Nissl-stained sections showing BLA and CA1 cells from a control rat that received saline in place of soman, a soman-exposed rat that did not receive anticonvulsant treatment, and a soman-exposed rat that received 15 mg/kg LY293558 at 20 minutes after soman exposure. Total magnification is 630× and scale bar is 50

*µ*m. (C) Group data (mean ± S.E.M.;*n*= 18 for the SOMAN group and*n*= 18 for the SOMAN+LY293558 group) of stereologic estimation of the total number of Nissl-stained neurons in the BLA (left) and CA1 area (right), expressed as percent of the control. There was significant neuronal loss in the soman-exposed rats that did not receive anticovulsant treatment, whereas there was no neuronal loss in the soman-exposed rats that were treated with LY293558. **P*< 0.05 in relation to the control group or the SOMAN+LY293558 group (ANOVA, LSD post hoc test).