(Abst. 3.087 ), 2009
DBA/1 MICE ARE A USEFUL MODEL OF SUDEP FOR EVALUATING CHRONIC PREVENTION TREATMENTS
Authors: Carl Faingold, M. Randall and S. Tupal
Prevention of sudden unexpected death in epilepsy (SUDEP) is a major goal of epilepsy research. Respiratory malfunction following generalized convulsive seizures is implicated as a major cause of human SUDEP. One model of respiratory arrest (RA)-based SUDEP has been identified in DBA/2 mice, but DBA/2 mice only have a ~one week of consistent RA susceptibility. Since SUDEP prevention in patients would require chronic treatment, identification of a SUDEP model with chronic susceptibility is vital. This study identified a chronic model of SUDEP in DBA/1 mice with potential to test chronic drug preventions.
DBA/1 mice (21-77 day old) were evaluated for audiogenic seizures (AGS) and RA in response to acoustic stimulation (electrical bell 122 dB SPL). Seizures were induced 30 min following i.p. injection of normal saline or drug. Seizure behaviors were analyzed on videotape. DBA/1 mice that exhibited AGS+RA were resuscitated. DBA/1 mice that exhibited AGS+RA were given (24 h later) a selective serotonin (5-HT) reuptake inhibitor (SSRI), fluoxetine (Prozac) (single dose of 15-70 mg/kg i.p.) and were tested for RA after 30 min or were given fluoxetine sub-chronically (20 mg/kg daily for 5 days). Changes in seizure-related behavior were evaluated.
DBA/1 mice (N=103) beginning at 21-30 days of age were acoustically stimulated, and after 3 daily seizures 92% of mice exhibited AGS+RA. Susceptibility to RA between the 1st and 3rd AGS was significantly increased (p < 0.001 Wilcoxon signed rank test, N = 103). Once DBA/1 mice displayed AGS+RA, they exhibited long-lasting susceptibility [78% (of 18 mice) still exhibited RA at 77 days of age], which greatly exceeds that of DBA/2 mice. Fluoxetine induced a significant reduction of RA incidence at 50 mg/kg, while 85% of the mice remained susceptible to AGS. Complete suppression of RA was seen at 70 mg/kg, and the mice again displayed RA susceptibility by 7 days. Sub-chronic administration of fluoxetine resulted in significant reduction of RA in DBA/1 mice (p < 0.002, Chi Square, N = 9). Most DBA/1 mice returned to RA susceptibility 2-4 days following the last dose of fluoxetine.
These findings indicate that DBA/1 mice may be a useful respiration-based SUDEP model for testing chronic prevention therapies for SUDEP, because they exhibit extended susceptibility to seizure-associated RA. DBA/1 mice are easily resuscitated, allowing subsequent evaluation of the ability of drugs to prevent RA-mediated death. Fluoxetine induced significant reductions in RA both acutely and sub-chronically without preventing AGS. These findings support the importance of enhancing 5-HT neurotransmission in prevention of RA in this SUDEP model. 5-HT in the brainstem is important for normal respiration, which is consistent with the present finding that an SSRI can prevent SUDEP. These findings support the usefulness of DBA/1 mice as a chronic model of SUDEP and suggest that SSRIs are possible preventative agents for SUDEP in patients. (Support: Citizens United for Research in Epilepsy)
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