Purpose: The AY-9944 (AY)-treated rat is a reproducible and clinically relevant animal model of atypical absence seizures. AY inhibits cholesterol synthesis, but the relation between brain sterol levels and the spontaneously recurrent absence seizures has not been determined.
Methods: Long-Evans hooded rats were treated every 6 days from postnatal day (P)2 to P20 with AY (7.5 mg/kg, s.c.) or saline. Electrodes were permanently implanted under pentobarbital anesthesia at P50. Spike-and-wave discharge (SWD) duration and amplitude were quantified at P55. Changes in brain sterols after AY were examined in three different experiments, looking at brain regions (experiment 1), recovery after stopping AY (experiment 2), or gender differences (experiment 3).
Results: Experiment 1: AY caused spontaneously recurrent slow SWD that lasted 59 times longer and had a 3.2-fold higher amplitude than that in controls. At P55, brain cholesterol was reduced and 7-dehydrocholesterol was increased in all brain regions (p < 0.0001). Experiment 2: Four hundred days after stopping AY-9944 treatment (P420), brain sterol levels had returned to normal levels, but the AY-induced SWD lasted twice as long as at P55. Experiment 3: At P55, AY-induced changes in plasma and liver (but not brain) sterols were significantly more severe in females compared with males.
Conclusions: AY-induced seizures appear to be related to AY-induced changes in brain sterols but persisted long after the sterols had returned to normal after the last AY injection. Hence, there appears to be a critical developmental window during which the AY must be given but after which the AY-induced change in brain sterols is no longer essential to sustaining the seizures.