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AY-9944 (AY) exacerbates chronic recurrent seizures in rats that are analogous to atypical absence epilepsy in humans. The mechanism by which AY affects the slow spike-and-wave discharges associated with these seizures is not known, but is thought to involve inhibition of cholesterol synthesis. We tested the hypothesis that seizures seen with AY are due to significant reduction in brain cholesterol and/or elevated brain 7-dehydrocholesterol by assessing whether three other cholesterol synthesis inhibitors mimic AY seizures in rats. Effects of AY on brain sterols and spike-and-wave discharge duration were compared with those of two other late-stage cholesterol inhibitors [BM 15.766 (BM) and U18666A (UA)] and to an HMG-CoA reductase (early-stage cholesterol) inhibitor, lovastatin. With BM or UA, prolongation of seizure duration and brain sterol changes was similar to that caused by AY. AY effects on both brain sterols and seizure duration were dose-related. Lovastatin, with or without concurrent AY, mimicked AY seizures but reduced brain cholesterol by

Medically refractory seizure disorders in children usually have malignant neurodevelopmental outcomes and often are associated with the presence of congenital cortical dysplasias in the brain. To date, there are no animal models of these disorders by which to test hypotheses of pathogenesis or to screen novel drugs for antiepileptic activity. In rats, treatment with the antimitotic agent methylazoxymethanol acetate (MAM) on gestational day (G) 15 produces a neuronal migration disorder similar to the cortical dysplasias seen in human brain. We sought to produce chronic, recurrent, medically refractory seizures by administration of the cholesterol biosynthesis inhibitor AY-9944 (AY) during postnatal development in rats exposed prenatally to MAM. Prenatal MAM and postnatal AY treatments resulted in spontaneous, recurrent atypical absence seizures that were characterized by bilaterally synchronous slow spike-and-wave discharges (SWD) with a frequency of 6 Hz. The MAM-AY-induced seizures were refractory to ethosuximide, sodium valproate, and the GABABR antagonist CGP 35348, and were exacerbated by carbamazepine. Histological examination of brains from MAM-treated rats showed hippocampal heterotopias, in addition to atrophy and abnormalities of cortical lamination. The MAM-AY-treated rat represents a reproducible model of refractory atypical absence seizures in children with brain dysgenesis.

Background: Non-accidental head injury (NAHI) is a form of child abuse where a perpetrator may violently subject an infant to repeated acceleration-deceleration forces with or without head impact, producing injuries including retinal haemorrhages in most cases. Animal models have included laboratory shaking of mice and rats, but only a small fraction develop retinal haemorrhages presumably due to the small eyes, which would require unattainable force levels to mimic that sustained by the infant eye. Animal models are also problematic due to ethical issues raised by subjecting even anaesthetized animals to abusive injury. Methods: We investigated a naturally occurring event, where three animal victims were shaken by a canine. The eyes were harvested and examined histologically. Results: The victims' eyes showed no haemorrhage or retinoschisis. Conclusions: Our model may not be a complete NAHI mimic. The discrepancies may ensue from anatomical and mechanical differences in the injury mechanism. Other models must be sought to further study this form of abusive eye injury. Language: en

We studied daily rhythms of chronic seizure activity and behavior in adult rats and mice treated with the cholesterol biosynthesis inhibitor AY-9944 (AY) during early postnatal development. Chronic atypical absence seizures were verified in the AY-treated animals by the presence of spontaneous 5- to 6-Hz slow spike–wave discharges (SSWDs) in the neocortex. General behavioral activity, as measured by total movements (TM), movement time (MT), ambulatory movement time (AMT), time spent in center of arena (CT), jumps (JFP), and rotational behavior (TURNS), were continuously recorded under a 12-hour light:12-hour dark photocycle. The average SSWD duration in AY-treated rats varied daily, with two peaks occurring at approximately dark phase and light phase onset. Mice treated with AY exhibited significant increases in all behavioral measures during the light and dark phases, with the exception of light-phase CT, which did not differ from that of controls. Consequently, the daily rhythm of total behavioral activity (TM) exhibited a significantly higher mean oscillation (mesor) and amplitude without evidence of phase shift compared with the TM rhythm of controls. The occurrence of SSWD activity in the AY model appears to be subject to regulation by biological timing mechanisms and, furthermore, associated with motor hyperactivity that does not alter the timing of behavioral rhythmicity.

The ketogenic diet (KD), a treatment for drug-resistant epilepsy, elevates brain acetone. Acetone has been shown to suppress experimental seizures. Whether elevation of acetone is the basis of the anticonvulsant effects of the KD and whether acetone, like the KD, antagonizes many different types of seizures, however, is unknown. This study investigated the spectrum of the anticonvulsant effects of acetone in animal seizure models. Rats were injected with acetone intraperitoneally. Dose-response effects were measured in four different models: (1) the maximal electroshock test, which models human tonic-clonic seizures; (2) the subcutaneous pentylenetetrazole test, which models human typical absence seizures; (3) the amygdala kindling test, which models human complex partial seizures with secondary generalization; and (4) the AY-9944 test, which models chronic atypical absence seizures, a component of the Lennox-Gastaut syndrome. Acetone suppressed seizures in all of the models, with the following ED(50)'s (expressed in mmol/kg): maximal electroshock, 6.6; pentylenetetrazole, 9.7; generalized kindled seizures, 13.1; focal kindled seizures, 26.5; AY-9944, 4.0. Acetone appears to have a broad spectrum of anticonvulsant effects. These effects parallel the effects of the KD. Elevation of brain acetone therefore may account for the efficacy of the KD in intractable epilepsy.