A statin used to lower blood cholesterol levels, lovastatin, was seen to ease seizures and the excitatory neurotransmission that accompanies them in a mouse model of Angelman syndrome (AS)-associated epilepsy, researchers report.
The steps taken in this study, its authors suggest, may also serve as a model for testing potential anti-epilepsy therapies that might be of use to Angelman patients.
The study, “Lovastatin suppresses hyperexcitability and seizure in Angelman syndrome model,” by researchers working in four departments at Duke University School of Medicine in Durham, North Carolina, was published in the journal Neurobiology of Disease.
Epilepsy is a serious clinical problem in AS, affecting 80 to 95 percent of patients, and is often resistant to treatment. It is though that the UBE3A deficiency that drives the disease is responsible for these seizures, although the assocaition between the two is not fully understood.
Due to the spontaneous nature of seizure activity, it’s important to discover a unique local circuit that mimics the excitatory neurons excessive firing (hyperexcitability). This could lead to the development of an effective anti-seizure drug and a better understanding of epileptic seizure mechanisms in AS.
The AS mouse model (UBE3Am-/p+) is known to exhibit major AS clinical features. Researchers for this reason set out to describe a hyperexcitable local circuit activity in the hippocampus of this AS mouse model. The hippocampus is a brain region involved in epilepsy.
To do so, researchers cut the mice’s hippocampus into thin slices and placed them in artificial cerebral spinal fluid. They then stimulated the slices with different voltages (from 5 to 100 uA) and registered the response in terms of speed and discharge, which are indicative of neuronal excitability.
Next, they added lovastatin to the artificial cerebral spinal fluid, repeated the stimulation process, and compared results.
Lovastatin tablets, marketed as Mevacor by Merck, has already been shown to suppress hyperexcitability in fragile X syndrome mouse models. It acts by increasing the extracellular levels of potassium, activating the firing (depolarization) of surrounding neurons.
Results showed that high-voltage stimulation of brain tissue depolarized neurons in a similar way to that of lovastatin-driven stimulation.
Importantly, the hyperexcitability seen in the hippocampal slices was consistent with the abnormal electroencephalogram record in this AS mouse model. These findings attest to the value of brain slice preparation in determining mechanisms underlying seizures, and of its usefulness in testing anti-epilepsy treatments in AS, the researchers reported.
The team also injected the live AS mice with lovastatin to study their behavior and to gauge if loud sounds triggered seizures, also known as audiogenic seizures.
Results here showed that lovastatin, at single dose of 100 mg/kg, reduced the rate of such seizures in these mice.
“In summary, the local circuit activities described in this study will facilitate the study on the molecular and cellular mechanism for epileptogenesis in UBE3Am-/p+,” the researchers concluded, and recommended that further study be conducted into the “general anticonvulsant effect for lovastatin and other analogs.”