Recent discoveries about the circuitry of absence seizures have led to the development of two calcium channel blockers that could provide much better control over this form of epilepsy.
(A) EEG recordings o...Image Tools
The two drugs, known as Z941 and Z944, were designed to block T-type calcium channels, which are involved in pain as well as epilepsy, according to the authors of a Feb. 15 paper in Science Translational Medicine. The two drugs “attenuated burst firing of thalamic reticular nucleus neurons” in a rat model of absence seizures, the authors wrote, and “potently suppressed absence seizures by 85 to 90 percent” via a mechanism different from the effects of ethosuximide and valproic acid, the two first-line drugs for absence seizures.
The development of Z944 and Z941 exploits recent discoveries about the role of certain calcium channels in seizure activity, said lead author Terrance P. Snutch, PhD, professor and Canada Research Chair in the Michael Smith Laboratories at the University of British Columbia.
THE SEARCH FOR A GENETIC DEFECT
Working with researchers at the University of Melbourne, Dr. Snutch and his colleagues used an animal model — the genetic absence epilepsy rat from Strasbourg (GAERS) — to search for a genetic defect associated with absence seizures. The GAERS model displays the EEG, behavioral, and pharmacological functions of human forms of absence seizures.
“Our worked showed for the first time that a single missense mutation in the GAERS Cav3.2 gene resulted in a gain-of-function in Cav3.2 channel biophysical properties,” Dr. Snutch said. “Cav3.2 T-type channels are normally expressed in the thalamus and cortex, two regions known to be important in generating absence seizures. Of note, we found that Cav3.2 channels with the GAERS mutation allowed more calcium than normal to enter cells under certain electrical conditions that mimicked the firing patterns expected in the thalamacortical track during seizures.”
Dr. Snutch's team had already developed a small molecule, orally available N-type calcium channel blocker, Z160, which is scheduled to enter phase 2 trials for neuropathic pain later this year. Z944 and Z941 built upon this chemical backbone to selectively affect T-type calcium channels, and essentially abolished absence seizure activity in GAERS rats.
“We still don't know whether this favorable activity is due solely to the blocking of Cav3.2 channels since Z944 and Z941 also block other isoforms of T-type channels,” Dr. Snutch said. “Regardless, that the compounds do not appear to affect other types of ionic conductances tested points toward the notion that state-dependent T-type channel blockade is sufficient to effectively attenuate absence seizure activity.”
Absence or “petit-mal” seizures are most common among children ages 6 to 15. They produce a subtle seizure in which the child becomes very still and appears to “zone out” for a few seconds before resuming normal activity. The child retains no memory of the episode.
An absence seizure is like hitting a child's pause button, according to John Huguenard, PhD, professor of neurology and neurological sciences and molecular and cellular physiology at Stanford University School of Medicine. Those few seconds of stillness, however, belie an electrical storm in the brain caused by defective signaling between the cerebral cortex and the thalamus. Dr. Huguenard and his colleagues described the mechanism last year in a paper published in Nature Neuroscience.
They used the GluA4-deficient (Gria4-/-)mouse model of absence seizures to show that excitatory signals between those two areas are dampened by reticular thalamic nucleus (nRT) neurons, which help to maintain a stable flow of information.
The nRT defect engineered into the mouse model has not been identified in humans who have absence seizures. Their neurons and neural circuits appear to be normal. But the insights provided by the experiments on the mouse model of absence seizures suggest that blocking calcium channels and dampening over-excited neurons should help.
“The authors of the Science Translational Medicine study tested the very same cell group – the nRT cells – to see whether this drug would block the calcium channels and reduce the ability of those neurons to fire during seizures,” Dr. Huguenard said. “Our study shows that intense burst firing – when one neuron generates many action potentials in a short amount of time – can be triggered within the so-called thalamocortical network. They show that Z941 and Z944 can block bursting activity in this same cell class, which suggests that regulation of this one class of neurons might be very useful in controlling seizures.”
Dr. Huguenard was one of the authors of the 1989 paper that proposed that ethosuximide, a first-line treatment for absence seizures, was a blocker of T-type calcium channels, which explained its mechanism of action. But he has long recognized that ethosuximide (Zarontin), while highly efficacious, is not an ideal treatment.
“Ethosuximide is a dirty drug,” said Dr. Huguenard. “It has a lot of actions on sodium, potassium, and calcium channels, and so it has been difficult to evaluate if the calcium-channel-blocking activity was completely responsible for its anti-seizure effects. These new compounds provide an opportunity to test that, and indeed they're extremely efficacious in blocking seizures in this animal model – a rat that has spontaneous seizures.”
Z941 and Z944 appear to be very effective against absence seizures by blocking T-type calcium channels specifically, which is what makes them so exciting to Dr. Huguenard. “They're much more potent, and have the potential for a lower side-effect profile because of that,” he said. “Also, they're state-dependent blockers, which means their blocking action on this class of ion channels is dependent on activity within the channel. That's really useful in antiepileptic therapies because seizures depend on neuronal elements participating with very intense levels of activity, so the frequent opening and closing of their calcium channels exposes them to the blocking action of these compounds. They won't be very active in a neuron or a network that is not involved in epileptic activity, but as activity ramps up, and calcium channels open up, the compound comes in and has its greatest blocking action.”
Sodium channel blockers such as phenytoin and carbamazepine, which are used to treat partial and generalized tonic and tonic clonic seizures (but not absence seizures), produce a similar state-dependent blockade for sodium channels, Dr. Huguenard said.
Although Z941 and Z944 appear to show promise as treatments for absence seizures, they have a long way to go before they displace ethosuximide and valproic acid as first-line treatments, cautioned Jacqueline A. French, MD, professor of neurology at the New York University Langone Medical Center, co-director of epilepsy research and epilepsy clinical trials at the NYU Comprehensive Epilepsy Center, and Fellow of the AAN.
“Drugs that are brand new, whose risks and benefits we don't understand yet, are usually used initially, and for quite a long time, in people who are resistant to first-line treatments,” she said. “They're second-line therapies, and that's where we learn about their properties. The most likely use for these drugs in the near future would be for children whose absence epilepsy was not controlled by the available medications.”
• Tringham E, Powell KL, Snutch TP, et al. T-Type calcium channel blockers that attenuate thalamic burst firing and suppress absence seizures. Science Translat Med 2012;4(121).
• Paz JT, Bryant AS, Huguenard JR, et al. A new mode of corticothalamic transmission revealed in the Gria4-/- model of absence epilepsy. Nature Neurosci 2011;14:1167-1173.
• Coulter DA, Huguenard JR, Prince DA. Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons. Neurosci Lett