Collins, Thomas R.
ARTICLE IN BRIEF
In an animal model, investigators were able to prevent recurrent seizures by administering an inhibitor to a receptor for brain derived neurotrophic factor.
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Researchers have found that inhibiting the brain derived neurotrophic factor receptor — tyrosine receptor kinase B (TrkB) — in a mouse model after a prolonged seizure prevents recurrent seizures from developing later and diminishes anxiety-like behavior.
The findings, they say, suggest that preventing temporal-lobe epilepsy (TLE) might be possible by taking advantage of a treatment “window” after an episode of status epilepticus (SE) — and with only a relatively brief period on a drug.
Other researchers in the field who were not involved with the study, published in the June 19 online edition of Neuron, said the potential for prevention is encouraging, but cautioned that the findings are only in an animal model.
TLE comprises about 40 percent of all epilepsy cases. Prior studies have found that a majority of patients with severe TLE had undergone an episode of prolonged seizures — status epilepticus (SE) — early in life, followed by a period of recovery and then years later, recurrent seizures.
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“That led to the idea that perhaps this episode of prolonged seizures was sufficient to transform that brain from normal to epileptic,” said lead researcher James McNamara, MD, professor of neurosciences at Duke University Medical Center. That idea gained momentum when it became clear that [after] inducing an episode of SE in an otherwise normal animal, there was a period of recovery and the emergence of seizures some time thereafter, he said.
It's been hypothesized that activation of the TrkB receptor is needed for SE-induced TLE, but testing of the idea has previously been precluded because of “off-target” effects of TrkB inhibitors and because genetically modified animals have demonstrated inadequate temporal control, researchers said.
In this study, a mouse model genetically modified to be susceptible to TrkB inhibition was used along with a chemical blocker. Researchers induced prolonged seizure activity in wild-type mice and verified that TrkB activation was increased, compared with control mice.
They then turned to a mouse model, which is identical to a wild-type mouse except for a single amino acid in the TrkB receptor that's been modified, making it possible to inhibit the mutant receptor using the molecule 1NMPP1. Without treatment with 1NMPP1, the wild-type and mutant mice have no detectable differences in overt behavior or in behavior of the receptor.
The investigators induced seizures, then administered diazepam to stop them, and gave the inhibitor drug over a two-week period.
Over the next several weeks, the investigators observed a “striking reduction” in the number of seizures. The mice with the receptor inhibited had, on average, 0.5 spontaneous recurrent seizures, compared with 10 per mouse in those without inhibition of the TrkB receptor (p<.05).
In eight of the 10 experimental mice there were no recurrent seizures. In the two that did have seizures, one had only two and another had only three, and they occurred within three to five days after the induced seizure; none occurred nine days after that.
Researchers concluded that the diminished seizure activity wasn't caused by residual inhibition after the drug was stopped; they evoked seizures a week after treatment stopped, and found that TrkB activity was the same in those treated as it was in controls. It is the transient nature of the treatment that is key, Dr. McNamara said.
“What we think is [that] if you could inhibit this receptor during that time of enhanced activation following the prolonged seizures, that's what's critical in the development of the epilepsy,” he said. “It also provides a window in which clinicians could intervene to inhibit this receptor.”
Researchers also found that mice that had had the TrkB receptor inhibited exhibited less anxiety-like behavior in a dark-light emergence test, in which a mouse's willingness to move from a dark compartment to a lit compartment is observed.
The mice treated with the drug inhibiting TrkB showed “significantly reduced latency to enter the lighted compartment” (p<.01) and spent more time in the lighted compartment (p<.001), compared with those that had untreated seizures.
“We were very encouraged when the treatment that prevented the development of epilepsy also prevented the development of this anxiety-like behavior, because it raises hope that some of these other behavioral abnormalities that are evident in some people with epilepsy could also be prevented,” Dr. McNamara said.
The underlying process by which excessive TrkB activation leads to TLE after prolonged seizures is still unknown, and Dr. McNamara's lab is looking into that question.
“We think that it's impacting the function of synapses — and our guess is that it's enhanced activation of excitatory synapses and probably, as well, the impaired activation of inhibitor synapses,” he said. “We suspect that either or both is taking place to promote development of epilepsy.”
His lab is also still trying to answer exactly how soon treatment would have to be administered in order for it to work. Dr. McNamara noted that studies have shown that treatment shortly after onset of prolonged seizures is clinically possible.
Jeremy Slater, MD, associate professor of neurology at the University of Texas Medical School in Houston and director of the Texas Comprehensive Epilepsy Program, said the study's data “certainly support further investigation into the use of selective TrkB kinase inhibitors as agents to prevent epileptogenesis after an episode of SE.”
“The most important point about this study is its emphasis on the prevention of the development of epilepsy rather than simply blocking seizure activity,” he said. “We currently have no clinical agents available proven to do this.”
“Multiple questions remain,” he said. “What is the maximum amount of time that can pass before the ability to prevent the development of epilepsy is lost? And again, when this is translated to agents effective in human subjects, what will be the time window of efficacy then?”
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Lawrence Eisenman, MD, PhD, associate professor of neurology at Washington University in St. Louis, who specializes in epilepsy, said one of the “holy grails” in epilepsy research is to find a drug that would prevent the development of epilepsy in high-risk groups.
“Development of such drugs would represent a fundamental change in how we think about treating epilepsy and this study demonstrates in principle that it is possible,” he said.
Still, he said, “the list of promising findings in animal models that never panned out in human beings is depressingly long. Even if this approach works out in humans, it is unclear how broadly applicable it will be. Epilepsy is not a single disease and not every patient presents with an episode of status epilepticus. For example, would this work in patients with traumatic brain injury?”
An important note, he added, is that “there is not even a candidate medication in this study that can be further developed. The ‘inhibitor’ that they used in this study only works on mutant receptors.”
He said a better understanding of the biochemical pathways at work would improve the chances that a drug could be developed that would interrupt those pathways, and would help with understanding the potential side-effects. But he noted that that that's not an absolute barrier as that understanding is also lacking for many current antiepileptic therapies.
Early treatment, such as that administered in this study, has been shown to be possible, he said. “The caveat here is that the investigators gave the inhibitor immediately after they gave diazepam to abort the status. This would be equivalent to having paramedics give a drug right after they give diazepam in the field. Still possible, but clearly more complicated.”
Knowing the precise therapeutic window will be very important because “the longer the window, the more opportunity to treat patients; knowing when the window closes will prevent exposing patients who cannot benefit from treatment to the associated risks.”
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