Alexei Kondratyev: Research Probes the Yin and Yang of Brain Seizures

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You won’t find many medical researchers singing the praises of brain seizures, but few have studied these bursts of neural activity as much as Alexei Kondratyev, PhD, associate professor of pharmacology, has.

And what he has found has the potential to change medical practice – particularly in the use of some anti-seizure medications in pregnant women and in the young.

Kondratyev’s interest in seizures grew from his study of brain nerve growth factors, which he focused on while earning his PhD in organic chemistry, awarded to him in 1986 by the Moscow Academy of Sciences. He furthered that research in his own lab until the Soviet Union fell, and then came to the United States on invitation of the National Institutes of Health. In 1993, he joined Georgetown University Medical Center as a postdoctoral researcher and then as faculty in the Department of Pharmacology and later in Pediatrics.

All the while, he and his colleagues were discovering what few thought possible or even logical: that mild and moderate brain seizures actually stimulate brain nerve growth factors, resulting in the protection of neurons against severe injury. His work with animals shows that while severe seizures can damage the brain, mild ones can be neuroprotective.

“Like fever, seizures can become damaging, but if they are repeated and brief, they stimulate production of molecules that are beneficial,” he says.

This finding is bolstered by studies that have shown electroconvulsive shock can benefit patients with neurological disorders, such as severe depression, Kondratyev says. These brain shocks actually induce development of seizures, and he and others have been able to demonstrate that genes turned on during these episodes result in beneficial brain functioning.

That’s the “yin” of brain seizures – the “yang” is that if they continue, epilepsy can result, Kondratyev says.

After these findings in adults, Kondratyev shifted his research to neonatal seizures, since the newly born (neonates) are highly seizure-prone. This makes sense because human neonates are particularly susceptible to frequent seizures after being deprived of oxygen during birth. But while these seizures may eventually disappear and these children are left with no adverse brain damage, in some cases, seizures result in long-term behavioral and cognitive abnormalities and/or epilepsy, Kondratyev says.

Given that, he started studying the medications that are used to control seizures and to treat epilepsy, and found, to his surprise and dismay, that some of these drugs can cause substantial death of brain neurons, both on their own and especially in combination with other therapies, resulting in profound long-term behavioral abnormalities.

Using animal models, he performed studies that suggest that the drugs that suppress activity of neurons kill scores of nerve cells - which is extremely problematic in the developing nervous system. “The prevailing belief is that when an animal – or a human – develops, half of the neurons routinely die off after they help to establish proper neural networks in the brain. But these drugs, by silencing neurons, make the developing brain think that many more nerve cells than that are not needed, and they are therefore eliminated.

“These agents, even at very low doses, kill off millions of neurons, some of which are very necessary for brain function,” he says.

They also identified anti-seizure medications that do not have this effect.

Kondratyev believes that the drug outcomes he has found in young animals also apply to human biology – particularly to the developing fetus. It’s a notion that he can’t obviously test, but he says this concept is being discussed ever more widely. “This occurs in rats and in monkeys, and there is every reason to believe it is happening in humans,” he says. “Some people are even suggesting that brain disorders such as autism may have its roots in the medications pregnant women take, with the blessing of their physicians, such as anti-seizure agents used to treat migraines. Alcohol also can cause a similar type of damage.”

The possibility of this interaction is now being discussed at some pharmaceutical companies that are willing to undertake studies that would examine effects of these drugs “regardless of the outcome,” Kondratyev says. “They want to know the truth, as we all do. There are no current warnings against use of some of these drugs.

“This discussion is just starting nationwide as I, and other scientists, continue to bring in research showing these new potential dangers,” he says.

By Renee Twombly, GUMC Communications