image: MCG Neuroscientist Sergei Kirov. view more
Credit: Phil Jones
Brain damage that occurs even days after a stroke, increasing stroke size and devastation, is the focus of researchers trying to identify new treatments.
"This would be a death wave coming through; neurons are dying here," says Medical College of Georgia Neuroscientist Sergei Kirov as he watches moving images of compounding events that kill brain tissue in the stroke's core.
Within seconds of a clot or hemorrhage cutting off blood, oxygen and glucose, the neuron's powerhouses, or mitochondria, shut down and the key energy source ATP goes away. Energy loss shuts down the sodium-potassium pump and the membrane that keeps the right substances inside and outside the cell becomes dysfunctional. Neurons swell and the proper electrical balance – essential for neuronal activity – is lost.
"This is what is happening in the ischemic core; dendrites get beaded, spines are lost and synapses are probably lost at the same time," says Dr. Kirov describing rapidly deteriorating communication points for neurons. "This is not recoverable; everything dies here," he says of the destruction, termed anoxic depolarization.
Damage doesn't stop there. In the minutes, hours and even days following stroke, waves of peri-infarct depolarization pound surrounding brain tissue, where blood flow is reduced by about 60 percent.
"It's enough oxygen and energy for neurons to survive for some time, but not enough to function properly," says Dr. Kirov, who received a $1.4 million, five-year grant from the National Institute of Neurological Disorders and Stroke, to study this compromised tissue around the stroke core called the penumbra. His grant was ranked among the top 1 percent of those reviewed by the study section.
"If the recurring waves continue, finally they will kill cells," says Dr. Kirov who wants to better understand this depolarizing event with the goal of stopping it. "We are trying to block this event to save the penumbra. Part of the recovery is if you can restore the normal electrical activity of neurons. We need some energy to do that."
He's using real-time microscopical imaging to monitor changes in neurons and their dendrites and spines following a stroke, and pharmaceuticals – including an antibiotic and an anesthetic – to try to stop it. Disintegration of a neuron's dendrites and spines, which receive messages from other neurons via synapses, is an early indicator of trouble. Studies are being done in an animal model for stroke and dissected but still-viable brain tissue.
"The penumbra exists for several days, so this is basically a window of opportunity to save this region, but we don't yet have good drugs to do this. We need to target this area for drug treatment," Dr. Kirov says.
So Dr. Kirov studies dendrite and spine damage that occurs in anoxic depolarization and peri-infarct depolarization and watches their recovery after a short simulated stroke.
He believes by finding a way to inhibit anoxic depolarization in a slice of living brain, he can protect neurons by stopping structural and functional damage and promoting recovery.
His previous work has shown that cold also inhibits the sodium-potassium pump, resulting in dendrite beading and spine loss, and that warming of brain tissue and pump revival quickly heals old spines and induces new ones.
Now he wants to know if the new spines function and last and if this adaptive recovery also occurs when stroke is the culprit.