A researcher from Loma Linda University School of Medicine recently learned that the National Institutes of Health (NIH) approved his application for a $1.9 million grant to develop a promising treatment for a deadly form of stroke.
John H. Zhang, MD, PhD, professor of neuroscience and physiology and director of the Zhang Neuroscience Research Laboratories at LLU School of Medicine, says the grant will address subarachnoid hemorrhage, the deadliest form of stroke, by developing a new nasal spray to deliver a synthetic form of Osteopontin, a human gene protein, to the site of the injury.
Dr. Zhang explains that there are two main types of stroke—ischemia and hemorrhage. In lay terms, ischemia refers to blood clots and hemorrhage refers to the bleeding that occurs when a blood vessel ruptures.
“Ischemia accounts for approximately 80 percent of all strokes,” he says. “Hemorrhagic stroke accounts for the remaining 20 percent.”
Hemorrhagic stroke is further divided into two categories: intracerebral and subarachnoid. Dr. Zhang and his colleagues are investigating the second variety. Subarachnoid hemorrhage refers to bleeding in the protective membranes surrounding the brain.
“Subarachnoid hemorrhage affects relatively younger females,” he observes. “Women get it more often than men at a ratio of about two to one in many countries, most often in the range of 20 to 50 years of age. It is an extremely deadly type of stroke.”
Dr. Zhang points out that approximately 15 percent of people who experience a subarachnoid hemorrhage die before reaching the hospital, and 50 percent die in the first 30 days after the initial incident. He says that in the case of ischemia, fewer than 10 percent die.
“Basically, subarachnoid hemorrhage is caused by a small aneurysm, a defect in a blood vessel in the brain, that ruptures for some reason,” he notes. The main symptom people report is an extreme headache. “People say it’s the worst headache of their lives.”
Currently, there are two main forms of treatment for subarachnoid stroke. The first, the one Dr. Zhang calls “conservative treatment,” involves maintaining the vital signs with no surgical intervention. “That is prescribed for patients in poor health or who are very old,” he says.
The second type of treatment is surgery, and once again, there are two options available to physicians: clipping and coiling.
“Clipping involves clipping off the neck of the aneurysm to prevent further bleeding,” he says. “But in the last five years, endovascular coiling has become more common. It involves inserting a catheter into the patient’s brain through the femoral artery and inserting small coils into the site of the aneurysm.”
The coils plug the aneurysm to prevent it from re-bleeding. However, neither the clipping nor the coiling procedures are able to reduce brain injury in the aftermath of treatment. As a result, the overall mortality and morbidity remain high even with these advanced procedures.
The new NIH grant funds a continuation of a previous investigation conducted by Dr. Zhang and his associates. That first study identified an effective treatment to reduce the early phase of brain injury that will not be helped with surgical procedures. That study was conducted using a rodent model of subarachnoid hemorrhage. The second study aims to develop it into a pre-clinical procedure that will save human lives.
“Our new grant is a renewal of the five-year study we just completed,” he explains.
The treatment identified by the first study was the administration of the drug Osteopontin to the cerebral ventricular space. Dr. Zhang observes that the brain produces small amounts of the protein found in the drug, but in quantities too small to help, and that Osteopontin is proven effective in experimental studies of neonatal and other forms of brain injury.
“When we inject it directly into cerebral ventricles as a treatment,” he notes, “Osteopontin is very effective. In experimental models, it was found to reduce cell death, protect the blood-brain barrier, reduce brain edema, or swelling, and improve neurological functions.”
However, there is a problem with administering the synthesized version of the drug to the trouble spot in the brain.
“The difficulty,” he explains, “is that in order to deliver the drug to the site of the hemorrhage, we have to open the skull and stick a needle into the brain. There aren’t many people willing to submit to that.”
Fortunately, Dr. Zhang and his team have already found a solution.
“In the next five years, we’ll be exploring a method of delivering Osteopontin as a nasal spray or nose drops,” he reveals. “With the nasal application, we can bypass the blood-brain barrier and get straight into the brain. It will be absorbed into the frontal lobe, and from there, into the cerebrospinal fluid to protect the brain. The nasal passage bypasses the blood-brain barrier. That’s why nose region infections are so dangerous. They can go right to the brain.”
Dr. Zhang is hopeful the study will result in a rapidly adaptable clinical protocol.
“We’re trying to be as translational as possible,” he concludes, using a term that refers to laboratory findings that translate directly into effective clinical treatments and breakthroughs.
“Although the nasal admission of Osteopontin has been used for other conditions, we are the first to propose that it be employed as a treatment for subarachnoid hemorrhage.”
