BALTIMORE—Stimulation of the sphenopalatine ganglion (SPG) may be a safe and effective method of temporarily disrupting the blood–brain barrier to deliver therapeutics to the brain. In an animal model of stroke, SPG stimulation enhances the delivery of mesenchymal stem cells and improves functional outcomes, according to research presented at the 141st Annual Meeting of the American Neurological Association. The technique does not entail unwanted systemic effects and potentially could be applied in the treatment of other neurologic disorders.
Although it would be undesirable to deliver bone-marrow stem cells to the human brain, SPG stimulation could aid the delivery of neural stem cells, viral vectors, antibody infusions, and gene therapies, said Lorraine Iacovitti, PhD, Director of the Jefferson Stem Cell and Regenerative Neuroscience Center at Thomas Jefferson University in Philadelphia. She and her colleagues plan to investigate the mechanisms responsible for the response to SPG stimulation. In addition, they will examine various stimulation frequencies and determine the size of therapies that can be delivered to the brain.
Disruption of the Blood–Brain Barrier
Modifying the blood–brain barrier has been a longstanding goal of medicine. Achieving this goal would “improve treatments for many neurologic diseases and disorders, particularly if you could combine it with a focused endovascular delivery system so that these reagents get to the appropriate regions,” said Dr. Iacovitti. In 2004, Yarnitsky et al found that stimulating the SPG caused a transient, reversible increase in blood–brain barrier permeability in animals. The technique enabled Evans blue to penetrate nearly the entire side of the brain that received stimulation.
Michael Lang, MD, a fifth-year neurosurgical resident, led Dr. Iacovitti’s group in a study of SPG stimulation in rats with middle cerebral artery (MCA) occlusion. The researchers previously had found that injection of exogenous bone-marrow mesenchymal stem cells reduced infarct size, improved behavioral deficits, and decreased proinflammatory factors in this model of stroke. Although some stem cells reached the brain, most collected in the lungs, the kidneys, and the liver. Dr. Iacovitti’s group hypothesized that SPG stimulation would increase mesenchymal stem cell engraftment following intra-arterial delivery.
SPG Stimulation in a Stroke Model
The investigators studied three groups of rats. One group received MCA occlusion. The second group received MCA occlusion and an intra-arterial infusion of mesenchymal stem cells at one day post stroke. The third group underwent MCA occlusion, intra-arterial infusion of mesenchymal stem cells, and SPG stimulation at one day post stroke. The stimulation frequency was 10 Hz, and the potential was 5 V. Stimulation continuously alternated between 90-s on and 60-s off for a total of 20 minutes.
In the absence of SPG stimulation, few, if any, stem cells reached the parenchyma. The cells did reach the parenchyma, however, in rats that received SPG stimulation. In addition, SPG stimulation was associated with an improvement in functional outcome. At day 7 and at day 14, the researchers observed a difference in function between animals that received mesenchymal stem cells alone and those that received mesenchymal stem cells plus SPG stimulation. At day 14, the Modified Neurologic Severity score was approximately 50% lower in rats that received stem cells and SPG stimulation, compared with untreated rats.
Electron microscopy revealed that most tight junctions in the rats’ brains appeared normal after SPG stimulation, although tight junction discontinuity was common. The effect was similar to that of a mannitol infusion, said Dr. Iacovitti. “It is possible that stem cells are moving out of circulation into the brain in a fashion similar to what you would see after tumor-necrosis-factor-alpha-stimulated inflammation, where you would get immune cells to move out of the blood vessels and into the damaged brain area through a process of diapedesis.” Unlike mannitol administration, which causes dangerous systemic side effects, SPG stimulation has no observed adverse side effects.
“The combination of endovascular selectivity with SPG stimulation is potentially an extremely powerful tool to deliver [therapies] across the blood–brain barrier into the brain,” she continued. “We have just started to look at getting viruses across…. This work has really just begun.”
Dr. Iacovitti’s research was funded by grants awarded by the NIH, the Joseph and Marie Field Family Foundation, and the Mary E. Groff Charitable Trust.