A team of scientists from Johns Hopkins University (JHU) School of Medicine, Baltimore, Maryland, and elsewhere have developed nano-devices that successfully cross the brain-blood barrier and deliver a drug that tames brain-damaging inflammation in rabbits with cerebral palsy. This holds therapeutic potential for a variety of neurologic disorders in humans that stem from neuro-inflammation, including Alzheimer’s disease, stroke, autism, multiple sclerosis, and cerebral palsy, the investigators say.
Photograph by Lewis Gorman, courtesy of the U.S. Fish and Wildlife Service.
A report on the experiments, conducted at Wayne State University, Detroit, Michigan, in collaboration with the Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Detroit, before the lead and senior investigators moved to JHU, is published in the April 18 issue of Science Translational Medicine.
Neuro-inflammatory damage occurs when two types of brain cells called microglia and astrocytes-normally deployed to protect the brain during infection and inflammation-actually damage it by going into overdrive and destroying healthy brain cells along with damaged ones. Directly treating cells in the brain has long proven difficult because of the biological and physiological systems that have evolved to protect the brain from blood-borne infections. The quest to deliver the drug to the brain also involved developing a technique to get past the brain-blood barrier, spare healthy brain cells, and deliver the anti-inflammatory drug exclusively inside the rogue cells.
For the study, researchers used tiny, manmade molecules, known as a dendrimer, laced with N-acetyl-L-cysteine (NAC), an anti-inflammatory drug used as antidote in acetaminophen poisoning. The researchers precision-targeted brain cells gone awry to halt brain injury. Not only did the drug-loaded dendrimers make their way inside the brain but, once there, were rapidly swallowed by the overactive astrocytes and microglia.
“The dendrimers not only successfully crossed the blood-brain barrier but, perhaps more importantly, zeroed in on the very cells responsible for neuro-inflammation, releasing the therapeutic drug directly into them,” says senior investigator Rangaramanujam Kannan, PhD, professor of ophthalmology at the Center for Nanomedicine/Ophthalmology Wilmer Eye Institute JHU School of Medicine.
Rabbits treated with dendrimer-borne NAC showed marked improvement in motor control and coordination within five days after birth, nearly reaching the motor skill of healthy rabbits. By comparison, rabbits treated with dendrimer-free NAC showed minimal, if any, improvement, even at doses ten times higher than the dendrimer-borne version. Animals treated with the dendrimer-delivered drug also showed better muscle tone and less stiffness in the hind leg muscles, both hallmarks of CP. Further, brain-tissue analysis revealed that rabbits treated with dendrimer-borne NAC had notably fewer “bad” microglia as well as markedly lower levels of other inflammation markers. They also had better preserved myelin. And even though CP is marked by neuron death in certain brain centers, the animals that received dendrimer-borne NAC had higher number of neurons in the brain regions responsible for coordination and motor control, compared with untreated animals and those treated with NAC only. The findings suggest that the treatment not only reduces inflammation in the cells, but may also prevent cell damage and cell death, the researchers said.
The scientists caution that the findings are a long way from human application, but that the simplicity and versatility of the drug-delivery system make it an ideal candidate for translation into clinical use.
Kannan and co-researcher and wife Sujatha Kannan, MD, visiting associate professor of anesthesiology and critical care medicine at JHU School of Medicine, say they plan to follow some treated animals into adulthood to ensure the improvements are not temporary.
