We studied blood-brain barrier (BBB) disruption in animal models as well as in patients. We discovered that even slight changes in BBB permeability cause altered brain homeostasis which can lead to acute seizures or delayed autoimmune disorders. We used anti-inflammatory corticosteroids to restore BBB integrity, as judged by MRI. This resulted in a therapeutic benefit in a pediatric population of drug resistant epileptics.
We study intraoperative detection of therapeutic drugs in brain. We measured drug levels in epileptics but plan to do so also in patients undergoing brain resections for any other reasons. The main outcome of this study is the unexpected discovery of a toxic metabolite of carbamazepine, an antiepileptic drug. This metabolite was produced by the blood-brain barrier and not, as predicted by other studies, by hepatocytes.
In another study we are measuring serum markers of blood-brain barrier function. These are useful diagnostic tools to detect even slight alterations in BBB as seen in minor head injury, metastatic brain tumors or stroke. The use of one of these markers, S100B, is used as means to rule out TBI in the emergency room.
The use of serum markers of brain injury has been applied to atheletes involved in high risk sports, such as football and hockey. We have collected blood samples from athletes involved in college football and detected elevated markers of potential clinical relevance in athose players who experienced the most head impacts.
We study how the blood vessels that feed the brain also protect the neurons from outside molecules. This phenomenon is due to the presence of a blood-brain barrier which acts as a bouncer, by allowing entry of the good guys and keeping out the riff-raff.
We discovered that even small and transient breaches in this barrier may cause acute (seizures) and delayed (trauma) consequences. We also found that inflammation occurring elsewhere in the body is the cause of this barrier leakage. We also found that using inexpensive drugs that have been used for arthritis pr other peripheral diseases can effectively prevent seizures in animals or treat epileptic seizures in human subjects.
Most of our work is done in humans and only a few experiments use rats or other animals. In one of the most recent studies we tested blood samples taken from young athletes and discovered that even the mildest forms of concussion (so-called "ding injuries") cause an opening of the protective shield that isolates the brain from the periphery.
1. Janigro,D., Are you in or out? Leukocyte, ion, and neurotransmitter permeability across the epileptic blood-brain barrier, Epilepsia, 53 Suppl 1 (2012) 26-34.
2. Ghosh,C., Marchi,N., Hossain,M., Rasmussen,P., Alexopoulos,A.V., Gonzalez-Martinez,J., Yang,H., and Janigro,D., A pro-convulsive carbamazepine metabolite: quinolinic acid in drug resistant epileptic human brain, Neurobiol. Dis., 46 (2012) 692-700.
3. Cucullo,L., Hossain,M., Puvenna,V., Marchi,N., and Janigro,D., The role of shear stress in Blood-Brain Barrier endothelial physiology, BMC Neurosci., 12 (2011) 40.
4. Marchi,N., Tierney,W., Alexopoulos,A.V., Puvenna,V., Granata,T., and Janigro,D., The etiological role of blood-brain barrier dysfunction in seizure disorders, Cardiovasc. Psychiatry Neurol., 2011 (2011) 482415.