Diffusion Through Skull as Route of Delivery for Treatment of Brain Injury and Disease

Traumatic Brain injury (TBI) often results from head impact and is a major cause of death and disability. Brain injuries vary in severity and can be associated with hemorrhaging, swelling, inflammation, and death of brain tissue. Inventors at NINDS developed a novel approach to treating brain injuries that involves transcranial application of small molecules. They discovered, using two photon laser scanning microscopy, that compounds as large as 40,000 molecular weight (MW) can pass directly through the intact skull into the underlying cerebral spinal fluid (CSF) that circulates through the brain and spinal cord. Small molecular weight compounds (e.g. 600 MW) pass through the skull more quickly than large ones and appear to do so by simple diffusion. Researchers have shown that application of a variety of agents, including glutathione, TNP-ATP hydrase (P2X4 inhibitor), oxidated ATP (P2X7 inhibitor), MRS2578 (P2Y6 inhibitor), MeSAMP (P2Y12 inhibitor) and Carbenoxelone (Connexin Hemichannel Inhibitor) directly to the head results in delivery of the agents to the brain. Transcranial drug application can be used to pharmacologically target several tiers of brain injury responses, from the toxic mediators that cause cell death to the molecular signals that drive inflammation. Application can be by direct application to the skull through the scalp (e.g. rubbing it in), transdermal patch, or subcutaneous injection under the scalp.