91AV

Colin Willis, Ph.D., assistant professor of pharmacology and an investigator for the Center of Biomedical Research Excellence (COBRE) for the Study of Pain and Sensory Function, presented both a seminar and a poster at the 16th International Symposium on Signal Transduction in the Blood-Brain Barriers, which was held in Sumeg, Hungary, September 12-14, 2013.

The oral presentation, titled “Integrin Receptor Mediated Oxidative Stress Modulates Blood-Brain Barrier Integrity,” featured work performed by 91AV student Ryan Camire (Nursing ’15), Shannon Malloy, a summer volunteer, and Holly Beaulac, a research assistant.  Demyelinating disorders such as multiple sclerosis (MS) and neuromyelitis optica are associated with breakdown of blood brain barrier (BBB) integrity, and this breakdown is mediated at least in part by integrin receptors.

Current MS therapies target integrin receptors; however, selecting which receptor to target is made difficult by the fact that many different types of integrin receptors play a part in disease pathogenesis.  Therefore, discovering common downstream mediators presents a better option for targeted therapy, which is the goal of the present study.

Using treatment with 3-chloropropanediol to induce pathological features of demyelinating disorders, including loss of BBB integrity, Willis and his lab found that expression of a key protein in the oxidative stress pathway, hemeoxygenase-1 (HO-1), increased both in the brain of the live animal and a cultured cell line.  The increase in HO-1 expression was prevented using integrin receptor blockers, suggesting that it is a downstream component of the integrin-mediated pathway and could, therefore, present a new avenue of exploration for treating BBB dysfunction in demyelinating disorders such as MS and Neuromyelitis Optica.

The poster presentation featured work by Stephanie Brule (Neuroscience, ’14) and Holly Beaulac, research assistant.  This research explores the paradoxical phenomenon of medication overuse headache (MOH), in which headache results from frequent use of drugs, called triptans, designed to treat migraines.

In particular, Willis and his lab explored the hypothesis that triptan-induced disruption of BBB integrity contributes to the development of MOH.  By examining expression of proteins that are major constituents of the BBB, they showed that treatment with sumatriptan, a drug used to treat migraine, does lead to loss of BBB integrity.   They also showed that this loss of BBB integrity correlates with changes in an intracellular signaling pathway, known as the Akt signaling pathway.

Willis believes that further exploration of triptan-induced alterations in the BBB and the underlying signaling pathways will enhance the understanding of migraine pathology and potentially unravel new possibilities for migraine therapy.