Brain Disorders & Therapy

Pharmacologically induced hypothermia for the treatment of stroke and TBI

Global Summit on Stroke

August 03-05, 2015 Birmingham, UK

Shan Ping Yu and O Wayne Rollins

Posters-Accepted Abstracts: Brain Disord Ther

Abstract:

Stroke and traumatic brain injury (TBI) are leading cause of human death and disability across the globe. Unfortunately,
there are very few effective therapies for stroke and TBI patients. Most previous and current experimental treatments
have focused on affecting one signaling pathway, regulating an individual membrane protein/channel/receptor (e.g. NMDA
receptor) or targeting one type of cell death mechanism (e.g. apoptosis). The failure of many clinical trials that have used
these approaches in recent years has generated the consensus that for a therapy to be effective against complicated CNS
disorders such as cerebral ischemia and TBI, it requires overwhelming protective effects on multiple pathways and multiple
cell types. So far, there has been no therapy that is truly multifaceted and clinically feasible for acute stroke/TBI patients. One
potential therapy, however, stands out for its versatile protective effects on the brain, heart and other organs: Hypothermia
therapy. Mild-to-moderate hypothermia has shown remarkable neuroprotective effects (up to 90% infarct reduction) against
brain ischemia in animal and human studies. Some of the drawbacks to available cooling techniques of physical means are
that they are slow (�?�3 hrs) and not practical, which have hampered clinical applications of hypothermia therapy. Thus,
chemical compounds that can be utilized for hypothermia therapy have long been sought after for clinical treatments. Using
drug-induced hypothermia, it is expected that even a small drop in body temperature (1-2°C) is beneficial for preventing
the detrimental post-injury hyperthermia, delay the evolution of the secondary injury, and thereafter extend the therapeutic
window for other interventions. We have developed novel neurotensin derivatives such as ABS201, ABS601, and ABS363
that can pass through the blood-brain barrier to induce “regulated hypothermia”, reducing body and brain temperature by
3-5°C in around 30 min without causing shivering. Systemic studies, blood tests, and autopsy examinations showed no toxic
or adverse effects of these compounds. Post-ischemic administration of these compounds markedly attenuates ischemiainduced
neuronal cell death, blood-brain barrier damage and improved functional recovery. In a hemorrhagic stroke model
of the mouse, ABS201 administration 24 hrs after the onset of stroke still showed significant neuroprotection and functional
benefits. Our recent investigation also showed protective effects of drug-induced hypothermia against TBI. These compounds
thus provide a novel therapy that takes full advantage of therapeutic hypothermia but with no obvious side effects. It is
expected that drug-induced hypothermia can be developed as a new category of global brain protection drugs and help to
translate the chemical/pharmacological hypothermic therapy into clinical applications.