Stroke is the third leading cause of death in the United States. In spite of intensive investigations, clinical therapies for treating acute stroke patients remain limited and unsatisfactory. There are consistent animal and human data that mild to moderate hypothermia (reducing body temperature to 32-34oC) is generally safe and improves outcome after brain ischemia even when initiated hours after ischemia occurs. Different from most neuroprotective drugs that usually target only one mechanism, hypothermia therapy has the advantage of global protection on all cell types and tissues in both gray and white matters. Several important limitations, however, have precluded the widespread use of hypothermia therapy in stroke patients. The major obstruction is that existing "forced cooling" techniques are ineffectual and/or impractical in clinical settings. To overcome the shortcomings of current methods, the concept of "regulated hypothermia" induced by pharmacological means has been proposed as a new strategy in hypothermia therapy;although there have been no drugs that can be used for regulated hypothermia therapy. To this end, we have synthesized and tested novel neurotensin(NT)[8-13] derivatives, such as ABS201 and ABS601, that are potent hypothermic compounds and have dramatic neuroprotective activity in animal stroke models. These NT compounds show no toxic effects, attenuate infarct formation by nearly 50% even when administered 45 min after the onset of ischemia. The mechanism of protection appears to involve their ability to cross the blood brain barrier, bind to the NT receptor as agonists, and reduce the "set point" of the central temperature control so that systemic hypothermia in the absence of shivering is promoted. It is thus hypothesized that NT/ABS derivatives have strong potential of being developed for regulated hypothermia therapy. In the Phase I study, we will compare the hypothermic potency of six NT/ABS derivatives. Two leading compounds without detectable side effects will be tested and compared for their neuroprotection in aged rats of two stroke models of transient and permanent ischemia. This translational investigation is not intended to delineate the mechanism of hypothermia protection, which has been extensively studied so far. Rather, we aim to demonstrate the feasibility of the chemical-induced hypothermia therapy and move to more systematic preclinical examinations of a Phase II investigation. Our ultimate goal is to advance the drug-induced hypothermia therapy to the clinic.
Ischemic stroke is the third leading cause of human death and disability in the US. This investigation will develop a chemical-induced hypothermia therapy for stroke patients. The comprehensive neuroprotective effects of clinically feasible hypothermia therapy will be studied in two different stroke models, which will facilitate the translation of the therapy to clinical applications.
|Lee, Jin Hwan; Wei, Ling; Gu, Xiaohuan et al. (2014) Therapeutic effects of pharmacologically induced hypothermia against traumatic brain injury in mice. J Neurotrauma 31:1417-30|
|Wei, Ning; Yu, Shan Ping; Gu, Xiaohuan et al. (2013) Delayed intranasal delivery of hypoxic-preconditioned bone marrow mesenchymal stem cells enhanced cell homing and therapeutic benefits after ischemic stroke in mice. Cell Transplant 22:977-91|
|Wei, S; Sun, J; Li, J et al. (2013) Acute and delayed protective effects of pharmacologically induced hypothermia in an intracerebral hemorrhage stroke model of mice. Neuroscience 252:489-500|
|Wei, Ling; Fraser, Jamie L; Lu, Zhong-Yang et al. (2012) Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis 46:635-45|
|Choi, Ko-Eun; Hall, Casey L; Sun, Jin-Mei et al. (2012) A novel stroke therapy of pharmacologically induced hypothermia after focal cerebral ischemia in mice. FASEB J 26:2799-810|