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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
Project #
1R41NS073378-01A1
Application #
8205426
Study Section
Special Emphasis Panel (ZRG1-ETTN-C (11))
Program Officer
Fertig, Stephanie
Project Start
2011-09-30
Project End
2013-08-31
Budget Start
2011-09-30
Budget End
2012-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$441,864
Indirect Cost
Name
Halimed Pharmaceuticals, Inc.
Department
Type
DUNS #
831342022
City
MT. Pleasant
State
SC
Country
United States
Zip Code
29464
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Song, Mingke; Mohamad, Osama; Gu, Xiaohuan et al. (2013) Restoration of intracortical and thalamocortical circuits after transplantation of bone marrow mesenchymal stem cells into the ischemic brain of mice. Cell Transplant 22:2001-15
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

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