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.
|Chen, Dongdong; Wei, Ling; Liu, Zhi-Ren et al. (2018) Pyruvate Kinase M2 Increases Angiogenesis, Neurogenesis, and Functional Recovery Mediated by Upregulation of STAT3 and Focal Adhesion Kinase Activities After Ischemic Stroke in Adult Mice. Neurotherapeutics 15:770-784|
|Lee, Jin Hwan; Zhang, James Ya; Wei, Zheng Zachory et al. (2018) Impaired social behaviors and minimized oxytocin signaling of the adult mice deficient in the N-methyl-d-aspartate receptor GluN3A subunit. Exp Neurol 305:1-12|
|Wang, Li-Li; Li, Jimei; Gu, Xiaohuan et al. (2017) Delayed treatment of 6-Bromoindirubin-3'-oxime stimulates neurogenesis and functional recovery after focal ischemic stroke in mice. Int J Dev Neurosci 57:77-84|
|Jiang, Michael Qize; Zhao, Ying-Ying; Cao, Wenyuan et al. (2017) Long-term survival and regeneration of neuronal and vasculature cells inside the core region after ischemic stroke in adult mice. Brain Pathol 27:480-498|
|Lee, Jin Hwan; Wei, Zheng Z; Cao, Wenyuan et al. (2016) Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice. Neurobiol Dis 96:248-260|
|Lee, Jin Hwan; Wei, Ling; Deveau, Todd C et al. (2016) Expression of the NMDA receptor subunit GluN3A (NR3A) in the olfactory system and its regulatory role on olfaction in the adult mouse. Brain Struct Funct 221:3259-73|
|Lee, Jin Hwan; Espinera, Alyssa R; Chen, Dongdong et al. (2016) Neonatal inflammatory pain and systemic inflammatory responses as possible environmental factors in the development of autism spectrum disorder of juvenile rats. J Neuroinflammation 13:109|
|Lee, Jin Hwan; Wei, Zheng Z; Chen, Dongdong et al. (2015) A neuroprotective role of the NMDA receptor subunit GluN3A (NR3A) in ischemic stroke of the adult mouse. Am J Physiol Cell Physiol 308:C570-7|
|Sun, Jinmei; Wei, Zheng Zachory; Gu, Xiaohuan et al. (2015) Intranasal delivery of hypoxia-preconditioned bone marrow-derived mesenchymal stem cells enhanced regenerative effects after intracerebral hemorrhagic stroke in mice. Exp Neurol 272:78-87|
|Gu, Xiaohuan; Wei, Zheng Zachory; Espinera, Alyssa et al. (2015) Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats. Exp Neurol 267:135-142|
Showing the most recent 10 out of 18 publications