臺美(US)國合計畫－腦傷害的新診斷和新治療之轉譯研究－Thalidomide新衍生藥與p53新抑制劑用於治療急性腦創傷:投藥 途徑、劑量效果及多重機制之探討(2/3)

PFT-a derivatives, therapeutic efficacy, neuroprotective mechanism In this project, the research collaboration between USA and Taiwanese principle investigators (PIs) is a continuation of a previous project beginning at 2012 on the therapeutic strategies in neuroprotection against traumatic brain injuries (TBI). Both USA PI (Dr. Nigel H. Greig, NIH) and Taiwanese PI (Dr. Jia-Yi Wang, TMU) work collaboratively to develop novel drugs with therapeutic effects for TBI. Designed compounds will be provided by Co-PI (Dr. Greig in USA) of this project. Since these compounds have been proved effective in preventing neuronal cell loss in models of degenerative diseases (stroke, Parkinson disease and Alzheimer disease) in culture and animals, we will examine the therapeutic effects and time windows of these compounds in animal and cell (culture) models of TBI. The central hypothesis of this project is that intervening in common biochemical cascades leading to cell death that are shared between degenerative diseases and TBI will help to optimize the translation of drugs from the bench to the bedside. In the first year, we will evaluate the post-trauma therapeutic effects of thalidomide derivatives, pomalidomide, lenalidamide (both are less toxic than thalidomide and are already FDA approved for multiple myeloma, readily translatable to TBI once therapeutic efficacy proved) and 3,6'-dithiothalidomide (newly designed by our co-PI Dr. Nigel Greig at NIA/NIH) in vivo and in vitro. In the second year, we will evaluate the effects of pifithrin-alpha (PFT-a)、PFT-u with PFT-a(O) (newly designed by our co-PI Dr. Nigel Greig at NIA/NIH) in vivo and in vitro. In the 3rd year, we will optimize the doses to produce maximal beneficial effect and to elucidate the (multiple) mechanism(s) underlying the beneficial effects in TBI for these drugs. Importantly, pharmacokinetic measures will be undertaken to match plasma drug levels across animal studies to match those in humans to determine the appropriate dose for human to aid rapid translation to future clinical studies. Using the established animal models, the Taiwanese PI (Dr. Wang) will systematically examine the time course for the pathophysiology and for the therapeutic benefit of these compounds through evaluating neurological functions by multiple behavioral tests and measurement of contusion volume by cresyl violet staining of brain sections. Biochemical and histological analysis for the major molecular pathways leading to the outcome will also be examined. Several of these experimental drugs have already moved to the clinic and, if effective in TBI, can be rapidly translated to clinical efficacy trials for TBI treatment. Conducting this joint project will allow us to strengthen the scientific collaboration between the two institutions (NIH in USA and TMU in Taiwan) and to prepare for future collaborations between the two institutions and larger multi-national research project.