Since 2002, we have used the mice stroke model to screen over 1000 compounds. The most effective pure compound among all samples was the molecular with code number of MJ-39. Treatment with MJ-39 protected the brain from infarction in rats after ischemia/reperfusion (I/R) injury. The biochemical screen assay results from MDS show that MJ-39 is a potent and specific inhibitor for both 5-lipoxygenase (5-LOX) and 12/15-lipoxygenase (12/15-LOX). A number of studies have indicated that leukotrienes derived from 5-LOX cause inflammation and are involved in pathobiology of neurodegeration diseases. Since the MJ-39 is not a new compound, we then screen more related compound and found a more effective derivative than MJ-39. This new compound entity, CTS-12, protected the brain from damage following ischemia/reperfusion of MCA in rat and significantly increased the dopaminergic neurons number in mesencephalic neuron-glia co-cultures after MPP+ treatment. Furthermore, CTS-12 inhibits MPTP-induced decrease of dopamine contents in striatum in mice. These experiments have highlighted that LOXs may play an important role in the pathology of stroke and Parkinson’s disease. We plan to achieve our goal by addressing the following aims, based on relevantly basic or clinical evidence and our preliminary results. (1) To focus on the lead CTS-12-related compounds for the treatment of stroke and Parkinson’s disease. (year 1-2) (2) We have got several new compounds from computer modeling system. These compounds will be synthesized by co-PI and we will evaluate its efficacy in neuroprotection both in vitro and in vivo. (year 1-2) (3) To explore the action mechanism of CTS-12-related compounds for the treatment of stroke and Parkinson’s disease. (year 1-2) (4) Further studies of these novel neuroprotective actions of LOXs inhibitors may provide new therapeutic opportunities to treat other neurodegenerative diseases, such as Alzheimer's disease. (year 3) Therefore, CTS-12 is a potent lead compound for the development of new category of drug to treat stroke and Parkinson’s disease.CTS-12 and its related compounds will be filed provisional patent (in USA) recently. Thus, our findings will reveal the role of lipoxygenase in pathology of stroke and Parkinson's disease. On the other hand, these results will offer a new therapeutic strategy to treat those neurodegenerative diseases.
