Discovery and development of SCM-198, a novel compound from Chinese herb for ischemic stroke

Stroke especially ischemic stroke is a key factor for causing high mortality in Asian populations. Many therapeutic approaches have been investigated to solve this problem though it remains a main issue for treating stroke. Recently, we found a unique single compound Leonurine (named also as SCM-198, J CVP 2009, Atherosclerosis 2012a and Atherosclerosis 2012b) extracted from Chinese herb-herba leonuri could prevent (Stroke 2010) and treat ischemic stroke (to be submitted). Middle cerebral artery occlusion (MCAO) was used and the animals were pretreated with orally for 7 days and the surgery was done. SCM-198 pretreatment reduced infarct volume, improved neurological deficit in stroke groups, increased activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase, and decreased levels from the lipid peroxidation marker malondialdehyde. SCM-198 further inhibited mitochondrial reactive oxygen species production and adenosine triphosphate biosynthesis. In the acute treatment group, rats were treated by i.v. with SCM-198 15 mg/kg at 0.5h, 1h and 2h after surgery and continued for 7 days. PET/CT and the neurological deficit score showed a significant amelioration in the treated group compared to vehicle group. TTC staining after 3 days' treatment showed a reduced infarct volume. Results in immunohistochemical staining, Iba-1 immunoreactivity in hippocampal CA1 region were markedly decreased in the treated groups. Further, a significant better maintenance of neuronal structure in hippocampal CA1 region and fewer activated microglia in the treated groups (especially in the 0.5h group) was observed than the vehicle group. SCM-198 could go through BBB rapidly with T_1/2 of 25.4mins analyzed by microdialysis. Our results demonstrated that SCM-198 not only served as a prophylactic agent for ischemic stroke but also a potential drug candidate for acute treatment of stroke.