The Study of Therapeutic Effects for Stroke with Phenserine, an Amyloid Precursor Protein Inhibitor, in Rodent Focal Cerebral Ischemia Model(2/3)

Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatment strategies for stroke primarily focus on reducing the size of ischemic damage and on rescuing dying cells early after occurrence. Treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window 1,2. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment 3. Understanding the proliferation, differentiation, migration of endogenous stem or progenitor cells will provide insights in therapeutic interventions that modulate the intrinsic processes of neuroregeneration and lead to potential enhanced repair and functional recovery. Utilizing a specific p53 inhibitor (Pifithrin alpha, PFT-α), our group has successfully enhanced the proliferation and survival of endogenous progenitor cells in vivo, leading to enhanced functional recovery in stroke animals 4. To further enhance the neuronal differentiation of the endogenous progenitor cells, we propose to utilize an amyloid precursor protein inhibitor (+)-phenserine 8. It has been reported that secreted amyloid precursor protein (sAPP) is upregulated after cerebral ischemia 5,6 and that high concentrations of secreted amyloid-precursor protein (sAPP) inhibit neuronal differentiation in neural stem cells 7. Furthermore, (+)-phenserine, which has demonstrated ability to inhibit sAPP levels both in vitro and in vivo, is able to enhance the neuronal differentiation and migration of transplanted neural stem cells in hippocampus and cortex in mice 8. Our preliminary data also demonstrate enhanced functional recovery in stroke animals treated with (+)-phenserine. Therefore, we hypothesize that upregulation and accumulation of APP fragments in ischemic brain may prevent neuronal differentiation of endogenous brain progenitor cells, leading to insufficient neural repair, and that modulating the APP process will lead to altered functional outcome in stroke recovery. Further test this hypothesis and the underlying mechanisms of APP-regulated neurogenesis, we have developed a three years proposal that consists of three specific aims. Specific Aim 1. Examination of the efficacy of the APP inhibitor, (+)-phenserine, in an animal stroke model using pre-stroke and post-stroke delivery. Specific Aim 2. Examination of the efficacy of combined treatment of the APP inhibitor, (+)-phenserine and p53 inhibitor (PFT-α), in an animal stroke model by post-stroke delivery. Specific Aim 3. Examination of the mechanisms of APP-related neurogenesis regulation in vitro. These studies will provide a preclinical basis for exploring new potential methods to treat ischemic stroke based on the APP-related neurogenensis regulation.