R01 CA216863 (Chemical Inhibitors of 15-prostaglandin dehydrogenase potentiate hematopoietic stem cell transplant) has supported optimization of our novel class of 15-PGDH inhibitors, validation of 15-PGDH as a drug target for potentiating hematopoietic recovery following bone marrow transplantation using radiation conditioning, and also for potentiating hematopoietic recovery and protecting from enterocolitis following bone marrow transplantation using melphalan conditioning. We now propose to evaluate the efficacy of 15-PGDH inhibition in Alzheimer?s disease (AD). Through collaboration with Dr. Andrew Pieper (Morley-Mather Chair in Neuropsychiatry and Investigator at the Harrington Discovery Institute, Director of the Alzheimer?s Drug Discovery Foundation ? Harrington Scholar program, University Hospitals Cleveland Medical Center) we have discovered a previously unanticipated role of 15-PGDH in the brain. Specifically, 15-PGDH expression is enriched in axonal processes in the brain, which are energetically demanding parts of the neuron that serve as focal points for neuronal dysfunction and neurodegeneration in injury and disease. We see dramatic and chronic increases in 15-PGDH levels after traumatic brain injury (TBI), with similar but less extensive effect in the normally aging brain. We have shown that inhibition of 15-PGDH with a lead inhibitor generated by this program is highly protective of mice from TBI, and that 15-PGDH inhibition in the brain supports survival of newborn hippocampal neurons, which play an important role in cognitive function in injury and disease. Given the epidemiological association of TBI with risk of AD, and the overlapping aspects of TBI pathology with AD, we hypothesized that 15-PGDH might play a role in AD. We have observed significantly elevated 15-PGDH levels in the brains of symptomatic TgF344-AD rats, a preclinical model of AD that overexpresses two mutations known to cause AD: APPSW and PS1?E9. These animals develop amyloid plaques, hyperphosphorylated tau, neuroinflammation, neuronal cell loss, and behavioral deficits akin to human AD, rendering them well-suited for preclinical studies. Indeed, TgF344-AD rats are uniquely applicable to the human condition in that these animals display anxiety- and depression-like behavior prior to onset of cognitive deficits, as is typically seen in people with AD. We have also discovered that 15-PGDH expression is increased in post-mortem brain tissue from people with AD. Having established that our lead 15-PGDH inhibitor is operative in the brain of rats after peripheral administration, we are now seeking support to test the hypothesis over the next 12 months that 15-PGDH inhibition might be therapeutic for AD. We propose to chronically administer our lead 15-PGDH inhibitor to aging TgF344-AD rats and wild type littermates, and then assess outcome measures of neuropsychiatric function related to depression and cognition, as well as pathological measures of brain anatomy related to AD. We will also assess blood, brain, and urine for potential biomarkers throughout treatment. Our hope is to provide evidence for a novel way of treating patients suffering from AD.
Our goal is to test the hypothesis that 15-PGDH inhibition offers a novel approach to treating Alzheimer?s disease (AD). We have already shown that our lead synthetic small molecule 15-PGDH inhibitor safely inhibits 15-PGDH in rodents with therapeutic efficacy in peripheral systems, and we will now administer this 15-PGDH inhibitor to a rigorously established rat model of AD, using outcome measures of neuropsychiatric behavioral impairment and histological measures of AD-related pathology. Animals will also be used to pilot candidate biomarkers for treatment, and successful completion of this work over the next 12 months could provide a mechanistic rationale for a novel way of treating patients suffering from AD and AD-related dementias.
|Desai, Amar; Zhang, Yongyou; Park, Youngsoo et al. (2018) A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independently of age, transplant dose and granulocyte colony-stimulating factor support. Haematologica 103:1054-1064|
|Antczak, Monika I; Zhang, Yongyou; Wang, Changguang et al. (2017) Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair. J Med Chem 60:3979-4001|
|Kishore, Annavarapu Hari; Liang, Hanquan; Kanchwala, Mohammed et al. (2017) Prostaglandin dehydrogenase is a target for successful induction of cervical ripening. Proc Natl Acad Sci U S A 114:E6427-E6436|