People with schizophrenia often find that symptoms that impair their cognition (thinking, remembering, and planning) significantly reduce their ability to function in the community. Today there are no pharmaceutical therapies for these symptoms. Working with Dr. Steven McKnight, Dr. Andrew Pieper, winner of a Rising Star Research Award in 2009, has discovered a compound that improves such symptoms beautifully in rodents, by enhancing the proliferation of new neurons in the hippocampus. Because this compound actually acts by preventing neurons from dying prematurely, Dr. Pieper and colleagues have found evidence that may also improve symptoms of dementia, Parkinson’s disease and ALS (Lou Gehrig’s disease).
In this Brain Waves segment, Dr. Pieper discusses these discoveries. Due to a scheduling mismatch, this interview is presented in text form. The public Q&A period is now closed.
If you feel moved to support research like Dr. Pieper’s, please make a tax-deductible donation.
Andrew Pieper, M.D., Ph.D., is Director of Translational Neuroscience at the University of Iowa Carver College of Medicine, and a winner of a Rising Star Research Award in 2009. As we will see in this interview, he has been very productive in investigating potential therapies for a wide range of brain diseases.
BKS: Andrew, thank you for doing this Brain Waves interview.
AP: Thank you, Brandon, for this opportunity and for the generous support that One Mind has provided over the years.
BKS: When you first set out on the study you proposed for your Rising Star Award, you were pursuing a means to fix the cognitive deficits that come with schizophrenia. What inspired you to this particular path, and how did you hope to accomplish it?
AP: Well, although there are reasonably effective treatments for the hallucinations associated with schizophrenia, there is a complete lack of treatment for the cognitive deficits suffered by patients. Since the cognitive deficits are tightly linked to the morbidity associated with schizophrenia, I wanted to find ways to address this unmet need. At the time of my proposal for the Rising Star award, I had recently shown in my postdoctoral work with Dr. Steven McKnight that mice missing a gene for NPAS3, which was known to be disrupted in some patients with forms of schizophrenia with prominent cognitive symptoms, suffered from drastically impaired, in fact virtually abolished, adult hippocampal neurogenesis. Given the well-characterized role of the hippocampus in cognition and schizophrenia, I wondered whether therapeutic agents that could selectively fix the deficit in hippocampal neurogenesis might boost cognition.
BKS: During the study, you and Dr. Steven McKnight conducted a large-scale blind screening of safe compounds in mice. What did you discover from this approach?
AP: Through this target-agnostic screen, we discovered a small aminopropyl carbazole that can be safely administered to mice and rats for extended periods of time to potently enhance survival of newborn hippocampal neurons, and thus increase the magnitude of hippocampal neurogenesis. We named this compound P7C3, to reflect the order in which it was discovered in the screen – pool #7, compound #3. Administration of P7C3 to NPAS3-deficient mice restored normal hippocampal neurogenesis, and also normalized synaptic transmission in hippocampal circuits.
BKS: Next, you and Dr. McKnight demonstrated that P7C3 also enhanced laboratory ratsÃ¢â‚¬â„¢ cognitive abilities as they got very old. What was the biological mechanism that allowed this preservation? What applications might it eventually have for humans?
AP: Although we havenÃ¢â‚¬â„¢t determined the molecular target of P7C3, we are making progress in understanding how it helps block neuronal degeneration by stabilizing mitochondria. Our hope is that the P7C3-series of neuroprotective molecules will one day lead to the development of a new class of neuroprotective drugs. Such a medicine could have wide applicability to many forms of neurodegenerative disease.
BKS: In 2012, you, Dr. McKnight and your team published 2 papers describing your discoveries that P7C3 and the even better version you invented, P7C3A20, were able to impede the large-scale death of dopamine neurons in the substantia nigra that takes place in a mouse version of Parkinson disease. You also found that these 2 compounds slowed down the mass death of motor neurons in the spinal cord that comes with a mouse model of ALS, or Lou Gehrig ‘s disease. What were the effects on the ability of these mice to move around, even though they had a model of the disease?
AP: We have joined forces with Dr. Joe Ready, and his medicinal chemistry laboratory has synthesized over 350 novel analogs of P7C3, including P7C3A20. This has enabled us to improve key characteristics of the original molecule, and we have applied some of these new molecules in the studies you mention here. Briefly, we wanted to know whether active analogs of P7C3 might also afford neuroprotection of mature neurons elsewhere in the central nervous system. To address this question, we evaluated their efficacy in two mouse models of neurodegenerative disease: the MPTP-model of Parkinson’s disease, and the G93A-SOD1 transgenic mouse model of ALS. In the first model, a study led by Hector De Jesus-Cortes, administration of active analogs of P7C3 fully 24 hours after the MPTP insult was complete potently blocked death of dopaminergic neurons in the substantia nigra. In the ALS study, led by Rachel Tesla, we showed that administration of one of our most potent analogs, P7C3A20, at the time of disease onset protected ventral horn spinal cord motor neurons from cell death. This protection from cell death correlated with preservation of motor function in assays of walking gait and in the accelerating rotarod test.
BKS: So, P7C3 and P7C3A20 are able to keep neurons alive in many sections of the brain, and potentially address a wide range of cognitive and neurodegenerative disorders. Fortunately, these compounds cross the blood-brain barrier, so mice at least can ingest them orally. They seem to me like they would be very feasible to develop into useful drugs. Last time I spoke with you, you were seeking to partner with a to-be-determined biotech firm to develop these compounds into drugs. How is that effort going?
AP: We are still actively seeking partnership for drug development.
BKS: Is there anything else youÃ¢â‚¬â„¢d like to add?
AP: Not for now, but IÃ¢â‚¬â„¢ll be happy to answer more questions as time goes.
BKS: Thanks, Andrew, for this interview!
AP: Thank you Brandon.