Cognitive deficits in learning, memory, attention and decision-making represent chronically disabling aspects of many forms of mental illness, including schizophrenia. Age-related decline in cognitive abilities can also be debilitating to a substantial fraction of the human population. Cognitive dysfunction has been linked to deficient functioning of the hippocampal formation of the brain. The dentate gyrus, as part of the hippocampal formation, represents a site where new neurons are formed on a regular basis in the adult brain. Studies in laboratory mice have shown that the rate of new neuron formation in the dentate gyrus is stimulated by healthy activities such as wheel running, access to an enriched environment, and access to social interaction. It is hypothesized that pharmacological agents that specifically augment dentate gyrus-specific neurogenesis may benefit patients suffering from cognitive deficits. Over the past three years the investigators authoring this application have conducted an unbiased in vivo screen to identify drug-like chemicals capable of stimulating hippocampal neurogenesis. These efforts have led to the discovery of eight distinct, pro-neurogenic compounds. One of these compounds has been found to be orally bioavailable, endowed with a favorable half life, capable of crossing the blood brain barrier, and devoid of toxicity following multi-month administration at a level 10X the minimal therapeutic dose. Detailed studies have shown that this most advanced compound enhances both the birth and survival of hippocampal neurons. The putative efficacies of these eight compounds are being studied in an animal model of schizophrenia unique to the laboratory of the investigators. Likewise, biochemical methods will be employed to identify the molecular targets of as many of the eight pro-neurogenic compounds as possible. It is hoped that this work will provide a basis for the discovery of new treatment options for patients suffering from cognitive deficits associated with mental illness.
Deficits in learning, memory, attention and decision-making represent chronically disabling aspects of many forms of mental illness and age-related decline in mental capacity. Cognitive dysfunction has been linked to deficient functioning of the hippocampal formation of the brain. McKnight and Pieper seek to augment hippocampal functioning through pharmacologic agents that stimulate the birth and functional incorporation of new neurons in this region of the brain. Our goal is to provide a basis for the discovery of new treatment options for patients suffering from cognitive deficits.
|Walker, A K; Rivera, P D; Wang, Q et al. (2015) The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis. Mol Psychiatry 20:500-8|
|Blaya, Meghan O; Bramlett, Helen M; Naidoo, Jacinth et al. (2014) Neuroprotective efficacy of a proneurogenic compound after traumatic brain injury. J Neurotrauma 31:476-86|
|Yin, Terry C; Britt, Jeremiah K; De Jesús-Cortés, Héctor et al. (2014) P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury. Cell Rep 8:1731-40|
|Naidoo, Jacinth; De Jesus-Cortes, Hector; Huntington, Paula et al. (2014) Discovery of a neuroprotective chemical, (S)-N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [(-)-P7C3-S243], with improved druglike properties. J Med Chem 57:3746-54|
|Pieper, Andrew A; McKnight, Steven L; Ready, Joseph M (2014) P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases. Chem Soc Rev 43:6716-26|
|Wang, Gelin; Han, Ting; Nijhawan, Deepak et al. (2014) P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell 158:1324-34|
|MacMillan, Karen S; Naidoo, Jacinth; Liang, Jue et al. (2011) Development of proneurogenic, neuroprotective small molecules. J Am Chem Soc 133:1428-37|
|Pieper, Andrew A; Xie, Shanhai; Capota, Emanuela et al. (2010) Discovery of a proneurogenic, neuroprotective chemical. Cell 142:39-51|