An unbiased discovery approach has identified chemically distinct compounds that safely enhance hippocampal neurogenesis in living animals.
Medicines aimed at enhancing neuronal survival, growth, development and function hold promise for developing new and effective treatment strategies directed at a wide variety of neuropsychiatric and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, schizophrenia, major depression, stroke, traumatic brain injury, mental retardation, cognitive decline associated with aging, amyotrophic lateral sclerosis and spinocerebellar ataxia. An experimental window for studying the complicated physiologic process of birth, growth, development, and death of neurons has fortunately been provided by nature in the dentate gyrus of the adult hippocampus, a region of the brain that is critically involved in mood and cognitive functioning. The dentate gyrus exhibits the birth and death of thousands of new neurons every day throughout development and adulthood. These newborn neurons can readily be quantified through immunohistochemical detection of a nucleotide analog that is incorporated into replicating cells in the brain following routine peripheral administration to animals, as illustrated below (depicted by black dots).
Four years ago we embarked on an unconventional initiative of in vivo screening in living mice to identify chemical compounds having pro-neurogenic efficacy in the adult mouse hippocampus. Rather than focus on suspected mechanisms of regulating hippocampal neurogenesis, we designed our screen to be blind to physiologic mechanism, with the simple goal of discovering new molecules that function in the intact animal to safely enhance neurogenesis. This unbiased in vivo screening approach has allowed accurate and reproducible assessment of pro-neurogenic efficacy of small molecules that are, by definition of our screening approach, safely tolerated in the living organism. Our work has culminated in the discovery and characterization of eight chemically distinct compounds that enhance hippocampal neurogenesis in living mice. The chemical diversity represented by these eight compounds indicates that most, if not all, will exert their pro-neurogenic effect via entirely distinct molecular targets.