The Role of Neurogenesis in Neurodegenerative Diseases and its Implications for Therapeutic Development
Abstract:Neurodegenerative diseases are characterised by a net loss of neurons from specific regions of the central nervous system (CNS). Until recently, research has focused on identifying mechanisms that lead to neurodegeneration, while therapeutic approaches have been primarily targeted to prevent neuronal loss. This has had limited success and marketed pharmaceuticals do not have dramatic benefits. Here we suggest that the future success of therapeutic strategies will depend on consideration and understanding of the role of neurogenesis in the adult CNS. We summarize evidence suggesting that neurogenesis is impaired in neurodegenerative diseases such as Parkinson's, Alzheimer's and Amyotrophic Lateral Sclerosis, while it is enhanced in stroke. We review studies where stimulation of neurogenesis is associated with restored function in animal models of these diseases, suggesting that neurogenesis is functionally important. We show that many current therapeutics, developed to block degeneration or to provide symptomatic relief, serendipitously stimulate neurogenesis or, at least, do not interfere with it. Importantly, many receptors, ion channels and ligand-gated channels implicated in neurodegeneration, such as NMDA, AMPA, GABA and nicotinic acetylcholine receptors, also play an important role in neurogenesis and regeneration. Therefore, new therapeutics targeted to block degeneration by antagonizing these channels may have limited benefit as they may also block regeneration. Our conclusion is that future drug development must consider neurogenesis. It appears unlikely that drugs being developed to treat neurodegenerative diseases will be beneficial if they impair neurogenesis. And, most tantalizing, therapeutic approaches that stimulate neurogenesis might stimulate repair and even recovery from these devastating diseases.
Document Type: Research Article
Publication date: April 1, 2008
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- CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.