title: Target- and mechanism-based therapeutics for neurodegenerative diseases: strength in numbers.
abstract: The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this Perspective we examine recent progress in the areas of neurodegenerative drug discovery, focusing on some of the most common targets and mechanisms: N-methyl-d-aspartic acid (NMDA) receptors, voltage gated calcium channels (VGCCs), neuronal nitric oxide synthase (nNOS), oxidative stress from reactive oxygen species, and protein aggregation. These represent the key players identified in neurodegeneration and are part of a complex, intertwined signaling cascade. The synergistic delivery of two or more compounds directed against these targets, along with the design of small molecules with multiple modes of action, should be explored in pursuit of more effective clinical treatments for neurodegenerative diseases.
authors: Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
authors: Paul C
authors: PC
authors: Trippier
authors: Kristin
authors: K
authors: Jansen Labby
authors: Dustin D
authors: DD
authors: Hawker
authors: Jan J
authors: JJ
authors: Mataka
authors: Richard B
authors: RB
authors: Silverman
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology; D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology; D000975:Antioxidants / Q000627:therapeutic use; D015220:Calcium Channels / Q000187:drug effects; D004338:Drug Combinations; D015195:Drug Design; D006801:Humans; D006816:Huntington Disease / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000503:physiopathology; D017510:Protein Folding / Q000187:drug effects; D020836:Protein Structure, Quaternary / Q000187:drug effects; D057165:Proteostasis Deficiencies / Q000503:physiopathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects
chemical_list: D000975:Antioxidants; D015220:Calcium Channels; D004338:Drug Combinations; D016194:Receptors, N-Methyl-D-Aspartate; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I