title: A compound CP-31398 suppresses excitotoxicity-induced neurodegeneration.
abstract: Neurodegeneration causes dysfunction and degeneration of neurons and is triggered by various factors including genetic defects, free radicals, injury, and glutamate excitotoxicity. Among those, glutamate excitotoxicity is implicated in chronic disorders including AD and ALS, and in acute insults in the CNS including traumatic brain injury. Neurological disorders show hallmark morphological abnormalities such as axon degeneration and cell body death. The molecular mechanisms underlying excitotoxicity-induced neurodegeneration are complex and deciphering a molecular mechanism from one angle is beneficial to understand the process, however, still difficult to develop strategies to suppress excitotoxicity-induced degeneration due to existence of other mechanisms. Thus, directly identifying compounds that can modulate excitotoxicity-induced neurodegeneration and subsequently clarifiying the molecular mechanism is a valid approach to develop effective strategies to suppress neurodegeneration. We searched for compounds that can suppress excitotoxicity-induced neurodegeneration and found that CP-31398, a known compound that can rescue the structure and function of the tumor suppressor protein p53 mutant form and stabilize the active conformation of the p53 wild-type form, suppresses excitotoxicity-induced axon degeneration and cell body death. Moreover, CP-31398 suppresses mitochondrial dysfunction which has a strong correlation with excitotoxicity. Thus, our findings identify a compound that can serve as a novel modulator of neurodegeneration induced by glutamate excitotoxicity.
authors.affiliation: Biomolecular Dynamics Laboratory, Department of Biomolecular Networks, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan. Electronic address: fujiwara@anat3.med.osaka-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Koji
authors.initials: K
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D010088:Oxidoreductases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018691:Excitatory Amino Acid Antagonists; D011743:Pyrimidines; D018698:Glutamic Acid; D010088:Oxidoreductases; C402665:CP 31398
keywords: 4′,6′-diamidino-2-phenylindole; AD; ALS; Alzheimer’s disease; CNS; CP-31398; DAPI; DIV; Excitotoxicity; GFP; Mitochondrial dysfunction; Neurodegeneration; N′-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride; PD; PI; Parkinson’s disease; amyotrophic lateral sclerosis; central nervous system; days in vitro; green fluorescent protein; p53; propidium iodide