title: Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis.
abstract: Caspase-mediated cell death contributes to the pathogenesis of motor neuron degeneration in the mutant SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS), along with other factors such as inflammation and oxidative damage. By screening a drug library, we found that melatonin, a pineal hormone, inhibited cytochrome c release in purified mitochondria and prevented cell death in cultured neurons. In this study, we evaluated whether melatonin would slow disease progression in SOD1(G93A) mice. We demonstrate that melatonin significantly delayed disease onset, neurological deterioration and mortality in ALS mice. ALS-associated ventral horn atrophy and motor neuron death were also inhibited by melatonin treatment. Melatonin inhibited Rip2/caspase-1 pathway activation, blocked the release of mitochondrial cytochrome c, and reduced the overexpression and activation of caspase-3. Moreover, for the first time, we determined that disease progression was associated with the loss of both melatonin and the melatonin receptor 1A (MT1) in the spinal cord of ALS mice. These results demonstrate that melatonin is neuroprotective in transgenic ALS mice, and this protective effect is mediated through its effects on the caspase-mediated cell death pathway. Furthermore, our data suggest that melatonin and MT1 receptor loss may play a role in the pathological phenotype observed in ALS. The above observations indicate that melatonin and modulation of Rip2/caspase-1/cytochrome c or MT1 pathways may be promising therapeutic approaches for ALS.
authors.affiliation: Neuroapoptosis Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Anna
authors.initials: A
authors.lastname: Cook
authors.forename: Jinho
authors.initials: J
authors.lastname: Kim
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Baranov
authors.forename: Jiying
authors.initials: J
authors.lastname: Jiang
authors.forename: Karen
authors.initials: K
authors.lastname: Smith
authors.forename: Kerry
authors.initials: K
authors.lastname: Cormier
authors.forename: Erik
authors.initials: E
authors.lastname: Bennett
authors.forename: Robert P
authors.initials: RP
authors.lastname: Browser
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Day
authors.forename: Diane L
authors.initials: DL
authors.lastname: Carlisle
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Robert M
authors.initials: RM
authors.lastname: Friedlander
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects* / Q000941:ethics*; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D008550:Melatonin / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D000975:Antioxidants; D044122:Receptor, Melatonin, MT1; D045304:Cytochromes c; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D053148:Caspase 3; D008550:Melatonin
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