Melatonin alters cell death processes in response to age-related oxidative stress in the brain of senescence-accelerated mice.
We studied the effect of age and melatonin on cell death processes in brain aging. Senescence-accelerated prone mice 8 (SAMP8) and senescence-accelerated resistant mice (SAMR1) at 5 and 10 months of age were used as models of the study. Melatonin (10 mg/kg) or its vehicle (ethanol at 0.066%) was administered in the drinking water from 1 to 9 months of age. Neurodegeneration, previously shown in the aged brain of SAMP8 and SAMR1 at 10 months of age, may be due to a drop in age-related proteolytic activities (cathepsin D, calpains, and caspase-3). Likewise, lack of apoptotic and macroautophagic processes were found, without apparent modification by melatonin. However, the caspase-independent cell death, owing to high p53 and apoptosis-inducing factor (AIF) levels, might be an alternative pathway of cell death in the aged brain. The main effects of melatonin treatment were observed in the aged SAMR1 mice; in this strain we observed a marked increase in antioxidant activity (catalase and superoxide dismutase). Likewise, a key antioxidant role of apoptosis-related proteins, Bcl-2 and AIF, was suggested in the aged brain of SAM mice, which was clearly influenced by melatonin. Moreover, the age-related increase of lysosomal activity of cathepsin B and a lysosomal membrane-associated protein 2 supports the possibility of the maintenance of lysosomal viability in addition to age-related impairments of the proteolytic or macroautophagic activities. The effectiveness of melatonin against the oxidative stress-related impairments and apoptosis during the aging process is, once more, corroborated in this article.
Caballero
Beatriz
B
Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain.
Vega-Naredo
Ignacio
I
Sierra
Verónica
V
Huidobro-Fernández
Covadonga
C
Soria-Valles
Clara
C
De Gonzalo-Calvo
David
D
Tolivia
Delio
D
Pallás
Mercé
M
Camins
Antonio
A
Rodríguez-Colunga
María Josefa
MJ
Coto-Montes
Ana
A
D019588:Aging, Premature / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D005980:Glutathione Reductase / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018709:Statistics, Nonparametric; D013482:Superoxide Dismutase / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494828:Bax protein, rat; D052119:Lysosomal-Associated Membrane Protein 2; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D002374:Catalase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D002402:Cathepsin D; D008550:Melatonin