Extracellular ADP prevents neuronal apoptosis via activation of cell antioxidant enzymes and protection of mitochondrial ANT-1.
Apoptosis in neuronal tissue is an efficient mechanism which contributes to both normal cell development and pathological cell death. The present study explores the effects of extracellular ADP on low [K(+)]-induced apoptosis in rat cerebellar granule cells. ADP, released into the extracellular space in brain by multiple mechanisms, can interact with its receptor or be converted, through the actions of ectoenzymes, to adenosine. The findings reported in this paper demonstrate that ADP inhibits the proapoptotic stimulus supposedly via: i) inhibition of ROS production during early stages of apoptosis, an effect mediated by its interaction with cell receptor/s. This conclusion is validated by the increase in SOD and catalase activities as well as by the GSSG/GSH ratio value decrease, in conjunction with the drop of ROS level and the prevention of the ADP protective effect by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), a novel functionally selective antagonist of purine receptor; ii) safeguard of the functionality of the mitochondrial adenine nucleotide-1 translocator (ANT-1), which is early impaired during apoptosis. This effect is mediated by its plausible internalization into cell occurring as such or after its hydrolysis, by means of plasma membrane nucleotide metabolizing enzymes, and resynthesis into the cell. Moreover, the findings that ADP also protects ANT-1 from the toxic action of the two Alzheimer's disease peptides, i.e. Aβ1-42 and NH2htau, which are known to be produced in apoptotic cerebellar neurons, further corroborate the molecular mechanism of neuroprotection by ADP, herein proposed.
Institute of Biomembranes and Bioenergetics, CNR, Bari, Italy.
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Bobba
Institute of Translational Pharmacology, CNR, Roma, Italy.
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Amadoro
Clinical and Preclinical Pharmacology Lab, National Cancer Research Centre, Istituto Tumori G. Paolo II, Bari, Italy.
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Azzariti
Department of Health Sciences, University of Molise, Campobasso, Italy.
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Pizzuto
Institute of Biomembranes and Bioenergetics, CNR, Bari, Italy. Electronic address: a.atlante@ibbe.cnr.it.
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Atlante
D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016875:tau Proteins / Q000633:toxicity
D033741:Adenine Nucleotide Translocator 1; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D016875:tau Proteins; D000244:Adenosine Diphosphate; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
ADP; Adenine nucleotide translocator; Antioxidant enzyme; Apoptosis; Mitochondria; Protection