Insulin restores metabolic function in cultured cortical neurons subjected to oxidative stress.
We previously demonstrated that insulin has a neuroprotective role against oxidative stress, a deleterious condition associated with diabetes, ischemia, and age-related neurodegenerative diseases. In this study, we investigated the effect of insulin on neuronal glucose uptake and metabolism after oxidative stress in rat primary cortical neurons. On oxidative stress, insulin stimulates neuronal glucose uptake and subsequent metabolism into pyruvate, restoring intracellular ATP and phosphocreatine. Insulin also increases intracellular and decreases extracellular adenosine, counteracting the effect of oxidative stress. Insulin effects are apparently mediated by phosphatidylinositol 3-K and extracellular signal-regulated kinase signaling pathways. Extracellular adenosine under oxidative stress is largely inhibited after blockade of ecto-5'-nucleotidase, suggesting that extracellular adenosine results preferentially from ATP release and catabolism. Moreover, insulin appears to interfere with the ATP release induced by oxidative stress, regulating extracellular adenosine levels. In conclusion, insulin neuroprotection against oxidative stress-mediated damage involves 1) stimulation of glucose uptake and metabolism, increasing energy levels and intracellular adenosine and, ultimately, uric acid formation and 2) a decrease in extracellular adenosine, which may reduce the facilitatory activity of adenosine receptors.
Duarte
Ana I
AI
Department of Zoology, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
Proença
Teresa
T
Oliveira
Catarina R
CR
Santos
Maria S
MS
Rego
A Cristina
AC
D000227:Adenine Nucleotides / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D002867:Chromones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress; D010725:Phosphocreatine / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077191:Wortmannin
D000227:Adenine Nucleotides; D000730:Androstadienes; D002867:Chromones; D005419:Flavonoids; D007328:Insulin; D009025:Morpholines; D010725:Phosphocreatine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019344:Lactic Acid; D013868:Thioinosine; D019289:Pyruvic Acid; C001789:4-nitrobenzylthioinosine; D005947:Glucose; D000241:Adenosine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin