Orally administered melatonin reduces oxidative stress and proinflammatory cytokines induced by amyloid‐β peptide in rat brain: a comparative, in vivo study versus vitamin C and E

Abstract: To determine the efficacy of antioxidants in reducing amyloid‐β‐induced oxidative stress, and the neuroinflammatory response in the central nervous system (CNS) in vivo, three injections of fibrillar amyloid‐β (fAβ) or artificial cerebrospinal fluid (aCSF) into the CA1 region of the hippocampus of the rat were made. Concomitantly, one of the three free radical scavengers, i.e. melatonin, vitamin C, or vitamin E was also administered. Besides being a free radical scavenger, melatonin also has immunomodulatory functions. Antioxidant treatment reduced significantly oxidative stress and pro‐inflammatory cytokines. There were no marked differences between melatonin, vitamin C, and vitamin E regarding their capacity to reduce nitrites and lipoperoxides. However, melatonin exhibited a superior capacity to reduce the pro‐inflammatory response induced by fAβ.

[1]  George Perry,et al.  The neuroprotective activities of melatonin against the Alzheimer β‐protein are not mediated by melatonin membrane receptors , 2002, Journal of pineal research.

[2]  R. Reiter Melatonin: Lowering the High Price of Free Radicals. , 2000, News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society.

[3]  M. Meltz,et al.  EFFECT OF MELATONIN ON NF‐κB DNA‐BINDING ACTIVITY IN THE RAT SPLEEN , 1996 .

[4]  S. Cuzzocrea,et al.  Pharmacological action of melatonin in shock, inflammation and ischemia/reperfusion injury. , 2001, European journal of pharmacology.

[5]  M. Mattson,et al.  Alzheimer's disease. Amyloid ox-tox transducers. , 1996, Nature.

[6]  R. Reiter,et al.  Genotoxicity of paraquat: micronuclei induced in bone marrow and peripheral blood are inhibited by melatonin. , 2000, Mutation research.

[7]  W. Pryor,et al.  Reaction of peroxynitrite with melatonin: A mechanistic study. , 1999, Chemical research in toxicology.

[8]  M. Meltz,et al.  Effect of melatonin on NF-kappa-B DNA-binding activity in the rat spleen. , 1996, Cell biology international.

[9]  L. Swanson The Rat Brain in Stereotaxic Coordinates, George Paxinos, Charles Watson (Eds.). Academic Press, San Diego, CA (1982), vii + 153, $35.00, ISBN: 0 125 47620 5 , 1984 .

[10]  M. Mattson,et al.  Amyloid ox–tox transducers , 1996, Nature.

[11]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[12]  B. Yankner,et al.  Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[13]  R. Reiter,et al.  Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide , 1997, The Journal of Neuroscience.

[14]  H. Wong,et al.  Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: role of inhibition of NFκB activation , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  F. Holsboer,et al.  High Constitutive NFk B Activity Mediates Resistance to Oxidative Stress in Neuronal Cells , 1998 .

[16]  R. Reiter,et al.  Significance of Melatonin in Antioxidative Defense System: Reactions and Products , 2000, Neurosignals.

[17]  T. Bayer,et al.  Subacute NO generation induced by Alzheimer's β‐amyloid in the living brain: reversal by inhibition of the inducible NO synthase , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  F. Marcheselli,et al.  Melatonin: a peroxyl radical scavenger more effective than vitamin E. , 1994, Life sciences.

[19]  Josep M. Guerrero,et al.  Inhibition of cerebellar nitric oxide synthase and cyclic GMP production by melatonin via complex formation with calmodulin , 1997, Journal of cellular biochemistry.

[20]  K. Iqbal,et al.  Alzheimer's disease : biology, diagnosis, and therapeutics , 1996 .

[21]  S. Weintraub,et al.  Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation. , 2000, Free radical biology & medicine.

[22]  H. Esterbauer,et al.  Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. , 1990, Methods in enzymology.

[23]  G. Maestroni,et al.  Melatonin as a therapeutic agent in experimental endotoxic shock , 1996, Journal of pineal research.

[24]  D. Selkoe,et al.  Alzheimer's Disease: A Central Role for Amyloid , 1994, Journal of neuropathology and experimental neurology.

[25]  C. Behl,et al.  Hydrogen peroxide mediates amyloid beta protein toxicity. , 1994, Cell.

[26]  R. Reiter,et al.  Melatonin-immune system relationships. , 2002, Current topics in medicinal chemistry.

[27]  C. Gentile,et al.  The chemistry of melatonin's interaction with reactive species , 2003, Journal of pineal research.

[28]  D. Praticò,et al.  Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease. , 2000, The American journal of medicine.

[29]  S D Rogers,et al.  Fibrillar b-Amyloid Induces Microglial Phagocytosis , Expression of Inducible Nitric Oxide Synthase , and Loss of a Select Population of Neurons in the Rat CNS In Vivo , 1998 .

[30]  J. Knipe,et al.  Pharmacokinetics and oral bioavailability of exogenous melatonin in preclinical animal models and clinical implications , 1997, Journal of pineal research.