Melatonin’s Neuroprotective Actions on Hippocampal Neurons

  • Pooja SuhalkaEmail author
  • Chhavi Sharma
  • Neha Jaiswal
  • Piyu Sukhwal
  • Reena Chittora
  • Ayushi Jain
  • Maheep Bhatnagar


Melatonin is the pineal hormone, is an indoleamine, and has a persuasive role in the biological regulation of circadian rhythm, sleep–mood disorders, immunoregulation, cancer, neurodegenerative disorders, and aging. It passively diffuses into the bloodstream, exerting maximum effectiveness and protective action. This protective action is due to direct free radical scavenging and indirect antioxidative effects, especially in cases of neurodegenerative disorders like Alzheimer’s and Parkinson’s disease whose pathogenesis is associated with the cytotoxic effects of free radicals. Melatonin also promotes neurogenesis in adults, thus affecting hippocampal functions and enhancing cognitive and behavioral activities. Therapeutic trials with melatonin have been effective also in slowing down the progression of some neurodegenerative disorders. Studies suggest that melatonin have clinical potential for the treatment of neurodegenerative diseases.


Hippocampus Melatonin Neuroprotection Oxygen free radicals Neurodegenerative diseases Adult neurogenesis 





Protein kinase B (PKB)


Cornu ammonis 1


Calcium2+ ion


Cornu ammonis 3




Gamma-aminobutyric acid


Glutathione peroxidase


Reduced glutathione


Kainic acid kainate




Melatonin receptor 1


Melatonin receptor 2


Nicotinamide adenine dinucleotide phosphate-diaphorase




Neuronal nitric oxide synthase


Nitric oxide


Phosphatidylinositide 3-kinases


Reactive oxygen species


Superoxide dismutase


  1. 1.
    Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005;9:11–24.PubMedGoogle Scholar
  2. 2.
    Reiter RJ, Tan DX. Role of CSF in the transport of melatonin. J Pineal Res. 2002;33:61.PubMedGoogle Scholar
  3. 3.
    Zizapel N. Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting. Cell Mol Neurobiol. 2001;21:605–16.Google Scholar
  4. 4.
    Wurtman RJ, Zhdanova I. Improvement of sleep quality by melatonin. Lancet. 1995;346:1491.PubMedGoogle Scholar
  5. 5.
    Reiter RJ. The pineal and its hormone in the control of reproduction in mammals. Endocr Rev. 1980;1:109–31.PubMedGoogle Scholar
  6. 6.
    Reiter RJ, Tan DX. Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res. 2003;58:10–9.PubMedGoogle Scholar
  7. 7.
    Anton Tay F, Dfaz JL, Fernandez-guardiola A. On the effect of melatonin upon human brain: it’s possible therapeutic implications. Life Sci. 1971;10:841–50.Google Scholar
  8. 8.
    Lanas O, Olinescu R, Badescu I. Melatonin involvement in oxidation processes. Endocrinologie. 1991;29:147–53.Google Scholar
  9. 9.
    Reiter RJ. Cytoprotective properties of melatonin: presumed association with oxidative damage and aging. Nutrition. 1998;14:691–6.PubMedGoogle Scholar
  10. 10.
    Srinivasan V. Melatonin, oxidative stress and ageing. Curr Sci. 1999;76:46–54.Google Scholar
  11. 11.
    Tan DX, Manchester LC, Reiter RJ, et al. Significance of melatonin in antioxidative defense system: reactions and products. Biol Signals Recept. 2000;9:137–59.PubMedGoogle Scholar
  12. 12.
    Reiter RJ, Tan D-X, Leon J, Kilic U, Kilic E. When melatonin gets on your nerves: its beneficial actions in experimental models of stroke. Exp Biol Med (Maywood). 2005;230:104–17.Google Scholar
  13. 13.
    Tan DX, Reiter RJ, Manchester LC, et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem. 2002;2:181–97.PubMedGoogle Scholar
  14. 14.
    Reiter RJ. Oxidative damage in the central nervous system: protection by melatonin. Prog Neurobiol. 1998;56:359–84.PubMedGoogle Scholar
  15. 15.
    Tan DX, Chen LD, Poeggeler B, et al. Melatonin: a potent endogenous hydroxyl radical scavenger. Endocr J. 1993;1:57–60.Google Scholar
  16. 16.
    Reiter RJ, Acuna-Castroviejo D, Tan DX, Burkhardt S. Free radical–mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Ann N Y Acad Sci. 2001;939:200–15.PubMedGoogle Scholar
  17. 17.
    Kilic E, Kilic V, Yulug B, et al. Melatonin reduces disseminates neuronal death after mild focal ischemia in mice via inhibition of caspase-3 and is suitable as an add-on treatment to tissue-plasminogen activator. J Pineal Res. 2004;36:171–6.PubMedGoogle Scholar
  18. 18.
    Kim M, Kim HK, Kim BS, Yim S. Melatonin increases cell proliferation in the dentate gyrus of maternally separated rats. J Pineal Res. 2004;37:193–7.PubMedGoogle Scholar
  19. 19.
    Lissoni P, Barni S, Meregalli S, et al. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patient progressing under tamoxifen alone. Br J Cancer. 1995;71:854–6.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Floreani M, Skaper SD, Facci L, Lipartiti M, Giusti P. Melatonin maintains glutathione homeostasis in kainic acid-exposed rat brain tissues. FASEB J. 1997;11:1309–15.PubMedGoogle Scholar
  21. 21.
    Sainz RM, Mayo JC, Rodriguez C, et al. Melatonin and cell death: differential actions on apoptosis and cancer cells. Cell Mol Life Sci. 2003;60:1407–26.PubMedGoogle Scholar
  22. 22.
    Stephen DS, Biancamaria A, Laura F, Davide F, Pietro G. Melatonin prevents the delayed death of hippocampal neurons by enhanced excitatory neurotransmission and the nitridergic pathway. FASEB J. 1998;12:725–31.Google Scholar
  23. 23.
    Pang SF, Tsang CW, Hong GX, Yip PC, Tang PL, Brown GM. Fluctuation of blood melatonin concentrations with age: result of changes in pineal melatonin secretion, body growth, and aging. J Pineal Res. 1990;8:179–92.PubMedGoogle Scholar
  24. 24.
    Hogan MV, El-Sherif Y, Wieraszko A. The modulation of neuronal activity by melatonin: in vitro studies on mouse hippocampal slices. J Pineal Res. 2001;309:87–96.Google Scholar
  25. 25.
    El-Sherif Y, Hogan MV, Tesoriero J, Wieraszko A. Factors regulating the influence of melatonin on hippocampal evoked potentials: comparative studies on different strains of mice. Brain Res. 2002;945:191–201.PubMedGoogle Scholar
  26. 26.
    Dubocovich ML, Hudson RL, Sumaya IC, Masana MI, Manna E. Effect of MT1 melatonin receptor deletion on melatonin mediated phase shift of circadian rhythms in the C57BL/6 mouse. J Pineal Res. 2005;39:113–20.PubMedGoogle Scholar
  27. 27.
    Dubocovich ML. Melatonin receptors: role on sleep and circadian rhythm regulation. Sleep Med. 2007;8(3):34–42.PubMedGoogle Scholar
  28. 28.
    Benitez-King G, Huerto-Delgadillo L, Anton-Tay F. Binding of 3H-melatonin to calmodulin. Life Sci. 1993;53:201–7.PubMedGoogle Scholar
  29. 29.
    Benitez-King G, Hernandez ME, Tovar R, Ramirez G. Melatonin activates PKC-alpha but not PKC-epsilon in N1E-115 cells. Neurochem Int. 2001;39:95–102.PubMedGoogle Scholar
  30. 30.
    Soto-Vega E, Meza I, Ramirez-Rodriguez G, Benitez-King G. Melatonin stimulates calmodulin phosphorylation by protein kinase C. J Pineal Res. 2004;37:98–106.PubMedGoogle Scholar
  31. 31.
    Reiter RJ. The melatonin rhythm: both a clock and a calendar. Experientia. 1993;49:654–64.PubMedGoogle Scholar
  32. 32.
    Dawson D, Armstrong SM. Chronobiotics–drugs that shift rhythms. Pharmacol Ther. 1996;69:15–36.PubMedGoogle Scholar
  33. 33.
    Kunz D. Chronobiotic protocol and circadian sleep propensity index: new tools for clinical routine and research on melatonin sleep. Pharmacopsychiatry. 2004;37:139–46.PubMedGoogle Scholar
  34. 34.
    Hardeland R, Pandi-Perumal SR, Cardinali DP. Molecules in focus–melatonin. Int J Biochem Cell Biol. 2006;38:313–6.PubMedGoogle Scholar
  35. 35.
    Esquifino AI, Pandi-Perumal SR, Cardinali DP. Circadian organization of the immune response: a role for melatonin. Clin Appl Immunol Rev. 2004;4:423–33.Google Scholar
  36. 36.
    Guerrero JM, Reiter RJ. Melatonin-immune system relationships. Curr Top Med Chem. 2002;2:167–79.PubMedGoogle Scholar
  37. 37.
    Monti JM, Alvarino F, Cardinali DP, Savio I, Pintos A. Polysomnographic study of the effect of melatonin on sleep in elderly patients with chronic primary insomnia. Arch Gerontol Geriatr. 1999;28:85–98.PubMedGoogle Scholar
  38. 38.
    Doolen S, Krause DN, Dubocovich ML, Duckles SP. Melatonin mediates two distinct responses in vascular smooth muscle. Eur J Pharmacol. 1998;345:67–9.PubMedGoogle Scholar
  39. 39.
    Scheer FA, Van Montfrans GA, van Someren EJ, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. 2004;43:192–7.PubMedGoogle Scholar
  40. 40.
    Blask DE, Sauer LA, Dauchy C. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem. 2002;2:113–32.PubMedGoogle Scholar
  41. 41.
    Srinivasan V. Psychoactive drugs, pineal gland and affective disorders. Prog Neuropsycopharmacol Biol Psychiatry. 1989;13:653–64.Google Scholar
  42. 42.
    Srinivasan V. The pineal gland, its physiological and pharmacological role. Indian J Physiol Pharmacol. 1989;33:263–72.PubMedGoogle Scholar
  43. 43.
    Srinivasan V. Melatonin, biological rhythm disorders and phototherapy. Indian J Physiol Pharmacol. 1997;41:309–28.PubMedGoogle Scholar
  44. 44.
    Wiechmann AF. Melatonin parallels in pineal gland and retina. Exp Eye Res. 1986;42:507–27.PubMedGoogle Scholar
  45. 45.
    Marchiafava PL, Longoni B. Melatonin as an antioxidant in retinal photoreceptors. J Pineal Res. 1999;26:184–9.PubMedGoogle Scholar
  46. 46.
    Liang FQ, Green L, Wang C, Alssadi R, Godley BF. Melatonin protects human retinal pigment epithelial cells against oxidative stress. Exp Eye Res. 2004;78:1069–75.PubMedGoogle Scholar
  47. 47.
    Uchida K, Okamoto N, Ohara K, Morita Y. Daily rhythm of serum melatonin in patients with dementia of degenerative type. Brain Res. 1996;717:154–9.PubMedGoogle Scholar
  48. 48.
    Mesulam MM. Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron. 1999;24(3):521–9.PubMedGoogle Scholar
  49. 49.
    Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P. β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286(5440):735–41.PubMedGoogle Scholar
  50. 50.
    Pappolla MA, Chyan YJ, Omar RA, Hsiao K, Perry G, Smith MA, Bozner P. Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer’s disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. Am J Pathol. 1998;152:871–7.PubMedGoogle Scholar
  51. 51.
    Blanchard B, Pompon D, Ducrocq C. Nitrosation of melatonin by nitric oxide and peroxynitrite. J Pineal Res. 2000;29:184–92.PubMedGoogle Scholar
  52. 52.
    Pappolla MA, Chyan Y-J, Poeggeler B, Frangione B, Wilson G, Ghiso J, Reiter RJ. An assessment of the antioxidant antiamyloidogenic properties of melatonin: implications for Alzheimer’s disease. J Neural Transm. 2000;107:203–31.PubMedGoogle Scholar
  53. 53.
    Ferrari E, Arcaini A, Gornati R, Pelanconi L, Cravello L, Fioravanti M, Solerte SB, Magri F. Pineal and pituitary-adrenocortical function in physiological aging and in senile dementia. Exp Gerontol. 2000;35:1239–50.PubMedGoogle Scholar
  54. 54.
    Cardinali DP, Brusco LI, Liberczuk C, Furio AM. The use of melatonin in Alzheimer’s disease. Neuro Endocrinol Lett. 2002;23:20–3.PubMedGoogle Scholar
  55. 55.
    Srinivasan V, Pandi-Perumal SR, Maestroni GJM, Esquifino AI, Hardeland R, Cardinali DP. Role of melatonin in neurodegenerative diseases. Neurotox Res. 2005;7:293–318.PubMedGoogle Scholar
  56. 56.
    Magri F, Locatelli M, Balza G, et al. Changes in endocrine circadian rhythms as marker of physiological and pathological brain aging. Chronobiol Int. 1997;14:385–96.PubMedGoogle Scholar
  57. 57.
    Skene DJ, Swaab DF. Melatonin rhythmicity: effects of age and Alzheimer’s disease. Exp Gerontol. 2003;38:199–206.PubMedGoogle Scholar
  58. 58.
    Beal MF. Mitochondria, free radicals and neurodegeneration. Curr Opin Neurol. 1996;6:661–6.Google Scholar
  59. 59.
    Skene DJ, Viven-Roels B, Sparks Hunsaker JC, et al. Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer’s disease. Brain Res. 1990;528:170–4.PubMedGoogle Scholar
  60. 60.
    Bordet R, Devos D, Brique S, et al. Study of circadian melatonin secretion pattern at different stages of Parkinson’s disease. Clin Neuropharmacol. 2003;26:65–72.PubMedGoogle Scholar
  61. 61.
    Poeggeler B. Melatonin, ageing and age-related diseases: perspectives for prevention, intervention and therapy. Endocrine. 2005;27:201–12.PubMedGoogle Scholar
  62. 62.
    Gupta YK, Gupta M, Kohli K. Neuroprotective role of melatonin in oxidative stress vulnerable brain. Indian J Physiol Pharmacol. 2003;47:373–86.PubMedGoogle Scholar
  63. 63.
    Lezoualc’h F, Skutella T, Widmann M, et al. Melatonin prevents oxidative stress-induced cell death in hippocampal cells. Neuroreport. 1996;7:2071–7.PubMedGoogle Scholar
  64. 64.
    Skaper SD, Ancona B, Facci L, et al. Melatonin prevents the delayed death of hippocampal neurons induced by enhanced excitatory neurotransmission and the nitridergic pathway. FASEB J. 1998;12:725–31.PubMedGoogle Scholar
  65. 65.
    Giusti P, Franceschini D, Petrone M, et al. In vitro and in vivo protection against kainate-induced excitotoxicity by melatonin. J Pineal Res. 1996;20:226–31.PubMedGoogle Scholar
  66. 66.
    Tan DX, Manchester LC, Reiter RJ, et al. Melatonin protects hippocampal neurons in vivo against kainic acid-induced damage in mice. J Neurosci Res. 1998;54:382–9.PubMedGoogle Scholar
  67. 67.
    Franceschini D, Skaper SD, Floreani M, et al. Further evidences for neuroprotective effects of melatonin. Adv Exp Med Biol. 1999;467:207–15.PubMedGoogle Scholar
  68. 68.
    Cagnoli CM, Atabay C, Kharlamova E, et al. Melatonin protects neurons from singlet oxygen-induced apoptosis. J Pineal Res. 1995;18:222–6.PubMedGoogle Scholar
  69. 69.
    Guerrero JM, Reiter RJ, Ortiz GG, et al. Melatonin prevents increases in neural nitric oxide and cyclic GMP production after transient brain ischemia and reperfusion in the Mongolian gerbil (Meriones unguiculatus). J Pineal Res. 1997;23:24–31.PubMedGoogle Scholar
  70. 70.
    Manev H, Uz T, Kharlamov A, et al. Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats. FASEB J. 1996;10:1546–51.PubMedGoogle Scholar
  71. 71.
    Joo JY, Uz T, Manev H. Opposite effects of pinealectomy and melatonin administration on brain damage following cerebral focal ischemia in rat. Restor Neurol Neurosci. 1998;13:185–91.PubMedGoogle Scholar
  72. 72.
    Tang YP, Ma YL, Chao CC, et al. Enhanced glial cell line-derived neurotrophic factor mRNA expression upon (−)-deprenyl and melatonin treatments. J Neurosci Res. 1998;53:593–604.PubMedGoogle Scholar
  73. 73.
    Anhe GF, Caperuto LC, Pereira-Da-Silva M, et al. In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus. J Neurochem. 2004;90:559–66.PubMedGoogle Scholar
  74. 74.
    Henshall DC, Araki T, Schindler CK, et al. Activation of Bcl-2-associated death protein and counter-response of Akt within cell populations during seizure-induced neuronal death. J Neurosci. 2002;22:8458–65.PubMedGoogle Scholar
  75. 75.
    Kim AH, Yano H, Cho H, et al. Akt1 regulates a JNK scaffold during excitotoxic apoptosis. Neuron. 2002;35:697–709.PubMedGoogle Scholar
  76. 76.
    Rodriguez C, Mayo JC, Sainz RM, et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res. 2004;36:1–9.PubMedGoogle Scholar
  77. 77.
    Giusti P, Gusella M, Lipartiti M, Milani D, Zhu W, Vicini S, Manev H. Melatonin protects primary cultures of cerebellar granule neurons from kainate but not from N-methyl-D aspartate excitotoxicity. Exp Neurol. 1995;133:39–46.Google Scholar
  78. 78.
    Cho S, Joh TH, Baik HH, Dibinis C, Volpe BT. Melatonin administration protects CA1 hippocampal neurons after transient forebrain ischemia in rats. Brain Res. 1997;755:335–8.PubMedGoogle Scholar
  79. 79.
    Uz T, Giusti P, Franceschini D, Kharlamov A, Manev H. Protective effect of melatonin against hippocampal DNA damage induced by intraperitoneal administration of kainate to rats. Neuroscience. 1996;73:631–6.PubMedGoogle Scholar
  80. 80.
    Mukherjee R, Desai F, Singh S, Gajaria T, Singh PK, Baxi DB, Sharma D, Bhatnagar M, Ramachandran AV. Melatonin protects against alterations in hippocampal cholinergic system, trace metals and oxidative stress induced by gestational and lactational exposure to cadmium. EXCLI J. 2010;9:119–32.Google Scholar
  81. 81.
    Lin AMY, Fang SF, Chao PL, et al. Melatonin attenuates arsenite-induced apoptosis in rat brain: involvement of mitochondrial and ER pathways and aggregation of a-synuclein. J Pineal Res. 2007;43:163–71.PubMedGoogle Scholar
  82. 82.
    Wang X. The antiapoptotic activity of melatonin in neurodegenerative diseases. CNS Neurosci Ther. 2009;15:345–57.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Harms C, Lautenschlager M, Bergk A, et al. Melatonin is protective in necrotic but not in caspase-dependent, free radical-independent apoptotic neuronal cell death in primary neuronal cultures. FASEB J. 2000;14:1814–24.PubMedGoogle Scholar
  84. 84.
    Camins A, Sureda FX, Junyent F, et al. An overview of investigational antiapoptotic drugs with potential application for the treatment of neurodegenerative disorders. Expert Opin Investig Drugs. 2010;19:587–604.PubMedGoogle Scholar
  85. 85.
    Guo Y, Wang J, Wang Z, et al. Melatonin protects N2 a against ischemia/reperfusion injury through autophagy enhancement. J Huazhong Univ Sci Technolog Med Sci. 2010;30:1–7.PubMedGoogle Scholar
  86. 86.
    Nopparat C, Porter J, Ebadi M, et al. The mechanism for the neuroprotective effect of melatonin against methamphetamine induced autophagy. J Pineal Res. 2010;49:382–9.PubMedGoogle Scholar
  87. 87.
    Kempermann G, Krebs J, Fabel K. The contribution of failing adult hippocampal neurogenesis to psychiatric disorders. Curr Opin Psychiatry. 2008;21:290–5.PubMedGoogle Scholar
  88. 88.
    Duman RS. Depression: a case of neuronal life and death? Biol Psychiatry. 2004;56:140–5.PubMedGoogle Scholar
  89. 89.
    Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10:1110–5.PubMedGoogle Scholar
  90. 90.
    Holmes A, Yang RJ, Murphy DL, Crawley JN. Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Neuropsychopharmacology. 2002;27:914–23.PubMedGoogle Scholar
  91. 91.
    Mueller AD, Pollock MS, Lieblich SE, Epp JR, Galea LA, Mistlberger RE. Sleep deprivation can inhibit adult hippocampal neurogenesis independent of adrenal stress hormones. Am J Physiol Regul Integr Comp Physiol. 2008;294:1693–703.Google Scholar
  92. 92.
    Moriya T, Horie N, Mitome M, Shinohara K. Melatonin influences the proliferative and differentiative activity of neural stem cells. J Pineal Res. 2007;42:411–8.PubMedGoogle Scholar
  93. 93.
    Kong X, Li X, Cai Z, Yang N, Liu Y, Shu J, et al. Melatonin regulates the viability and differentiation of rat midbrain neural stem cells. Cell Mol Neurobiol. 2008;28:569–79.PubMedGoogle Scholar
  94. 94.
    Collins DR, Davies SN. Melatonin blocks the induction of long term potentiation in an N-methyl-D-aspartate independent manner. Brain Res. 1997;767:162–5.PubMedGoogle Scholar
  95. 95.
    El-Sherif Y, Tesoriero J, Hogan MV, Wieraszko A. Melatonin regulates neuronal plasticity in the hippocampus. J Neurosci Res. 2003;72:454–60.PubMedGoogle Scholar
  96. 96.
    Nonno R, Lucini V, Stankov B, Fraschini F. 2-[125I] Iodomelatonin binding sites in the bovine hippocampus are not sensitive to guanine nucleotides. Neurosci Lett. 1995;194:113–6.PubMedGoogle Scholar
  97. 97.
    Reppert SM, Godson C, Mahle CD, et al. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the mellb melatonin receptor. Proc Natl Acad Sci U S A. 1995;92:8734–8.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Mazzuchelli C, Pannacci M, Nonno R, Lucini V, Fraschini F, Stankov BM. The melatonin receptor in the human brain: cloning experiments and distribution studies. Mol Brain Res. 1996;39:117–26.Google Scholar
  99. 99.
    Reppert SM. Melatonin receptors: molecular biology of a new family of G protein-coupled receptors. J Biol Rhythms. 1997;12:528–31.PubMedGoogle Scholar
  100. 100.
    Wan Q, Man H-Y, Liu F, Braunton J, Niznik HB, Pang SF, Brown GM, Wang YT. Differential modulation of GABAA receptor function by Mel1a and Mel1b receptors. Nat Neurosci. 1999;2:401–3.PubMedGoogle Scholar
  101. 101.
    Nosjean O, Nicolas JP, Klupsch F, Delagrange P, Canet E, Boutin JA. Comparative pharmacological studies of melatonin receptors: MT1, MT2 and MT3/QR2. Tissue distribution of MT3/QR2. Biochem Pharmacol. 2001;61:1369–79.PubMedGoogle Scholar
  102. 102.
    Von Gall C, Stehle JH, Weaver DR. Mammalian melatonin receptors: molecular biology and signal transduction. Cell Tissue Res. 2002;309:151–62.Google Scholar
  103. 103.
    Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron. 1994;13:1177–85.PubMedGoogle Scholar
  104. 104.
    Musshoff U, Riewenherm D, Berger E, Fauteck J-D, Speckmann E-J. Melatonin receptors in rat hippocampus: molecular and functional investigations. Hippocampus. 2002;12:165–75.PubMedGoogle Scholar
  105. 105.
    Nadel L. The hippocampus and space revisited. Hippocampus. 1991;1:221–9.PubMedGoogle Scholar
  106. 106.
    Eichenbaum H. The hippocampal system and declarative memory in animals. J Cogn Neurosci. 1992;4:217–31.PubMedGoogle Scholar
  107. 107.
    Zeise ML, Semm P. Melatonin lowers excitability of guinea pig hippocampal neurons in vitro. J Comp Physiol A. 1985;157:23–9.PubMedGoogle Scholar
  108. 108.
    Halliwell B, Gutteridge JM. Free radicals in biology and medicine, vol. 3. Oxford: Oxford University Press; 1999. p. 1–543.Google Scholar
  109. 109.
    Pei Z, Pang SF, Cheung RT. Administration of melatonin after onset of ischemia reduces the volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model. Stroke. 2003;34:770–5.PubMedGoogle Scholar
  110. 110.
    Jain A. In vitro and In vivo study of neuroprotective properties of melatonin. PhD thesis. Udaipur: Mohanlal Sukhadia University; 2009.Google Scholar
  111. 111.
    Reiter RJ, Manda K. Melatonin maintains adult hippocampal neurogenesis and cognitive functions after irradiation. Prog Neurobiol. 2010;90(1):60–8.PubMedGoogle Scholar
  112. 112.
    Cheeseman KH, Slater TF. An introduction to free radical biochemistry. Br Med Bull. 1993;49(3):481–93.PubMedGoogle Scholar
  113. 113.
    Marklund SL, Westman NG, Lundgren E, Roos G. Copper-and zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase, and glutathione peroxidase in normal and neoplastic human cell lines and normal human tissues. Cancer Res. 1982;42(5):1955–61.PubMedGoogle Scholar
  114. 114.
    Martilla RJ, Roytta M, Lorentz H, Rinne UK. Oxygen toxicity protecting enzymes in human brain. J Neural Transm. 1988;74:87–90.Google Scholar
  115. 115.
    Benzi G, Moretti A. Are reactive oxygen species involved in Alzheimer’s disease? Neurobiol Aging. 1995;16(4):661–74.PubMedGoogle Scholar
  116. 116.
    Joseph JA, Villalobos-Molina R, Yamagami K, Roth GS, Kelly J. Age-specific alterations in muscarinic stimulation of K(+)-evoked dopamine release from striatal slices by cholesterol and S-adenosyl-L-methionine. Brain Res. 1995;673(2):185–93.PubMedGoogle Scholar
  117. 117.
    Bhatnagar M, Sharma D, Salvi M. Neuroprotective effects of Withania somnifera dunal. A possible mechanism. Neurochem Res. 2009;34(11):1975–83.PubMedGoogle Scholar
  118. 118.
    Das A, McDowell M, Pava MJ, Smith JA, Reiter RJ, Woodward JJ, Varma AK, Ray SK, Banik NL. The inhibition of apoptosis by melatonin in VSC4.1 motoneurons exposed to oxidative stress, glutamate excitotoxicity, or TNF‐α toxicity involves membrane melatonin receptors. J Pineal Res. 2010;48(2):157–69.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Kim JE, Choi HC, Song HK, Jo SM, Kim DS, Choi SY, Kang TC. Levetiracetam inhibits interleukin-1β inflammatory responses in the hippocampus and piriform cortex of epileptic rats. Neurosci Lett. 2010;471(2):94–9.PubMedGoogle Scholar
  120. 120.
    Chen JC, Ng CJ, Chiu TF, et al. Altered neutrophil apoptosis activity is reversed by melatonin in liver ischemia–reperfusion. J Pineal Res. 2003;34:260–4.PubMedGoogle Scholar
  121. 121.
    Bardgett ME, Henry JD. Locomotor activity and accumbens Fos expression driven by ventral hippocampal stimulation require D1 and D2 receptors. Neuroscience. 1999;94(1):59.PubMedGoogle Scholar
  122. 122.
    Culmsee C, Bondada S, Mattson MP. Hippocampal neurons of mice deficient in DNA-dependent protein kinase exhibit increased vulnerability to DNA damage, oxidative stress and excitotoxicity. Mol Brain Res. 2001;87(2):257–62.PubMedGoogle Scholar
  123. 123.
    Suzuki WA, Clayton NS. The hippocampus and memory: a comparative and ethological perspective. Curr Opin Neurobiol. 2000;10(6):768–73.PubMedGoogle Scholar
  124. 124.
    Zafra F, Castrén E, Thoenen H, Lindholm D. Interplay between glutamate and γ-aminobutyric acid transmitter systems in the regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc Natl Acad Sci U S A. 1991;88:10037–41.PubMedCentralPubMedGoogle Scholar
  125. 125.
    Akhlaq AF, Wei Y, Xin-Rong L, Barry H, Llyod AH. Neurochemical consequences of kainate-induced toxicity in brain: involvement of arachidonic acid release and prevention of toxicity by phospholipase A2 inhibitors. Brain Res. 2001;38:61–78.Google Scholar
  126. 126.
    Benesova P, Langmeier M, Betka J, Trojan S. Long-lasting changes in the density of nitrergic neurons following kainic acid administration and chronic hypoxia. Physiol Res. 2005;54:565–71.PubMedGoogle Scholar
  127. 127.
    White BC, Sullivan JM, Degracia DJ, Oneil BJ, Neumar RW, Grossman LI, Rafols JA, Krause GS. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci. 2000;179:1–33.PubMedGoogle Scholar
  128. 128.
    Montecot C, Borredon J, Seylaz J, Pinard E. Nitric oxide of neuronal origin is involved in cerebral blood flow increase during seizures induced by kainate. J Cereb Blood Flow Metab. 1997;17:94–9.PubMedGoogle Scholar
  129. 129.
    Benesova P, Langmeier M, Betka J, Trojan S. Changes in the number of nitrergic neurons following kainic acid administration and repeated long-term hypoxia. Physiol Res. 2004;53:343–9.PubMedGoogle Scholar
  130. 130.
    Jain A, Bhatnagar M. Melatonin–a “magic biomolecule”. Ann Neurosci. 2010;14(4):108–14.Google Scholar
  131. 131.
    Tapias V, Escames G, López LC, López A, Camacho E, Carrión MD, Entrena A, Gallo MA, Espinosa A, Acuna-Castroviejo D. Melatonin and its brain metabolite N(1)-acetyl-5-methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice. J Neurosci Res. 2009;13:3002–10.Google Scholar
  132. 132.
    Chung SY, Han SH. Melatonin attenuates kainic acid-induced hippocampal neurodegeneration and oxidative stress through microglial inhibition. J Pineal Res. 2003;34:95–102.PubMedGoogle Scholar
  133. 133.
    Moreno N, López JM, Sánchez-Camacho C, González A. Development of NADPH-diaphorase/nitric oxide synthase in the brain of the urodele amphibian Pleurodeles waltl. J Chem Neuroanat. 2002;23:105–21.PubMedGoogle Scholar
  134. 134.
    Ben-Ari Y, Cossart R. Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci. 2000;23:580–7.PubMedGoogle Scholar
  135. 135.
    Langmeier MJ, Folbergrova J, Haugvicova R, Riljak V. Neuronal cell death in hippocampus induced by homocysteic acid in immature rats. Epilepsia. 2003;44:299–304.PubMedGoogle Scholar
  136. 136.
    Wojtal K, Gniatkowska-Nowakowska A, Czuczwar SJ. Is nitric oxide involved in the anticonvulsant action of antiepileptic drugs? Pol J Pharmacol. 2003;55:535–42.PubMedGoogle Scholar
  137. 137.
    Kotler M, Rodriguez C, Sainz RM, Antolin I, Menéndez-Peláez A. Melatonin increases gene expression for antioxidant enzymes in rat brain cortex. J Pineal Res. 1998;24:83–9.PubMedGoogle Scholar
  138. 138.
    Chang HM, Liao WC, Lue JH, Wen CY, Shieh JY. Upregulation of NMDA receptor and neuronal NADPH-d/NOS expression in the nodose ganglion of acute hypoxic rats. J Chem Neuroanat. 2003;25:137–47.PubMedGoogle Scholar
  139. 139.
    Tan DX, Manchester LC, Sainz RM, Mayo JC, Alvares FL, Reiter RJ. Antioxidant strategies in protection against neurodegenerative disorders. Curr Opin Ther Patents. 2003;13:1513–43.Google Scholar

Copyright information

© Springer India 2014

Authors and Affiliations

  • Pooja Suhalka
    • 1
    Email author
  • Chhavi Sharma
    • 1
  • Neha Jaiswal
    • 1
  • Piyu Sukhwal
    • 1
  • Reena Chittora
    • 1
  • Ayushi Jain
    • 1
  • Maheep Bhatnagar
    • 1
  1. 1.Department of ZoologyUniversity College of Science, MLSUUdaipurIndia

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