Take a look at the Recent articles

Endogenous regulator of brain aging and neurodegeneration-One target multiple therapeutic interventions

Shukla M

Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Kamphaeng Phet 6 Road, Lak Si, Bangkok, Thailand

Govitrapong P

Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Kamphaeng Phet 6 Road, Lak Si, Bangkok, Thailand

Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakornpathom, Thailand

DOI: 10.15761/GDT.1000125

Article
Article Info
Author Info
Figures & Data

Abstract

Most of the calamitous brain diseases are neurodegenerative in nature and undergo progressive degeneration with advancing age and eventually death. Inspite of the immense human affliction and economic impact the medical need for such diseases is largely unmet and is currently facing many drug-development challenges. The potential of the disease modifying drugs pertaining to its cure, slowing the progression, or prevention of the onset is by itself an expensive and time consuming process. Therefore, therapeutic development in this particular area should emphasize on addressing the underlying cause, drug safety, efficacy, cost effectiveness and since the brain cells are rarely replaced in such disorders, priority should be given to interventions which along with preventing the degeneration of neurons also have the ability to stimulate neurogenesis with least toxic effects. Melatonin the pineal neuro hormone is one such therapeutic agent which not only has proved to halt or reverse the progression of most neurodegenerative diseases but its physiology (synthesis, secretion and endogenous levels) provides information about the development and progression of the disease which aids in identifying successful drug targets thus offering assurance in breakthrough treatment strategies.

Introduction

Neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HT) are age-related and the most challenging of all the central nervous system (CNS) diseases. Characterized by progressive decline in neurological function they pose a great socioeconomic burden also. Aging by itself is one of the major risk factor for these neurodegenerative diseases causing changes in brain size, vasculature and cognition with progressive memory loss along with disturbed neurotransmitter and hormonal homeostasis. There are many challenges confronted when it comes to treatment strategies for these diseases and require a deep exploration of specialized mechanisms like safe and efficient delivery of the drugs across the blood brain barrier (BBB), drug toxicity and tolerance, from pharmacokinetics to pharmacodynamics along with drug side effects. In this line of therapeutic intervention melatonin the pineal neurohormone qualifies to be one of the most potent endogenous regulators of brain aging and neurodegenerative diseases as mentioned above.

Therapeutic potential of melatonin in neurodegenerative and neuropsychiatric disorders

Melatonin is a functionally versatile indoleamine which modulates the physiological and molecular homeostasis. In humans melatonin levels decrease with advancing age and interestingly its levels are reduced in AD [1,2] and HT [3]. Whereas in PD; reduced concentration of circulating melatonin has been reported in PD patients [4] with different variations [5]. Changes in melatonin levels have also been observed in multiple sclerosis and cerebral ischemia [6] along with altered secretion and levels in cancer patients (for review; [7]. CSF melatonin levels are significantly decreased in bipolar disorder whereas decreased serum melatonin levels have been reported in major depressive disorder [8]. Decreased nocturnal synthesis of melatonin has also been accounted in age-related cardiovascular diseases like acute myocardial infarction and coronary artery diseases [9,10]. So, it could be envisioned how melatonin endogenously regulates aging and a plethora of brain disorders.

Melatonin stimulates the neuroprotective mechanisms and prevents neuronal vulnerability to toxic damage. Aging brain is vulnerable to oxidative damage perhaps due to reduced melatonin secretion. In this context, melatonin due to its antioxidant properties [11] provides neuroprotection [12,13]to the aging brain. It has proven to be efficient in treating AD and MCI patients [14] and our latest research delineated a novel mechanism by which melatonin aids in preventing AD pathology [15,16] and reveres age related changes in aged mouse hippocampus [17]. Hippocampal neurogenesis is associated with cognitive abilities and is decreased in AD [18] and melatonin increases stem cell proliferation in hippocampus [19] in a receptor dependent manner [20] whereas when used as a supplement in culture medium it improves the efficiency of in vitro produced mammalian embryos [21]. Several lines of evidence have been accounted regarding neuroprotective role of melatonin in PD [22-24] along with its possible therapeutic use in Multiple sclerosis and cerebral ischemia [6]. Not only that melatonin delays disease onset and mortality in a transgenic mouse model of HT [25] and its administration in cancer patients has been associated with improved outcomes and survival along with better tolerance of chemotherapy in such patients [26]. Interestingly, melatonin can exert both direct and indirect anticancer effects [27].

The complex etiology of mental diseases also complicates the development of antipsychotic drugs. Although, role of melatonin in psychiatric treatment has been discussed before (for review; [28]), recent advances in melatonin research have focused on mental diseases like anxiety, depression, schizophrenia, autism, attention deficit hyperactivity disorder etc.; emphasizing on alterations in melatonin secretion with associated changes in biological rhythms of such disorders [29]. Melatonin and its agonists (ramelteon and tasimelteon) are recommended for patients with Bipolar disorder [30] and agomelatine, which is an analogue of melatonin shows similar antidepressant effects like venlafaxine, fluoxetine, and sertraline [31] but with negligible adverse reactions.

Therapeutic effects ascribed to melatonin are not only restricted to above mentioned disorders. This magical neurohormone also regulates and modulates the cardiovascular [32], immune [33] systems and hormone secretion and metabolism [34]. With antitumor [35,36], anti-inflammatory [37], and pain modulating properties [38] it qualifies to be a broad-spectrum therapeutic agent. Although substantial research based studies have well documented the beneficial and therapeutic effects of melatonin; advancement in identifying and developing melatonin and its analogues should be targeted to analyze its potential and mechanisms involved in onset and progression of various diseases for more effective and standardized treatments and drug development.

References

  1. Skene DJ, Vivien-Roels B, Sparks DL, Hunsaker JC, Pevet P, et al. (1990) Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer's disease. Brain Res 528: 170-174.
  2. Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF, et al. (1999) Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype. J Clin Endocrinol Metab 84: 323-327.
  3. Kalliolia E, Silajdzic E, Nambron R, Hill NR, Doshi A, et al. (2014) Plasma melatonin is reduced in Huntington's disease. Mov Disord 29: 1511-1515.
  4. Sandyk R (1990) Pineal melatonin functions: possible relevance to Parkinson's disease. Int J Neurosci 50: 37-53.
  5. Schernhammer E, Chen H, Ritz B (2006) Circulating melatonin levels: possible link between Parkinson's disease and cancer risk? Cancer Causes Control 17: 577-582.
  6. Escribano BM, Colin-Gonzalez AL, Santamaria A, Tunez I (2014) The role of melatonin in multiple sclerosis, Huntington's disease and cerebral ischemia. CNS Neurol Disord Drug Targets 13: 1096-1119.
  7. Rondanelli M, Faliva MA, Perna S, Antoniello N (2013) Update on the role of melatonin in the prevention of cancer tumorigenesis and in the management of cancer correlates, such as sleep-wake and mood disturbances: review and remarks. Aging Clin Exp Res 25: 499-510.
  8. Bumb JM, Enning F, Mueller JK, van der List T, Rohleder C, et al. (2016) Differential melatonin alterations in cerebrospinal fluid and serum of patients with major depressive disorder and bipolar disorder. Compr Psychiatry 68: 34-39.
  9. Yaprak M, Altun A, Vardar A, Aktoz M, Ciftci S, et al. (2003) Decreased nocturnal synthesis of melatonin in patients with coronary artery disease. Int J Cardiol 89: 103-107.
  10. Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia MJ, Sanchez J, Marrero F, et al. (2002) Decreased nocturnal melatonin levels during acute myocardial infarction. J Pineal Res 33: 248-252.
  11. Sofic E, Rimpapa Z, Kundurovic Z, Sapcanin A, Tahirovic I, et al. (2005) Antioxidant capacity of the neurohormone melatonin. J Neural Transm (Vienna) 112: 349-358.
  12. Srinivasan V, Pandi-Perumal SR, Cardinali DP, Poeggeler B, Hardeland R, et al. (2006) Melatonin in Alzheimer's disease and other neurodegenerative disorders. Behav Brain Funct 2: 15.
  13. Medeiros CA, Carvalhedo de Bruin PF, Lopes LA, Magalhaes MC, de Lourdes Seabra M, et al.  (2007) Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson's disease. A randomized, double blind, placebo-controlled study. J Neurol 254: 459-464.
  14. Cardinali DP, Furio AM, Brusco LI (2010) Clinical aspects of melatonin intervention in Alzheimer's disease progression. Curr Neuropharmacol 8: 218-227.
  15. Shukla M, Htoo HH, Wintachai P, Hernandez JF, Dubois C, et al. (2015) Melatonin stimulates the nonamyloidogenic processing of betaAPP through the positive transcriptional regulation of ADAM10 and ADAM17. J Pineal Res 58: 151-165.
  16. Panmanee J, Nopparat C, Chavanich N, Shukla M, Mukda S, et al. (2015) Melatonin regulates the transcription of betaAPP-cleaving secretases mediated through melatonin receptors in human neuroblastoma SH-SY5Y cells. J Pineal Res 59: 308-320.
  17. Mukda S, Panmanee J, Boontem P, Govitrapong P (2016) Melatonin administration reverses the alteration of amyloid precursor protein-cleaving secretases expression in aged mouse hippocampus. Neurosci Lett 621: 39-46.
  18. Martinez-Canabal A (2014) Reconsidering hippocampal neurogenesis in Alzheimer's disease. Front Neurosci 8: 147.
  19. Sotthibundhu A, Phansuwan-Pujito P, Govitrapong P (2010) Melatonin increases proliferation of cultured neural stem cells obtained from adult mouse subventricular zone. J Pineal Res 49: 291-300.
  20. Tocharus C, Puriboriboon Y, Junmanee T, Tocharus J, Ekthuwapranee K, Govitrapong P (2014) Melatonin enhances adult rat hippocampal progenitor cell proliferation via ERK signaling pathway through melatonin receptor. Neuroscience 275: 314-321.
  21. Komninou ER, Remiao MH, Lucas CG, Domingues WB, Basso AC, et al. (2016) Effects of Two Types of Melatonin-Loaded Nanocapsules with Distinct Supramolecular Structures: Polymeric (NC) and Lipid-Core Nanocapsules (LNC) on Bovine Embryo Culture Model. PLoS One 11: e0157561.
  22. Mayo JC, Sainz RM, Tan DX, Antolin I, Rodriguez C, et al. (2005) Melatonin and Parkinson's disease. Endocrine 27: 169-178.
  23. Stull ND, Polan DP, Iacovitti L (2002) Antioxidant compounds protect dopamine neurons from death due to oxidative stress in vitro. Brain Res 931: 181-185.
  24. Ortiz GG, Crespo-Lopez ME, Moran-Moguel C, Garcia JJ, Reiter RJ, et al. (2001) Protective role of melatonin against MPTP-induced mouse brain cell DNA fragmentation and apoptosis in vivo. Neuro Endocrinol Lett 22: 101-108.
  25. Wang X, Sirianni A, Pei Z, Cormier K, Smith K, et al. (2011) The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity. J Neurosci 31: 14496-14507.
  26. Cutando A, Lopez-Valverde A, Arias-Santiago S, J DEV, RG DED, et al. (2012) Role of melatonin in cancer treatment. Anticancer Res 32: 2747-2753.
  27. Di Bella G, Mascia F, Gualano L, Di Bella L (2013) Melatonin anticancer effects: review. Int J Mol Sci 14: 2410-2430.
  28. Pacchierotti C, Iapichino S, Bossini L, Pieraccini F, Castrogiovanni P, et al. (2001) Melatonin in psychiatric disorders: a review on the melatonin involvement in psychiatry. Front Neuroendocrinol 22: 18-32.
  29. Sun X, Wang Y, Jiang N, Du Z, Sun H, et al. (2016) The Potential Role of Melatonin on Mental Disorders: Insights from Physiology and Pharmacology. Bipolar Disorder 2: 1-4.
  30. Geoffroy PA, Etain B, Franchi JA, Bellivier F, Ritter P, et al. (2015) Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders. Curr Pharm Des 21: 3352-3358.
  31. Hickie IB, Rogers NL (2011) Novel melatonin-based therapies: potential advances in the treatment of major depression. Lancet 378: 621-631.
  32. Sewerynek E (2002) Melatonin and the cardiovascular system. Neuro Endocrinol Lett 23 Suppl 1: 79-83.
  33. Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernandez-Montesinos R, et al. (2006) The modulatory role of melatonin on immune responsiveness. Curr Opin Investig Drugs 7: 423-431.
  34. Barrenetxe J, Delagrange P, Martinez JA (2004) Physiological and metabolic functions of melatonin. J Physiol Biochem 60: 61-72.
  35. Blask DE, Sauer LA, Dauchy RT (2002) 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 2: 113-132.
  36. Mills E, Wu P, Seely D, Guyatt G (2005) Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res 39: 360-366.
  37. Genovese T, Mazzon E, Muia C, Bramanti P, De Sarro A, et al. (2005) Attenuation in the evolution of experimental spinal cord trauma by treatment with melatonin. J Pineal Res 38: 198-208.
  38. Peres MF (2005) Melatonin, the pineal gland and their implications for headache disorders. Cephalalgia 25: 403-411.

Editorial Information

Editor-in-Chief

Yukio Yoneda
Kanazawa University

Article Type

Mini Review

Publication history

Received: February 03, 2017
Accepted: March 08, 2017
Published: March 11, 2017

Copyright

©2017 Govitrapong P. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Govitrapong P, Shukla M (2017) Endogenous regulator of brain aging and neurodegeneration-One target multiple therapeutic interventions. Glob Drugs Therap 2: DOI: 10.15761/GDT.1000125

Corresponding author

Piyarat Govitrapong

Piyarat Govitrapong, Chulabhorn Graduate Institute, Research Center for Neuroscience, Thailand

No Data.