Progress and Prospects in Parkinson's Research/Causes/Deficiencies/Melatonin

The hypothesis that melatonin deficiency might be a causative factor for Parkinson’s Disease was stated by Sandyk (1990) Definitive proof is currently lacking, but there is sufficient circumstantial evidence to make it worthy of serious consideration.

The Pineal Gland

In humans the pineal gland reaches its maximum size at the age of 2 and is about the size of a grain of rice. It is reddish-gray in colour, shaped like a pine cone, and tucked away in the centre of the brain at the top of the spinal column between the two hemispheres. It is a singular object: the only part of the brain not to have bipolar symmetry. Also, unlike the rest of the brain, the pineal gland is not insulated from the rest of the body by the blood brain barrier. It is rich in trace elements (zinc, iron, manganese, magnesium, strontium and copper) and its function could be affected if any of these prove to be deficient. It also accounts for a vigorous blood flow.

The anatomical structure of the gland shows it to have many features in common with the eye, and it may in the course of its evolution have been involved in visualisation. This, its concealed location, and its uniqueness have led several religions and beliefs to equate it with the concepts of The Third Eye and Second Sight. These give indoctrinates mystical powers of observation, insight and clairvoyance. Others earmark it as the seat of the Soul. Eastern statues show this as an outline of an eye in the centre of the forehead and adherents to the Hindu religion denote its presence by a ‘tilaka’, a crimson dot placed on the brows. There are nine ‘gates’ or openings into the body and the third eye is conceptualized as the tenth gate.

Where the pineal gland is severely damaged in children, it results in accelerated development of the sexual organs and the skeleton. In animals, the pineal gland appears to play a major role in sexual development, hibernation, metabolism, and seasonal breeding.

The gland has been shown to be susceptible to calcification and the degree of calcification increases steadily with age.

Melatonin

One of the gland’s main functions is the production of a hormone, a derivative of serotonin, called N-acetyl-5-methoxy-tryptamine, better known as melatonin. This production is geared to light reception in the retinas such that it follows a 24 hour cycle known as the Circadian Rhythm. The gland is active primarily during the hours of darkness. Secretion of melatonin as well as its level in the blood, peaks in the middle of the night, and gradually falls during the second half of the night.

Arendt and Skene (2005) have assessed the daily output of melatonin in mammals as a nocturnal maximum of about 200 pg/ml and a daytime nadir of less than 10 pg/ml.

It is principally blue light, around 460 to 480nm. that suppresses melatonin production. Special photoreceptive retinal ganglion cells containing melanopsin as a photopigment are involved in the projection from retina. Fibres from the suprachiasmatic nucleus pass through a circuitous route involving the paraventricular nucleus of the hypothalamus, medial forebrain bundle, reticular formation, lateral horn cells of the spinal cord, superior cervical ganglion, and then proceed to innervate pineal gland as postganglionic sympathetic fibres.

Wearing glasses that block blue light in the hours before bedtime may avoid melatonin loss. The use of blue-blocking goggles in the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime such as dealing with jet lag, as melatonin promotes sleepiness. 5mg. of melatonin taken half an hour before retiring is sometimes prescribed as a treatment for sleep disorders. Its use at other times of the day is not recommended because of its potential narcoleptic effects.

Melatonin was isolated and named by Aaron B. Lerner and colleagues at Yale University in (1958). It performs a number of functions around the body, not all of which are fully understood. It has been shown that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine. It also determines the diurnal sleep pattern.

Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin (50 mg) dramatically increased REM sleep time.

Many psychoactive drugs such as cannabis and lysergic acid diethylamide (LSD), increase melatonin synthesis.

Individuals with autism have been found to have reduced levels of melatonin and have been successfully treated with melatonin supplements.

Melatonin has been shown to have anti-aging properties. Its supplemental use has been shown to increase the levels of gene expression in older people.

Incomplete clinical trials have shown that melatonin may interact with the immune system and induce cytokine production. Some studies also suggest that melatonin might be useful fighting infections including viral diseases, such as HIV, and bacterial infections, and potentially in the treatment of cancer.

Melatonin and neuroprotection

2002

Cuzzocrea and Reiter reviewed the evidence for the neuroprotective qualities of melatonin and concluded that:-

A vast number of experimental and clinical studies implicates oxygen-derived free radicals (especially, superoxide and the hydroxyl radical) and high energy oxidants (such as peroxynitrite) as mediators of acute and chronic inflammation.

Reactive oxygen species can modulate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane sodium/potassium ATPase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins.

Reactive oxygen species (e.g., superoxide, peroxynitrite, hydrogen peroxide and hydroxyl radical) are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. These toxic reactions are likely to play a role in the pathophysiology of inflammation. Melatonin has been shown to possess both in vitro and in vivo important antioxidant activities as well as to inhibit the activation of poly (ADP ribose) synthetase. A large number of experimental studies have documented that melatonin exerts important anti-inflammatory actions.

2003

Mayo et al have evaluated the neuroprotective qualities of melatonin and concluded;-

The experimental data collectively suggest melatonin use by PD subjects would reduce their disease burden. Additionally, epidemiological studies of individuals who use melatonin daily regularly should be carried out. The devastating nature of PD and the lack of currently available means of preventing the disease call for the use of imaginative treatments. Melatonin, as noted, has very low toxicity and is much less expensive than prescription drugs and, thus, it should be tested against the development or progression of PD.

2010

Reiter et al describe the toxic residue left after the processing of oxygen by cells:-

This high utilization of oxygen, however, comes at a heavy biological price. As important as oxygen is for the survival of neurons and glia, it also indirectly contributes to their destruction and death over time. The reason for this is that a small percentage (an estimated 1-4%) of the oxygen that enters cells is metabolized to derivatives that gradually erode and destroy essential molecules.. These destructive derivatives of oxygen are often referred to as free radicals (although some are not radicals per se) or reactive oxygen species (ROS).

And goes on to add:-

N-acetyl-5-methoxytryptamine (melatonin), was discovered as a potent antioxidant in 1993 . Since then, melatonin’s ability to protect all cells and organs from oxidative/nitrosative damage has been confirmed in more than a thousand publications.

2011

Srinivasan et al have published a good description of the Physiology of melatonin. There appears to be no consensus at present on levels of melatonin to be found in PWP compared to controls.

Srinivasan (Ibid) includes the following concluding remarks:-

Nonmotor symptoms of PD such as RBD, occur in many PD patients, and predate the manifestation of motor symptoms. Their early diagnosis and treatment are essential for improving the quality of life in PD patients. Melatonin and melatonin agonists can be useful tools in treating sleep and associated disorders in PD. ...The available evidence supports the inference that melatonin activity in PD can be substantial, and, further, that clinical investigations into the nature of this activity are warranted.

Research

1984

Lewy et al have suggested that although evening bright light exposure produces a momentary suppression of melatonin, it actually causes a rebound increase in melatonin secretion late in the night.

1999

Willis and Armstrong tested the effects of melatonin on experimental models of Parkinson's disease.

Sprague-Dawley rats were exposed to intracerebroventricular implants of slow release melatonin, pinealectomy (PX), or constant light (LL) and then injected with central 6-hydroxydopamine (6-OHDA) or i.p. 1-methyl-4-phenyl,1-1,2,3,6-tetrahydropyridine (MPTP). The resulting impairment of motor function and related behavioural impairment were exacerbated by melatonin implantation, while PX and exposure to LL significantly reduced the severity of experimental PD. Their observations included the statement:-

These findings illustrate that melatonin is not the universal remedy that it is currently claimed to be, and may pose considerable problems in neurological diseases characterised by dopamine degeneration.

2005

Some 90% of PD patients report sleep disorders among their prominent non-motor symptoms. Dowling et al carried out a multi-site double-blind placebo-controlled cross-over trial with 40 subjects over a period of 10-week protocol. Doses of melatonin from 5mg. to 50mg. were administered and nocturnal sleep and daytime sleepiness and function were assessed. All subjects were taking stable doses of antiparkinsonian medications during the course of the study. Their results showed that:-

There was a significant improvement in total nighttime sleep time during the 50 mg melatonin treatment compared to placebo. There was significant improvement in subjective sleep disturbance, sleep quantity, and daytime sleepiness during the 5 mg melatonin treatment compared to placebo. as assessed by the GSDS.

2007

Willis and Turner carried out an experiment with Light Therapy (LT). Twelve patients diagnosed with PD were exposed to white fluorescent light for 1-1.5 h at an intensity of 1000 to 1500 lux once daily commencing 1 h prior to the usual time of sleep onset, approximately 22:00 h in most patients. All patients were assessed before LT commenced and at two weeks, five weeks, and regular intervals thereafter. Their findings were:-

Within two weeks after commencing LT, marked improvement in bradykinaesia and rigidity was observed in most patients. Tremor was not affected by LT treatment; however, agitation, dyskinaesia, and psychiatric side effects were reduced, as verified by decreased requirement for DA replacement therapy. Elevated mood, improved sleep, decreased seborrhea, reduced impotence, and increased appetite were observed after LT. LT permitted the reduction of the dose of L-dopa, bromocriptine, or deprenyl in some patients by up to 50% without loss of symptom control.

2010

Reiter (Ibid) evaluated the results of a series of pieces of research in which neurons were exposed to toxins and then treated with melatonin. The toxins were Methamphetamine, Aminolevulinic Acid, 6-Hydroxydopamine, Rotenone, Iron (Fe), chromium (Cr), aluminum (Al), copper (Cu), vanadium (V) and cobalt (Co) mercury (Hg), cadmium (Cd) and nickel (Ni), toluene, Polychlorinated BiPhenyls, Kainic acid, Domoic acid, Cyanide

In summarising the results they stated:-

Almost uniformly, although there are exceptions, melatonin demonstrated its efficacy in safeguarding neurons and glia from the persistent molecular disfiguring that would otherwise occur. The problem with loss of neurons is that, again with few exceptions , once these cells undergo either apoptosis or necrosis, they are not replaced. Interestingly, neuron precursors in the brain in those select areas where cellular proliferation does occur, are also stimulated by melatonin.

Summary

The hypothesis that melatonin deficiency is a primary cause of Parkinson’s Disease may be summed up thus:-

Oxygen, the principal fuel that drives animal cells is a toxin. However evolution has produced a system whereby individual cells metabolise oxygen into Adenosine TriPhosphate (ATP), which is better tolerated. There is, however, a toxic residue in the form of Reactive Oxygen Species (ROS), which have the capability of inducing cell death. Melatonin plays a vital neuroprotective role in rendering ROS harmless. The substantia nigra is a major consumer of melatonin. The pineal gland, which is the prime source of melatonin and is not protected by the blood/brain barrier, calcifies through aging, which can reduce its production of melatonin to the point where neuroprotection breaks down and all of the other PD causative factors identified in other pages, which are waiting in the wings, are given free reign to attack neurons in a variety of ways.

The Holy Grail of PD research has been the search for an environmental toxin which initiates sporadic forms of the diseases. This hypothesis offers a candidate for such a toxin: it is air!

The hypothesis offers scope for further research in the pathological examination of the pineal glands of PD patients, the use of light therapy, and the clinical trials of melatonin-based drugs.

Further Reading

2006

Srinivasan, V: Pandi-Perumal, S.R.: Cardinali, D.P.: Poeggler, B and Hardeland, T. Behav. Brain Funct. 2: 15

Melatonin in Alzheimer’s Disease and other neurodegenerative disorder

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1483829/?tool=pmcentrez

2007

Bondy, Stephen C. and Sharman, Edward H. Neurochemistry Int. 50 (4) 571-580

Melatonin and the ageing brain

http://www.sciencedirect.com/science/article/pii/S0197018607000198

2008

Reiter, Russel J.; Paredes, Sergio D.; Korkmaz,A; Jou, Mei-Jie and Tan, Dun-Xian. Interdiscip. Toxicol. 1 (2) 137-149

Melatonin combats molecular terrorism at the mitochondrial level.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993480/?tool=pmcentrez

Ortiz, Genaro G; Benitez-King, Gloria A.; Rosales-Corral, Segio A.; Pacheco- Moisés, Fermin P. and Velázquez-Brizuela, Irma E. Curr. Neuropharmacol. 6 (3) 203-214

Cellular and Biochemical Actions of Melatonin which Protect Against Free Radiacls : Role in Neurodegenerative Disorders.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687933/?tool=pmcentrez

2010

Reiter, Russel J.; Machester, Lucien C. And Tan, Dun-Xian Curr. Neuropharmacol. 8 (3) 194-210 .

Neurotoxins:Free Radical Mechanisms and melatonin Protection

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001213/?tool=pmcentrez

Escames, Germaine; Lopez, Ana; Garcia, José Antonio; Garcia, Laura; Acuña-Castroviejo, Dario; Garcia, José Joaquín and López, Luis Carlos. Curr. Neuroharmacol. 8 (3) 182-193.

The role of Mitochondria in Brain Aging and the effects of Melatonin.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001212/?tool=pmcentrez

Dubocovich, Mararita L.; Delagrange, Philippe; Krause, Diana N.; Sugden, David; Cardinali, Daniel P. and Olcese,J. Pharmaco;. Rev. 62 (3) 343-380

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964901/?tool=pmcentrez

Escame, Germaine; Lopez, Ana; Garcia, José Antonio; Garcia, Laura; Acuna-Castroviejo; Garcia, José Joaquin and Lopez,Luis Carlos. Curr. Neuropharmacol. 8 (3) 182-193

The Role of Mitochondria in Brain Ageing and the Effects of Melatonin

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001212/?tool=pmcentrez

2011

Bubenik, G. A. and Konturek, S.J. Abstract J. Physiol. Pharmacol. 62 (1) 13-19.

Melatonin and aging: prospects for human treatment.

http://www.ncbi.nlm.nih.gov/pubmed/21451205

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Causes > Deficiencies

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References

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