PD Neuroprotection/Melatonin

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Melatonin acts as a neuroprotective agent in the substantia nigra and is the reason for the characteristic black appearance of its neurons.


Melatonin is a multi-purpose hormone produced by the pineal gland. Among its known purposes are the regulation of sleep patterns and neuroprotection of neurons, notably in the substsntia nigra.



Mayo et al [1] assessed the effect of melatonin on PD cases. The following is an abstract of their paper.

It was recently reported that low doses of 6-hydroxydopamine (6-OHDA) induce apoptosis of naive (undifferentiated) and neuronal (differentiated) PC12 cells, and this system has been proposed as an adequate experimental model for the study of Parkinson's disease. The mechanism by which this neurotoxin damages cells is via the production of free radicals. Given that the neurohormone melatonin has been reported 1) to be a highly effective endogenous free radical scavenger, 2) to increase the mRNA levels and the activity of several antioxidant enzymes, and 3) to inhibit apoptosis in other tissues, we have studied the ability of melatonin to prevent the programmed cell death induced by 6-OHDA in PC12 cells. We found that melatonin prevents the apoptosis caused by 6-OHDA in naive and neuronal PC12 cells as estimated by 1) cell viability assays, 2) counting of the number of apoptotic cells, and 3) analysis and quantification of DNA fragmentation. Exploration of the mechanisms used by melatonin to reduce programmed cell death revealed that this chemical mediator prevents the 6-OHDA induced reduction of mRNAs for several antioxidant enzymes. The possibility that melatonin utilized additional mechanisms to prevent apoptosis of these cells is also discussed. Since this endogenous agent has no known side effects and readily crosses the blood-brain-barrier, we consider melatonin to have a high clinical potential in the treatment of Parkinson's disease and possibly other neurodegenerative diseases, although more research on the mechanisms is yet to be done.


Mayo et al [2] continued previous research on melatonin and this is an abstract of their follow-on paper:-

6-Hydroxydopamine (6-OHDA) is a neurotoxin used in the induction of experimental Parkinson's disease in both animals and cultured neuronal cells. Biochemical and molecular approaches showed previously that low doses of 6-OHDA induced apoptosis in PC12 cells, while high doses of this neurotoxin induced necrosis. Melatonin has been shown to protect against the neuronal programmed cell death induced by 6-OHDA, although it was not able to prevent the massive necrotic cellular death occurring after the addition of high doses of the neurotoxin. In the present work, we demonstrate by ultrastructural analysis that although low doses of 6-OHDA induced apoptosis in PC12 cells, it also damaged the non-apoptotic cells, morphologically corresponding this damage to incipient and reversible necrotic lesions. When the doses of the neurotoxin increase, there are still apoptotic cells, although most of the cells show necrotic irreversible lesions. We also found that melatonin partially prevents the incipient necrotic lesions caused by low doses of 6-OHDA. The fact that melatonin was shown in previous work to prevent apoptosis caused by low doses of 6-OHDA, but not necrosis induced by high doses of the neurotoxin, seemed to indicate that this agent is only able to protect against apoptosis. However, our present results, melatonin preventing also the incipient necrotic neuronal lesions, suggest that this hormone may provide a general protection against cell death, suggesting that higher doses should be tried in order to prevent the necrotic cell death induced by high doses of the neurotoxin.


2005 Dowling et al [3] compared the effects of two doses of melatonin (5mg. and 50mg.) to placebo on sleep, daytime sleepiness, and level of function in patients with PD who complained of sleep disturbances.

The result 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.


Maharaj et al [4] reported the finding that 6-hydroxymelatonin administration proved successful in reducing Fe2+-induced neurotoxicity in rat hippocampus.

This study provides some evidence of the neuroprotective effects of 6-OHM.


Kim et al [5] gave melatonin to rats with Parkinsonism induced by the application of 6-OHDA.

When the results were analysed subsequently it was noted that melatonin treatment significantly reduced the motor deficit and also resulted in the survival of dopaminergic neurons in SN and TH-immunoreactive terminals in the dorsolateral striatum.

These behavioral and histochemical results may indicate a neuroprotective action of melatonin and suggest a potential pharmacological role in the treatment of Parkinson's disease.

Acuña-Castroviejo [6] administered melatonin to MPTP- induced Parkinsonian mice. When the mouse brains were examined a complete reversal of the microbiological changes normally expected from MPTP was noted. This led to the conclusion:-

These data show that melatonin is neuroprotective in this MPTP model of Parkinson's disease and suggest that melatonin, an endogenous antioxidant and nontoxic compound, may have potential beneficial effects for this neurodegenerative disorder.


Tapias et al [7] assessed the effects of melatonin on rats with PD induced by MPTP and Rotenone.

Our findings indicate that melatonin is not neuroprotective in the rotenone model of PD and may exacerbate neurodegeneration.


Videnovic et al[8] measured serum melatonin levels in blood samples from a cohort of 20 patients with PD receiving stable dopaminergic therapy and 15 age-matched control participants. The amplitude of melatonin levels were significantly lower in PD patients. Their conclusions were:-

Circadian function, such as timed exposure to bright light and exercise, might serve as complementary therapies for the nonmotor manifestations of PD.

Further Reading[edit]


Esposito, Emanuela and Cuzzocreal Full Text Curr. Neuropharmacol. 8(3): 228–242.

Antiinflammatory Activity of Melatonin in Central Nervous System.



Use the following links to query the PubMed, PubMed Central and Google Scholar databases using the Search terms:- Parkinson's_Disease Melatonin.

This will list the latest papers on this topic. You are invited to update this page to reflect such recent results, pointing out their significance.

Pubmed (abstracts)

Pubmed_Central (Full_Text)


Related pages[edit]

Therapy > Neuroprotection

Sub Pages:

Neuroprotective agents
Substances with possible neuroprotective properties:
Caffeine,--Celastrol,--Co-Enzyme Q10,--Creatine,--DHA,--Exendin-4 (EX-4),--GDNF,--Glutathione (GSH),--GM1,--Isradipine,--Melatonin,--Minocycline,--Nicotine,--NSAIDs,--Phenylbutyrate,--Phytic Acid,--Probucol,--Quinoxaline,--Rasagiline,--Riboflavin,--Statins,--Tolcapone,--Urate & Uric Acid,--Vitamin D,--Vitamin E,--

See also: Melatonin



  1. Mayo, J. C.; Sainz, R. M.; Uria, H.; Antolin, I.; Esteban, M. M. and Rodriguez, C. (1998) Abstract J Pineal Res. 24 (3):179 - 192. Melatonin prevents apoptosis induced by 6-hydroxydopamine in neuronal cells: implications for Parkinson's disease.http://www.ncbi.nlm.nih.gov/pubmed/9551855
  2. Mayo, J. C.; Sainz , R. M.; Antolín, I, and Rodriguez, C.(1999)Abstract Brain Res. 818 (2):221 - 227.Ultrastructural confirmation of neuronal protection by melatonin against the neurotoxin 6-hydroxydopamine cell damage. http://www.ncbi.nlm.nih.gov/pubmed/10082807
  3. Dowling, G. A.; Mastick, J.; Colling, E.; Carter J. H.; Singer, C. M. and Aminoff, M. J. (2005) Abstract Sleep Med. 6 (5):459 - 466. Melatonin for sleep disturbances in Parkinson's disease. http://www.ncbi.nlm.nih.gov/pubmed/16084125
  4. Maharaj D. S.; Maharaj, H.; Daya, S. and Glass, B. D. (2006) Abstract J. Neurochem. 96 (1):78-81. Melatonin and 6-hydroxymelatonin protect against iron-induced neurotoxicity. http://www.ncbi.nlm.nih.gov/pubmed/16300638
  5. Kim, Y. S.; Joo, W. S.; Jin, B. K.; Cho, Y. H.; Baik, H. H. and Park, C.W. (2008) Abstract Neuroreport. 9 (10):2387 - 2390. Melatonin protects 6-OHDA-induced neuronal death of nigrostriatal dopaminergic system. http://www.ncbi.nlm.nih.gov/pubmed/9694233
  6. Acuña-Castroviejo, D.; Coto-Montes, A.; Gaia Monti, M.; Ortiz, G. G. and Reiter R. J. (2008) Abstract Life Sci.60(2):PL23 - 29. Melatonin is protective against MPTP-induced striatal and hippocampal lesions. http://www.ncbi.nlm.nih.gov/pubmed/9000122
  7. Tapias, V.; Cannon, J.R. and Greenamyre, J. T. (2010) Abstract J. Neurosci. Res.88 (2):420 - 427. Melatonin treatment potentiates neurodegeneration in a rat rotenone Parkinson's disease model. http://www.ncbi.nlm.nih.gov/pubmed/19681169
  8. Videnovic, A.; Noble, C.; Reid, K.J.; Peng, J.; Turek, F.W.; Marconi, A.; Rademaker, A.W.; Simuni, T; Zadikoff, C.; and Zee, P.C(2014) Abstract. (2014) JAMA Neurol 2013.6239 Circadian Melatonin Rhythm and Excessive Daytime Sleepiness in Parkinson Disease. http://www.ncbi.nlm.nih.gov/pubmed/24566763