Emerging preclinical interest concerning the role of circadian function in Parkinson’s disease

Willis, Gregory L.; Freelance, Christopher B.

doi:10.1016/j.brainres.2017.09.027

Cited by 7 publications

(5 citation statements)

References 130 publications

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“…Their interrelationship has been hypothesized to mediate the effects of toxins in causing PD (29) and in the therapeutic effect of DA replacement (28, 39). In fact, recent studies have defined neurochemical systems in the retina that exert control over deep brain systems controlling movement (40) and embrace circadian involvement (41). However, caution should be exercised in ascribing a therapeutic response solely to retinal DA function given that we have never observed enhanced dyskinaesia and other adverse effects with extended use of light in PD patients experiencing DA overdosing phenomena (6, 8, 22).…”

Section: Discussionmentioning

confidence: 99%

“…The present results also provide further support for the recent suggestion that the circadian system is involved in PD (6–8, 11, 35). While the mechanism by which this is achieved remains somewhat elusive, we hypothesize that the retina may play a major role in defining how the circadian system is involved (28, 40, 41, 47) and from this will emerge less invasive therapeutic approaches. Whatever the outcome of such exploration, it is becoming increasingly evident that very subtle changes in neurochemistry at targets distant from the NSD can evoke a significant therapeutic response in PD.…”

Section: Discussionmentioning

confidence: 99%

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Polychromatic Light Exposure as a Therapeutic in the Treatment and Management of Parkinson's Disease: A Controlled Exploratory Trial

Willis¹,

Boda²,

Freelance³

2018

Front. Neurol.

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Parkinson's disease (PD) is a disorder characterized by loss of dopamine (DA) in the nigro-striatal dopamine (NSD) system with the primary symptoms of bradykinaesia, rigidity, tremor, and altered gate. Secondary symptoms including depression, insomnia, involuntary movement, and psychiatric side effects are also commonly observed. While the treatment focus for the past 50 years has been aimed at replacing deficient DA, to relieve the primary symptoms, more recent studies have suggested that the circadian system plays a critical role in the etiology and treatment of this disorder. Several case studies and open label trials have implemented bright light therapy (BT) in an attempt to repair sleep, depression and even the primary motor symptoms of this disorder, however controlled studies are yet to be fully implemented. In this controlled trial, patients that had been maintained on BT daily for 4 months to 5 years previously were assigned to one of three groups: continued polychromatic light, continued with red light or discontinued polychromatic light for a 2 week period. The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDSUPDRS), The Parkinson's Disease Questionnaire (PDQ-39), The Beck Depression Inventory II, The Beck Anxiety Inventory, The Epworth Sleep Scale (ESS) and a global rating scale were used to assess patients prior to and at 1 and 2 weeks after commencing the trial. Patients continuing polychromatic BT showed significant improvement on the MDSUPDRS Rating Scale (12 points; p = 0.028), the PDQ-39 (10 points; p = 0.011), ESS (4 points; p = 0.013), and numerous motor and secondary symptoms on a global rating scale. Performance on standardized motor tests also incrementally improved in this group while those exposed to red light and those that discontinued BT treatment deteriorated. These results demonstrate that strategically applied polychromatic light was beneficial in reducing many primary motor and secondary symptoms of PD. Further work investigating the role of light in mitigating PD symptoms and involvement of the circadian system will provide further advances in the treatment of PD.Clinical Trial Registration: http://www.anzctr.org.au, identifier ACTRN12617001309370.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Polychromatic Light Exposure as a Therapeutic in the Treatment and Management of Parkinson's Disease: A Controlled Exploratory Trial

Willis¹,

Boda²,

Freelance³

2018

Front. Neurol.

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“…However, suppression of melatonin secretion may not be the likely mechanism by which artificial light exerts its therapeutic effect, as shown in depressive patients subjected to phototherapy (221). In any event, the circadian system is considered a novel diagnostic and therapeutic target in PD (212, 222).…”

Section: Clinical Use Of Melatonin In Pdmentioning

confidence: 99%

Melatonin: Clinical Perspectives in Neurodegeneration

2019

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Prevention of neurodegenerative diseases is presently a major goal for our Society and melatonin, an unusual phylogenetically conserved molecule present in all aerobic organisms, merits consideration in this respect. Melatonin combines both chronobiotic and cytoprotective properties. As a chronobiotic, melatonin can modify phase and amplitude of biological rhythms. As a cytoprotective molecule, melatonin reverses the low degree inflammatory damage seen in neurodegenerative disorders and aging. Low levels of melatonin in blood characterizes advancing age. In experimental models of Alzheimer's disease (AD) and Parkinson's disease (PD) the neurodegeneration observed is prevented by melatonin. Melatonin also increased removal of toxic proteins by the brain glymphatic system. A limited number of clinical trials endorse melatonin's potentiality in AD and PD, particularly at an early stage of disease. Calculations derived from animal studies indicate cytoprotective melatonin doses in the 40–100 mg/day range. Hence, controlled studies employing melatonin doses in this range are urgently needed. The off-label use of melatonin is discussed.

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“…However, as shown in depressive patients undergoing phototherapy, the inhibition of melatonin release is not the likely mechanism by which artificial light exerts its therapeutic effect (Lewy et al, 1984). Collectively, the gathered information points out to the circadian apparatus as an important diagnostic and therapeutic tool in PD (Willis and Freelance, 2018). A summary of clinical trials with melatonin in PD is offered in Table 2.…”

Section: Clinical Use Of Melatonin In Parkinson's Disease and Rbdmentioning

confidence: 99%

Melatonin as a Chronobiotic and Cytoprotective Agent in Parkinson’s Disease

Pérez-Lloret

Cardinali

2021

Front. Pharmacol.

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This article discusses the role that melatonin may have in the prevention and treatment of Parkinson’s disease (PD). In parkinsonian patients circulating melatonin levels are consistently disrupted and the potential therapeutic value of melatonin on sleep disorders in PD was examined in a limited number of clinical studies using 2–5 mg/day melatonin at bedtime. The low levels of melatonin MT1 and MT2 receptor density in substantia nigra and amygdala found in PD patients supported the hypothesis that the altered sleep/wake cycle seen in PD could be due to a disrupted melatonergic system. Motor symptomatology is seen in PD patients when about 75% of the dopaminergic cells in the substantia nigra pars compacta region degenerate. Nevertheless, symptoms like rapid eye movement (REM) sleep behavior disorder (RBD), hyposmia or depression may precede the onset of motor symptoms in PD for years and are index of worse prognosis. Indeed, RBD patients may evolve to an α-synucleinopathy within 10 years of RBD onset. Daily bedtime administration of 3–12 mg of melatonin has been demonstrated effective in RDB treatment and may halt neurodegeneration to PD. In studies on animal models of PD melatonin was effective to curtail symptomatology in doses that allometrically projected to humans were in the 40–100 mg/day range, rarely employed clinically. Therefore, double-blind, placebo-controlled clinical studies are urgently needed in this respect.

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Emerging preclinical interest concerning the role of circadian function in Parkinson’s disease

Cited by 7 publications

References 130 publications

Polychromatic Light Exposure as a Therapeutic in the Treatment and Management of Parkinson's Disease: A Controlled Exploratory Trial

Polychromatic Light Exposure as a Therapeutic in the Treatment and Management of Parkinson's Disease: A Controlled Exploratory Trial

Melatonin: Clinical Perspectives in Neurodegeneration

Melatonin as a Chronobiotic and Cytoprotective Agent in Parkinson’s Disease

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