1: Rev Neurosci. 2008;19(4-5):245-316.

Parkinson's disease as a neuroendocrine disorder of circadian function:
dopamine-melatonin imbalance and the visual system in the genesis and progression
of the degenerative process.

Willis GL.

The Bronowski Institute of Behavioural Neuroscience, Neurosciences Section,
Coliban Medical Centre, Kyneton, Victoria, Australia. gwillbro@bigpond.com

For more than 50 years, Parkinson's disease (PD) has been conceptualized as a
product of nigro-striatal dopamine (NSD) system degeneration. In spite of a
growing body of evidence depicting the mammalian brain as an interrelated
complexity of circuitous systems, dopamine (DA) deficiency of the NSD is still
regarded as the main problem, with DA replacement being the purpose of
therapeutic intervention. For at least 191 years circadian involvement in various
aspects of PD, including depression and insomnia, has been recognized as an
integral part of the symptom matrix of PD and yet attempts to elucidate the
involvement of this system is uncharted territory. The present review attempts a
major reorganization of mammalian brain into a coordinated complex involving the
NSD and the retinal hypothalamic tract (RHT) as the primary systems involved in
the retino-diencephalic/mesencephalic-pineal (RDMP) axis. Secondary systems
including the lateral hypothalamus (LH), the area postraema (AP) and the
subthalamic nucleus (STN) also form an integral part of this system as they have
been shown to be either intimately related to the primary systems of the RDMP
axis or have been shown to be significantly involved in the expression and
treatment of PD. A large volume of evidence suggests that the RDMP axis is
activated during the course of PD and during therapeutic intervention. Four types
of neurotoxicity associated with melatonin are identified and the susceptibility
of various parts of the RDMP axis to undergo neuropathological change, the
tendency for melatonin to induce PD-like behavioural toxicity, and the
relationship of this to PD symptomotology are described. This includes adverse
effects of melatonin on motor function, hypotension, the adjuvant use of
benzodiazepines, depression, insomnia, body weight regulation and various
biochemical effects of melatonin administration: all problems currently facing
the proposal to introduce melatonin as an adjuvant. It is suggested further that
traditional DA replacement may well work by exerting its effect upon the
circadian system, rather than simply replacing deficient DA. Activation of the
circadian function by antagonizing melatonin with bright light not only has
therapeutic value in treating the primary symptoms of PD but it shares a common
mechanism with L-dopa in reducing the occurrence of seborrheic dermatitis.
Concepts at the centre of understanding pineal function in PD, including pineal
calcification, melatonin deficiency, symptomatic versus protective features of
melatonin and antioxidative effects, are explained in a counterintuitive context.
Intriguing propositions including the role of the retina in the aetiology of PD
and that the nigra functions as a retina in this disorder are presented with the
intention to provide a new understanding of the underlying compromised function
in PD and to provide new treatment strategies. For the first time, abundant
evidence is presented describing PD as an endocrine disorder of melatonin
hyperplasia. The role of circadian interventive therapies and internal
desynchrony in the aetiology and progression of PD provides a new direction for
understanding the underlying physiology of a disease which is currently in a
state of impasse and provides new hope for those who suffer from its debilitating
effects.


PMID: 19145986 [PubMed - in process]