Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917801 (insomnia)
 10,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID: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. 1914 86

Sleep disruption is a prevalent clinical feature in many neurodegenerative disorders, including human prion diseases where it can be the defining dysfunction, as in the case of the "eponymous" fatal familial insomnia, or an early-stage symptom as in certain types of Creutzfeldt-Jakob disease. It is important to establish the role of the cellular prion protein (PrPC), the key molecule involved in prion pathogenesis, within the sleep-wake system in order to understand fully the mechanisms underlying its contribution to both healthy circadian rhythmicity and sleep dysfunction during disease. Although severe disruption to the circadian rhythm and melatonin release is evident during the pathogenic phases of some prion diseases, untangling whether PrPC plays a role in circadian rhythmicity, as suggested in mice deficient for PrPC expression, is challenging given the lack of basic experimental research. We provide a short review of the small amount of direct literature focused on the role of PrPC in melatonin and circadian rhythm regulation, as well as suggesting mechanisms by which PrPC might exert influence upon noradrenergic and dopaminergic signaling and melatonin synthesis. Future research in this area should focus upon isolating the points of dysfunction within the retino-pineal pathway and further investigate PrPC mediation of pinealocyte GPCR activity.
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PMID:The Role of the Mammalian Prion Protein in the Control of Sleep. 2914 24