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INIZIO_TESTO_DA_INDICIZZARE

RESEARCH PROGRAM

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  • HUMAN NECESSITIES
    • MEDICAL OR VETERINARY SCIENCE; HYGIENE
      • ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY (measurement of bio-electric currents A61B; electrosurgical apparatus or circuits therefor A61B17/36; physical therapy arrangements in general A61H; anaesthetic apparatus in general A61M; incandescent lamps H01K; infra-red radiators for heating H05B)
      • PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES (bringing into special physical form A61J [N: mechanical aspects]; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; compounds per se C01, C07, C08, C12N; soap compositions C11D; micro-organisms per se C12N) [C0203]
Geographical classification
Bibliografia
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Argiolas A, Melis MR. The neuropharmacology of yawning. Eur J Pharmacol, 343, 1-16, 1998.

Arnulf I, Bonnet AM, Damier P, Bejjani BP, Seilhean D, Derenne JP, Agid Hallucinations, REM sleep, and Parkinson's disease: a medical hypothesis. Neurology. 2000 Jul 25;55(2):281-8

Arnulf, I, Konofal E, Merino–Andreu M, Houeto JL, Mesnage V, Welter ML, Lacomblez L, Golmard JL, Derenne JP, Agid Y Parkinson’s disease and sleepiness: An integral part of PD Neurology, 58, 1019-1024, 2002.

Arnulf I. Excessive daytime sleepiness in parkinsonism. Sleep Med Rev, 2005, 9,185-2005.

Baenninger (R.). On yawning and its functions. Psychonomic Bul Rev, 4, 98-207, 1997.

Baenninger R, Binkley S, Baenninger M. Field observations of yawni(9):1230-1.

Karasawa J, Kuriyama Y, Kuro M, Kikushi H, Sawada T, Mitsugi T. Monitoring system of cerebral blood flow and cerebral metabolism. Relationship between internal jugular oxygen tension and cerebral blood flow. Brain Nerve, 34, 239-245, 1982.

Hauser RA, Gauger L, Anderson WM, Zesiewicz TA. Pramipexole-induced somnolence and episodes of daytime sleep. Mov Disord. 2000 Jul;15(4):658-63.

Kish SJ, Shannak KS, Rajput AH, Gilbert JJ, Hornykiewicz O. Cerebellar norepinephrine in patients with Parkinson’s disease and control subjects. Arch Neurol 1984; 41:612-614.

Harik SI. Blood-bain barrier sodium/potassium pump: modulation by central noradrenergic innervation. Proc Natl Acad Sci USA 1986; 83:4067-4070.

Hobson DE, Lang AE, Martin WR, Razmy A, Rivest J, Fleming J. Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group. JAMA. 2002 Jan 23-30;287(4):455-63

Lal S, Tesfaye Y, Thavundayil JX, Thompson TR, Kiely ME, Vasavan Nair NP, Grassino A, Dubrovski B. Apomorphine: clinical studies on erectile impotence and yawning. Prog Neuropsychopharmacol Biol Psychiatry, 13, 329-339, 1989.

Melis MR, Argiolas A, Gessa GL. Apomorphine-induced penile erection and yawning: site of action in the brain. Brain Res, 415, 98-104, 1987.

Murphy MB. Dopamine: a role in the pathogenesis and treatment of hypertension. J HumHypertens 2000; 14(Suppl 1):S47-S50.
Piaget J. Play, dreams and imitation in childhood. New York: Norton, 1951.

Provine RR, Hamernik HB, Curchack BB. Yawning: relation to sleeping and stretching in humans. Ethology, 76, 152-160, 1987.

Provine RR. Yawning as a sterotyped action pattern and releasing stimulus. Ethology, 72, 109-122, 1986.

Pezzella FR, Colosimo C, Vanacore N, Di Rezze S, Chianese M, Fabbrini G, Meco G. Prevalence and clinical features of hedonistic homeostatic dysregulation in Parkinson's disease.
Mov Disord. 2005 Jan;20(1):77-81.

Pezzella FR, Di Rezze S, Chianese M, Fabbrini G, Vanacore N, Colosimo C, Meco G. Hedonistic homeostatic dysregulation in Parkinson's disease: a short screening questionnaire.
Neurol Sci. 2003 Oct;24(3):205-6.

Razmy A, Lang AE, Shapiro CM. Predictors of impaired daytime sleep and wakefulness in patients with Parkinson disease treated with older (ergot) vs newer (nonergot) dopamine agonists. Arch Neurol. 2004 Jan;61(1):97-102.

Redfield MM, Nicholson WJ, Edwards WD, Tajik AJ. 1992. Valve disease associated with ergot alkaloid use: echocardiographic and pathologic correlations. Ann Intern Med. 117(1):50-2.

Sarmento A, Borges N, Lima D. Influence of electrical stimulation of locus coeruleus on the rat blood-brain barrier permeability to sodium fluorescein. Acta Neurochir (Wien) 1994; 127:215-219.

Serratrice J, Disdier P, Habib G, Viallet F, Weiller PJ. 2002.Sato-Suzuki I, Kita I, Seki Y, Oguri M, Arita H. Cortical arousal induced by microinjection of orexins into the paraventricular nucleus of the rat. Behav Brain Res, 128, 169-77, 2002.

Tengvar C, Pettersson CA, Mohammed AK, Olsson Y. Effects of the noradrenaline neurotoxin N-2-chloroethyl-N-ethyl-2-bromo-benzylamine hydrochloride (DSP4) on the blood-brain barrier. An experimental study in the mouse using protein tracer and density determination techniques. Acta Neuropathol (Berl) 1989; 78:28-34.

Tintner R, Manian P, Gauthier P, Jankovic J. 2005. Pleuropulmonary fibrosis after long-term treatment with the dopamine agonist pergolide for Parkinson Disease. Arch Neurol. 62(8):1290-5.

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Van Camp G, Flamez A, Cosyns B, Weytjens C, Muyldermans L, Van Zandijcke M, De Sutter J, Santens P, Decoodt P, Moerman C, Schoors D. 2004. Treatment of Parkinson's disease with pergolide and relation to restrictive valvular heart disease. Lancet. 363(9416):1179-83.

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Keywords
PARKINSON'S DISEASE, HEART, CARDIAC VALVE, ENDOTHELIUM, FIBROSIS, HEDONISTIC HOMEOSTATIC DYSREGULATION (HHD), DOPAMINERGIC THERAPY, SLEEP, YAWNING

Parkinson’s disease and dopaminergic stimulation: cardiovascular, behavioural and vigilance’s alterations

Università degli Studi di Roma "La Sapienza"
Abstract
Drug therapy of Parkinson disease consists in levodopa and in dopamine-agonist drugs. They are used from the first occurrence of the disease symptoms, and often for the whole clinical couse of Parkinson, i.e. lifelong. However, after many years of clinical practice, it is appearing that, while these drugs have a demonstrated clinical efficacy against the motor symptoms of Parkinson, they can also induce several side-effects. Actually, after years of therapy with dopamine-agonist drugs, particularly if used at high dosage, patients can suffer from fibrosis at the levels of pleura, lung, and retroperitoneum. This is particularly true for ergot-derived drugs such as pergolide, cabergoline and bromocriptin.Recent studies have reported that in Parkinson patients using ergot-derived drugs the occurrence of pathologic abnormalities of heart valves is quite common. This has been observed with high dosages of pergolide , but also with other ergot-derived dopamine-agonist drugs. However, the frequency, severity, reversibility, specificity, association with dosages and physiopathological explanations of these effects are still unclear. Hedonistic homeostatic dysregulation (HHD) is a neuropsychiatric disorder recently described in PD. It seems to be more frequent in early-onset male PD patients and is characterized by self-medication and addiction to dopaminergic replacement therapy (DRT). Such patients frequently develop severe but surprisingly well-tolerated drug-induced dyskinesia >>>

Principal Investigator
Giuseppe Meco Università degli Studi di ROMA "La Sapienza"
Research Objectives
The aim of the present research is to study the effects of cronic dopaminergic stimulation in parkinsonian patients and animal models on cardiovascular system, behaviour and vigilance.
On the basis of the previous studies the first unit designed a short screening questionnaire for HHD that will be administered to 1500 parkinsonian patients consecutively to study HHD clinical feature and relationship with dopaminergic therapy.
The aim of the second unit is the following:
the research program will follow different steps:
A- The first step of the study will be dedicated to obtain an appropriate animal models, which incorporate the biochemical, pathophysiological, and morphological features of the Parkinson'disease. This model has to reproduce the characteristic of the disease both at central level, with the alteration of nigrostriatal pathway, and periferal level through the degeneration of noradrenergic neurons of Locus Coerules which in turn influencing the autonomic nervous activity affect the heart (parkinsonian heart).
B- The second step will be dedicated to verify in the animal model the causes of heart vulnerability and what facors might worsen or improve the degeneration. This step will be composed by three different task:
1- verify whether the vulnerability of the heart to developed fibrosis at valvolar level is enhanced by biochemical alteration characteristic of PD (first of all the role of NE innervation).
2 >>>

Timescale
24 months
National and international background
Drug therapy of Parkinson disease consists in levodopa and in dopamine-agonist drugs. They are used from the first occurrence of the disease symptoms, and often for the whole clinical couse of Parkinson, i.e. lifelong. However, after many years of clinical practice, it is appearing that, while these drugs have a demonstrated clinical efficacy against the motor symptoms of Parkinson, they can also induce several side-effects. Actually, after years of therapy with dopamine-agonist drugs, particularly if used at high dosage, patients can suffer from fibrosis at the levels of pleura, lung, and retroperitoneum. This is particularly true for ergot-derived drugs such as pergolide, cabergoline and bromocriptin (Danoff, 2001; Tintner, 2005). Moreover, other ergot-derived drugs, such as those used against migraine (ergotamine and methysergide) can cause a regurgitation of the aortic, mitral and tricuspid valves (Redfield, 1992). Recent studies have reported that in Parkinson patients using ergot-derived drugs the occurrence of pathologic abnormalities of heart valves is quite common. This has been observed with high dosages of pergolide (Van Camp, 2004; Baseman, 2004), but also with other ergot-derived dopamine-agonist drugs (Serratrice, 2002; Horvath, 2004). However, the frequency, severity, reversibility, specificity, association with dosages and physiopathological explanations of these effects are still unclear.
The altered autonomic functions (disautonomy) in the PD involve >>>