Meccanismi fisiopatologici delle discinesie da levodopa Università di Roma Tor Vergata Giuseppe Sancesario
Birkmayer W. [10 years of L-DOPA therapy of Parkinson's syndrome]   Wien Klin Wochenschr.  1971 Apr 2;83(13):221-7. Articl...
 
L-Dopa induces dyskinesia in normal monkeys: <ul><li>In normal monkeys dyskinesias were first apparent after 2–8 weeks,and...
 
 
APM: area premotoria AMS: area supplementare motoria M1: area motoria primaria Aree peri-rolandiche della corteccia cerebr...
 
Differential loss of striatal projection systems in Huntington’s disease: a quantitative immunohistochemical study Deng YP...
Emiballismo Causa: lesione del nucleo subtalamico
Disturbi ipocinetici ed ipercinetici:  Riduzione anomala degli impulsi eccitatori verso la corteccia:  Morbo di Parkinson ...
 
 
Internal Globus Pallidus Discharge Is Nearly Suppressed during Levodopa- Induced Dyskinesias <ul><li>Stella et al., Ann Ne...
Firing rates of each of 10 globus pallidus internal segment (GPi) neurons recorded continuously through the states of “off...
Slow oscillatory activity in the subthalamic nucleus and levodopa-induced dyskinesias in Parkinson’s disease Alonso-Frech ...
 
Persistent changes in the expression of (A-E) PDyn or (A’-E’) PPE mRNA on the 6-OHDA-lesioned side of the CPu Westin et al...
Effect of MPTP intoxication and L-dopa treatment on (A, B) striatal D2 messenger RNA (mRNA) expression and (C, D) striatal...
Effect of MPTP intoxication and L-dopa treatment on (A, B) striatal D1 messenger RNA (mRNA) expression and (C, D) D1 bindi...
Effect of MPTP intoxication and L-dopa treatment on the striatal D1 agonist– stimulated GTPS binding. Aubert et al., Ann N...
Persistent changes in striatal gene expression induced by long-term L-DOPA treatment in a rat model of Parkinson's disease...
Beyond the Dopamine Receptor: the DARPP-32/Protein Greengard   et al.,  Neuron, Vol. 23, 435–447, 1999
DARPP-32 phosphorylation at Thr34 is enhanced in Parkinsonian dyskinetic rats . Picconi et al., nature  neuroscience  • vo...
Diagram illustrating some of the changes in signaling associated with L-Dopa  Fisone et al,. Physiology & Behavior 92 (200...
Chronic L-DOPA treatment of Parkinsonian rats restores LTP and blocks depotentiation in dyskinetic rats Picconi et al., na...
PKA-mediated phosphorylation of DARPP-32 and GluR1 is associated with LID. Sham- or 6-OHDA-lesioned mice were treated with...
Phosphorylation of ERK1/2 is associated with LID
D1 dopamine receptor-mediated phosphorylation of ERK1/2 ( p-ERK1/2 ) in the dopamine-depleted striatum Gerfen et al., The ...
Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian the...
Journal of Neurochemistry, 2006, 96, 1718–1727
tyrosine hydroxylase (TH) immunoreactivity in ipsi- (I) and contralateral (C) striatum of rats with unilateral 6-OHDA lesi...
Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias Giorgi et al., E. J. Neuroscience, 28, 9...
 
PDE1B-immunoreactive neurons in the caudate–putamen 6-OHDA  control
Sancesario et al., E. J. of Neuroscience, Vol. 20, pp. 989–1000, 2004
Beyond the Dopamine Receptor: the DARPP-32/Protein Greengard   et al.,  Neuron, Vol. 23, 435–447, 1999 Calcium ≥ 1 µM ↓ PD...
Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias : new aspects in the pathogenetic mechan...
 
Facoltà di Medicina e Chirurgia M. Giorgi,1,* V. D’Angelo,2,* Z. Esposito,2 V. Nuccetelli,1 R. Sorge,2 A. Martorana,2 A. S...
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  • Figure 1. D1 dopamine receptor-mediated phosphorylation of ERK1/2 ( p-ERK1/2 ) in the dopamine-depleted striatum. Unilateral lesion of the nigrostriatal dopamine system is demonstrated by the loss of tyrosine hydroxylase immunoreactivity in the right lesioned striatum ( A ). After treatment (15 min) with the partial D1 dopamine agonist SKF38393 (2 mg/kg, i.p.), p-ERK1/2 is not evident in the dopamine-intact striatum ( B ) but is present in numerous neurons in the dopamine-depleted striatum ( C ). To determine the type of striatal neuron in which p-ERK1/2 is present, sections are processed to display both p-ERK1/2 with a green fluorescent label ( D ) and enkephalin mRNA with a red fluorescent label ( D ). Nearly all p-ERK1/2-immunoreactive neurons ( blue arrows ) are enkephalin negative. Only a small number of enkephalin-positive neurons display p-ERK1/2 immunoreactivity ( yellow arrow ), whereas the vast majority are p-ERK1/2 negative ( orange arrows ). The graph provides quantitative data of the average number of pERK-positive/enkephalin-negative ( blue arrows ), pERK-positive/enkephalin-positive ( yellow ), and pERK-negative/enkephalin-positive ( red ) neurons in a 500 m2 area from the lateral striatum of four animals. Enkephalin provides a marker of indirect projection neurons, with any given striatal area having an equal number of direct projecting, enkephalin-negative neurons (Gerfen and Young, 1988). Data indicate that, in the dopamine-intact striatum, there are few pERK1/2-immunoreactive neurons, whereas in the dopamine-depleted striatum, D1 agonist-induced p-ERK1/2 occurs selectively in enkephalin-negative, direct striatal projection neurons.
  • Presentazione Sancesario G.

    1. 1. Meccanismi fisiopatologici delle discinesie da levodopa Università di Roma Tor Vergata Giuseppe Sancesario
    2. 2. Birkmayer W. [10 years of L-DOPA therapy of Parkinson's syndrome] Wien Klin Wochenschr. 1971 Apr 2;83(13):221-7. Article in German] Lieberman AN, Pedersen B. Levodopa and adventitious movements. Lancet. 1970 Nov 7;2(7680):985.
    3. 4. L-Dopa induces dyskinesia in normal monkeys: <ul><li>In normal monkeys dyskinesias were first apparent after 2–8 weeks,and continued to intensify over 3 months </li></ul><ul><li>In severely denervated MPTP-lesioned monkeys dyskinesias arise within days, and reach a peak within 3–4 weeks </li></ul>Pearce et al., Psychopharmacology (2001) 156:402–409 In normal monkeys, only animals receiving the highest daily dose of L-dopa (80 mg/kg plus carbidopa 20 mg/kg), with or without entacapone (80 mg/kg), developed dyskinesias.
    4. 7. APM: area premotoria AMS: area supplementare motoria M1: area motoria primaria Aree peri-rolandiche della corteccia cerebrale
    5. 9. Differential loss of striatal projection systems in Huntington’s disease: a quantitative immunohistochemical study Deng YP et al. Journal of Chemical Neuroanatomy 27 (2004) 143–164
    6. 10. Emiballismo Causa: lesione del nucleo subtalamico
    7. 11. Disturbi ipocinetici ed ipercinetici: Riduzione anomala degli impulsi eccitatori verso la corteccia: Morbo di Parkinson Accentuazione anomala degli impulsi eccitatori verso la corteccia: corea e ballismo
    8. 14. Internal Globus Pallidus Discharge Is Nearly Suppressed during Levodopa- Induced Dyskinesias <ul><li>Stella et al., Ann Neurol 1999;46:732–738 </li></ul>
    9. 15. Firing rates of each of 10 globus pallidus internal segment (GPi) neurons recorded continuously through the states of “off,” “on,” and “on without dyskinesias” <ul><li>Stella et al., Ann Neurol 1999;46:732–738 </li></ul>
    10. 16. Slow oscillatory activity in the subthalamic nucleus and levodopa-induced dyskinesias in Parkinson’s disease Alonso-Frech et al., Brain (2006), 129, 1748–1757
    11. 18. Persistent changes in the expression of (A-E) PDyn or (A’-E’) PPE mRNA on the 6-OHDA-lesioned side of the CPu Westin et al., European Journal of Neuroscience, Vol. 14, pp. 1171±1176, 2001
    12. 19. Effect of MPTP intoxication and L-dopa treatment on (A, B) striatal D2 messenger RNA (mRNA) expression and (C, D) striatal D2 binding levels Aubert et al., Ann Neurol 2005;57:17–26
    13. 20. Effect of MPTP intoxication and L-dopa treatment on (A, B) striatal D1 messenger RNA (mRNA) expression and (C, D) D1 binding levels Aubert et al., Ann Neurol 2005;57:17–26
    14. 21. Effect of MPTP intoxication and L-dopa treatment on the striatal D1 agonist– stimulated GTPS binding. Aubert et al., Ann Neurol 2005;57:17–26
    15. 22. Persistent changes in striatal gene expression induced by long-term L-DOPA treatment in a rat model of Parkinson's disease FosB/DFosB-positive cells in the medial and the lateral CPu. Westin et al., European Journal of Neuroscience, Vol. 14, pp. 1171±1176, 2001
    16. 23. Beyond the Dopamine Receptor: the DARPP-32/Protein Greengard et al., Neuron, Vol. 23, 435–447, 1999
    17. 24. DARPP-32 phosphorylation at Thr34 is enhanced in Parkinsonian dyskinetic rats . Picconi et al., nature neuroscience • volume 6 no 5 • may 2003
    18. 25. Diagram illustrating some of the changes in signaling associated with L-Dopa Fisone et al,. Physiology & Behavior 92 (2007) 8–14
    19. 26. Chronic L-DOPA treatment of Parkinsonian rats restores LTP and blocks depotentiation in dyskinetic rats Picconi et al., nature neuroscience • volume 6 no 5 • may 2003
    20. 27. PKA-mediated phosphorylation of DARPP-32 and GluR1 is associated with LID. Sham- or 6-OHDA-lesioned mice were treated with saline, acute L-DOPA, or chronic L-DOPA. Santini et al., The Journal of Neuroscience, June 27, 2007 • 27(26):6995–7005
    21. 28. Phosphorylation of ERK1/2 is associated with LID
    22. 29. D1 dopamine receptor-mediated phosphorylation of ERK1/2 ( p-ERK1/2 ) in the dopamine-depleted striatum Gerfen et al., The Journal of Neuroscience, June 15, 2002, 22 (12):5042–5054
    23. 30. Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy Crittenden et al., PNAS , 2009; 106: 2892–2896
    24. 31. Journal of Neurochemistry, 2006, 96, 1718–1727
    25. 32. tyrosine hydroxylase (TH) immunoreactivity in ipsi- (I) and contralateral (C) striatum of rats with unilateral 6-OHDA lesion of the substantia nigra, 2 months after lesion
    26. 33. Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias Giorgi et al., E. J. Neuroscience, 28, 941–950, 2008
    27. 35. PDE1B-immunoreactive neurons in the caudate–putamen 6-OHDA control
    28. 36. Sancesario et al., E. J. of Neuroscience, Vol. 20, pp. 989–1000, 2004
    29. 37. Beyond the Dopamine Receptor: the DARPP-32/Protein Greengard et al., Neuron, Vol. 23, 435–447, 1999 Calcium ≥ 1 µM ↓ PDE1 B calcineurin (PP-2B) ↓ ↓ hydrolysis dephosphorylation c.nucleotides, DARPP-32 ↓ ↓ fast reduction activation of PP- 1 cAMP /cGMP
    30. 38. Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias : new aspects in the pathogenetic mechanisms We hypothesise that levodopa-induced dyskinesias in experimental parkinsonism are the result of biphasic actions of levodopa ⁄ dopamine, characterized by a phase of equilibrium between the synthesis and catabolism of cAMP and cGMP in cortico-striatal-pallidal neurons, followed by a phase of transient imbalance in the second messenger system, when catabolism is prevalent due to the combined effects of exceeding calcium levels and stimulation of calcium calmodulin-dependent PDE Giorgi et al., European Journal of Neuroscience, Vol. 28, pp. 941–950, 2008
    31. 40. Facoltà di Medicina e Chirurgia M. Giorgi,1,* V. D’Angelo,2,* Z. Esposito,2 V. Nuccetelli,1 R. Sorge,2 A. Martorana,2 A. Stefani,2 G. Bernardi2,3 and G. Sancesario M. Giorgi,1,* V. D’Angelo,2,* Z. Esposito,2 V. Nuccetelli,1 R. Sorge,2 A. Martorana,2 A. Stefani,2 G. Bernardi2,3 and G. Sancesario Mauro Giorgi, Valeria Nuccetelli, Department of Basic and Applied Biology, University of L’Aquila, L’Aquila , Department of Neuroscience, University of Rome Tor Vergata Vincenza D’Angelo Zaira Esposito Roberto. Sorge, Alessandro Martorana Davide Ferrazzoli Francesco Sica Giorgio Bernardi

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