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.
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. Article in German] Lieberman AN, Pedersen B. Levodopa and adventitious movements. Lancet. 1970 Nov 7;2(7680):985.
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.
APM: area premotoria AMS: area supplementare motoria M1: area motoria primaria Aree peri-rolandiche della corteccia cerebrale
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
Emiballismo Causa: lesione del nucleo subtalamico
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
Internal Globus Pallidus Discharge Is Nearly Suppressed during Levodopa- Induced Dyskinesias <ul><li>Stella et al., Ann Neurol 1999;46:732–738 </li></ul>
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>
Slow oscillatory activity in the subthalamic nucleus and levodopa-induced dyskinesias in Parkinson’s disease Alonso-Frech et al., Brain (2006), 129, 1748–1757
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
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
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
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
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
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 • volume 6 no 5 • may 2003
Diagram illustrating some of the changes in signaling associated with L-Dopa Fisone et al,. Physiology & Behavior 92 (2007) 8–14
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
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
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 Journal of Neuroscience, June 15, 2002, 22 (12):5042–5054
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
Journal of Neurochemistry, 2006, 96, 1718–1727
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
Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias Giorgi et al., E. J. Neuroscience, 28, 941–950, 2008
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 ↓ PDE1 B calcineurin (PP-2B) ↓ ↓ hydrolysis dephosphorylation c.nucleotides, DARPP-32 ↓ ↓ fast reduction activation of PP- 1 cAMP /cGMP
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
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