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:

• In normal monkeys dyskinesias were first apparent after 2–8 weeks,and continued to intensify over 3 months

• In severely denervated MPTP-lesioned monkeys dyskinesias arise within days, and reach a peak within 3–4 weeks

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 premotoriaAMS: area supplementare motoriaM1: area motoria primaria

Aree peri-rolandiche della corteccia cerebrale

Differential loss of striatal projection systems in Huntington’sdisease: a quantitative immunohistochemical study

Deng YP et al. Journal of Chemical Neuroanatomy 27 (2004) 143–164

EmiballismoCausa: 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 IsNearly Suppressed during Levodopa-

Induced Dyskinesias

•Stella et al., Ann Neurol 1999;46:732–738

Firing rates of each of 10 globus pallidus internal segment (GPi) neurons recorded continuously

through the states of “off,” “on,” and “on without dyskinesias”

•Stella et al., Ann Neurol 1999;46:732–738

Slow oscillatory activity in the subthalamic nucleus and levodopa-induceddyskinesias 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 D2messenger 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 D1messenger 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 bylong-term L-DOPA treatment in a rat model of Parkinson's

disease

FosB/DFosB-positive cells in the medialand 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 withL-Dopa

Fisone et al,. Physiology & Behavior 92 (2007) 8–14

Chronic L-DOPA treatment of Parkinsonian rats restores LTPand 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-GEFIIpredicts 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 duringlevodopa-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 dephosphorylationc.nucleotides, DARPP-32 ↓ ↓ fast reduction activation of PP- 1cAMP /cGMP

Lowered cAMP and cGMP signalling in the brain duringlevodopa-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 andG. 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 andG. 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 MartoranaDavide FerrazzoliFrancesco SicaGiorgio Bernardi