sirolimus and Dyskinesia--Drug-Induced

Parkinson's disease (PD), a common neurodegenerative disorder caused by the loss of the dopaminergic input to the basal ganglia, is commonly treated with l-DOPA. Use of this drug, however, is severely limited by the development of dystonic and choreic motor complications, or dyskinesia. This chapter describes the molecular mechanisms implicated in the emergence and manifestation of l-DOPA-induced dyskinesia (LID). Particular emphasis is given to the role played in this condition by abnormalities in signal transduction at the level of the medium spiny neurons (MSNs) of the striatum, which are the principal target of l-DOPA. Recent evidence pointing to pre-synaptic dysregulation is also discussed.

Topics: Amantadine; Animals; Antiparkinson Agents; Basal Ganglia; Dyskinesia, Drug-Induced; Genes, Immediate-Early; Humans; Levodopa; Neurons; Parkinson Disease; Receptor, Cannabinoid, CB1; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Signal Transduction; Sirolimus

Ras homolog enriched in striatum (Rhes) is a small GTP-binding protein that modulates signal transduction at dopamine receptors, and also activates mammalian target of rapamycin complex 1 (mTORC1). Rhes binding to mTORC1 is hypothesized to play a role in motor disorders such as levodopa-induced dyskinesia. Here, we investigate the behavioral and in vivo neurocircuitry changes associated with genetic deletion of Rhes or inhibition of mTORC1 signaling in the mouse model of levodopa-induced dyskinesia. 6-Hydroxydopamine-hemilesioned Rhes knockout mice and wild-type littermates were chronically treated with levodopa. In parallel, 6-hydroxydopamine-hemilesioned naïve mice were chronically treated with levodopa or levodopa plus rapamycin, to block mTORC1 pathway activation. Dyskinetic movements were monitored during levodopa treatment along with motor activity on the rotarod. Finally, dyskinetic mice underwent microdialysis probe implantation in the dopamine-depleted striatum and ipsilateral substantia nigra reticulata, and GABA and glutamate levels were monitored upon acute challenge with levodopa. Both Rhes knockouts and rapamycin-treated mice developed less dyskinesia than controls, although only rapamycin-treated mice fully preserved rotarod performance on levodopa. Levodopa elevated nigral GABA and glutamate in controls but not in Rhes knockouts or rapamycin-treated mice. Levodopa also stimulated striatal glutamate in controls and Rhes knockouts but not in rapamycin-treated mice. We conclude that both genetic deletion of Rhes and pharmacological blockade of mTORC1 significantly attenuate dyskinesia development by reducing the sensitization of striato-nigral medium-sized spiny neurons to levodopa. However, mTORC1 blockade seems to provide a more favorable behavioral outcome and a wider effect on neurochemical correlates of dyskinesia.

Topics: Animals; Antiparkinson Agents; Corpus Striatum; Disease Models, Animal; Dyskinesia, Drug-Induced; Female; Glutamic Acid; GTP-Binding Proteins; Levodopa; Male; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Multiprotein Complexes; Neurons; Neuroprotective Agents; Sirolimus; Substantia Nigra; TOR Serine-Threonine Kinases

The development of dyskinesia upon chronic L-DOPA treatment is a major complication for the management of the motor symptoms in Parkinson's disease (PD) patients. Efforts are made to understand the underlying mechanisms and identify targets for the pharmacological alleviation of dyskinesia without affecting the therapeutic effect of L-DOPA. Previous studies have shown that the mTOR pathway is hyperactive in dyskinesia as a consequence of D1 receptor hypersensitivity. We investigated the effect of the FDA-approved mTOR inhibitor Temsirolimus (CCI-779), currently used in the clinic, on the development of LID and on the severity of already established LID in hemi-parkinsonian rats. Systemic delivery of CCI-779 prevented the development of LID and significantly alleviated the severity of dyskinesia in L-DOPA-primed animals. This was associated with a reduced activation of the mTOR pathway in striatal medium spiny neurons. Drugs with mTOR inhibiting activity that are actively developed in cancer research may be of interest for the management of LID in PD patients.

Topics: Animals; Antiparkinson Agents; Dyskinesia, Drug-Induced; Female; Levodopa; Parkinson Disease; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

L-DOPA-induced dyskinesia, the rate-limiting side effect in the therapy of Parkinson's disease, is mediated by activation of mammalian target of rapamycin (mTOR) signaling in the striatum. We found that Ras homolog enriched in striatum (Rhes), a striatal-specific protein, binds to and activates mTOR. Moreover, Rhes(-/-) mice showed reduced striatal mTOR signaling and diminished dyskinesia, but maintained motor improvement on L-DOPA treatment, suggesting a therapeutic benefit for Rhes-binding drugs.

Topics: Adaptor Proteins, Signal Transducing; Adrenergic Agents; Animals; Antiparkinson Agents; Cell Line, Transformed; Corpus Striatum; Culture Media, Serum-Free; Disability Evaluation; Disease Models, Animal; Dyskinesia, Drug-Induced; Functional Laterality; Gene Expression Regulation; GTP-Binding Proteins; Humans; Immunosuppressive Agents; Levodopa; Mice; Mice, Knockout; Movement; Mutation; Neurons; Neurotoxicity Syndromes; Oxidopamine; Phosphorylation; Protein Binding; Radioligand Assay; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Transfection

Parkinson disease is caused by the progressive loss of dopamine innervation to the basal ganglia and is commonly treated with the dopamine precursor, L-DOPA. Prolonged administration of L-DOPA results in the development of severe motor complications or dyskinesia, which seriously hamper its clinical use. Recent evidence indicates that L-DOPA-induced dyskinesia (LID) is associated with persistent activation of the mammalian target of rapamycin complex 1 (mTORC1) in the medium spiny neurons (MSNs) of the striatum, the main component of the basal ganglia. This phenomenon is secondary to the development of a strong sensitization at the level of dopamine D1 receptors, which are abundantly expressed in a subset of MSNs. Such sensitization confers to dopaminergic drugs (including L-DOPA) the ability to activate the extracellular signal-regulated protein kinases 1/2, which, in turn promote mTORC1 signaling. Using a mouse model of LID, we recently showed that administration of the allosteric mTORC1 inhibitor, rapamycin, reduces dyskinesia. This finding is discussed with respect to underlying mechanisms and potential significance for the development of future therapeutic interventions.

Topics: Animals; Anti-Bacterial Agents; Antiparkinson Agents; Basal Ganglia; Dyskinesia, Drug-Induced; Levodopa; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Parkinson Disease; Proteins; Receptors, Dopamine D1; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases