mTOR inhibition alleviates L-DOPA-induced dyskinesia in parkinsonian rats.
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.
Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, Lund, Sweden. Mickael.Decressac@med.lu.se
Mickael
M
Decressac
Anders
A
Björklund
D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D005260:Female; D007980:Levodopa / Q000633:toxicity*; D010300:Parkinson Disease / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D000978:Antiparkinson Agents; D047428:Protein Kinase Inhibitors; D007980:Levodopa; C401859:temsirolimus; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus