The dopaminergic stabilizer pridopidine decreases expression of L-DOPA-induced locomotor sensitisation in the rat unilateral 6-OHDA model.

Abstract

Treatment-limiting motor complications occur in patients with Parkinson's disease after chronic levodopa (L-DOPA) treatment, and represent an unmet medical need. We examined the motor and neurochemical effects of the dopaminergic stabilizer pridopidine (NeuroSearch A/S, Ballerup, Denmark) in the unilateral rodent 6-OHDA lesion model, which is often used to evaluate the potential of experimental compounds for such dopamine-related motor complications. In total, 72 rats were hemi-lesioned and allocated to receive twice-daily injections of either vehicle; 6.5mg/kg L-DOPA; L-DOPA + 25 μmol/kg pridopidine; or L-DOPA + 25 μmol/kg (-)-OSU6162-a prototype dopaminergic stabilizer used previously in 6-OHDA hemi-lesion models. Animals were treated for 7, 14 or 21 days, and locomotor activity and ex vivo brain tissue neurochemistry analysed. In agreement with previous studies, L-DOPA sensitised the motor response, producing significantly more contralateral rotations than vehicle (P<0.05). Concomitant administration of pridopidine and L-DOPA significantly decreased the number of L-DOPA-induced contralateral rotations on day 7, 14 and 21 (P<0.05 versus L-DOPA alone), while still allowing a beneficial locomotor stimulant effect of L-DOPA. Concomitant pridopidine also reduced L-DOPA-induced rotation asymmetry (P<0.05 versus L-DOPA alone) and had no adverse effects on distance travelled. Brain neurochemistry was generally unaffected in all treatments groups. In conclusion, pridopidine shows potential for reducing motor complications of L-DOPA in Parkinson's disease and further testing is warranted.

• Authors: Henrik Ponten, Johan Kullingsjö, Clas Sonesson, Susanna Waters, Nicholas Waters, Joakim Tedroff
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 698 Issue 1-3 Pg. 278-85 (Jan 05 2013) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 23127496 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Dopamine Agents
• Piperidines
• Levodopa
• Oxidopamine
• pridopidine
• Dopamine

Topics

• Animals
• Central Nervous System Sensitization (drug effects)
• Dopamine (metabolism)
• Dopamine Agents (pharmacology)
• Levodopa (pharmacology)
• Locomotion (drug effects, physiology)
• Male
• Oxidopamine (pharmacology)
• Piperidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rotation
• Time Factors