NOP Receptor Agonists for Preventing Levodopa-induced Dyskinesia
Dyskinesia Challenge, 2013
Objective/Rationale: † † † † † ††
Dyskinesia (involuntary fractured, jerky movements) is a debilitating side effect of long-term levodopa treatment for Parkinsonís motor symptoms. Previous studies have shown that activating the nociceptin (NOP) receptor (a protein that plays a role in movement) can decrease the expression of levodopa-induced dyskinesia in pre-clinical models. This study will investigate whether NOP receptor agonists (activators) are also effective in preventing the development of dyskinesia, when given along with levodopa in pre-clinical models of PD.
Project Description: † † † † † ††
Models will be treated for three weeks with levodopa alone or in combination with NOP receptor agonists. Abnormal involuntary movements will be monitored and scored every four days. Motor performance will also be monitored to ascertain that NOP receptor agonists do not interfere with the antiparkinsonian effect of levodopa. Finally, to confirm that NOP receptor agonists interfere with the process of brain sensitization to levodopa, two days after the end of treatment, the models will be given levodopa alone.
Relevance to Diagnosis/Treatment of Parkinsonís Disease: † † † † † † † † † ††
The only marketed anti-dyskinetic drug is not very effective and not well-tolerated. If NOP receptor agonists, given chronically along with levodopa treatment, prove to be effective in preventing the development of dyskinesia, this novel therapeutic approach may prevent the adverse effects of long-term levodopa therapy.
Anticipated Outcome: † † † † †
We expect to prove that chronic administration of NOP receptor agonists in combination with levodopa decreases or prevents the development of dyskinesia. We expect to prove that NOP receptor agonists exert their antidyskinetic effect by selectively interfering with the cellular pathways associated with dyskinesia development and negatively interfere with the process of brain sensitization to levodopa. We expect to prove that the antidyskinetic effect of NOP receptor agonists is maintained over time.
The project investigated the ability of nociceptin receptor agonists to attenuate levodopa-induced dyskinesia under two paradigms ó (i) to reduce expression of abnormal involuntary movements when administered once (acute treatment) to levodopa-primed pre-clinical models, and (ii) to reduce development of levodopa-induced dyskinesia when administered chronically in combination with levodopa in models. The project tested different nociceptin agonists, with varying profiles of potency and selectivity in these two paradigms.
Acute administration of the NOP receptor agonist AT-326 did not attenuate the expression of abnormal involuntary movements in levodopa-primed rats, nor did it cause hypolocomotion. However, chronic administration of AT-326 appeared to reduce the development of abnormal involuntary movements, and significantly improved the rotarod performance on levodopa. This suggests that the doses of NOP agonists capable of preventing the development of dyskinesia are lower than those required to block their expression.
To confirm this observation, acute administration of the more potent and selective NOP full agonist AT-403 attenuated the expression of abnormal involuntary movements in levodopa-primed models, at a dose causing hypolocomotion. A chronic study with lower doses of AT-403 is currently ongoing, to determine whether the hypolocomotor effect can be dissociated from the anti-dyskinetic effect at lower doses of NOP agonists.
Acute administration of the NOP receptor partial agonist AT-127 slightly improved motor deficits in parkinsonian models, without affecting the expression of abnormal involuntary movements in already dyskinetic models. However, chronic administration of AT-127 seemed to prolong the prodykinetic effect of levodopa, suggesting that partial agonists may behave as antagonists in parkinsonian models.
President and Chief Scientific Officer at Astraea Therapeutics
Location: Mountain View, California, United States
Associate Professor of Pharmacology at University of Ferrara
Location: Ferrara, Italy