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Neuropharmacology. 2016 Jun;105:651-660. doi: 10.1016/j.neuropharm.2016.01.013. Epub 2016 Jan 9.

The novel 5-HT1A receptor agonist, NLX-112 reduces l-DOPA-induced abnormal involuntary movements in rat: A chronic administration study with microdialysis measurements.

Author information

1
Neurolixis Inc., 34145 Pacific Coast Highway #504, Dana Point, CA 92629, USA. Electronic address: amccrear@its.jnj.com.
2
Neurolixis Inc., 34145 Pacific Coast Highway #504, Dana Point, CA 92629, USA.
3
Neurolixis Inc., 34145 Pacific Coast Highway #504, Dana Point, CA 92629, USA. Electronic address: anewmantancredi@neurolixis.com.

Abstract

Although l-DOPA alleviates the motor symptoms of Parkinson's disease (PD), it elicits troublesome l-DOPA-induced dyskinesia (LID) in a majority of PD patients after prolonged treatment. This is likely due to conversion of l-DOPA to dopamine as a 'false neurotransmitter' from serotoninergic neurons. The highly selective and efficacious 5-HT1A receptor agonist, NLX-112 (befiradol or F13640) shows potent activity in a rat model of LID (suppression of Abnormal Involuntary Movements, AIMs) but its anti-AIMs effects have not previously been investigated following repeated administration. Acute administration of NLX-112 (0.04 and 0.16 mg/kg i.p.) reversed l-DOPA (6 mg/kg)-induced AIMs in hemiparkinsonian rats with established dyskinesia. The activity of NLX-112 was maintained following repeated daily i.p. administration over 14 days and was accompanied by pronounced decrease of striatal 5-HT extracellular levels, as measured by in vivo microdialysis, indicative of the inhibition of serotonergic activity. A concurrent blunting of l-DOPA-induced surge in dopamine levels on the lesioned side of the brain was observed upon NLX-112 administration and these neurochemical responses were also seen after 14 days of treatment. NLX-112 also suppressed the expression of AIMs in rats that were being primed for dyskinesia by repeated l-DOPA administration. However, when treatment of these rats with NLX-112 was stopped, l-DOPA then induced AIMs with scores that resembled those of control rats. The present study shows that the potent anti-AIMs activity of NLX-112 is maintained upon repeated administration and supports the ongoing clinical development of NLX-112 as a novel antidyskinetic agent for PD patients receiving l-DOPA treatment.

KEYWORDS:

5-HT(1A) receptor; 5-HT1A agonist; Befiradol; NLX-112; Parkinson's disease; l-DOPA-Induced dyskinesia

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