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NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat.
Exp Neurol. 2015 Sep; 271:335-50.EN

Abstract

L-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the 'false neurotransmitter' conversion of L-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT1A agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders. NLX-112 (0.16 mg/kg, i.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished L-DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT1A antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the L-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects. NLX-112 (0.16 mg/kg, i.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16 mg/kg, i.p.) and eliminated stress-induced ultrasonic vocalization at 0.08 mg/kg, i.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16 mg/kg, i.p.) did not impair the ability of L-DOPA to rescue forepaw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and forepaw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63 mg/kg, i.p., twice a day), flat body posture and forepaw treading subsided within 4 days of treatment. Taken together, these observations suggest that NLX-112 could exhibit a novel therapeutic profile, combining robust anti-dyskinetic properties without impairing the therapeutic properties of L-DOPA, and with additional beneficial effects on non-motor (affective) symptoms.

Authors+Show Affiliations

Basal Ganglia Pathophysiology Unit, Dept. of Experimental Medical Sciences, Lund University, Sweden.Brains On-Line BV, Groningen, The Netherlands.Neurolixis Inc., Dana Point, CA 92629, USA.Pierre Fabre Laboratories, 81100 Castres, France.Pierre Fabre Laboratories, 81100 Castres, France.Pierre Fabre Laboratories, 81100 Castres, France.Pierre Fabre Laboratories, 81100 Castres, France.Basal Ganglia Pathophysiology Unit, Dept. of Experimental Medical Sciences, Lund University, Sweden.Neurolixis Inc., Dana Point, CA 92629, USA. Electronic address: anewmantancredi@neurolixis.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26037043

Citation

Iderberg, H, et al. "NLX-112, a Novel 5-HT1A Receptor Agonist for the Treatment of L-DOPA-induced Dyskinesia: Behavioral and Neurochemical Profile in Rat." Experimental Neurology, vol. 271, 2015, pp. 335-50.
Iderberg H, McCreary AC, Varney MA, et al. NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat. Exp Neurol. 2015;271:335-50.
Iderberg, H., McCreary, A. C., Varney, M. A., Kleven, M. S., Koek, W., Bardin, L., Depoortère, R., Cenci, M. A., & Newman-Tancredi, A. (2015). NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat. Experimental Neurology, 271, 335-50. https://doi.org/10.1016/j.expneurol.2015.05.021
Iderberg H, et al. NLX-112, a Novel 5-HT1A Receptor Agonist for the Treatment of L-DOPA-induced Dyskinesia: Behavioral and Neurochemical Profile in Rat. Exp Neurol. 2015;271:335-50. PubMed PMID: 26037043.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat. AU - Iderberg,H, AU - McCreary,A C, AU - Varney,M A, AU - Kleven,M S, AU - Koek,W, AU - Bardin,L, AU - Depoortère,R, AU - Cenci,M A, AU - Newman-Tancredi,A, Y1 - 2015/05/30/ PY - 2015/03/16/received PY - 2015/05/22/revised PY - 2015/05/27/accepted PY - 2015/6/4/entrez PY - 2015/6/4/pubmed PY - 2015/12/23/medline KW - 5-HT1A agonist KW - 5-HT1A receptor KW - Befiradol KW - Mood deficits KW - NLX-112 KW - Parkinson's disease KW - l-DOPA-induced dyskinesia SP - 335 EP - 50 JF - Experimental neurology JO - Exp Neurol VL - 271 N2 - L-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the 'false neurotransmitter' conversion of L-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT1A agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders. NLX-112 (0.16 mg/kg, i.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished L-DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT1A antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the L-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects. NLX-112 (0.16 mg/kg, i.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16 mg/kg, i.p.) and eliminated stress-induced ultrasonic vocalization at 0.08 mg/kg, i.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16 mg/kg, i.p.) did not impair the ability of L-DOPA to rescue forepaw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and forepaw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63 mg/kg, i.p., twice a day), flat body posture and forepaw treading subsided within 4 days of treatment. Taken together, these observations suggest that NLX-112 could exhibit a novel therapeutic profile, combining robust anti-dyskinetic properties without impairing the therapeutic properties of L-DOPA, and with additional beneficial effects on non-motor (affective) symptoms. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/26037043/NLX_112_a_novel_5_HT1A_receptor_agonist_for_the_treatment_of_L_DOPA_induced_dyskinesia:_Behavioral_and_neurochemical_profile_in_rat_ DB - PRIME DP - Unbound Medicine ER -