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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.

Iderberg, Hanna LU ; McCreary, A C; Varney, M A; Kleven, M S; Koek, W; Bardin, L; Depoortère, R; Cenci Nilsson, Angela LU and Newman-Tancredi, A (2015) In Experimental Neurology 271(May 30). p.335-350
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 (0.16mg/kgi.p.) potently and completely reversed haloperidol-induced... (More)
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 (0.16mg/kgi.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 (0.16mg/kgi.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 0.16mg/kgi.p.) and eliminated stress-induced ultrasonic vocalization at 0.08mg/kgi.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16mg/kgi.p.) did not impair the abilityof L-DOPA to rescue fore-paw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and fore-paw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63mg/kgi.p., twice a day), flat body posture and fore-paw treading subsided within 4days 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Neurology
volume
271
issue
May 30
pages
335 - 350
publisher
Academic Press
external identifiers
  • pmid:26037043
  • wos:000362627200035
  • scopus:84936853380
ISSN
0014-4886
DOI
10.1016/j.expneurol.2015.05.021
language
English
LU publication?
yes
id
a41ba289-4c68-4ac3-b07e-3caa81626677 (old id 7508452)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26037043?dopt=Abstract
date added to LUP
2015-07-06 02:43:23
date last changed
2017-11-05 03:05:51
@article{a41ba289-4c68-4ac3-b07e-3caa81626677,
  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 (0.16mg/kgi.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 (0.16mg/kgi.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 0.16mg/kgi.p.) and eliminated stress-induced ultrasonic vocalization at 0.08mg/kgi.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16mg/kgi.p.) did not impair the abilityof L-DOPA to rescue fore-paw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and fore-paw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63mg/kgi.p., twice a day), flat body posture and fore-paw treading subsided within 4days 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.},
  author       = {Iderberg, Hanna and McCreary, A C and Varney, M A and Kleven, M S and Koek, W and Bardin, L and Depoortère, R and Cenci Nilsson, Angela and Newman-Tancredi, A},
  issn         = {0014-4886},
  language     = {eng},
  number       = {May 30},
  pages        = {335--350},
  publisher    = {Academic Press},
  series       = {Experimental Neurology},
  title        = {NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat.},
  url          = {http://dx.doi.org/10.1016/j.expneurol.2015.05.021},
  volume       = {271},
  year         = {2015},
}