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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/7508452
- author
- 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
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Experimental Neurology
- volume
- 271
- issue
- May 30
- pages
- 335 - 350
- publisher
- Elsevier
- external identifiers
-
- pmid:26037043
- wos:000362627200035
- scopus:84936853380
- pmid:26037043
- 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
- 2016-04-01 10:05:55
- date last changed
- 2022-04-12 01:43:41
@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 = {{Elsevier}},
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}},
doi = {{10.1016/j.expneurol.2015.05.021}},
volume = {{271}},
year = {{2015}},
}