Biology subjects

Depoortere, R. Y.

Publications and source records attributed to Depoortere, R. Y..

3 recordsLinked to original sources

bioRxiv2025

The 5-HT1A receptor selective agonist NLX-204 displays analgesic activity in the knee osteoarthritis and plantar incisional post-operative pain models in rats

BackgroundNLX-204 is a highly selective, high efficacy biased agonist at serotonin 5-HT1A receptors, which are well-established modulators of pain processing. ObjectiveTo evaluate the analgesic activity of NLX-204 in two rat models of nociceptive/inflammatory pain: the monoiodoacetate (MIA)-induced knee osteoarthritis (KOA) and the Brennans plantar incision model, using morphine as an active comparator, in both male and female rats. MethodsKOA was induced by left intra-articular MIA injection. Analgesic effects of NLX-204 (0.1-3 mg/kg p.o.) or morphine (6 mg/kg s.c.) were assessed on days 5 and 8 by measuring withdrawal threshold (WT) using von Frey filaments and dynamic weight bearing (DWB) on injured and contralateral limbs. In the Brennans model, the plantar surface of the left hind limb was incised with elevation and incision of the plantaris muscle. Mechanical allodynia (WT) and guarding behavior (GB) were assessed 24 h post-surgery. ResultsIn the MIA-KOA model, NLX-204 significantly attenuated DWB imbalance in males at 1-3 mg/kg (acute) and 0.1-3 mg/kg (repeated dosing), and in females at 3 mg/kg (repeated dosing only). NLX-204 demonstrated anti-allodynic activity (VF filaments) from 0.3 mg/kg in males (acute and repeated) and from 1 mg/kg in females. In the Brennans model, NLX-204 reduced GB scores at 1 mg/kg (males) and 0.3-1 mg/kg (females), and showed anti-allodynic effects from 0.3 mg/kg in both sexes. Morphine was effective in both models under acute and repeated administration. ConclusionsOral NLX-204 demonstrates dose-dependent analgesic and anti-allodynic activity in two rat models of nociceptive/inflammatory pain, supporting the therapeutic potential of selective, high-efficacy 5-HT1A receptor agonists as a novel non-opioid strategy for pain management.

neuroscience↗

bioRxiv2025

NLX-112 is anti-inflammatory, upregulates GDNF and is neuroprotective against MPTP-induced nigrostriatal dopaminergic degeneration in mice

NLX-112 is a potent and selective 5-HT1A agonist that has successfully completed phase 2A clinical trial for treatment of L-DOPA-induced dyskinesia in Parkinsons disease (PD). We investigated the neuroprotective activity of NLX-112 in a mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Four groups of mice received either saline (1ml/kg) daily for 15 days, MPTP (21.4 mg/kg for 5 days, preceded and followed by 5 days saline, NLX-112 (1mg/kg/day for 15 days) or combined MPTP + NLX-112. Two weeks following cessation of treatments, NLX-112-treated mice showed increased locomotor activity and reduced anxiety-like behaviour in an open-field test, consistent with sustained effects of 5-HT1A receptor activation. MPTP-treated male mice showed a significant reduction of dopaminergic (i.e., tyrosine hydroxylase immunoreactive; TH-ir) neurones in the substantia nigra (SN) and the striatum by 40 and 55%, respectively. NLX-112 treatment elicited a significant protection against MPTP-induced loss of TH-ir neurones and nerve terminals. MPTP also a markedly increased the levels of GFAP-ir astrocytes and Iba1-ir microglia in the SN, and co-expression of glial-derived neurotrophic factor (GDNF) in the GFAP-ir astrocytes in both the SN and the striatum. However, in MPTP treated mice, NLX-112, markedly reversed microglial expression in the SN, and upregulated GFAP/GDNF co-localisation in both the striatum and the SN. Overall, the present study demonstrates a robust neuroprotective effect of NLX-112 in a mouse model of PD by preventing microgliosis, upregulating GDNF and favouring sustained pro-locomotor activity.

pharmacology and toxicology↗

bioRxiv2025

The selective 5-HT1A receptor biased agonist, NLX-101, corrects anomalous behavioral phenotype in a mouse model of Fragile X syndrome

Fragile X syndrome (FXS) is the most prevalent X-linked dominant autism spectrum disorder, causing a range of developmental problems, notably characterized by mild to severe mood/cognitive dysfunctions. NLX-101 is a highly selective and fully efficacious biased agonist at post-synaptic 5-HT1A receptors, and has shown efficacy for reversal of sensory hypersensitivity and EEG anomalies in transgenic mouse models of FXS. Presently, we examined the ability of NLX-101 to normalize several aspects of behavioral anomalies displayed by adult male FMR1 KO2 mice, a transgenic murine model of FXS. FMR1 KO2 mice were treated with NLX-101 (0.64 & 2.5 mg/kg intraperitoneally) and tested sequentially in 1) the open-field test to study hyperactivity and stereotypies (self-grooming), 2) the three chamber partition test (social memory), 3) the nesting behavior test (daily living), 4) the novel object recognition test (working memory) and 5) the hyponeophagia (novelty suppression feeding) test (anxiety). Each test was separated by a three-day wash-out period. NLX-101 normalized hyperactivity and excessive self-grooming at both 0.64 and 2.5 mg/kg, whereas hyponeophagia, and deficits in working and social memory, were partially normalized at 0.64 mg/kg and fully at 2.5 mg/kg. Abnormal nest building was partially normalized at 2.5 mg/kg. In conclusion, NLX-101 exerts beneficial and dose-dependent activity against several behavioral and mood/cognitive deficits displayed by FMR1 KO2 mice. These results highlight the therapeutic potential of using a selective post-synaptic 5-HT1A receptor biased agonist as a novel strategy to treat FXS, for which there is currently no approved efficacious and safe pharmacotherapy. SUMMARYO_LIFragile X syndrome (FXS) is the most prevalent X-linked dominant autism spectrum disorder. C_LIO_LINLX-101, a highly selective serotonin 5-HT1A receptor agonist, was previously shown to reverse sensory hypersensitivity and brain electrical activity anomalies in a gene knock-out (FMR1 KO) mouse model of FXS. C_LIO_LIHere, NLX-101 corrected the anomalous behaviors (hyperactivity, stereotypies, anxiety, deficient social and working memories and nesting behavior) of FMR1 KO2 mice. C_LIO_LITreatment with a selective 5-HT1A receptor agonist such as NLX-101 could represent a promising strategy to treat cognitive and behavioral disturbance in FXS. C_LI

neuroscience↗