Biology subjects

Newman-Tancredi, A.

Publications and source records attributed to Newman-Tancredi, A..

5 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↗

bioRxiv2025

The 5-HT1A receptor agonist NLX-112 rescues motor swimming deficits in Spinocerebellar Ataxia type 3 mice

IntroductionSpinocerebellar ataxia 3 (SCA3) is a rare neurodegenerative disorder which causes progressive motor disturbances. There is no approved drug treatment but selective activation of serotonin 5-HT1A receptors may be a promising therapeutic strategy to attenuate ataxia symptoms. MethodsNLX-112, a highly selective 5-HT1A full agonist, was tested in the CMVMJD135 transgenic mouse model of SCA3. NLX-112 (1.25 and 5 mg/kg/day) was administered BID intraperitoneally for 14 weeks starting when the mice were 12 weeks of age, i.e., after ataxia signs had become established. The motor swimming test (MST), where mice are required to swim to a raised platform, was used to evaluate the motor behavior of SCA3 mice and their performance was compared with that of wild-type (WT) mice. ResultsBoth doses of NLX-112 were well tolerated by the SCA3 mice, as assessed by welfare parameters. In the MST, the latency of SCA3 mice to reach the platform was significantly longer than that of WT mice. However, when SCA3 mice were treated with either 1.25 or 5 mg/kg/day of NLX-112, they showed robust improvement of motor performance, with swimming latencies which were similar to those of WT mice. This effect of NLX-112 was maintained throughout the period of the study. ConclusionsThe improved motor function of SCA3 mice when treated with NLX-112 supports its investigation as a drug candidate for the treatment of ataxia and related movement disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/674027v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@f0a8e1org.highwire.dtl.DTLVardef@1df4d49org.highwire.dtl.DTLVardef@14af6a2org.highwire.dtl.DTLVardef@86096b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISpinocerebellar ataxia type 3 (SCA3) is marked by progressive motor disturbances C_LIO_LITargeting the serotonergic system is a promising strategy to treat SCA3 C_LIO_LITransgenic SCA3 mice were treated with NLX-112, a selective 5-HT1A agonist C_LIO_LIChronic NLX-112 normalized performance of mice in the motor swimming test C_LIO_LINLX-112 could constitute a drug candidate for treatment of the ataxia disorders C_LI

neuroscience↗

bioRxiv2025

Efficacy of chronic 5-HT1A receptor agonism by NLX-112 in a mouse model of Spinocerebellar Ataxia type 3

BackgroundSpinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by an elongated polyglutamine (polyQ) sequence in the ataxin-3 protein. This expansion triggers neuropathological events, leading to progressive motor disturbances. Currently, no approved therapy exists for this debilitating condition, but compelling evidence suggests that targeting the serotonergic system can significantly attenuate SCA3 disease progression in animal models. ObjectiveThis study aimed to assess the effects of NLX-112, a highly selective serotonin 1A receptor (5-HT1AR) full agonist, in the CMVMJD135 transgenic mouse model of SCA3. MethodsNLX-112 (0.625 and 5 mg/kg/day) and tandospirone (a 5-HT1AR partial agonist used as a comparator; 20 and 80 mg/kg/day) were administered chronically in drinking water for 34 weeks, starting prior to symptom onset. To evaluate the effects of the drugs on SCA3 mice, motor-related behavioral tests and neuropathological techniques were employed. ResultsTreatment with the higher dose of NLX-112 led to improvements in motor coordination and balance, and slowing of symptom deterioration as the disease progressed. These beneficial effects were not achieved with tandospirone. NLX-112 treatment also elicited neuroprotective effects, reducing dopaminergic (tyrosine hydroxylase-positive) cell loss and astrocyte reactivity in the substantia nigra. ConclusionsNLX-112 treatment, started pre-symptomatically, enhanced motor function, slowed disease progression and elicited neuroprotective effects in SCA3 mice, supporting its further development as a drug candidate for treatment of ataxia and related movement disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/671624v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@548b2corg.highwire.dtl.DTLVardef@7d2f51org.highwire.dtl.DTLVardef@ad8ee4org.highwire.dtl.DTLVardef@80213c_HPS_FORMAT_FIGEXP M_FIG C_FIG Key findingsO_LINLX-112 attenuated motor deficits of SCA3 mice, when administered chronically prior to disease onset. C_LIO_LINLX-112 reduced neuropathological biomarkers in SCA3 mice, namely by restoring dopaminergic neuron loss and decreasing astrocyte reactivity. C_LIO_LINLX-112 is a potential candidate for addressing ataxia-related deficits in SCA3 patients. C_LI

neuroscience↗