NLX-101 aids breathing issues, cognitive deficits in Rett mice
Researchers see promise in targeting serotonin receptors
NLX-101 improves breathing and cognitive function in a female mouse model of Rett syndrome, a study found.
The potential therapy activates the receptors that bind serotonin, a signaling molecule found at low levels in the brains of Rett patients.
“This work provides compelling evidence of the therapeutic potential of targeting [serotonin] receptors to improve cognitive function in patients with [Rett] while supporting its respiratory-rescue properties,” the researchers wrote.
The study, “Rescue of respiratory and cognitive impairments in Rett Syndrome mice using NLX-101, a selective 5-HT1A receptor biased agonist,” was published in Biomedicine & Pharmacotherapy.
Rett syndrome is a rare, genetic disorder that affects brain function and results in cognitive, emotional, sensory, and motor dysfunction, as well as problems with the heart, breathing, and digestion.
Breathing issues, cognitive impairment, mood issues linked to serotonin deficit
Low levels of serotonin, a brain signaling molecule, are a feature of Rett syndrome and are thought to contribute to various symptoms, including cognitive impairment and mood disturbances, as well as breathing deficits. That makes serotonin receptors are a potential therapeutic target for Rett.
Sarizotan is an oral therapy developed to treat breathing problems in Rett patients by targeting the serotonin receptor called 5-HT1AR. However, its development was terminated after it failed to demonstrate breathing benefits in a Phase 2/3 clinical trial. It’s thought sarizotan lacked target selectivity, limiting its therapeutic effect.
NLX-101 (also called F15599) is a highly selective and potent activator of 5-HT1AR with marked therapeutic efficacy in animal models of mood and cognition. Treatment with NLX-101 appeared to ease breathing deficits in a Rett mouse model.
Building on these findings, a team led by scientists at the University of Minho in Portugal tested a wide range of NLX-101 doses in female Rett mice to assess the treatment’s impact on breathing and other Rett syndrome symptoms.
A single injection of NLX-101 into the abdomen improved breathing in Rett mice. In particular, NLX-101 reduced the number and length of apnea events, an involuntary pause in breathing, in a dose-dependent manner compared with untreated controls. NLX-101 also lowered the elevated breathing rate of Rett mice, with no major change in tidal volume, the amount of air that moves into and out of the lungs during one breath.
Rett mice exhibited severe short- and long-term memory deficits at 17 and 22 weeks, as indicated by the novel object recognition test, a memory task in which animals recall previous exposure to an object while also being presented with a new one.
Daily treatment with NLX-101 during the early symptomatic phase prevented these cognitive impairments in both short- and long-term memory at 17 weeks, which were sustained to 22 weeks. Long-term memory after treatment was not significantly different from that of healthy mice. Moreover, healthy mice were unaffected by repeated NLX-101 dosing, “highlighting that the observed beneficial effects are specific to Rett mice,” the researchers wrote.
During a fear conditioning test, Rett mice showed a decreased freezing response when re-exposed to a noxious stimulus or light paired with a foot shock, a sign of cognitive impairment. Daily NLX-101 treatment restored the freezing behavior to healthy levels, “suggesting preservation of cognitive function,” they added.
However, NLX-101 did not improve motor symptoms in Rett mice, as indicated by a similar performance to untreated mice in multiple tests. Similar findings were observed in social memory preference: NLX-101-treated animals could not distinguish between a familiar mouse and a new one.
Given the benefits of daily NLX-101 treatment on cognitive performance, the team tested just five days of treatment. Still, short-term NLX-101 failed to improve the cognitive deficits in Rett mice using the novel object recognition test.
“The present findings provide a rationale for targeting post-synaptic 5-HT1A receptors as a treatment for [Rett] and, potentially, other intellectual disability syndromes involving serotonergic dysfunction,” the team wrote.
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