Rett syndrome is a neurodevelopment disorder affecting around 1 out of 10,000 girls, usually due to de novo mutations in the X-located gene MECP2. It is a complex disorder, both clinically and at a molecular level, and is typically characterized by a neurodevelopment regression starting at age 6 to 18 months after a normal early postnatal development. Patients experience a loss in the acquired abilities, such as speech and non-verbal communication, a severe form of autism, loss of purposeful use of the hands, apnea/hyperpnea, seizures… Despite its great complexity, it appears to be clear that, among other neurological events, main neurotransmitter systems are altered in Rett syndrome together with a decreased synaptic plasticity.

Serotonin receptor 7 (5-HT7R), a recently discovered receptor for the neurotransmitter serotonin recently discovered in hippocampal neurons in vitro, has been proved to be key in synaptic plasticity and many neuro-physiologic events, as it regulates synaptic morphology and plasticity. This regulation occurs via activation of a signaling protein family: Rho GTPases. Dysfunction of this signaling pathway has been related with different forms of intellectual disabilities and aberrant cognitive function.

A few years ago, it was proved by De Filippis and collaborators that the selective activation of these proteins by treatment with a specific peptide rescued the neurobehavioral aspects of Rett mice model. Even though the translational value of those results was limited due to the administration route, in more advanced studies, the same group proved that treatment with LP-211 has enduring effects on Rho GTPases activation in in vivo Rett-mice, which results in the restoration of some aspects of the mice phenotype.

 

PERSISTENT EFFECTS of LP-211 ON 5-HT7R IN RETT-MODEL MICE

LP-211 is a selective, brain-penetrant 5-HT7R agonist: that is, a molecule that can pass the brain-blood barrier and get into the brain (this is a bottleneck in brain-targeted drug discovery, as many molecules fail in that process) and bind to the mentioned serotonin receptor, activating it and producing a biological response.

In their studies, De Filippis and collaborators revealed that stimulation of 5-H7T receptor with daily treatment of LP-211 through a week improved some Rett-related impairments in mice, ranging from behavioral domains to others such as spatial memory or synaptic plasticity. Moreover, they proved a long-lasting beneficial effect on general health status, as they evaluated the outcomes of the treatment 2 months after last LP-211 injection.

Notably, a delayed beneficial effect of the LP-211 treatment was observed, as they became evident three weeks after the beginning of the treatment, which suggests it is a result of the stimulation of the neuroplasticity.

 

LP-211 TREATMENT RESCUES MITOCHONDRIAL DISFUNCTION IN RETT MICE

Recent studies proved that Rho GTPases (which were re-activated by LP-211 treatment in disease models, accounting for the observed changes) are involved in regulation of brain mitochondria. Mitochondria is a cellular organelle that constitutes a critical signaling and powerhouse center, and which dysfunction has been related to many intellectual disabilities and other diseases. In their studies, Valenti and collaborators reported a complete restoration of mitochondrial function on brain samples from mice one month after treatment with LP-211. They studied mitochondrial function based on two parameters: ROS overproduction (this is, Reactive Oxygen Species, that in normal situations have great importance in cellular signaling but that upon mitochondrial damage are present at increased concentrations, toxic for the cell) and the energetic capacity of the mitochondria. Both parameters were recovered through LP-211 treatment.

Again, as previously done, they evaluated the long-lasting effects of the treatment, by analyzing the mitochondrial performance one month after the last LP-211 injection. Consistent with the previously explained data, LP-211 effects were perdurable over time.

They performed these studies in two different Rett-mice characterized models; these showed different phenotype and mitochondrial affectation. Noteworthy, the effect of the treatment was different between the two strains, even though both showed important improvements, confirming that LP-211 exerts its effect in both mouse models.

 

Final Remarks

Having used through all these studies both female Rett-mice brides and being LP-211 a brain penetrant drug, this increased the translational value and potential of the positive results. Even though further analysis is necessary to uncover the organic effects of 5-HT7R stimulation and to increase the knowledge of the molecular mechanisms underlying the beneficial observed effects, all the results taken together constitute preclinical evidence of the potential therapeutic value of LP-211 and 5-HT7 receptor as a target for Rett-syndrome treatment.

 

 

References:

De Filippis, B., V. Chiodi, W. Adriani, E. Lacivita, C. Mallozzi, M. Leopoldo, M. R. Domenici, A. Fuso and G. Laviola (2015). “Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome.” Front Behav Neurosci 9: 86.

De Filippis, B., P. Nativio, A. Fabbri, L. Ricceri, W. Adriani, E. Lacivita, M. Leopoldo, F. Passarelli, A. Fuso and G. Laviola (2014). “Pharmacological stimulation of the brain serotonin receptor 7 as a novel therapeutic approach for Rett syndrome.” Neuropsychopharmacology 39(11): 2506-2518.

Valenti, D., L. de Bari, D. Vigli, E. Lacivita, M. Leopoldo, G. Laviola, R. A. Vacca and B. De Filippis (2017). “Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome.” Neuropharmacology.

 

This summary has been written by Alfonso Oyarzábal, postdoctoral researcher of the synaptic metabolism laboratory of the FSJD (Fundació Sant Joan de Deu), Barcelona.

 

 

 

The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).