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Levitt ES, Hunnicutt BJ, Knopp SJ, Williams JT, Bissonnette JM.
J Appl Physiol (1985). 2013 Dec;115(11):1626-33. Epub 2013 Oct 3.

Rett syndrome is a neurological disorder caused by loss of function mutations in the gene that encodes the DNA binding protein methyl-CpG-binding protein 2 (Mecp2). A prominent feature of the syndrome is disturbances in respiration characterized by frequent apnea and an irregular interbreath cycle. 8-Hydroxy-2-dipropylaminotetralin has been shown to positively modulate these disturbances (Abdala AP, Dutschmann M, Bissonnette JM, Paton JF, Proc Natl Acad Sci USA 107: 18208-18213, 2010), but the mode of action is not understood. Here we show that the selective 5-HT1A biased agonist 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone (F15599) decreases apnea and corrects irregularity in both heterozygous Mecp2-deficient female and in Mecp2 null male mice. In whole cell voltage-clamp recordings from dorsal raphe neurons, F15599 potently induced an outward current, which was blocked by barium, reversed at the potassium equilibrium potential, and was antagonized by the 5-HT1a antagonist WAY100135. This is consistent with somatodendritic 5-HT1A receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels (GIRK). In contrast, F15599 did not activate 5-HT1B/D receptors that mediate inhibition of glutamate release from terminals in the nucleus accumbens by a presynaptic mechanism. Thus F15599 activated somatodendritic 5-HT1A autoreceptors, but not axonal 5-HT1B/D receptors. In unanesthetized Mecp2-deficient heterozygous female mice, F15599 reduced apnea in a dose-dependent manner with maximal effect of 74.5 ± 6.9% at 0.1 mg/kg and improved breath irrregularity. Similarly, in Mecp2 null male mice, apnea was reduced by 62 ± 6.6% at 0.25 mg/kg, and breathing became regular. The results indicate respiration is improved with a 5-HT1A agonist that activates GIRK channels without affecting neurotransmitter release.

Promising pipeline

Neurolixis Inc. has in-licensed early-stage clinical assets (Phase 1 and Phase 2) for repurposing in indications with unmet needs in psychiatric and neurological disorders. Read more...

Research

Neurolixis has been awarded several research grants by private foundations, including Parkinson's UK, the Michael J. Fox Foundation for Parkinson's Research, the Rett Syndrome Research Trust and the International Rett Syndrome FoundationRead more...

Therapeutic focus

Neurolixis is developing clinical phase drugs targeting dyskinesia in Parkinson's disease and breathing deficits in Rett syndrome, a devastating orphan disorder. Read more...