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• W3038710321 endingPage "108214" @default.
• W3038710321 startingPage "108214" @default.
• W3038710321 abstract "Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene. One of the major RTT features is breathing dysfunction characterized by periodic hypo- and hyperventilation. The breathing disorders are associated with increased brainstem neuronal excitability, which can be alleviated with GABA agonists. Since neuronal hypoexcitability occurs in the forebrain of RTT models, it is necessary to find pharmacological agents with a relative preference to brainstem neurons. Here we show evidence for the improvement of breathing disorders of Mecp2-disrupted mice with the brainstem-acting drug cloperastine (CPS) and its likely neuronal targets. CPS is an over-the-counter cough medicine that has an inhibitory effect on brainstem neuronal networks. In Mecp2-disrupted mice, CPS (30 mg/kg, i.p.) decreased the occurrence of apneas/h and breath frequency variation. GIRK currents expressed in HEK cells were inhibited by CPS with IC50 1 μM. Whole-cell patch clamp recordings in locus coeruleus (LC) and dorsal tegmental nucleus (DTN) neurons revealed an overall inhibitory effect of CPS (10 μM) on neuronal firing activity. Such an effect was reversed by the GABAA receptor antagonist bicuculline (20 μM). Voltage clamp studies showed that CPS increased GABAergic sIPSCs in LC cells, which was blocked by the GABAB receptor antagonist phaclofen. Functional GABAergic connections of DTN neurons with LC cells were shown. These results suggest that CPS improves breathing dysfunction in Mecp2-null mice by blocking GIRK channels in synaptic terminals and enhancing GABA release." @default.
• W3038710321 created "2020-07-10" @default.
• W3038710321 creator A5016477165 @default.
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• W3038710321 creator A5061868395 @default.
• W3038710321 date "2020-10-01" @default.
• W3038710321 modified "2023-10-07" @default.
• W3038710321 title "The antitussive cloperastine improves breathing abnormalities in a Rett Syndrome mouse model by blocking presynaptic GIRK channels and enhancing GABA release" @default.
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• W3038710321 doi "https://doi.org/10.1016/j.neuropharm.2020.108214" @default.
• W3038710321 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7530036" @default.
• W3038710321 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/32622786" @default.
• W3038710321 hasPublicationYear "2020" @default.
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