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Effect of Securinine on Genioglossus Muscle Activity and Modulation of Hypoglossal Motor Neuron Excitability in Rats
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A1246 - Effect of Securinine on Genioglossus Muscle Activity and Modulation of Hypoglossal Motor Neuron Excitability in Rats
Author Block: W. Xu; Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
RATIONALE: The genioglossus (GG) muscle, which is innervated by the medial branch of the hypoglossal nerve, is the largest upper airway dilator muscle that promotes oropharyngeal airway widening. The root cause of airway collapse underlying the pathogenesis of obstructive sleep apnea (OSA) is suppression of hypoglossal motoneuron (HM) excitability, which activity is influenced by a variety of neuromodulators, and also determined by the balance between excitatory glutamatergic transmission and inhibitory transmission mediated by glycine or GABA. Pharmacological manipulation that attempts to increase the excitability of HMs is clinically crucial. As a kind of central respiratory stimulant, securinine is perhaps an effective pharmacological strategy capable of counteraction the state-dependent suppression of HMs. Therefore, the present study aimed at the effect of securinine on HMs and possible mechanisms underlying it. METHODS: To examine the effect of securinine on genioglossus muscle activities, GG signals were recorded under intraperitoneal injection of securinine (0.06mg/kg and 0.24mg/kg) and intracerebroventricular microinjections (20, 40 and 80 g/L), respectively. Whole cell patch-clamp recordings were made after securinine applied to the HMs in neonatal brain stem slices. RESULTS: Unilateral micro-injection of securinine into the hypoglossal nucleus significantly enhanced ipsilateral GG activity in adult rats. The electrophysiological studies demonstrated securinine had a marked excitatory effect on HM activity by membrane potential depolarization without changing input resistance, induced a decrease in mAHP amplitude, enhanced firing response to current injection and altered shape of single AP by hyperpolarization of threshold potential and reduction of amplitude. Further, using pharmacological methods, GABAA receptors mediated the postsynaptic excitation of HMs in the presence of TTX. In voltage clamp, securinine largely reduced the amplitude and frequency of GABAergic spontaneous events (sIPSCs) and the amplitude of GABAergic miniature inhibitory postsynaptic currents (mIPSCs), while glycinergic mIPSCs and frequency of GABAergic mIPSCs were unaffected. CONCLUSIONS: That suggested securinine influenced inhibitory GABAergic transmission via postsynaptic mechanisms. These results unravel the mechanisms controlling HMs activity by a novel and promising drug, and also draw great attention to researchers and clinicians who are interested in understanding OSA pathogenesis and treatment.
Author Block: W. Xu; Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
RATIONALE: The genioglossus (GG) muscle, which is innervated by the medial branch of the hypoglossal nerve, is the largest upper airway dilator muscle that promotes oropharyngeal airway widening. The root cause of airway collapse underlying the pathogenesis of obstructive sleep apnea (OSA) is suppression of hypoglossal motoneuron (HM) excitability, which activity is influenced by a variety of neuromodulators, and also determined by the balance between excitatory glutamatergic transmission and inhibitory transmission mediated by glycine or GABA. Pharmacological manipulation that attempts to increase the excitability of HMs is clinically crucial. As a kind of central respiratory stimulant, securinine is perhaps an effective pharmacological strategy capable of counteraction the state-dependent suppression of HMs. Therefore, the present study aimed at the effect of securinine on HMs and possible mechanisms underlying it. METHODS: To examine the effect of securinine on genioglossus muscle activities, GG signals were recorded under intraperitoneal injection of securinine (0.06mg/kg and 0.24mg/kg) and intracerebroventricular microinjections (20, 40 and 80 g/L), respectively. Whole cell patch-clamp recordings were made after securinine applied to the HMs in neonatal brain stem slices. RESULTS: Unilateral micro-injection of securinine into the hypoglossal nucleus significantly enhanced ipsilateral GG activity in adult rats. The electrophysiological studies demonstrated securinine had a marked excitatory effect on HM activity by membrane potential depolarization without changing input resistance, induced a decrease in mAHP amplitude, enhanced firing response to current injection and altered shape of single AP by hyperpolarization of threshold potential and reduction of amplitude. Further, using pharmacological methods, GABAA receptors mediated the postsynaptic excitation of HMs in the presence of TTX. In voltage clamp, securinine largely reduced the amplitude and frequency of GABAergic spontaneous events (sIPSCs) and the amplitude of GABAergic miniature inhibitory postsynaptic currents (mIPSCs), while glycinergic mIPSCs and frequency of GABAergic mIPSCs were unaffected. CONCLUSIONS: That suggested securinine influenced inhibitory GABAergic transmission via postsynaptic mechanisms. These results unravel the mechanisms controlling HMs activity by a novel and promising drug, and also draw great attention to researchers and clinicians who are interested in understanding OSA pathogenesis and treatment.
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