Beta-asarone Inhibits Synaptic Inputs To Airway Preganglionic Parasympathetic Motoneurons

Therapeutic application of Asarum, a herbal medicine that has been used for centuries, reportedly causes acute respiratory disturbance. The responsible constituents, the sites of action, and the mechanisms involved in this side effect are unclear. It is generally believed, however, that components of Asarum volatile oils may be the cause of Asarum-induced respiratory disturbance, because the risk of this complication is reduced when Asarum is boiled prior to use. Researchers have isolated many of the Asarum volatile oil constituents, including α-and (3-asarone (cis-l-Propenyl-2,4,5-trimethoxybenzene), methyl eugenol, and safrole. In one recent study, intragastric application of Asarum pulvis inhibited the frequency and intensity of phrenic nerve discharges in anesthetized rabbits, suggesting the acute respiratory disturbance caused by Asarum may be a result of actions at the medullary respiratory centers.Respiratory rhythm is generated in the Pre-Botzinger complex (PBC) and nearby in the ventrolateral medulla. Pacemaker neurons in this area are interconnected by excitatory synapses and gap junctions, and send projections to cranial premotor circuits and bulbospinal inspiratory excitatory neurons that project to spinal phrenic and intercostal inspiratory motoneurons. Some evidence has suggested that the respiratory rhythm generator and the airway preganglionic parasympathetic motoneurons (APPMs) may be coupled both anatomically and functionally. The airway parasympathetic nerves or their preganglionic cell bodies fire in phase with the hypoglossal and the phrenic nerves. A subset of the medullary respiratory neurons that project to the phrenic motoneurons also innervate the APPMs.The brainstem slice is a well-established model to study the respiratory rhythm generator and the airway autonomic premotor neurons. In the present work, we utilized this model to investigate the effects of β-asarone, a volatile constituent of Asarum, on the central respiratory drive and the tonic postsynaptic activity of the APPMs.Asarum ethanol extract inhibited the frequency and intensity of the hypoglossal respiratory-like bursts. β-Asarone caused progressive decreases in the duration and area of the hypoglossal bursts in a concentration-dependent manner. The frequency and amplitude of the bursts were initially unaltered or temporarily increased, but were then inhibited progressively after prolonged exposure. As with the inhibition of the hypoglossal bursts, the tonic and the phasic excitatory and inhibitory postsynaptic currents in the APPMs were attenuated. These data suggest that the Asarum-caused acute respiratory disturbance involves β-asarone-induced inhibition of neurotransmission in the medullary respiratory neuronal network.