Seizure protection by intrapulmonary delivery of midazolam in mice

The lung provides a portal of entry that could be used to rapidly deliver anticonvulsant substances to the brain to treat seizures. In the present study, we demonstrate that midazolam, a water-soluble anticonvulsant benzodiazepine, confers potent seizure protection when administered via the intrapulmonary route. High dose (100 mg/kg) intraperitoneal midazolam induced loss-of-righting reflex in mice. Lower doses of midazolam (100-1000 μg/kg) when administered intraperitoneally did not induce loss-of-righting reflex but protected animals against pentylenetetrazol (PTZ)-induced seizures. Intrapulmonary administration of midazolam via a tracheal cannula protected against intraperitoneal PTZ seizures at lower doses. The minimal intraperitoneal and intravenous doses of midazolam required to elevate the threshold for seizure signs induced by intravenous PTZ were 500 and 100 μg/kg, respectively, whereas the minimal intrapulmonary midazolam dose was 12.5 μg/kg. Intratracheal midazolam caused a large increase in intravenous PTZ threshold 5 min after administration but the effect declined rapidly over 60 min and no antiseizure activity was evident at 120 min. The minimal intraperitoneal doses of midazolam required to elevate the threshold for seizure signs induced by intravenous picrotoxin and kainic acid were 100 and 2000 μg/kg, respectively; the corresponding values for intratracheal midazolam were 25 and 100 μg/kg, respectively. We conclude that midazolam is a highly effective anticonvulsant when administered by the intrapulmonary route. Midazolam is substantially more potent when delivered into the lung than when administered intraperitoneally or intravenously. Inhalation could be an alternative to other routes of administration for the delivery of midazolam to rapidly abort acute seizures.