Seizure Protection by Intrapulmonary Delivery of Propofol Hemisuccinate

Ashish Dhir, University of California - Davis
Dorota Zolkowska, University of California - Davis
Randall B. Murphy, Medkura Pharmaceuticals
Michael A. Rogawski, University of California - Davis

Abstract

The lung provides a portal of entry for drug delivery that could be used to administer anticonvulsant substances to prevent or abort seizures. Here we demonstrate that intrapulmonary propofol hemisucinate (PHS) rapidly confers seizure protection in various rodent chemoconvulsant models. Propofol is a powerful anticonvulsant substance at subanesthetic doses but it is a viscous, water-immiscible oil that is not suitable for intrapulmonary administration. We found that PHS can be formulated as an aqueous solution that is well tolerated when instilled into the lung. High dose intraperitoneal PHS induced loss-of-righting reflex in rats and mice. The onset of action of PHS was delayed in comparison with propofol, suggesting that conversion to propofol by de-esterification is required for activity. A lower dose of PHS (40 mg/kg, i.p.) did not cause general anesthesia, but protected against pentylenetetrazol (PTZ)-induced myoclonic jerks and clonic and tonic seizures in rats. Intrapulmonary administration of an aqueous PHS solution via a tracheal cannula at lower doses (5 and 10 mg/kg) conferred equivalent seizure protection without acute motor toxicity. In mice, intraperitoneal PHS (60 - 80 mg/kg) was associated with an elevation in the thresholds for myoclonic jerks and clonic and tonic seizures induced by PTZ, bicuculline, picrotoxin, and kainic acid. Intratracheal PHS was markedly more potent, producing seizure threshold elevations at doses of 10 - 15 mg/kg. In the PTZ threshold model in mice, PHS was active at 5 min, maximally active at 10 min and no longer active at 20 min. Intratracheal PHS (10 mg/kg) also prolonged the onset of 4-aminopyridine-induced convulsions in mice. However, it did not affect the threshold for convulsions induced by intravenous N-methyl-D-aspartate in mice. We conclude that intratracheal administration of an aqueous solution of PHS, a putative propofol prodrug, provides potent seizure protection of rapid onset and brief duration. Intrapulmonary PHS may be useful to prevent the spread of seizures or to abort seizure clusters without causing prolonged sedation.