Seizure protection by intrapulmonary delivery of propofol hemisuccinate

Ashish Dhir, Dorota Zolkowska, Randall B. Murphy, Michael A Rogawski

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 hemisuccinate (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 intraperitoneally administered 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 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 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 PTZ, bicuculline, picrotoxin, and kainic acid seizure thresholds. Intratracheal PHS was markedly more potent, producing seizure threshold elevations at doses of 10 to 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 In the PTZ threshold model in mice, PHS was active at 5 min, maximally active at 10 min, and no longer active at 20 min.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 also prolonged the onset of 4-aminopyridine- induced convulsions but did not affect the threshold for N-methyl-D-aspartate-induced convulsions. 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 for preventing the spread of seizures or aborting seizure clusters without causing prolonged sedation.

Original languageEnglish (US)
Pages (from-to)215-222
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume336
Issue number1
DOIs
StatePublished - Jan 2011

Fingerprint

Propofol
Seizures
Pentylenetetrazole
Anticonvulsants
Righting Reflex
Picrotoxin
Lung
4-Aminopyridine
Bicuculline
Kainic Acid
Prodrugs
N-Methylaspartate
General Anesthesia

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Seizure protection by intrapulmonary delivery of propofol hemisuccinate. / Dhir, Ashish; Zolkowska, Dorota; Murphy, Randall B.; Rogawski, Michael A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 336, No. 1, 01.2011, p. 215-222.

Research output: Contribution to journalArticle

Dhir, Ashish ; Zolkowska, Dorota ; Murphy, Randall B. ; Rogawski, Michael A. / Seizure protection by intrapulmonary delivery of propofol hemisuccinate. In: Journal of Pharmacology and Experimental Therapeutics. 2011 ; Vol. 336, No. 1. pp. 215-222.
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