Biochemical and Electrophysiologic Evidence That Propofol Enhances GABAergic Transmission in the Rat Brain

Peduto, V. A.; Concas, Alessandra; Santoro, G; Biggio, G.; Gl, Gessa

doi:10.1097/00000542-199112000-00012

Cited by 150 publications

(71 citation statements)

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“…These data again demonstrate a higher susceptibility of heterozygote animals for the development of epileptic seizures. Since PTZ is a blocker of GABA A receptors, and propofol is thought to enhance the GABA A receptor mediated Cl Ϫ conductance (Peduto et al, 1991), our data are consistent with the idea that the difference between wild-type and heterozygote genotypes most likely involves the amount of Cl Ϫ flowing through the receptors upon activation. However, it remains to be determined if other aspects of GABA A receptor function are affected by the disruption of the KCC2 gene.…”

Section: __________________________________________________________ Esupporting

confidence: 87%

Hyperexcitability and epilepsy associated with disruption of the mouse neuronal‐specific K–Cl cotransporter gene

et al. 2002

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Four genes encode electroneutral, Na+-independent, K-Cl cotransporters. KCC2, is exclusively expressed in neurons where it is thought to drive intracellular Cl- to low concentrations and shift the reversal potential for Cl- conductances such as GABA(A) or glycine receptor channels, thus participating in the postnatal development of inhibitory mechanisms in the brain. Indeed, expression of the cotransporter is low at birth and increases postnatally, at a time when the intracellular Cl- concentration in neurons decreases and gamma-aminobutyric acid switches its effect from excitatory to inhibitory. To assert the significance of KCC2 in neuronal function, we disrupted the mouse gene encoding this neuronal-specific K-Cl cotransporter. We demonstrate that animals deficient in KCC2 exhibit frequent generalized seizures and die shortly after birth. We also show upregulation of Fos, the product of the immediate early gene c-fos, and the significant loss of parvalbumin-positive interneurons, both indicative of brain injury. The regions most affected are the hippocampus and temporal and entorhinal cortices. Extracellular field potential measurements in the CA1 hippocampus exhibited hyperexcitability. Application of picrotoxin, a blocker of the GABA(A) receptor, further increased hyperexcitability in homozygous hippocampal sections. Pharmacological treatment of pups showed that diazepam relieved the seizures while phenytoin prevented them between postnatal ages P4-P12. Finally, we demonstrate that adult heterozygote animals show increased susceptibility for epileptic seizure and increased resistance to the anticonvulsant effect of propofol. Taken together, these results indicate that KCC2 plays an important role in controlling CNS excitability during both postnatal development and adult life.

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Section: __________________________________________________________ Esupporting

confidence: 87%

Hyperexcitability and epilepsy associated with disruption of the mouse neuronal‐specific K–Cl cotransporter gene

et al. 2002

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“…The efficacy of PHS in the diverse seizure models we examined likely results in part from the well recognized action of propofol as a GABA A receptor-positive modulator (Hales and Lambert, 1991;Peduto et al, 1991;Hara et al, 1994) and a direct activator of GABA A receptors (Hara et al, 1993). Seizures induced by GABA A receptor antagonists are sensitive to GABA A receptor-positive modulators (Rastogi and Ticku, 1986), as are seizures induced by kainic acid, whereas NMDA-induced seizures are relatively resistant to such agents (Kokate et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Propofol is especially active in animal models of status epilepticus (De Riu et al, 1992;Ahuja and Germano, 1998;Lee and Cheun, 1999), and it is commonly used in the treatment of refractory status epilepticus in humans (Prasad et al, 2001;Arif and Hirsch, 2008). Propofol protects against seizures, at least in part, via its action as a powerful GABA A receptor positive modulator with greater potency than barbiturates (Hales and Lambert, 1991;Peduto et al, 1991;Hara et al, 1994;Lingamaneni and Hemmings, 2003).…”

Section: Introductionmentioning

confidence: 99%

Seizure Protection by Intrapulmonary Delivery of Propofol Hemisuccinate

Dhir

Żółkowska

Murphy³

et al. 2010

J Pharmacol Exp Ther

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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.

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“…2 Numerous mechanisms for the neuroprotective effect of propofol have been postulated, including decrement in CBF in conjunction with decreased cerebral metabolic rate for oxygen 19,20,31 and reduced cerebral electric activity. 4,32 The mechanism of reduced CBF with propofol remains unclear; however, a vascular origin is not likely because propofol causes vasodilation in isolated vessels. 33 Propofol had no effect on subsequent postanesthetic cerebral vasodilator responses to hypercapnia in our previous study.…”

Section: Discussionmentioning

confidence: 99%

Anesthetic Choice of Halothane Versus Propofol

Bhardwaj

Castro

Alkayed

et al. 2001

Stroke

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Background and Purpose-It is not known whether preischemic exposure to anesthetic agents affects the amount of damage from transient focal ischemia that occurs after cessation of the anesthetic. We compared the effect of prior exposure to halothane or propofol on infarction size after transient middle cerebral artery occlusion (MCAO) induced in the awakening animal to test the hypothesis that anesthetic type and exposure duration would independently affect the amount of brain injury. Methods-Male Wistar rats (weight, 200 to 300 g) were anesthetized briefly with halothane for placement of hemodynamic instrumentation. Twenty-four hours later, rats were treated with either a short (approximately 1 hour) or long (8 hours) duration of inhaled halothane (1% to 2%) or intravenous propofol (10 mg/kg bolus, 30 mg/kg per hour infusion). Each cohort (nϭ8 per group) was then subjected to 2-hour MCAO by the intraluminal suture technique. All anesthesia was discontinued once MCAO was achieved. Infarct volume was measured at 22 hours of reperfusion. In a second cohort, regional cerebral blood flow (CBF) was measured ([ 14 C]iodoantipyrine autoradiography) at end-occlusion in shortduration halothane (nϭ5) or short-duration propofol (nϭ5) anesthesia groups and in corresponding surgical shams (nϭ3 each). Results-Pericranial temperature, PaO 2 , PaCO 2 , and blood pressure were controlled and not different among groups before or during occlusion. MCAO resulted in a similar immediate reduction in laser-Doppler flow signal after discontinuation of anesthesia in the awakening animals. Infarct volume was smaller in rats exposed to short-duration halothane in cortex (87.5Ϯ16.6 mm 3 ) (meanϮSEM) and caudoputamen (38.3Ϯ13.7 mm 3 ) compared with rats exposed to short-duration propofol (cortex, 177.5Ϯ16.9 mm 3 ; caudoputamen, 47.8Ϯ2.9 mm 3 ). Infarct volume was not different in long-duration halothane versus long-duration propofol treatment. Absolute cortical or caudoputamen intraischemic CBF was not different between short-duration halothane or short-duration propofol treatment.Conclusions-These data demonstrate that short-duration halothane exposure before MCAO in the awakening animal attenuates infarction volume compared with propofol. This protection by halothane is not mediated through preservation of intraischemic CBF. Longer durations of halothane exposure may activate secondary injury pathways, which negate the protective effects of short-term halothane preischemic treatment.

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Biochemical and Electrophysiologic Evidence That Propofol Enhances GABAergic Transmission in the Rat Brain

Cited by 150 publications

References 0 publications

Hyperexcitability and epilepsy associated with disruption of the mouse neuronal‐specific K–Cl cotransporter gene

Hyperexcitability and epilepsy associated with disruption of the mouse neuronal‐specific K–Cl cotransporter gene

Seizure Protection by Intrapulmonary Delivery of Propofol Hemisuccinate

Anesthetic Choice of Halothane Versus Propofol

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