Introduction of intravenous or intraperitoneal propofol on global and

Brain Research 883 2000 69–76 www.elsevier.com locate bres Research report Intracerebroventricular propofol is neuroprotective against transient global ischemia in rats: extracellular glutamate level is not a major determinant Toshiyuki Yano , Ryosuke Nakayama, Kazuo Ushijima Surgical Center , Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto 860-8556, Japan Accepted 22 August 2000 Abstract Excessive glutamate accumulation in extracellular space due to ischemia in the central nervous system CNS is believed to initiate the cascade toward irreversible neuronal damage. An intravenous general anesthetic, propofol 2,6-diisopropylphenol has been implicated to be neuroprotective against cerebral ischemia. The purpose of this study was to test the hypothesis that intracerebroventricular propofol produced a reduction in extracellular glutamate level during global ischemia and the resultant neuroprotection. Adult male Wistar rats  were anesthetized with halothane in nitrous oxide oxygen and mechanically ventilated. Propofol 3 or 10 mg kg, Intralipid as a vehicle for propofol, or artificial cerebrospinal fluid aCSF was administered into the cerebral ventricles 15 min prior to a 10-min forebrain ischemia elicited by the four-vessel occlusion. Extracellular glutamate concentration in the hippocampal CA1 was continuously monitored during the peri-ischemic period with a microdialysis biosensor. Neuronal cell loss in the hippocampal CA1 was evaluated by cresyl-violet staining of sections 7 days later. Propofol 3 and 10 mg kg and Intralipid, compared with aCSF, similarly reduced the extracellular glutamate accumulation during the peri-ischemic period P,0.05, indicating that the extracellular glutamate reduction that was seen primarily reflects the effect of Intralipid. The number of intact neurons in the hippocampal CA1 in propofol 10 mg kg-treated rats was significantly higher than that in rats treated with propofol 3 mg kg, Intralipid, or aCSF P,0.05. We conclude that intracerebroventricu- lar propofol exhibits neuroprotection against transient global forebrain ischemia; however, the extracellular glutamate level during ischemia is not a major determinant of this neuroprotection.  2000 Elsevier Science B.V. All rights reserved. Theme : Disorders of the nervous system Topic : Ischemia Keywords : Delayed neuronal death; Hippocampus; Dialysis electrode; Neurotoxicity

1. Introduction of intravenous or intraperitoneal propofol on global and

focal cerebral ischemia in animal models is still contro- Propofol 2,6-diisopropylphenol in a lipid emulsion is versial [2,45,19,43,30,38,42]. used clinically as an intravenous general anesthetic and as Glutamate, the major excitatory neurotransmitter in the a sedative for critically ill patients. Propofol depresses mammalian CNS, activates post-synaptic receptors when electroencephalographic activity [14] and decreases the released from the pre-synapse. Excessive activation of cerebral metabolic rate for oxygen CMRO [39,21] and post-synaptic glutamate receptors has been implicated in 2 the cerebral blood flow [21,41]. Propofol also has anti- initiating the cascade that leads to neuronal cell death oxidant effects [24]. These features of propofol may [31,10]. Extracellular glutamate concentrations in the CNS provide protection against ischemia of the central nervous are normally low, but increase during ischemia [18,3]. The system CNS. To date, however, a neuroprotective effect extracellular glutamate level depends on glutamate release into the extracellular space and its uptake into cells [5,4]. For this reason, regulation of glutamate release and of its Corresponding author. Tel.: 181-96-373-5720; fax: 181-96-373- re-uptake during the peri-ischemic period could be a 5721. E-mail address : tymackaiju.medic.kumamoto-u.ac.jp T. Yano. promising strategy for alleviating neuronal injury. The 0006-8993 00 – see front matter  2000 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 2 8 8 9 - 4 70 T effect of propofol on the extracellular glutamate level Sycopel International, Ltd., Boldon, Tyne and Wear, UK during cerebral ischemia remains to be elucidated. In this for continuous measurement of extracellular glutamate study, we tested the hypothesis that propofol delivered concentration as described previously in detail [3,26]. In directly to the CNS produced a reduction in extracellular brief, the microdialysis biosensor was made up of a glutamate level during global ischemia and the resultant platinum working electrode, a silver silver chloride coun- neuroprotection in the hippocampal CA1 region of the rat. ter electrode, a silver reference electrode, and two vitreous silica tubes for changing the solution inside the biosensor, all of which were set inside a hollow semi-permeable

2. Materials and methods membrane, 230 mm in outside diameter. The biosensor was