The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties

Abstract

Propofol (2,6-diisopropylphenol) is a versatile, short-acting, intravenous (i.v.) sedative-hypnotic agent initially marketed as an anesthetic, and now also widely used for the sedation of patients in the intensive care unit (ICU). At the room temperature propofol is an oil and is insoluble in water. It has a remarkable safety profile. Its most common side effects are dose-dependent hypotension and cardiorespiratory depression. Propofol is a global central nervous system (CNS) depressant. It activates gamma-aminobutyric acid (GABA A) receptors directly, inhibits the N-methyl-d-aspartate (NMDA) receptor and modulates calcium influx through slow calcium-ion channels. Furthermore, at doses that do not produce sedation, propofol has an anxiolytic effect. It has also immunomodulatory activity, and may, therefore, diminish the systemic inflammatory response believed to be responsible for organ dysfunction. Propofol has been reported to have neuroprotective effects. It reduces cerebral blood flow and intracranial pressure (ICP), is a potent antioxidant, and has anti-inflammatory properties. Laboratory investigations revealed that it might also protect brain from ischemic injury. Propofol formulations contain either disodium edetate (EDTA) or sodium metabisulfite, which have antibacterial and antifungal properties. EDTA is also a chelator of divalent ions such as calcium, magnesium, and zinc. Recently, EDTA has been reported to exert a neuroprotective effect itself by chelating surplus intracerebral zinc in an ischemia model. This article reviews the neuroprotective effects of propofol and its mechanism of action.

Figure 1

The chemical structure of propofol.

Figure 2

Both propofol and propofol EDTA reduced the cell damage induced by OGD in PC12 culture. Cell viability was assessed following immersion in 10% resazurin solution for 3 h at 37 °C, and fluorescence was recorded at 560/590 nm. OGD induced cell death, and propofol and EDTA each inhibited this OGD‐induced cell death. Propofol plus EDTA reduced cell death by more than propofol alone. Data are expressed as mean ± SD. *P < 0.05, **P < 0.01 versus OGD‐treatment alone (Dunnett's test or Student's t‐test); n= 4. Data from Kotani et al. (2008).

Figure 3

(A) Effects of propofol EDTA and propofol on infarct volume at 24 h after permanent MCA occlusion (each treatment being given intravenously [1, 5, or 10 mg/kg, given over 90 second, at 0.1 mL/10 g] 10 min before MCA occlusion). *P < 0.05, **P < 0.01 versus vehicle (Dunnett's test); n= 10–14. (B) The effects of propofol EDTA and propofol on brain swelling 24 h after permanent MCA occlusion in mice. *P < 0.05 versus vehicle (Dunnett's test); n= 10–14. (C) Effects of propofol EDTA and propofol (details as in B) on neurological deficits at 24 h after permanent MCA occlusion. *P < 0.05 versus vehicle (Mann‐Whitney U‐test); n= 10–14. Values are mean ± SD. Data from Kotani et al. (2008).

Figure 4

Effect of propofol EDTA on TUNEL staining after MCA occlusion. Propofol EDTA (10 mg/kg i.v.) was administered 10 min before MCA occlusion, and mice were sacrificed at 12 or 24 h after the occlusion. (A) Schematic drawing showing the brain regions at a level 0.4–1.0 mm anterior to bregma (through the anterior commissure); 1, ischemic core; 2 and 3, ischemic penumbra. The number of TUNEL‐positive cells was counted in each of these areas, the average for areas 2 and 3 being taken as the number for the ischemic penumbra. (B) Propofol EDTA appeared to reduce the number of TUNEL‐positive cells (versus vehicle treatment) in the ischemic penumbra, but not in the ischemic core. (C and D) Quantitative representation of TUNEL‐positive cells in ischemic brains treated with propofol EDTA or vehicle. White part of bar shows number of apoptotic cells among all positive cells. Note that at 24 h in the ischemic penumbra, a considerably smaller number of TUNEL‐positive cells was observed in mice treated with propofol EDTA than in mice treated with vehicle. However, in the ischemic core no such difference was detected. Data are expressed as mean ± SD. *P < 0.05, **P < 0.01 versus vehicle (Student's t‐test); n= 4–6. Scale bar = 100 μm. Data from Kotani et al. (2008).