Neuroprotective effects of propofol in acute cerebral injury

Abstract

Propofol (2,6-diisopropylphenol) is one of the most popular agents used for induction of anesthesia and long-term sedation, owing to its favorable pharmacokinetic profile, which ensures a rapid recovery even after prolonged administration. A neuroprotective effect, beyond that related to the decrease in cerebral metabolic rate for oxygen, has been shown to be present in many in vitro and in vivo established experimental models of mild/moderate acute cerebral ischemia. Experimental studies on traumatic brain injury are limited and less encouraging. Despite the experimental results and the positive effects on cerebral physiology (propofol reduces cerebral blood flow but maintains coupling with cerebral metabolic rate for oxygen and decreases intracranial pressure, allowing optimal intraoperative conditions during neurosurgical operations), no clinical study has yet indicated that propofol may be superior to other anesthetics in improving the neurological outcome following acute cerebral injury. Therefore, propofol cannot be indicated as an established clinical neuroprotectant per se, but it might play an important role in the so-called multimodal neuroprotection, a global strategy for the treatment of acute injury of the brain that includes preservation of cerebral perfusion, temperature control, prevention of infections, and tight glycemic control.

Figure 1

Chemical structure of propofol (2,6‐diisopropylphenol).

Figure 2

Schematic model providing a possible explanation for the neuroprotective effects of propofol. Following acute cerebral injury, excessive release and reduced glial uptake of glutamate activates NMDA receptors and produces a sustained influx of Ca²⁺ in neurons. The rapid buildup of intracellular Ca²⁺ promotes the deleterious formation of reactive oxygen species (ROS) and lipid peroxidation and, on the other hand, leads to the opening of the mitochondrial membrane permeability transition pore (MPTP), release of cytochrome C (Cyt‐C) into the cytosol, and apoptotic cell death. Propofol can interfere with these toxic mechanisms at many levels: (1) by directly activating GABA_A receptors, thus potentiating the inhibitory effects of GABA on excitatory postsynaptic neurons and on glutamate release; (2) by inibiting the fatty acid amide hydrolase (FAAH), thereby increasing the levels of endocannabinoids like anandamide (AEA) and their action on presynaptic CB1 receptors that exert an inhibitory control on glutamate release; (3) by preventing the inhibitory effects of ROS on astrocytic high‐affinity glutamate transporters (EAAT) and on the Na⁺/H⁺ exchanger (NHE1) that regulates intracellular pH and the efficiency of EAAT; (4) by increasing the expression of the antioxidant enzyme heme oxygenase 1 (HO‐1) in astrocytes; (5) by preventing mitochondrial swelling caused by acute overload of Ca²⁺; (6) by preventing the elevation of the proapoptotic factor Bax and increasing the concentrations of the antiapoptotic factor Bcl‐2; and (7) by directly scavenging ROS and inhibiting lipid peroxidation.Other abbreviations: AA = arachidonic acid; Eth = ethanolamine; PE = phosphatidylethanolamine.