Acute brain injuries, such as trauma or ischemic and hemorrhagic stroke, are critical conditions in clinical settings which are often the result of oxidative stress; therefore, creating an anesthesia regime which bears in mind an anti-oxidative approach is crucial for the treatment of acute brain injury. Oxidative stress occurs when there is an increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS); these free radicals normally contribute to metabolism, solute transport and neurodevelopment [1]. However, their increased numbers lead to cell damage by triggering apoptosis, neuroinflammation and DNA damage [2]. Due to the brain’s high levels of peroxidizable lipids, it is especially vulnerable to ROS/RNS increases and as a result, oxidative stress [3].
Natural anti-oxidative systems, of which nuclear factor-like 2 (Nrf2) is a key component, exist to protect against oxidative stress [3]. Nrf2 is a major transcription factor controlling anti-oxidative enzymes, predominantly those of the glutathione system (GSH) [4]. GSH is fundamental to cellular self-defense and redox homeostasis, so much so that it is present in the millimolar range in most CNS neurons. Oxidative stress releases Nrf2 from cellular cytosol, where it translocates to the nucleus and upregulates expression of anti-oxidative genes, including GSH and thioredoxin reductases (TrxRs), indispensable enzymes in neuroprotection [5]. A preclinical study from 2015 found administration of sevoflurane increased Nrf2 and HO-1 (haemoxygenase-2, an anti-oxidative enzyme) in a rat model of global cerebral ischemia [6]. Since previous investigations have indicated the role of protein kinase C (PKC) in phosphorylation of Nrf2 [7], Lee et. al. (2015) found chelerythrine (a PKC inhibitor) nulled the increase in Nrf2 associated with sevoflurane administration [6]. A 2010 review named several inhalational and intravenous anesthetics to upregulate HO-1, including xenon, ketamine, propofol, isoflurane, sevoflurane, and desflurane [8,9].
Isoflurane administration has been reported to reduce the brain injury caused by ischemic stroke through inhibiting excessive microglia activation [10,11]. Additionally, rats preconditioned with sevoflurane and then subjected to filament occlusion of the middle cerebral artery showed significant decreases in infarct volume and suppressed expression of NF-kappa-B (an inflammatory gene inducing several pro-inflammatory cytokines like interleukin-1, interleukin-6, and tumor necrosis factor-a) [12]. An in vitro model demonstrated xenon’s neuroprotective effect after traumatic brain injury is mediated by its inhibition of NMDA glutamate receptors, specifically at the glycine site [13]. Another in vitro study using human neuroblastoma cells found the inhalational anesthesia isoflurane, sevoflurane, and desflurane increased phosphorylation of glycogen synthase kinase 3β (GSK3β), one of the primary regulators of Nrf2 [14]. Phosopho-GSK3β inhibits GSK3β activity, meaning these anesthesia agents indirectly protect against acute brain injury by upregulating Nrf2. Similarly, sevoflurane can activate PKC, which reliably increases Nrf2 [6].
A 2022 systematic review analyzed 53 human studies on ketamine’s role in traumatic brain injury (TBI), finding potentially positive benefits after ketamine infusion [15]. The authors conclude ketamine does not increase intracranial pressure after TBI, which is a major clinical concern; in fact, it can increase cerebral perfusion pressure and decrease the dosage of vasopressors required to counteract opioid-based sedatives. They suggest ketamine, when used continuously, may be preferable to opioid-based sedation since they have similar efficacy yet ketamine is associated with fewer risks [15].
Certain inhalational and intravenous anesthesia offer anti-oxidative and neuroprotective effects against acute brain injury. While the evidence in support of using these anesthetics is promising, several factors need to be clarified before clinical translation, namely the optimal dose for delivery and the mechanisms by which these agents activate the Nrf2 pathway and stimulate anti-oxidative enzymes.
References
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