Advances in Neuroprotection - Bench to Bedside
By Bhiken I. Naik, MBBCH
Zhiyi Zuo, MD, PhD
Department of Anesthesiology and Neurosurgery
University of Virginia
Cerebral ischemia and injury are associated with significant short and long-term morbidity and mortality. The most common cause of focal and global cerebral ischemia in adults includes acute ischemic stroke and cardiac arrest respectively. Early restoration of cerebral blood flow with intravenous and/or mechanical re-perfusion therapy with ischemic stroke and restoration of cardiac function utilizing cardiopulmonary resuscitation remains the mainstay of therapy for these conditions. However, despite the early administration of these interventions, significant neuronal loss occurs due to a variety of systemic, cellular and sub-cellular pathways. Recent studies have elucidated novel neuroprotective benefits of anesthetic agents commonly utilized during the perioperative period. This brief review will focus on the basic science and clinical evidence supporting the neuroprotective effects of dexmedetomidine and volatile anesthetics.
A. Dexmedetomidine-induced Neuroprotection
Dexmedetomidine is a selective α2 adrenergic receptor (α2AR) agonist with sedative, anxiolytic, sympatholytic and analgesic effects that are utilized in both the intraoperative and postoperative/critical care setting. Furthermore, there is increasing evidence that dexmedetomidine has significant neuroprotective effects in a variety of neuronal injury models including cerebral ischemia and subarachnoid hemorrhage.
A.1 Cerebral Ischemia
Hoffman et al. first described the neuroprotective effects of dexmedetomidine in a model of carotid artery ligation with hemorrhagic hypotension. Rats receiving intraperitoneal injection of either 10 or 100 μg/kg of dexmedetomidine 30 minutes prior to ischemia had a dose-dependent decrease in plasma catecholamine levels with improved neurological function and histopathological outcomes.1 These effects were reversed when the α2 antagonist atipamezole was co-administered with dexmedetomidine, suggesting that the primary neuroprotective effects were mediated via α2 adrenoreceptor and sympatholysis. The beneficial effects of dexmedetomidine are also evident when administered post ischemia and this is of particular benefit as most cases of cerebral ischemia are not predictable. Maier et al. utilized a two-hour occlusion model of the left internal carotid, anterior cerebral, and middle cerebral arteries followed by a four-hour re-perfusion period in rabbits.2 Ten minutes post occlusion animals received either saline or an intravenous dexmedetomidine infusion to maintain a steady state plasma concentration with both groups receiving halothane to maintain anesthesia. Rabbits in the dexmedetomidine group sustained significantly less cortical neuronal damage [halothane alone, 38.2 +/- 6.0% (mean ± SEM) vs. halothane plus dexmedetomidine, 20.0 +/- 2.7%, P = 0.018]. Our group has also previously reported post-ischemic neuronal injury reduction in perinatal global hypoxic ischemic models.3
The proposed mechanism of dexmedetomidine-induced neuronal protection may be via dexmedetomidine-mediated modulation of catecholamines. However, it does not appear that there are any effects on glutamate (an excitatory neurotransmitter) release.4,5 An additional mechanism of neuroprotection may involve the extracellular signal-regulated kinase (ERK) pathway. Rats were subject to middle cerebral artery occlusion followed by saline, dexmedetomidine and dexmedetomidine plus the phosphatidylinositide 3-kinases (PI3K) inhibitor LY294002 and the mitogen-activated protein kinase kinase (MEK) inhibitor U0126 administration.6 Outcomes included neurological deficit scores, cerebral infarct volumes, brain edema, and neuron survival. The dexmedetomidine group had significantly better neurological function and histopathological outcomes than the saline group, which were reversed in the group with LY294002 and U0126, suggesting that PI3K/Akt and ERK1/2 pathways play an important role in dexmedetomidine-induced neuroprotection. Finally, we have shown that dexmedetomidine pretreatment provides neuroprotection against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats by preserving PI3K/Akt pathway activity.7
Although there is a paucity of clinical data on the effects of dexmedetomidine administration prior to and after focal and global cerebral ischemia, there is increasing pre-clinical data elucidating biologically plausible pathways for neuroprotection.
A.2 Subarachnoid Hemorrhage
Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease and accounts for 5% of all strokes. Neurological injury can occur at the time of the ictus, with re-bleeding and later in the clinical course when cerebral vasospasm and delayed cerebral ischemia occur. Current measures to mitigate neurological injury after rupture includes early exclusion of the aneurysm (clipping or endovascular treatment) to prevent re-bleeding and supportive therapy for vasospasm and delayed cerebral ischemia (nimodipine, hypertension and euvolemia). Dexmedetomidine applied during the peri-ictal period has potential benefits due to its primary sympatholytic and neuroprotective effects. Dexmedetomidine given intraperitoneally after SAH improves neurological outcome reduces water content and blood-brain barrier permeability. These effects are evident even when the first dose of dexmedetomidine is given two hours after the onset of SAH.8 The potential mechanism of dexmedetomidine-induced neuroprotection after SAH is likely via activation of the ERK pathway with increased cell survival. Pathways for ERK up-regulation include activation of α2ARs, with release of epidermal growth factor or epidermal growth factor-like growth factor, and then activates/phosphorylates ERK. A second α2AR-independent pathway is via dexmedetomidine activation of imidazoline I1 receptors, which then increases protein kinase C activity to activate ERK. Application of PD98095, an ERK inhibitor, inhibits this increase and blocks the effects of dexmedetomidine on neurological scores, water content, and Evans blue content in the brain.
The findings of this study have significant clinical implications. However, prospective studies are needed to confirm them in patients with aneurysmal SAH.
B. Volatile Anesthetics
Volatile anesthetics remain the most common agent utilized for maintenance of general anesthesia. Commonly used modern volatile anesthetics include desflurane, sevoflurane, and isoflurane, which are all halogenated hydrocarbons. Increasing evidence suggests that volatile anesthetics have dichotomous effects on neuronal function with both neuroprotective and neurotoxic effects reported.
B.1 Anesthetic-Induced Neuroprotection
Anesthetics, especially volatile anesthetics, showed protective effects against cell injury process, neuroapoptosis, degeneration, and ischemia, although most evidence has been in adult animals. This neuroprotection can occur when anesthetics are applied during, before (preconditioning), or after (postconditioning) periods of ischemia. Neuroprotection induced by applying anesthetics during ischemic brain injury has been reported with volatile agents, although the experimental data is mostly derived from rodent stroke models. Anesthetics-induced protective effect may be explained by several hypotheses:
- General anesthesia decreases the metabolic rate of the brain, and thereby reduces oxygen consumption and improves oxygen demand and supply balance.
- Inhibition of glutamate glutamate receptor over-activation.
- Activation of mitochondrial adenosine-5’-triphosphate sensitive potassium channels.
- Preservation of calcium/calmodulin dependent protein kinase II (CaMKII) levels as possible mechanisms of anesthetic induced neuroprotection.
B.2 Anesthetic-Induced Neurotoxicity
A study in 2003 described structural and long-term functional deficits in neonatal rats after prolonged exposure to a combination of isoflurane, nitrous oxide, and midazolam. These findings have been reproduced in other rodent models. One of the pathophysiological mechanisms of injury involves accelerated neuroapoptosis. Simultaneous potentiation of gamma-amino-butyric acidA (GABAA) receptors and antagonism of glutamate receptors has a synergistic effect in potentiating neuroapoptosis. The pattern of apoptosisis is not uniformly distributed, with higher preponderance in the primary visual cortex, temporal/somatosensory cortices, and the frontal cortex being reported. Furthermore, there is a notable decrease of hippocampal stem cell pool, neurogenesis, and cell density. The effects of anesthetics appear to be dependent upon the timing of exposure. When comparing seven-day-old rodents and sixty-day-old rodents exposed to isoflurane, there is significant impairment in learning and recognition in young but not adult animals.
Caution should be exercised when extrapolating the animal data in the clinical arena. Studies demonstrate that a brief, single exposure to relatively minor procedures is associated with minimal risk of long-term cognitive impairment (GAS and PANDA study).9,10 In contrast long-term adverse neurodevelopmental effects observed after prolonged or repeated anesthesia administration with surgeries are difficult to interpret because of various confounding variables. Results of the Mayo Safety in Kids (MASK) study confirmed that children with multiple or single anesthesia exposure with surgery did not have significant impairment in their intelligence.
The neuroprotective and neurotoxic effects of volatile anesthetics in humans are not clearly defined. Further research is required to demonstrate whether the pre-clinical animal data supporting neuroprotective and neurotoxic effects of anesthetics are applicable in humans. These studies will no doubt help to improve the outcome of patients under our care during the perioperative period, especially in the context that perioperative stroke and brain hypoxia are not uncommon events.
- Hoffman WE, Kochs E, Werner C, Thomas C, Albrecht RF: Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha 2-adrenergic antagonist atipamezole. Anesthesiology 1991; 75: 328-32.
- Maier C, Steinberg GK, Sun GH, Zhi GT, Maze M: Neuroprotection by the alpha 2-adrenoreceptor agonist dexmedetomidine in a focal model of cerebral ischemia. Anesthesiology 1993; 79: 306-12
- Ren X, Ma H, Zuo Z: Dexmedetomidine Postconditioning Reduces Brain Injury after Brain Hypoxia-Ischemia in Neonatal Rats. J Neuroimmune Pharmacol 2016; 11: 238-47.
- Engelhard K, Werner C, Kaspar S, Mollenberg O, Blobner M, Bachl M, Kochs E: Effect of the alpha2-agonist dexmedetomidine on cerebral neurotransmitter concentrations during cerebral ischemia in rats. Anesthesiology 2002; 96: 450-7.
- Goyagi T, Nishikawa T, Tobe Y, Masaki Y: The combined neuroprotective effects of lidocaine and dexmedetomidine after transient forebrain ischemia in rats. Acta Anaesthesiol Scand 2009; 53: 1176-83.
- Zhu YM, Wang CC, Chen L, Qian LB, Ma LL, Yu J, Zhu MH, Wen CY, Yu LN, Yan M: Both PI3K/Akt and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury in rats. Brain Res 2013; 1494: 1-8.
- Li Y, Zeng M, Chen W, Liu C, Wang F, Han X, Zuo Z, Peng S: Dexmedetomidine reduces isoflurane-induced neuroapoptosis partly by preserving PI3K/Akt pathway in the hippocampus of neonatal rats. PLoS One 2014; 9: e93639.
- Wang Y, Han R, Zuo Z: Dexmedetomidine post-treatment induces neuroprotection via activation of extracellular signal-regulated kinase in rats with subarachnoid haemorrhage. Br J Anaesth 2016; 116: 384-92.
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- Sun LS, Li G, Miller TL, Salorio C, Byrne MW, Bellinger DC, Ing C, Park R, Radcliffe J, Hays SR, DiMaggio CJ, Cooper TJ, Rauh V, Maxwell LG, Youn A, McGowan FX: Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA 2016; 315: 2312-20.