Neuroprotective effects of dexmedetomidine conditioning strategies: Evidences from an in vitro model of cerebral ischemia

Abstract

Aims

Dexmedetomidine is a selective agonist of α₂-adrenergic receptors with clinical anesthetic and analgesic properties that has also shown neuroprotective effects on several models of brain injury. Because perioperative stroke and brain damage are frequent causes of death in critical care units, we aimed to investigate neuroprotective properties of dexmedetomidine using an in vitro model of cerebral ischemia.

Main methods

Primary mixed rat brain cortical cultures were subjected to oxygen and glucose deprivation and treated with different doses of dexmedetomidine in order to analyze three conditioning strategies: preconditioning, intraconditioning and postconditioning.

Key findings

All dexmedetomidine pre-, intra- and postconditioning treatments showed neuroprotective effects reducing brain cell necrosis, although only preconditioning showed antiapoptotic effects. Dexmedetomidine treatments also reduced IL-6 and TNF-α levels, especially in the preconditioning groups. Oxidative stress was attenuated with all dexmedetomidine preconditioning treatments, but only with the higher dose in the intraconditioning group, and no effects were observed in the postconditioning. All conditioning strategies increased BDNF levels.

Significance

Dexmedetomidine-mediated neuroprotective effects in an in vitro model of cerebral ischemia involve the attenuation of inflammation and oxidative stress and the increment of BDNF expression.

Introduction

Dexmedetomidine is a selective agonist of α2-adrenoreceptors used in clinical practice with sedative, analgesic and amnesic properties that has also shown a relevant neuroprotective effect on different experimental models of brain injury [1], [2], [3], [4]. Importantly, dexmedetomidine attenuates ischemia-induced damage administrated both before [5], [6] and after [7] an ischemic episode.

An important complication of many surgical procedures is perioperative acute ischemic stroke, which is associated with high morbidity and mortality [8]. Results from a recent study show an association between the perioperative use of dexmedetomidine and a decrease in postoperative mortality, overall complications and delirium incidence in patients undergoing cardiac surgery [9].

Despite several experimental studies have demonstrated the neuroprotective effect of dexmedetomidine, underlying molecular mechanisms still remain poorly explored. Using in vitro approaches, it has been suggested that plausible mechanisms in its neuroprotective effects on brain injury involve the α2-adrenoreceptor-FAK-PI3-Akt and I1 receptor-ERK1&2-MitoK_ATP pathways [10] as well as the regulation of brain-derived neurotrophic factor (BDNF) expression in astrocytes [11]. Dexmedetomidine has also shown beneficial effects in other experimental models, decreasing inflammatory mediators in endotoxin-induced shock in rats [12], or lipopolysaccharide-stimulated astrocytes [13]. Therefore, besides its sedative properties, current evidence from experimental and clinical studies supports a beneficial role of dexmedetomidine in brain disorders.

On the other hand, the protective effects of dexmedetomidine in cerebral ischemia has been achieved with both pre- and postconditioning strategies (drug administration before or after the ischemic episode, respectively) [6], [10], which is important in the clinical context, since its ability to protect brain tissue even after the onset of ischemia increases its therapeutic opportunities as a neuroprotective agent.

Therefore, our aim was to investigate whether inflammation, oxidative stress or BDNF expression could be involved in dexmedetomidine-mediated neuroprotection using an established in vitro model of cerebral ischemia and three different conditioning strategies.