Abstract
Ischemic stroke induces microglial activation and release of proinflammatory cytokines, contributing to the expansion of brain injury and poor clinical outcome. Propofol has been shown to ameliorate neuronal injury in a number of experimental studies, but the precise mechanisms involved in its neuroprotective effects remain unclear. We tested the hypothesis that propofol confers neuroprotection against focal ischemia by inhibiting microglia-mediated inflammatory response in a rat model of ischemic stroke. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by 24 h of reperfusion. Propofol (50 mg/kg/h) or vehicle was infused intravenously at the onset of reperfusion for 30 minutes. In vehicle-treated rats, MCAO resulted in significant cerebral infarction, higher neurological deficit scores and decreased time on the rotarod compared with sham-operated rats. Propofol treatment reduced infarct volume and improved the neurological functions. In addition, molecular studies demonstrated that mRNA expression of microglial marker Cd68 and Emr1 was significantly increased, and mRNA and protein expressions of proinflammatory cytokines tumor necrosis factor-α, interleukin-1β and interleukin-6 were augmented in the peri-infarct cortical regions of vehicle-treated rats 24 h after MCAO. Immunohistochemical study revealed that number of total microglia and proportion of activated microglia in the peri-infarct cortical regions were markedly elevated. All of these findings were ameliorated in propofol-treated rats. Furthermore, vehicle-treated rats had higher plasma levels of interleukin-6 and C-reactive protein 24 h after MCAO, which were decreased after treatment with propofol. These results suggest that propofol protects against focal cerebral ischemia via inhibition of microglia-mediated proinflammatory cytokines. Propofol may be a promising therapeutic agent for the treatment of ischemic stroke and other neurodegenerative diseases associated with microglial activation.
Highlights
Stroke is the leading cause of death and the most frequent cause of long-term disability in the adult population worldwide [1]
Experimental studies have shown that resident microglia in the brain are activated within minutes of ischemia onset and release multiple proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), which play a crucial role in the progression of neuronal loss and brain injury following ischemic stroke [7,8,9]
The novel finding of this study is that treatment with propofol early after ischemic stroke suppressed microglia activation and proliferation in the peri-infarct cortical regions, reduced the production of proinflammatory cytokines in the brain as well as in peripheral blood, and improved neurological outcome
Summary
Stroke is the leading cause of death and the most frequent cause of long-term disability in the adult population worldwide [1]. Experimental studies have shown that resident microglia in the brain are activated within minutes of ischemia onset and release multiple proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), which play a crucial role in the progression of neuronal loss and brain injury following ischemic stroke [7,8,9]. Development of agents that reduce microglial activation in the brain and inhibit the release of proinflammatory cytokines is considered to be an important therapeutic strategy for ischemic stroke. An in vitro study recently showed that propofol almost completely inhibits lipopolysaccharide-induced activation of microglia and the production of proinflammatory cytokines [11]. We tested the hypothesis that propofol attenuates cerebral ischemic injury by inhibiting microglia-mediated inflammatory response in a rat model of ischemic stroke
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