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Propofol Protects Against Focal Cerebral Ischemia via
Inhibition of Microglia-Mediated Proinflammatory
Cytokines in a Rat Model of Experimental Stroke

Rong Zhou, Zailiang Yang, Xiaofeng Wu
1 Department of Operating Room, Children's Hospital, Chongqing Medical University, Chongqing, China, 2 Ministry of Education Key Laboratory of Child
Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing, China, 3 Hematopoietic Stem Cell Transplantation and Gene
Therapy Center, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China, 4 State Key Laboratory of Trauma, Burn and Combined Injury,
Daping Hospital, Third Military Medical University, Chongqing, China, 5 Research Institute of Surgery, Daping Hospital, Third Military Medical University,
Chongqing, China, 6 Department of Anesthesiology, Children's Hospital, Chongqing Medical University, Chongqing, China
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.
Citation: Zhou R, Yang Z, Tang X, Tan Y, Wu X, et al. (2013) Propofol Protects Against Focal Cerebral Ischemia via Inhibition of Microglia-Mediated
Proinflammatory Cytokines in a Rat Model of Experimental Stroke. PLoS ONE 8(12): e82729. doi:10.1371/journal.pone.0082729
Editor: Tobias Eckle, University of Colorado Denver, United States of America
Received September 24, 2013; Accepted November 5, 2013; Published December 9, 2013
Copyright:, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The work was supported by Chongqing Medical University Research Foundation. The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: liuf-cmu@hotmail.com Microglia are major immune cells in the central nervous system, which are activated rapidly in response to brain injury Stroke is the leading cause of death and the most frequent or during neurodegenerative processes and produce cause of long-term disability in the adult population worldwide proinflammatory cytokines, growth factors, reactive oxygen ]. Ischemic strokes are the most common type of stroke, species, nitric oxide, and glutamate []. Although activation of representing about 87% of all strokes ]. Cerebral ischemia microglia is necessary and crucial for host defense, the over- induces acute inflammation by triggering excessive production activation of microglia results in deleterious and neurotoxic of proinflammatory cytokines in the brain as well as in consequences. Experimental studies have shown that resident peripheral blood, which exacerbate brain damage and are microglia in the brain are activated within minutes of ischemia related to poor clinical outcome in patients with ischemic stroke onset and release multiple proinflammatory cytokines, such astumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), which play a crucial role in the progression PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729 Propofol and Neuroprotection of neuronal loss and brain injury following ischemic stroke Induction of MCAO
Thus, development of agents that reduce microglial activation Transient MCAO was induced by the intraluminal suture in the brain and inhibit the release of proinflammatory cytokines method as previously described [Briefly, rats were is considered to be an important therapeutic strategy for anesthetized with an intraperitoneal (i.p.) injection of ischemic stroke.
pentobarbital sodium (50 mg/kg). Body core temperature was Propofol (2,6-diisopropylphenol) is an intravenous hypnotic maintained within a normothermic range (37°C to 38°C) with a agent widely used for induction and maintenance of anesthesia temperature-controlled heating pad. A 4/0 surgical nylon during surgeries. In addition, Propofol has antiinflammatory monofilament with a silicone-beaded tip was introduced into the properties, reducing production of proinflammatory cytokines, right internal carotid artery through the external carotid artery to altering expression of nitric oxide, and inhibiting neutrophil occlude the origin of the middle cerebral artery. After 2 h of function An in vitro study recently showed that propofol occlusion, the monofilament was removed to allow reperfusion for 24 h. In addition, the left femoral artery was cannulated for activation of microglia and the production of proinflammatory monitoring blood pressure (BP) and heart rate (HR) and for cytokines [A number of experimental studies have reported arterial blood gas measurements. The left femoral vein was that propofol ameliorates neuronal injury in animal models of cannulated for the administration of drugs. BP and HR were ischemic stroke []. However, the precise mechanisms continuously recorded on a computer using the PowerLab involved in its neuroprotective effects remain unclear. In this software (PowerLab/8SP, Chart 5.0; ADInstruments Pty, Ltd., study, we tested the hypothesis that propofol attenuates Castle Hill, Australia). Blood gas measurements were cerebral ischemic injury by inhibiting microglia-mediated performed 15 min after the onset of ischemia or reperfusion inflammatory response in a rat model of ischemic stroke.
using a blood gas analyzer (Compact 3, AVL Medizintechnik).
Assessment of neurological outcome
Eight rats from each group were used for assessment of neurological outcome. Neurological deficit scores were Male Sprague-Dawley rats weighing 250-300 g were evaluated 24 h after ischemia using an eight-point scale as purchased from Beijing Laboratory Animal Research Center described previously The score was 0 for no apparent (Beijing, China). Animals were housed and cared for in the deficits; 1 for failure to extend left forepaw fully; 2 for decreased Animal Resource Center and allowed free access to food and grip of the left forelimb; 3 for spontaneous movement in all water. All procedures were reviewed and approved by the directions, contralateral circling only if pulled by the tail; 4 for Institutional Animal Care and Use Committee at the Chongqing circling or walking to the left; 5 for walking only if stimulated; 6 Medical University and were performed in accordance with the for unresponsiveness to stimulation and with depressed level of "Guiding Principles for Research Involving Animals and Human consciousness; and 7 for death.
Measurement of motor coordination was performed 24 h before and after ischemia, respectively. The experimental procedure was described previously []. Briefly, the time that The animals were randomly assigned to 3 groups (n=20 for the rats stayed on a rotating rod was recorded automatically in each group) as follows: (1) middle cerebral artery occlusion each case for up to 3 minutes. The trial was conducted five (MCAO) group treated with propofol (MCAO+PRO). Rats were times for each rat, and the mean riding time was used as the subjected to MCAO for 2 h followed by 24 h of reperfusion and mean value for this test. When the time of riding was over 3 infused intravenously with propofol (50 mg/kg/h) using syringe minutes, the rat was released from the rod, and the riding time pump at the onset of reperfusion for 30 minutes; (2) MCAO was recorded as 3 minutes.
group treated with vehicle (saline) (MCAO+VEH). Same as At the end of the observation period, these rats were group (1), but these rats were infused intravenously with saline euthanized with an overdose of anesthesia and brains were at the onset of reperfusion for 30 minutes; (3) sham-operated quickly removed for assessment of infarct volume, as group (SHAM). Rats were subjected to sham MCAO without previously described ]. Briefly, brains were sectioned at 2- treatment. The dose for intravenous infusion of propofol was mm intervals throughout the rostrocaudal axis of the striatum.
derived from a previous study in which such dose of propofol Slices were then staining with 2% 2,3,5 triphenyltetrazolium significantly reduced infarct size 24 h after MCAO in rats chloride (TTC) for 15 min at 37°C. Slice images were Based on a formula for dose translation from animal to human digitalized and infarct areas were analyzed using NIH Image ], a dose of 50 mg/kg/h of propofol in rats is roughly 1.60. The Complete lack of staining with TTC was defined as equivalent to a dose of 8.1 mg/kg/h in human, which is within the infarct lesion. The infarct volume was expressed as a the infusion rates of propofol for clinical use in human. At the percentage of the contralateral hemisphere.
end of the protocol (24 h after MCAO and reperfusion),neurological deficit scores and motor coordination were Real-time PCR analysis
evaluated. Rats were then sacrificed, the blood samples were The mRNA expression of microglial markers (CD68 and collected for biochemical measurements and the brains were Emr1) and proinflammatory cytokines (TNF-α, IL-1β and IL-6) removed for infarct volume assessment, molecular analysis or in the peri-infarct cortical tissue was measured with real-time PCR. Rats (n=8 for each group) were euthanized 24 h after PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729 Propofol and Neuroprotection Table 1. Primer sequences for real-time PCR.
Primer name
Forward primer (5'→3')
Reverse primer (5'→3')
MCAO, and the brains were removed and cut into seven serial antibody penetration. Subsequently, the sections were 2-mm-thick coronal sections. The peri-infarct cortical tissue incubated for 72 h with a mouse monoclonal primary antibody was dissected from the coronal brain sections for extraction of directed against CD11b (clone OX-42) (1:100, Chemicon, total RNA and protein using an operating microscope as Temecula, USA) in 2% normal horse serum and 0.2% Triton described previously ]. The total RNA was extracted using X-100 in phosphate buffered saline. This was followed by TRI Reagent (Molecular Research Center, Inc) and reverse incubations in a biotinylated antimouse secondary antibody transcribed into cDNA. mRNA levels for CD68, Emr1, TNF-α, raised in horse (1:100, Vector Laboratories, Burlingame, USA) IL-1β, IL-6 and GAPDH were measured with SYBR green real- for 2 h. The sections were exposed to DAB reagent (Vector time PCR. The sequences for primers used were summarized in . Real-time PCR was performed using the ABI prism hematoxylin, dehydrated in ethanol, cleared with xylene, and 7000 Sequence Detection System (Applied Biosystems, coverslipped with mounting medium.
Carlsbad, CA). The values were normalized to GAPDH and Morphological analysis and quantification of microglia were expressed as a fold change relative to the SHAM group.
performed with a light microscope as described ]. Non-activated microglia were distinguished by their small soma from Western blot analysis
which there emanated extensive, highly branched, long, thin The protein levels of proinflammatory cytokines TNF-α, IL-1β processes, a morphology termed ramified. Activated microglia and IL-6 in the peri-infarct cortical tissue were measured by immunohistochemical staining for the marker CD11b (clone Western blot. The peri-infarct cortical tissue was dissected from OX-42), the presence of a clearly enlarged soma and marked the coronal brain sections and homogenized in lysis buffer. The changes in the appearance of the processes which were now protein concentration in the supernatant was measured with reduced in number, but considerably thicker and shorter giving the BCA protein assay Kit (Pierce, Rockford, IL, USA).
a stubby appearance. The number of activated and non- Equivalent amounts of protein were separated on 12% SDS- activated microglia was counted in several 0.2 × 0.2 mm polyacrylamide gels and transferred to polyvinylidene difluoride squares and the average was calculated.
membranes (Millipore Corporation, Bedford, MA, USA). Themembranes were blocked with 3% nonfat dry milk and thenincubated using primary antibody to TNF-α, IL-1β, IL-6 and β- actin (Santa Cruz Biotechnology Inc, Santa Cruz, CA) at 4°C Blood samples were collected 24 h after MCAO for overnight. After three washing, the membranes were incubated measurements of plasma proinflammatory cytokines (TNF-α, with horseradish peroxidase-conjugated second antibody IL-1β, IL-6 and C-reactive protein) by ELISA kits (Biosource (Santa Cruz Biotechnology Inc, Santa Cruz, CA) for 1 h at International Inc, Camarillo, CA or R&D Systems Inc, room temperature. The signal was visualized using the Minneapolis, MN).
enhanced chemiluminescence (ECL) detection system(Amersham) and the densities of the immunobands were quantitated. All data were corrected and normalized to β-actin.
Data are expressed as mean±SEM. The significance of differences in mean values was analyzed by one-way or two- way repeated-measure ANOVA followed by Fisher's post hoc Twenty-four hours after MCAO, four rats from each group test. P<0.05 was considered statistically significant.
were perfused transcardially with heparinized saline followedby ice-cold 4% paraformaldehyde in phosphate buffered saline.
Brains were removed and fixed overnight in 4%paraformaldehyde at 4°C and then immersed in 30% sucrose.
Hemodynamic and physiological variables
Brain tissue was sliced into 20-μm serial coronal sections using To eliminate potential confounding factors on neurological a cryostat. Standard immunohistochemical procedures were outcomes, hemodynamic and physiological variables, including performed according to a previous study ]. Briefly, the BP, HR and arterial blood gases, were monitored and sections were blocked by 0.5% H O for 30 min and then controlled before, during and after MCAO. As shown in incubated in 10% normal horse serum for 60 min to facilitate and , no significant differences among groups in mean BP, PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729 Propofol and Neuroprotection Table 2. Systemic hemodynamic variables during MCAO and reperfusion.
Ischemia 15 min
Ischemia 35 min
Reperfusion 5 min
Reperfusion 35 min
MBP (mmHg) HR (beats/min) Table 3. Physiological variables during MCAO and reperfusion.
HR, arterial pH, carbon dioxide tension (Pco ) and arterial sham rats, but there were few microglia with an activated oxygen tension (Po ) were observed at each time point before, morphology (). The average number of total microglia during MCAO and during reperfusion.
and the proportion of activated microglia counted in the peri-infarct cortical tissue were significantly Propofol ameliorated MCAO-induced neuronal injury
increased in vehicle-treated rats 24 h after MCAO compared A 2-h MCAO followed by 24 h reperfusion induced an infarct with those in sham rats. In contrast, both the number of total volume of 23 ± 2% in vehicle-treated rats microglia and the proportion of activated microglia in the peri- In contrast, treatment with propofol after MCAO reduced infarct infarct cortical tissue were reduced in rats treated with propofol.
volume significantly by approximately 35% (p < 0.05).
The time spent on rotarod among three groups was similar Propofol attenuated MCAO-induced proinflammatory
before MCAO (average time on rotarod was 154 ± 17 sec).
Twenty-four hours after MCAO, vehicle-treated rats exhibited Multiple proinflammatory cytokines play an important role in markedly higher neurological deficit scores () and the regulation of inflammation. TNF-α, IL-1β and IL-6 are major reduced time on rotarod (than sham rats. Whereas early response cytokines that trigger a cascade of inflammatory rats treated with propofol after MCAO demonstrated significant mediators, including other cytokines, chemokines, reactive decrease in neurological deficit scores and improvement in nitrogen or oxygen intermediates In the brain, microglia rotarod performance compared with vehicle-treated rats.
produce all 3 cytokines. C-reactive protein is an exquisitelysensitive systemic marker of inflammation and tissue damage.
In the present study, the neuroprotective actions of propofol Propofol inhibited MCAO-induced microglial activation
administrated after MCAO could be due to its inhibitory effects Real-time PCR showed that mRNA expression of Cd68 and on microglia and subsequent production of proinflammatory Emr1, two microglia specific markers, markedly increased by cytokines in the brain and periphery. To test this hypothesis, 178% and 290%, respectively, in the peri-infarct cortical tissue we measured the levels of above proinflammatory cytokines in in vehicle-treated rats 24 h after MCAO as compared to those the brain and plasma. The mRNA () and protein in sham rats ). Compared with vehicle-treated rats, ) expressions of the proinflammatory cytokines TNF-α, propofol-treated rats had significantly decreased mRNA IL-1β and IL-6 were significantly augmented in the peri-infarct expression of Cd68 and Emr1 in the peri-infarct cortical tissue cortical tissue of vehicle-treated rats compared with sham rats.
24 h after MCAO.
After treatment with propofol, mRNA and protein expressions of OX42 antibody is a specific microglial marker and stains all IL-1β and IL-6 were significantly reduced, and mRNA and microglia. Activated microglia were defined as cells that exhibit protein expressions of TNF-α were normalized in the peri- strong OX-42 immunoreactivity, an enlarged soma, fewer and infarct cortical tissue of rats at 24 h following MCAO.
shorter processes. Using immunohistochemical study, we There were no differences in plasma levels of TNF-α and found that microglia were presented in the cortical tissue of IL-1β across the 3 experimental groups PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729


Propofol and Neuroprotection Figure 1. Representative coronal brain slices stained with TTC (A), infarct volume (B), neurological deficit scores (C) and
motor coordination (D) 24 h after middle cerebral artery occlusion (MCAO) in rats treated with vehicle (VEH) or propofol
(PRO).
Sham-operated rats (SHAM) without treatment were used as control. Values are mean ± SEM (n = 8 for each group). *P<
0.05 vs. SHAM, †P< 0.05 MCAO+PRO vs. MCAO+VEH.
doi: 10.1371/journal.pone.0082729.g001
PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729 Propofol and Neuroprotection Figure 2. mRNA expression for microglia specific markers Cd68 (A) and Emr1 (B) in the peri-infarct cortical tissue 24 h
after MCAO in rats treated with VEH or PRO.
SHAM rats without treatment were used as control. Values are mean ± SEM (n = 8
for each group) and expressed as a fold change relative to SHAM. *P< 0.05 vs. SHAM, †P< 0.05 MCAO+PRO vs. MCAO+VEH.
doi: 10.1371/journal.pone.0082729.g002
However, vehicle-treated rats had higher plasma levels of IL-6 ], but the underlying mechanisms remain unclear. In the and C-reactive protein, which were significantly reduced after present study, we found that a 2-h MCAO followed by 24 h treatment with propofol ( reperfusion elicited large brain infarct in the frontoparietalcortex. Administration of propofol early after MCAO reduced infarct volume, improved neurological outcome as evidencedby decrease neurological deficit scores and increased time in The novel finding of this study is that treatment with propofol rotarod performance. These results are consistent with early after ischemic stroke suppressed microglia activation and previous studies, suggesting a protective effect of propofol on proliferation in the peri-infarct cortical regions, reduced the ischemic brain injury. More importantly, our data extend production of proinflammatory cytokines in the brain as well as previous findings by revealing that the beneficial effects of in peripheral blood, and improved neurological outcome. To our propofol on ischemic brain injury are associated with knowledge, this is the first study in vivo to demonstrate that the suppression of microglial activation and proliferation in the peri- propofol confers neuroprotection against ischemic brain injury by modulating microglial function. Our finding provides new understanding of the protective mechanisms of anesthetic The inflammatory responses in the brain to ischemic stroke propofol, which may be applicable in the immediate aftermath are characterized by a rapid activation and proliferation of of stroke as well as to patients with a stroke history undergoing microglial cells, followed by the infiltration of circulating surgery, patients in the intensive care unit under sedation, and inflammatory cells, including neutrophils, T cells, monocyte/ patients undergoing neurosurgery.
macrophages, and other cells in the ischemic brain region, as Propofol has become the most widely used anesthetics in demonstrated in animal models and in stroke patients neurosurgery. More recently, the anti-inflammatory functions of ]. The microglia are activated within minutes after onset propofol have been received much attention because this of focal cerebral ischemia and may last for several weeks after agent has been shown to exert protective effects during acute initial injury ]. Activated microglia produce a plethora of inflammatory in neurologic and cardiovascular diseases proinflammatory mediators in the brain, including TNF-α, IL-1β For example, experimental studies in animals showed and IL-6, which contribute to the expansion of brain injury and that propofol inhibits cytokine release during sepsis the delayed loss of neurons It has been shown that neutrophil-mediated intraventricular injection of IL-1 and TNF-α increases infarct pulmonary injury ]. Clinical studies revealed that propofol volume and brain edema after MCAO in rats, whereas the attenuates myocardial reperfusion injury and pulmonary injection of microglial inhibitor minocycline [or PPAR-γ
dysfunction following cardiopulmonary bypass by reducing free agonist pioglitazone that suppresses microglial activation and radical release and modulating the inflammatory process expression of proinflammatory cytokines [], or administration In addition, a number of studies have reported that of antibodies against IL-1 and TNF-α [reduces brain propofol protects against ischemic brain injury in animal models injury. The data of present study showed that, at 24 h after PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729


Propofol and Neuroprotection Figure 3. Representative photomicrographs of microglia stained with CD11b (A), total number of microglia (B) and the
proportion of activated microglia (expressed as percent of total microglia) (C) in the peri-infarct cortical tissue 24 h after
MCAO in rats treated with VEH or PRO.
SHAM rats without treatment were used as control. Activated microglia were defined as
strong CD11b immunoreactivity, an enlarged soma, and fewer and shorter processes. Scale bar, 200 μm. Values are mean ± SEM
(n = 4 for each group). *P< 0.05 vs. SHAM, †P< 0.05 MCAO+PRO vs. MCAO+VEH.
doi: 10.1371/journal.pone.0082729.g003
MCAO, mRNA expression of microglial markers Cd68 and cytokines is mostly co-localized with activated microglia Emr1 in the peri-infarct cortical tissue was augmented, and the indicating that activated microglial cells are the main number of total microglia and the proportion of activated source of proinflammatory cytokines in the brain after ischemic microglia were increased, suggesting that ischemic stroke stroke. Furthermore, we found that early treatment with results in microglial activation and proliferation in this brain propofol reduced mRNA expression of Cd68 and Emr1, area. In addition, expression of proinflammatory cytokines decreased the number of total microglia and the proportion of TNF-α, IL-1β and IL-6 in this brain area was also increased.
activated microglia in the peri-infarct cortical tissue, These results are consistent with previous findings showing accompanied by decreased mRNA and protein expressions of that cerebral ischemia substantially activates microglia and proinflammatory cytokines 24 h after MCAO. These findings increases expression of proinflammatory cytokines in the provided evidence for suppressive effects of propofol on frontoparietal cortex adjacent to the ischemic core 24 h after microglial activation and release of proinflammatory cytokines MCAO, and increased immunoreactivity for proinflammatory in vivo in rats after ischemic stroke. Our current data are PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729 Propofol and Neuroprotection Figure 4. mRNA expression for proinflammatory cytokines TNF-α (A), IL-1β (B) and IL-6 (C) in the peri-infarct cortical
tissue 24 h after MCAO in rats treated with VEH or PRO.
SHAM rats without treatment were used as control. Values are mean ±
SEM (n = 8 for each group) and expressed as a fold change relative to SHAM. *P< 0.05 vs. SHAM, †P< 0.05 MCAO+PRO vs.
MCAO+VEH.
doi: 10.1371/journal.pone.0082729.g004
supported by recent in vitro studies showing that propofol important, as they may be valuable tools in the search for an dramatically reduced levels of proinflammatory cytokines TNF- optimal management of stroke patients. It is notable that α, IL-1β and IL-6, and activation of microglia induced by cerebral ischemia did not change the levels of plasma lipopolysaccharide [or extracellular pressure []. Taken proinflammatory cytokines TNF-α and IL-1β, but significantly together, these observations demonstrate that the beneficial increased the levels of plasma IL-6 and C-reactive protein, effects of propofol on infarct volume and neurological outcome which were attenuated by propofol treatment. Inflammation in are associated with inhibition of microglia activation and the brain is known to modulate inflammation in the periphery in suppression of the exaggerated production of proinflammatory ischemic stroke, and measurement of peripheral inflammatory cytokines in ischemic brain early after ischemic stroke.
response has been suggested to be a far more practical The use of biochemical markers as predictors of stroke lesion evolution and prognosis is becoming increasingly proinflammatory cytokines and C-reactive protein in plasma PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729


Propofol and Neuroprotection Figure 5. Protein levels for proinflammatory cytokines TNF-α (A), IL-1β (B) and IL-6 (C) in the peri-infarct cortical tissue 24
h after MCAO in rats treated with VEH or PRO.
SHAM rats without treatment were used as control. Representative Western blots
are shown in figure D. Values are expressed as mean ± SEM (n= 8 for each group) and corrected by β-actin. *P< 0.05 vs. SHAM,
P< 0.05 MCAO+PRO vs. MCAO+VEH.
doi: 10.1371/journal.pone.0082729.g005
after ischemic stroke have been reported in both clinical and ischemia also induces activation of astrocytes, another resident experimental studies [The acute-phase response, cells in the brain, which can produce the proinflammatory characterized by elevated plasma concentrations of IL-6, C- cytokines including TNF-α, IL-1β and IL-6. Intervention to reactive protein and neutrophil leukocytosis, is induced within inhibit astrocyte activation has been shown to enhance hours of ischemic stroke []. Parameters of the acute-phase neuronal survival and improve outcome following cerebral response, particularly plasma IL-6 and C-reactive protein ischemia [However, the present study focused only on concentrations, are positively associated with stroke severity the role of microglia activation in ischemic brain injury, further and infarct volume, and predict a higher risk of early clinical studies are needed to determine whether neuroprotective worsening ].Thus, reductions in plasma proinflammatory effects of propofol observed in this study are partially due to cytokines IL-6 and C-reactive protein after treatment with inhibition of astrocyte activation. Second, although propofol propofol in our study are likely to reflect decreased risk of early treatment suppressed microglia activation and reduced the production of proinflammatory cytokines in the brain as well as Two major limitation of the present study should be in peripheral blood, accompanied by decreased infarct size and acknowledged. First, it has been reported that cerebral improved neurological outcome, but the finding of decreases in PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729 Propofol and Neuroprotection Figure 6. Plasma levels of proinflammatory cytokines TNF-α (A), IL-1β (B), IL-6 (C) and C-reactive protein (D) 24 h after
MCAO in rats treated with VEH or PRO.
SHAM rats without treatment were used as control. Values are mean ± SEM (n = 8 for
each group). *P< 0.05 vs. SHAM, †P< 0.05 MCAO+PRO vs. MCAO+VEH.
doi: 10.1371/journal.pone.0082729.g006
these inflammatory markers does not prove that these cause direct relationship between the levels of these proinflammatory the decrease in infarct size. Other important mediators cytokines and infarct size after ischemic stroke.
associated with ischemic neuronal injury might also be reduced In conclusion, the present study demonstrates that by propofol and contributed to the decrease in infarct size.
administration of propofol early after cerebral ischemia reduces Further research is necessary to determine whether there is a infarct volume and improves neurological function by inhibition PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729 Propofol and Neuroprotection of microglia activation and proinflammatory cytokine release in the brain. Propofol may be a promising therapeutic agent forthe prevention and/or treatment of ischemic brain injury and Conceived and designed the experiments: RZ FL. Performed other neurodegenerative diseases associated with microglial the experiments: RZ ZY XT YT XW FL. Analyzed the data: RZZY XT FL. Contributed reagents/materials/analysis tools: RZ ZY XT YT XW. Wrote the manuscript: RZ FL.
1. Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 19. Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Tabira T (2002) 371: 1612-1623. PubMed: Chronic stress impairs rotarod performance in rats: implications for depressive state. Pharmacol Biochem Behav 71: 79-84. doi: 2. Schellinger PD, Kaste M, Hacke W (2004) An update on thrombolytic therapy for acute stroke. Curr Opin Neurol 17: 69-77. doi: 20. Arrick DM, Sun H, Mayhan WG (2012) Influence of exercise training on ischemic brain injury in type 1 diabetic rats. J Appl Physiol (1985) 113: 3. Vila N, Castillo J, Dávalos A, Chamorro A (2000) Proinflammatory 1121-1127. doi:.
cytokines and early neurological worsening in ischemic stroke. Stroke 21. Patzer A, Zhao Y, Stöck I, Gohlke P, Herdegen T et al. (2008) Peroxisome proliferator-activated receptorsgamma (PPARgamma) 4. Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic differently modulate the interleukin-6 expression in the peri-infarct stroke: role of inflammatory cells. J Leukoc Biol 87: 779-789. doi: cortical tissue in the acute and delayed phases of cerebral ischaemia.
Eur J Neurosci 28: 1786-1794. doi: 5. Block ML, Hong JS (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog 22. Rana I, Stebbing M, Kompa A, Kelly DJ, Krum H et al. (2010) Microglia Neurobiol 76: 77-98. doi:PubMed: activation in the hypothalamic PVN following myocardial infarction.
Brain Res 1326: 96-104. PubMed: 6. Stolp HB, Dziegielewska KM (2009) Review: Role of developmental 23. Dinarello CA (2000) Proinflammatory cytokines. Chest 118: 503-508.
neurodevelopmental and neurodegenerative diseases. Neuropathol Appl Neurobiol 35: 132-146. doi: 24. Yang SC, Chung PJ, Ho CM, Kuo CY, Hung MF et al. (2013) Propofol inhibits superoxide production, elastase release, and chemotaxis in 7. Banati RB, Gehrmann J, Schubert P, Kreutzberg GW (1993) formyl peptide-activated human neutrophils by blocking formyl peptide Cytotoxicity of microglia. Glia 7: 111-118. receptor 1. J Immunol 190: 6511-6519. doi: 8. Barone FC, Arvin B, White RF, Miller A, Webb CL et al. (1997) Tumor 25. Taniguchi T, Yamamoto K, Ohmoto N, Ohta K, Kobayashi T (2000) necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke Effects of propofol on hemodynamic and inflammatory responses to endotoxemia in rats. Crit Care Med 28: 1101-1106. doi: 9. Rothwell N, Allan S, Toulmond S (1997) The role of interleukin 1 in acute neurodegeneration and stroke: pathophysiological and 26. Taniguchi T, Kanakura H, Yamamoto K (2002) Effects of posttreatment therapeutic implications. J Clin Invest 100: 2648-2652. doi: with propofol on mortality and cytokine responses to endotoxin-induced immunomodulating 27. Chen HI, Hsieh NK, Kao SJ, Su CF (2008) Protective effects of propofol on acute lung injury induced by oleic acid in conscious rats.
11. Ye X, Lian Q, Eckenhoff MF, Eckenhoff RG, Pan JZ (2013) Differential Crit Care Med 36: 1214-1221. doi: general anesthetic effects on microglial cytokine expression. PLOS 28. Corcoran TB, Engel A, Sakamoto H, O'Callaghan-Enright S, O'Donnell A et al. (2004) The effects of propofol on lipid peroxidation and 12. Zhao XC, Zhang LM, Tong DY, An P, Jiang C et al. (2013) Propofol inflammatory response in elective coronary artery bypass grafting. J increases expression of basic fibroblast growth factor after transient Cardiothorac Vasc Anesth 18: 592-604. doi: cerebral ischemia in rats. Neurochem Res 38: 530-537. doi: 29. An K, Shu H, Huang W, Huang X, Xu M et al. (2008) Effects of propofol 13. Liang C, Cang J, Wang H, Xue Z (2013) Propofol attenuates cerebral on pulmonary inflammatory response and dysfunction induced by ischemia/reperfusion injury partially using heme oxygenase-1. J cardiopulmonary bypass. Anaesthesia 63: 1187-1192. 30. Wang X (2005) Investigational anti-inflammatory agents for the 14. Wang H, Luo M, Li C, Wang G (2011) Propofol post-conditioning treatment of ischaemic brain injury. Expert Opin Investig Drugs 14: induced long-term neuroprotection and reduced internalization of AMPAR GluR2 subunit in a rat model of focal cerebral ischemia/ 31. Yilmaz G, Granger DN (2008) Cell adhesion molecules and ischemic stroke. Neurol Res 30: 783-793. 15. Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from 32. Zhou H, Chen S, Wang W, Wang Z, Wu X et al. (2012) Nanog inhibits animal to human studies revisited. FASEB J 22: 659-661. PubMed: lipopolysaccharide-induced expression of pro-inflammatory cytokines by blocking NF-kappaB transcriptional activity in rat primary microglial 16. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible cells. Mol Med Rep 5: 842-846. PubMed: middle cerebral artery occlusion without craniectomy in rats. Stroke 20: 33. Yrjänheikki J, Keinänen R, Pellikka M, Hökfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in 17. Li D, Huang B, Liu J, Li L, Li X (2013) Decreased brain KATP channel global brain ischemia. Proc Natl Acad Sci U S A 95: 15769-15774. doi: contributes to exacerbating ischemic brain injury and the failure of neuroprotection by sevoflurane post-conditioning in diabetic rats. PLOS 34. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J (2001) Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J 18. Chen Y, Wu X, Yu S, Lin X, Wu J et al. (2012) Neuroprotection of Neurosci 21: 2580-2588. PubMed: .
tanshinone IIA against cerebral ischemia/reperfusion injury through 35. Zhao Y, Patzer A, Gohlke P, Herdegen T, Culman J (2005) The inhibition of macrophage migration inhibitory factor in rats. PLOS ONE intracerebral application of the PPARgamma-ligand pioglitazone confers neuroprotection against focal ischaemia in the rat brain. Eur J PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729 Propofol and Neuroprotection translation to experimental research. J Neuroimmune Pharmacol 8: 36. Yamasaki Y, Matsuura N, Shozuhara H, Onodera H, Itoyama Y et al.
41. Ferrarese C, Mascarucci P, Zoia C, Cavarretta R, Frigo M et al. (1999) (1995) Interleukin-1 as a pathogenetic mediator of ischemic brain Increased cytokine release from peripheral blood cells after acute damage in rats. Stroke 26: 676-680; discussion: 42. Emsley HC, Smith CJ, Gavin CM, Georgiou RF, Vail A et al. (2003) An 37. Wei Z, Chigurupati S, Arumugam TV, Jo DG, Li H et al. (2011) Notch early and sustained peripheral inflammatory response in acute activation enhances the microglia-mediated inflammatory response ischaemic stroke: relationships with infection and atherosclerosis. J associated with focal cerebral ischemia. Stroke 42: 2589-2594. doi: Neuroimmunol 139: 93-101. 43. Wang YY, Chen CJ, Lin SY, Chuang YH, Sheu WH et al. (2013) 38. Gui B, Su M, Chen J, Jin L, Wan R et al. (2012) Neuroprotective effects Hyperglycemia is associated with enhanced gluconeogenesis in a rat of pretreatment with propofol in LPS-induced BV-2 microglia cells: role model of permanent cerebral ischemia. Mol Cell Endocrinol 367: 50-56.
of TLR4 and GSK-3beta. Inflammation 35: 1632-1640. doi: 44. Barreto G, White RE, Ouyang Y, Xu L, Giffard RG (2011) Astrocytes: 39. Yu G, Dymond M, Yuan L, Chaturvedi LS, Shiratsuchi H et al. (2011) targets for neuroprotection in stroke 11. Cent Nerv Syst Agents Med Propofol's effects on phagocytosis, proliferation, nitrate production, and Chem. pp. 164-173.
cytokine secretion in pressure-stimulated microglial cells. Surgery 150: 45. Dinapoli VA, Benkovic SA, Li X, Kelly KA, Miller DB et al. (2010) Age exaggerates proinflammatory cytokine signaling and truncates signal 40. Smith CJ, Lawrence CB, Rodriguez-Grande B, Kovacs KJ, Pradillo JM transducers and activators of transcription 3 signaling following et al. (2013) The immune system in stroke: clinical challenges and their ischemic stroke in the rat. Neuroscience 170: 633-644. doi:.
PLOS ONE www.plosone.org December 2013 Volume 8 Issue 12 e82729

  • Induction of MCAO
  • Assessment of neurological outcome
  • Real-time PCR analysis
  • Western blot analysis
  • Hemodynamic and physiological variables
  • Propofol ameliorated MCAO-induced neuronal injury
  • Propofol inhibited MCAO-induced microglial activation
  • Propofol attenuated MCAO-induced proinflammatory cytokines
  • Source: http://congresoscare.com.co/cali/concursos/documentos-adicionales-juicio-del-siglo.html?download=105:propofol-protects-against-focal-cerebral-ischemia-via-inhibition-of-microglia-mediated-proinflammatory-cytokines-in-a-rat-model-of-experimental-stroke&start=100

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