Neuroprotective Effects Of Propofol Research Articles

Propofol inhibits neuroinflammation and metabolic reprogramming in microglia in vitro and in vivo.

Microglial activation-induced neuroinflammation is closely related to the development of sepsis-associated encephalopathy. Accumulating evidence suggests that changes in the metabolic profile of microglia is crucial for their response to inflammation. Propofol is widely used for sedation in mechanically ventilated patients with sepsis. Here, we investigate the effect of propofol on lipopolysaccharide-induced neuroinflammation, neuronal injuries, microglia metabolic reprogramming as well as the underlying molecular mechanisms. The neuroprotective effects of propofol (80mg/kg) in vivo were measured in the lipopolysaccharide (2mg/kg)-induced sepsis in mice through behavioral tests, Western blot analysis and immunofluorescent staining. The anti-inflammatory effects of propofol (50μM) in microglial cell cultures under lipopolysaccharide (10ng/ml) challenge were examined with Seahorse XF Glycolysis Stress test, ROS assay, Western blot, and immunofluorescent staining. We showed that propofol treatment reduced microglia activation and neuroinflammation, inhibited neuronal apoptosis and improved lipopolysaccharide-induced cognitive dysfunction. Propofol also attenuated lipopolysaccharide-stimulated increases of inducible nitric oxide synthase, nitric oxide, tumor necrosis factor-α, interlukin-1β and COX-2 in cultured BV-2 cells. Propofol-treated microglia showed a remarkable suppression of lipopolysaccharide-induced HIF-1α, PFKFB3, HK2 expression and along with downregulation of the ROS/PI3K/Akt/mTOR signaling pathway. Moreover, propofol attenuated the enhancement of mitochondrial respiration and glycolysis induced by lipopolysaccharide. Together, our data suggest that propofol attenuated inflammatory response by inhibiting metabolic reprogramming, at least in part, through downregulation of the ROS/PI3K/Akt/mTOR/HIF-1α signaling pathway.

Propofol Inhibits Ferroptotic Cell Death Through the Nrf2/Gpx4 Signaling Pathway in the Mouse Model of Cerebral Ischemia-Reperfusion Injury.

Ferroptosis is characterized by excessive accumulation of iron and lipid peroxides, which are involved in ischemia, reperfusion-induced organ injury, and stroke. Propofol, an anesthetic agent, has neuroprotective effects due to its potent antioxidant, anti-ischemic, and anti-inflammatory properties. However, the relationship between propofol and ferroptosis is still unclear. In the current study, we elucidated the role of ferroptosis in the neuroprotective effect of propofol in mouse brains subjected to cerebral ischemia reperfusion injury (CIRI). Ferroptosis was confirmed by Western blotting assays, transmission electron microscopy, and glutathione assays. Propofol regulated Nrf2/Gpx4 signaling, enhanced antioxidant potential, inhibited the accumulation of lipid peroxides in CIRI-affected neurons, and significantly reversed CIRI-induced ferroptosis. Additionally, Gpx4 inhibitor RSL3 and Nrf2 inhibitor ML385 attenuated the effects of propofol on antioxidant capacity, lipid peroxidation, and ferroptosis in CIRI-affected neurons. Our data support a protective role of propofol against ferroptosis as a cause of cell death in mice with CIRI. Propofol protected against CIRI-induced ferroptosis partly by regulating the Nrf2/Gpx4 signaling pathway. These findings may contribute to the development of future therapies targeting ferroptosis induced by CIRI.

The effect of propofol on hypoxia-modulated expression of heat shock proteins: potential mechanism in modulating blood-brain barrier permeability.

Heat shock proteins (HSPs) may be induced by hypoxia and alleviate blood-brain barrier (BBB) damage. The neuroprotective effect of propofol has been reported. We aimed to identify whether propofol induced HSPs expression and protected BBB integrity. Mouse astrocytes and microglia cells were cultured and exposed to hypoxia and propofol. The expression of HSP27, HSP32, HSP70, and HSP90, and the translocation of heat shock factor 1 (HSF1) and Nuclear factor-E2-related factor 2 (Nrf2) were investigated. Mouse brain microvascular endothelial cells, astrocytes, and microglial cells were co-cultured to establish in vitro BBB model, and the effects of hypoxia and propofol as well as HSPs knockdown/overexpression on BBB integrity were measured. Hypoxia (5% O2, 5% CO2, 90% humidity) treatment for 6h and 12h induced HSP27, HSP32, and HSP70 expression. Propofol (25μΜ) increased HSP27 and HSP32 expression, starting with exposure to hypoxia for 3h. Propofol induced HSF1 translocation from cytoplasmic to nuclear compartment, and blockade of HSF1 inhibited HSP27 expression in mouse astrocytes when they were exposed to hypoxia for 3h. Propofol induced Nrf2 translocation, and blockade of Nrf2 inhibited HSP32 expression in mouse microglial cells when they were exposed to hypoxia for 3h. Propofol protected hypoxia-impaired BBB integrity, and the effects were abolished by blockade of HSF1 and Nrf2. Overexpression of HSP27 and HSP32 alleviated hypoxia-impaired BBB integrity, and blockade of HSP27 and HSP32 expression ameliorated propofol-mediated protection against BBB impairment. Propofol may protect hypoxia-mediated BBB impairment. The mechanisms may involve HSF1-mediated HSP27 expression and Nrf2-mediated HSP32 expression.

Propofol improved hypoxia-impaired integrity of blood-brain barrier via modulating the expression and phosphorylation of zonula occludens-1.

SummaryAimsHypoxia may damage blood‐brain barrier (BBB). The neuroprotective effect of propofol has been reported. We aimed to identify whether and how propofol improved hypoxia‐induced impairment of BBB integrity.MethodsMouse brain microvascular endothelial cells (MBMECs) and astrocytes were cocultured to establish in vitro BBB model. The effects of hypoxia and propofol on BBB integrity were examined. Further, zonula occludens‐1 (ZO‐1) expression and phosphorylation, hypoxia‐inducible factor‐1α (HIF‐1α) and vascular endothelial growth factor (VEGF) expression, intracellular calcium concentration and Ca2+/calmodulin‐dependent protein kinase II (CAMKII) activation were measured.ResultsHypoxia‐impaired BBB integrity, which was protected by propofol. Hypoxia‐reduced ZO‐1 expression, while induced ZO‐1 phosphorylation. These effects were attenuated by propofol. The expression of HIF‐1α and VEGF was increased by hypoxia and was alleviated by propofol. The hypoxia‐mediated suppression of ZO‐1 and impaired BBB integrity was reversed by HIF‐α inhibitor and VEGF inhibitor. In addition, hypoxia increased the intracellular calcium concentration and induced the phosphorylation of CAMKII, which were mitigated by propofol. The hypoxia‐induced phosphorylation of ZO‐1 and impaired BBB integrity was ameliorated by calcium chelator and CAMKII inhibitor.ConclusionPropofol could protect against hypoxia‐mediated impairment of BBB integrity. The underlying mechanisms may involve the expression and phosphorylation of ZO‐1.

Propofol attenuates inflammatory damage on neurons following cerebral infarction by inhibiting excessive activation of microglia.

The overall incidence rate of stroke is increasing worldwide. Inflammatory damage following a stroke is a leading cause for the poor prognosis and high disability rate observed in stroke patients. Microglia are considered to be the main causative agents of inflammatory injury following cerebral infarction, as they secrete various inflammatory cytokines and cytotoxic factors. The aim of the present study was to identify novel methods for attenuating inflammatory injury and improving the prognosis of stroke patients. Lipopolysaccharide-stimulated microglia were treated using propofol invitro and a transient middle cerebral artery occlusion/reperfusion model was constructed in rats. Expression of cytotoxic factors, microglia proliferation and the neuroprotective effects of propofol were measured invitro and invivo. The invitro studies demonstrated that propofol inhibits the expression of multiple cytotoxic factors, prevents structural changes to cytoskeletal proteins, and suppresses microglial migration via the adenosineA2b receptors. The results of the invivo experiments revealed that propofol inhibits the abnormal proliferation of microglia, as well as reduces the expression levels of interleukin (IL)-6, IL-1β, tumor necrosis factor α, and the cytotoxic factor nitric oxide through the A2b receptor. In conclusion, propofol inhibited the excessive activation of microglia through the A2b receptor and attenuated the inflammatory injury following cerebral infarction. The current study may provide a reliable basis for further clinical studies on propofol and its putative role in improving the prognosis of patients with cerebral infarction.

Anesthetics alleviate learning and memory impairment induced by electroconvulsive shock by regulation of NMDA receptor-mediated metaplasticity in depressive rats.

Along with its outstanding antidepressant effect, electroconvulsive shock (ECS) can induce learning and memory impairment. Propofol and ketamine have shown to be useful in alleviating the learning and memory impairment. Nevertheless, the mechanism still remains unclear. This study investigated the role of NMDA receptor (NMDAR)-mediated metaplasticity in the learning and memory impairment induced by ECS, as well as the neuroprotective effect of propofol and ketamine in depressive rats. Rats received ECS or ECS under anesthetics after chronic unpredictable mild stress procedure. Long-term potentiation (LTP) was tested by extracellular recording. LTD/LTP threshold was assessed by stimulation of different frequencies. Additionally, NMDAR-mediated field excitatory postsynaptic potential (fEPSP) and NMDAR input/output relationship were detected under hippocampal slice perfusion. Results showed that propofol or low-dose ketamine could partially alleviate ECS-induced LTP impairment, while propofol combined with low-dose ketamine almost reversed the LTP impairment. LTP under ECS was increased by stronger stimulation. ECS could up-regulated LTD/LTP threshold, while propofol or ketamine could down-regulate it. Moreover, ECS activated NMDAR, while propofol and ketamine could inhibit the activation of NMDAR. NMDAR input/output relationship decrease was induced by preconditioning (an analog of ECS in hippocampal slice), however, NMDAR input/output relationship increased by propofol or ketamine. In conclusion, ECS-induced cognitive impairment is caused by NMDAR-mediated metaplasticity via up-regulation of LTD/LTP threshold. Propofol or ketamine alleviates the cognitive impairment, possibly by down-regulating the threshold via inhibition of NMDAR activation induced by ECS.

Intracellular Ca2+ homeostasis and JAK1/STAT3 pathway are involved in the protective effect of propofol on BV2 microglia against hypoxia-induced inflammation and apoptosis.

BackgroundPerioperative hypoxia may induce microglial inflammation and apoptosis, resulting in brain injury. The neuroprotective effect of propofol against hypoxia has been reported, but the underlying mechanisms are far from clear. In this study, we explored whether and how propofol could attenuate microglia BV2 cells from CoCl2-induced hypoxic injury.MethodsMouse microglia BV2 cells were pretreated with propofol, and then stimulated with CoCl2. TNF-α level in the culture medium was measured by ELISA kit. Cell apoptosis and intracellular calcium concentration were measured by flow cytometry analysis. The effect of propofol on CoCl2-modulated expression of Ca2+/Calmodulin (CaM)-dependent protein kinase II (CAMKIIα), phosphorylated CAMKIIα (pCAMKIIα), STAT3, pSTAT3Y705, pSTAT3S727, ERK1/2, pERK1/2, pNFκB(p65), pro-caspase3, cleaved caspase 3, JAK1, pJAK1, JAK2, pJAK2 were detected by Western blot.ResultsIn BV2 cell, CoCl2 treatment time-dependently increased TNF-α release and induced apoptosis, which were alleviated by propofol. CoCl2 (500μmol/L, 8h) treatment increased intracellular Ca2+ level, and caused the phosphorylation of CAMKIIα, ERK1/2 and NFκB (p65), as well as the activation of caspase 3. More importantly, these effects could be modulated by 25μmol/L propofol via maintaining intracellular Ca2+ homeostasis and via up-regulating the phosphorylation of JAK1 and STAT3 at Tyr705.ConclusionPropofol could protect BV2 microglia from hypoxia-induced inflammation and apoptosis. The potential mechanisms may involve the maintaining of intracellular Ca2+ homeostasis and the activation of JAK1/STAT3 pathway.

Neuroprotective effect of propofol against excitotoxic injury to locomotor networks of the rat spinal cord invitro.

Although neuroprotection to contain the initial damage of spinal cord injury (SCI) is difficult, multicentre studies show that early neurosurgery under general anaesthesia confers positive benefits. An interesting hypothesis is that the general anaesthetic itself might largely contribute to neuroprotection, although invivo clinical settings hamper studying this possibility directly. To further test neuroprotective effects of a widely used general anaesthetic, we studied if propofol could change the outcome of a rat isolated spinal cord SCI model involving excitotoxicity evoked by 1h application of kainate with delayed consequences on neurons and locomotor network activity. Propofol (5μm; 4-8h) enhanced responses to GABA and depressed those to NMDA together with decrease in polysynaptic reflexes that partly recovered after 1day washout. Fictive locomotion induced by dorsal root stimuli or NMDA and serotonin was weaker the day after propofol application. Kainate elicited a significant loss of spinal neurons, especially motoneurons, whose number was halved. When propofol was applied for 4-8h after kainate washout, strong neuroprotection was observed in all spinal areas, including attenuation of motoneuron loss. Although propofol had minimal impact on recovery of electrophysiological characteristics 24h later, it did not further depress network activity. A significant improvement in disinhibited burst periodicity suggested potential to ameliorate neuronal excitability in analogy to histological data. Functional recovery of locomotor networks perhaps required longer time due to the combined action of excitotoxicity and anaesthetic depression at 24h. These results suggest propofol could confer good neuroprotection to spinal circuits during experimental SCI.

Propofol Prevents Hippocampal Neuronal Loss and Memory Impairment in Cerebral Ischemia Injury Through Promoting PTEN Degradation.

Neuroprotective effect of propofol against cerebral ischemia injury was widely investigated. However, its mechanisms remain unclear. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is supposed as a cell survival pathway, and phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a negative regulator of AKT phosphorylation. Whether PTEN was involved in the protective effect of propofol against cerebral ischemia injury was not elucidated. In this study, the function of PTEN in the acute phase of cerebral ischemia injury was investigated. Our data showed that propofol promoted the PTEN degradation in the acute phase of cerebral ischemia injury and concurrently activated AKT phosphorylation. The increase of ubiquitinated PTEN caused by cerebral ischemia injury were degraded in propofol-pretreated rats. Moreover, we evidenced that proteasome activity was stimulated in propofol-treated rats. These data pointed that PTEN degradation was facilitated in the acute phase after propofol treatment possibly through activating ubiquitin-proteasome system. Therefore, we applied PTEN inhibitor-bpV before cerebral ischemia injury. Like propofol, bpV pretreatment also mitigated cerebral ischemia injury-induced cell loss in CA1 region and memory impairment. Taken together, our data suggest that PTEN degradation is neuroprotective against cerebral ischemia injury and propofol facilitates PTEN degradation to prevent hippocampal neuronal loss and memory deficit in cerebral ischemia injury.

Propofol protects hippocampal neurons from apoptosis in ischemic brain injury by increasing GLT-1 expression and inhibiting the activation of NMDAR via the JNK/Akt signaling pathway.

Ischemic brain injury(IBI) can cause nerve injury and is a leading cause of morbidity and mortality worldwide. The neuroprotective effects of propofol against IBI have been previously demonstrated. However, the neuroprotective effects of propofol on hippocampal neurons are not yet entirely clear. In the present study, models of IBI were established in hypoxia-exposed hippocampal neuronal cells. Cell viability assay and apoptosis assay were performed to examine the neuroprotective effects of propofol on hippocampal neurons in IBI. A significant decrease in cell viability and a significant increase in cell apoptosis were observed in the IBI group compared with the control group, accompanied by a decrease in glial glutamate transporter-1(GLT‑1) expression as determined by RT-qPCR and western blot analysis. The effects of IBI were reversed by propofol treatment. The siRNA-mediated knockdown of GLT‑1 in the hypoxia-exposed hippocampal neuronal cells led to an increase in cell apoptosis, JunN-terminal kinase(JNK) activation and N-methyl-D‑aspartate(NMDA) receptor(NR1 and NR2B) activation, as well as to a decrease in cell viability and a decrease in Akt activation. The effects of RNA interference-mediated GLT‑1 gene silencing on cell viability, JNK activation, NMDAR activation, cell apoptosis and Akt activation in the hippocampal neuronal cells were slightly reversed by propofol treatment. The JNK agonist, anisomycin, and the Akt inhibitor, LY294002, both significantly blocked the effects of propofol on hippocampal neuronal cell viability and apoptosis in IBI. The decrease in JNK activation and the increase in Akt activation caused by GLT‑1 overexpression were reversed by NMDA. Collectively, our findings suggest that propofol treatment protects hippocampal neurons against IBI by enhancing GLT‑1 expression and inhibiting the activation of NMDAR via the JNK/Akt signaling pathway.

Propofol Enhances Hemoglobin-Induced Cytotoxicity in Neurons.

It has been increasingly suggested that propofol protects against hypoxic-/ischemic-induced neuronal injury. As evidenced by hemorrhage-induced stroke, hemorrhage into the brain may also cause brain damage. Whether propofol protects against hemorrhage-induced brain damage remains unknown. Therefore, in this study, we investigated the effects of propofol on hemoglobin-induced cytotoxicity in cultured mouse cortical neurons. Neurons were prepared from the cortex of embryonic 15-day-old mice. Hemoglobin was used to induce cytotoxicity in the neurons. The neurons were then treated with propofol for 4 hours. Cytotoxicity was determined by lactate dehydrogenase release assay. Caspase-3 activation was examined by Western blot analysis. Finally, the free radical scavenger U83836E was used to examine the potential involvement of oxidative stress in propofol's effects on hemoglobin-induced cytotoxicity. We found that treatment with hemoglobin induced cytotoxicity in the neurons. Propofol enhanced hemoglobin-induced cytotoxicity. Specifically, there was a significant difference in the amount of lactate dehydrogenase release between hemoglobin plus saline (19.84% ± 5.38%) and hemoglobin plus propofol (35.79% ± 4.41%) in mouse cortical neurons (P = 0.00058, Wilcoxon Mann-Whitney U test, n = 8 in the control group or the treatment group). U83836E did not attenuate the enhancing effects of propofol on hemoglobin-induced cytotoxicity in the neurons, and propofol did not significantly affect caspase-3 activation induced by hemoglobin. These data suggested that caspase-3 activation and oxidative stress might not be the underlying mechanisms by which propofol enhanced hemoglobin-induced cytotoxicity. Moreover, these data suggested that the neuroprotective effects of propofol would be dependent on the condition of the brain injury, which will need to be confirmed in future studies. These results from our current proof-of-concept study should promote more research in vitro and in vivo to develop better anesthesia care for patients with hemorrhagic stroke.

Angiotensin II-induced mouse hippocampal neuronal HT22 cell apoptosis was inhibited by propofol: Role of neuronal nitric oxide synthase and metallothinonein-3

Background: The activation of renin angiotensin system is involved in multiple pathological processes. The neuroprotective effect of propofol has been reported. We hypothesized that propofol may attenuate Angiotensin II (Ang II)-induced apoptosis in mouse hippocampal HT22 cells and aimed to identify the underlying mechanisms. Methods: Mouse hippocampal HT22 cells were pre-treated with propofol, and stimulated with Ang II. Apoptosis was examined by transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay. The effect of propofol on Ang II-modulated neuronal nitric oxide synthase (nNOS) expression, nitric oxide (NO) production, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression and activity, caspase activity and metallothinonein-3 (MT-3) expression were measured. Results: Compared with control, Ang II concentration- and time-dependently induced apoptosis, which was attenuated by propofol in a concentration-dependent manner. Ang II (1μM, 3h) induced the expression of nNOS and NADPH oxidase, caused NO and superoxide anion accumulation, thus leading to excessive oxidative stress. Ang II also induced cytochrome C release and the activation of caspase 9 as well as caspase 3. In addition, Ang II reduced the expression of MT-3. Importantly, these effects were alleviated by 50μM propofol, nNOS inhibitor S-methyl-l-thiocitrulline (SMTC) and angiotensin type 1 receptor (AT1R) blocker losartan, but not AT2R blocker PD123319. Conclusions: Ang II via AT1R induced oxidative stress and apoptosis in hippocampal HT22 cells, and the neuroprotective anti-apoptotic effect of propofol was mediated through inhibiting oxidative stress.

Does the intrathecal propofol have a neuroprotective effect on spinal cord ischemia?

The neuroprotective effects of propofol have been confirmed. However, it remains unclear whether intrathecal administration of propofol exhibits neuroprotective effects on spinal cord ischemia. At 1 hour prior to spinal cord ischemia, propofol (100 and 300 µg) was intrathecally administered in rats with spinal cord ischemia. Propofol pre-treatment greatly improved rat pathological changes and neurological function deficits at 24 hours after spinal cord ischemia. These results suggest that intrathecal administration of propofol exhibits neuroprotective effects on spinal cord structural and functional damage caused by ischemia.

Endoplasmic reticulum stress is involved in the neuroprotective effect of propofol.

Propofol is a common clinically used intravenous anaesthetic agent with antioxidative property. It has been thought to have neuroprotection in vitro and in vivo. However, the underlying mechanisms remain unclear. Endoplasmic reticulum (ER) stress plays an important role in regulating the signaling pathways concerning cell death and survival. Therefore, we wondered whether the neuroprotective effects of propofol are associated with its regulation on ER stress. In this study, we found that propofol up-regulated BiP and attenuated tunicamycin-induced neural cell death. Propofol pretreatment also inhibited tunicamycin-induced up-regulation of C/EBP homologous protein (CHOP). We also found that propofol or tunicamycin alone increased the levels of spliced XBP1 (XBP1s) and cleaved activating transcription factor 6 (ATF6), an active form of ATF6. However, pretreatment with propofol attenuated the levels of phosphorylated protein kinase receptor-like ER kinase, phosphorylated elF2α, ATF4, and caspase-3, but failed to affect the increase of cleaved ATF6 and XBP1s, induced by tunicamycin. Knockdown endogenous BiP with siRNA abolished the suppression of propofol on tunicamycin-mediated activation of CHOP and caspase-3. Meanwhile, knockdown BiP attenuated the protective effects of propofol on the neural cells exposed to tunicamycin. These data suggest that ER stress is involved in the neuroprotection of propofol via differentially regulating the unfolded protein response pathway, in which BiP plays an important role in initiating the adaptive ER stress and inhibiting the apoptotic ER stress.

Neuroprotective effects of propofol on ER stress-mediated apoptosis in neuroblastoma SH-SY5Y cells

Anesthetic treatment has been associated with widespread apoptotic neurodegeneration in the neonatal rodent brain. It has recently been suggested that propofol, a short-acting intravenous anesthetic agent, may have a potential as a neuroprotective agent. An apoptotic pathway mediated through endoplasmic reticulum (ER) stress has been attracting attention. ER stress is associated with accumulation of unfolded or misfolded proteins in ER, and ER stress-induced apoptosis is implicated in a wide range of diseases, including ischemia/reperfusion injury, neurodegeneration, and diabetes. We investigated whether thapsigargin-induced ER stress is prevented by propofol in human neuroblastoma SH-SY5Y cells. SH-SY5Y cells were pretreated with various concentrations of propofol (1–10μM) for 3h before co-treatment with 0.5μM thapsigargin and propofol for 20h. Levels of ssDNA, specific evidence of apoptosis, and biomarkers of ER stress (mRNA expression of Chop and sXbp-1) were determined. We also assayed calpain and caspase-4 activities and intracellular Ca2+ ([Ca2+]i) levels. Thapsigargin-induced increases in ssDNA levels, expressions of ER stress biomarkers, activities of caspase-4 and calpain, and level of [Ca2+]i were suppressed by co-incubation with propofol. Our data indicate the possibility that propofol inhibits the Ca2+ release from ER at clinically employed dose levels. These results demonstrate that propofol suppresses the ER stress-induced apoptosis in this cell system, and may have the neuroprotective potency. It may also be a promising agent for preventing damage from cerebral ischemia or edema.

Hippocampal Neuron Protecting Effect of Propofol Against Hypoxia/Reoxygenation via Inducing Nerve Growth Factor

Propofol, an intravenous anesthetic agent, exhibits neuroprotective effects against cerebral ischemia–reperfusion injury. Here, we used a model of Hypoxia/Re-Oxygenation (H/R) injury to examine the hippocampal neuroprotective effect of propofol, and explored the role of Nerve Growth Factor (NGF) and NGF receptor TrkA in this action. Rat hippocampal neuron cells were subjected to H/R with different concentrations propofol, the viability and apoptosis of the cells were then determined by MTT assay and annexin V flow cytometry, respectively. Meanwhile, expression of NGF and TrkA were measured by RT-PCR and Western blot. The results showed that H/R significantly reduced viability and increased apoptosis of cultured hippocampal neuron cells, along with the significantly decreased expressions of NGF and TrkA. However, pretreatment of propofol recovered the expressions of NGF and the receptor TrkA, resulting in significantly decreased H/R-induced neurotoxicity. C-Jun N-terminal kinase (JNK) inhibitor suppressed the effect of propofol on the NGF expression, and the TrkA was decreased by PD98059, the Erk1/2 signal blocker. Administration of TrkA inhibitor altered the neuroprotective effect of propofol. These findings suggested the potential of propofol for protecting hippocampal neuron against H/R through at least partly, NGF/TrkA signaling pathway.

Neural and Immune Consequences of Traumatic Brain Injury

Neural and Immune Consequences of Traumatic Brain Injury

TLR4 signaling is involved in the protective effect of propofol in BV2 microglia against OGD/reoxygenation

Propofol exhibits neuroprotective effects against hypoxic-ischemic brain injury, but the underlying mechanisms are still not clear. Toll-like receptor 4 (TLR4) plays a considerable role in the induction of innate immune and inflammatory responses. The purposes of this study are to investigate the effect of propofol on the oxygen and glucose deprivation (OGD)/reoxygenation (OGD/R) BV2 microglia and to explore the role of TLR4/myeloid differentiation protein 88 (MyD88)/nuclear factor-kappa B (NF-κB) pathway in the neuroprotective effects of propofol. BV2 microglia were placed into an airtight chamber and in glucose-free medium for OGD/reoxygenation. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay. TLR4 and its downstream signaling molecules, MyD88 and NF-κB expressions were detected by Western blotting. Level of tumor necrosis factor alpha (TNF-α) in culture medium was determined with enzyme-linked immunosorbent assay. BV2 microglia apoptosis was determined by flow cytometry. We found that pretreatment with propofol significantly alleviated the hypoxic injury in BV2 microglia. Propofol inhibited upregulation of TLR4, MyD88, and NF-κB expressions in BV2 microglia exposed to OGD/reoxygenation. Propofol pretreatment also significantly reduced the production of TNF-α and apoptosis in OGD/reoxygenation BV2 microglia. The results indicated that TLR4 and its downstream MyD88-dependent signaling pathway contributed to neuroprotection of propofol to microglia exposed to OGD/reoxygenation.

Propofol improved neurobehavioral outcome of cerebral ischemia–reperfusion rats by regulating Bcl-2 and Bax expression

Propofol is an intravenous anesthetic with neuroprotective effects against cerebral ischemia–reperfusion (I/R) injury. Few studies regarding the neuroprotective and neurobehavioral effects of propofol have been conducted, and the underlying mechanisms are still unclear. Because I/R may result in neuronal apoptosis, the apoptosis regulatory genes B-cell leukemia-2 (Bcl-2) and Bcl-2-associated X protein (Bax) may be involved in the neuroprotective process. In this study, 120 Wistar rats were randomly divided into three groups (sham, I/R-induced, and propofol-treated). Cerebral ischemia was induced by clamping the bilateral common carotid arteries for 10 min. Propofol (1.0 mg/kg/min) was administered intravenously for 1 h before the induction of ischemia. Neuronal damage was evaluated by neurobehavioral scores and histological examination of the brain sections at the level of the dorsal hippocampus at 6 h, 24 h, 48 h, 72 h, 4 days, 5 days, 6 days, and 7 days after I/R. The apoptotic rate of hippocampal neurons was detected by flow cytometry. The expression of Bcl-2 and Bax was evaluated using immunohistochemical and Western blot methods. The results of this study showed that neurobehavioral scores were higher in propofol-treated rats compared with I/R-induced rats with no propofol treatment. Moreover, the hippocampal expression of Bcl-2 was significantly higher, while the expression of Bax was significantly lower in propofol-treated rats compared with I/R-induced rats at 24 h after ischemia. Hence, this study suggests that the neuroprotective effects of propofol against neuronal apoptosis may be a consequence of the regulation of Bcl-2 and Bax.

The neuroprotective effect of propofol against brain ischemia mediated by the glutamatergic signaling pathway in rats

Several mechanisms are involved in the neuroprotection of propofol against ischemia, but influences of propofol on the binding properties of glutamate receptors and the uptake of glutamate in brain ischemia are not known. The present study was undertaken to investigate these issues in rat global brain ischemic model using methods of neuropathological evaluation, radioligand binding assay with and uptake test for L-(3)H-glutamate. It was shown that propofol used in anesthetic doses protected pyramidal neurons in the hippocampal CA1 subfield against delayed neuronal death normally induced by global brain ischemia. Simultaneously, the propofol decreased the value of maximal number of binding sites (Bmax), increased the value of equilibrium dissociation constant (Kd), and increased the glutamate uptake in the CA1 subfield. These findings indicate that it is, at least partly, via modulating the binding properties of glutamate receptors and the uptake of glutamate that propofol protects neurons against ischemic injury.