PubMed Health⌕ Search

Biomedical subjects

Lin Xu

Publications and source records attributed to Lin Xu.

At least 127 records · Page 7Linked to original sources
PubMed2004

Stress-facilitated LTD induces output plasticity through synchronized-spikes and spontaneous unitary discharges in the CA1 region of the hippocampus.

Long-term potentiation (LTP) and long-term depression (LTD) of the excitatory synaptic inputs plasticity in the hippocampus is believed to underlie certain types of learning and memory. Especially, stressful experiences, well known to produce long-lasting strong memories of the event themselves, enable LTD by low frequency stimulation (LFS, 3 Hz) but block LTP induction by high frequency stimulation (HFS, 200 Hz). However, it is unknown whether stress-affected synaptic plasticity has an impact on the output plasticity. Thus, we have simultaneously studied the effects of stress on synaptic plasticity and neuronal output in the hippocampal CA1 region of anesthetized Wistar rats. Our results revealed that stress increased basal power spectrum of the evoked synchronized-spikes and enabled LTD induction by LFS. The induction of stress-facilitated LTD but not LFS induced persistent decreases of the power spectrum of the synchronized-spikes and the frequency of the spontaneous unitary discharges; However, HFS induced LTP in non-stressed animals and increased the power spectrum of the synchronized-spikes, without affecting the frequency of the spontaneous unitary discharges, but HFS failed to induce LTP in stressed animals without affecting the power spectrum of the synchronized-spikes and the frequency of the spontaneous unitary discharges. These observations that stress-facilitated LTD induces the output plasticity through the synchronized-spikes and spontaneous unitary discharges suggest that these types of stress-related plasticity may play significant roles in distribution, amplification and integration of encoded information to other brain structures under stressful conditions.

Action Potentials↗
PubMed2004

Biotransformation of N-ethyl-N-(2-hydroxyethyl)perfluorooctanesulfonamide by rat liver microsomes, cytosol, and slices and by expressed rat and human cytochromes P450.

Perfluorooctanesulfonic acid (PFOS) and its derivatives have been used in a range of industrial and commercial applications, including the manufacture of surfactants, adhesives, anticorrosion agents, and insecticides. PFOS is found at detectable concentrations in human and wildlife tissues and in the global environment. N-Substituted perfluorooctanesulfonamides are believed to be degraded to PFOS and, therefore, contribute to the accumulation of PFOS in the environment. N-Ethyl-N-(2-hydroxyethyl)perfluorooctanesulfonamide (N-EtFOSE) is converted to PFOS in experimental animals. The objective of this study was to elucidate the pathways for the biotransformation of N-EtFOSE, which is a major precursor and component of PFOS-based compounds. N-EtFOSE and several putative metabolites were incubated with liver microsomes and cytosol and with liver slices from male Sprague-Dawley rats. Microsomal fractions fortified with NADPH catalyzed the N-deethylation of N-EtFOSE to give N-(2-hydroxyethyl)perfluorooctanesulfonamide (FOSE alcohol) and of FOSE alcohol to give perfluorooctanesulfonamide (FOSA). These N-dealkylation reactions were catalyzed mainly by male rat P450 2C11 and P450 3A2 and by human P450 2C19 and 3A4/5. Rat liver microsomal fractions incubated with UDP-glucuronic acid catalyzed the O-glucuronidation of N-EtFOSE and FOSE alcohol and the N-glucuronidation of FOSA. Cytosolic fractions incubated with NAD(+) catalyzed the oxidation of FOSE alcohol to perfluooctanesulfonamidoacetate (FOSAA). The oxidation of N-EtFOSE to N-ethylperfluorooctanesulfonamidoacetate (N-EtFOSAA) was observed in liver slices but not in cytosolic fractions. FOSA was biotransformed in liver slices to PFOS, albeit at a low rate. These results show that the major pathway for the biotransformation of N-EtFOSE is N-dealkylation to give FOSA. The biotransformation of FOSA to PFOS explains the observation that PFOS is found in animals given N-EtFOSE.

Animals↗
PubMed2004

Inhibition of tumor necrosis factor-alpha-converting enzyme by a selective antagonist protects brain from focal ischemic injury in rats.

Tumor necrosis factor alpha (TNFalpha) is an immunomodulatory and proinflammatory cytokine implicated in neuroinflammation and neuronal damage in response to cerebral ischemia. Tumor necrosis factor-alpha converting enzyme (TACE or ADAM17) is a key sheddase that releases TNFalpha from its inactive cell-bound precursor. Using a selective small molecule inhibitor of TACE, DPH-067517, we tested the hypothesis that inhibition of TNFalpha formation might have a salutary effect in ischemic stroke induced by embolic occlusion of the middle cerebral artery (MCAO). DPH-067517 selectively inhibited TACE enzyme activity in vitro (K(i) = 2.8 nM), and effectively suppressed ischemia-induced increase in soluble TNFalpha in brain tissue after systemic administration. DPH-067517 (3 and 30 mg/kg, i.p. administered 15 min before MCAO) produced 43% (n = 8, p = 0.16) and 58% (n = 8, p < 0.05) reduction in infarct size and 36% (p < 0.05) and 23% (p < 0.05) reduction in neurological deficits, respectively. The salutary effect of DPH-067517 in ischemic brain injury was also observed when the first dose was administrated 60 min after the onset of ischemia. Inhibition of TACE had no effect on apoptosis measured by levels of active caspase-3 expression and DNA fragmentation. Our data suggest that inhibition of TACE might be a potential therapeutic strategy for neuroprotection after focal ischemic stroke.

ADAM Proteins↗
PubMed2004

[Changes of thioredoxin mRNA level in neurons with mitochondrial dysfunction insulted by H2O2].

Oxidative stress and mitochondrial deficiency have been considered to be associated with the mechanisms of many neurodegenerative diseases. Sodium azide (NaN3) is a special inhibitor of mitochondrion cytochrome c oxidase (COX), which can be used to mimic neuronal damage induced by mitochondrial deficiency. In this experiment, the neurotoxic effects of H2O2 on primary cultured neurons and NaN3-induced mitochondrial dysfunctional neurons were detected by means of cell viability measurement (MTT) and analyzed through morphological observation. Furthermore, the changes of thioredoxin mRNA level in both normal and abnormal cultured neurons insulted by H2O2 were analyzed by semiquantitative RT-PCR in order to explore the role of Trx, an important redox regulatory protein, in modulating the process of neuronal injury. It was found that mitochondrial dysfunctional neurons could be damaged by H2O2 in a dose- and time-dependent manner and the expression of Trx decreased during certain dose (0-200 mumol/L) and time (0-4 h) of H2O2 treatment. But in normal neurons the effects of H2O2 treatment seemed to be less evident. It suggests that in neurons with mitochondrial dysfunction, the redox modulation of thioredox seems to be more prominent.

Animals↗
PubMed2004

Diagnosis and surgical treatment of giant splenic artery aneurysms with portal hypertension: report of 4 cases.

BACKGROUND: Giant splenic artery aneurysm (GSAA) is a rare but clinically relevant disease. Its importance lies in potential rupture and hemorrhage. Early diagnosis and treatment before rupture of GSAA are crucial to GSAA patients especially to GSAA patients with portal hypertension(PHT). METHODS: Four patients of GSAA with PHT treated at our hospital from December 1999 to September 2001 were retrospectively reviewed. RESULTS: GSAA was found in all patients with digital substracted angiography (DSA) and/or magnetic resonance angiography (MRA) before operation. Resection of GSAA and treatment of PHT were carried out successfully with no perioperative mortality. CONCLUSIONS: Patients with GSAA are apt to have PHT or segmental PHT because of suppression of the splenic vein or formation of aneurysm-portal vein fistula. Operation should be focused on GSAA, and PHT complications.

Aged↗
PubMed2004

[Application and progress of Fourier transform attenuated total reflection infrared spectroscopy].

With the application of Fourier transform infrared spectrograph and the development of chemical metrology, Fourier Transform Attenuated Total Reflection Infrared spectroscopy (ATR-FTIR) has become a kind of beneficial tool and means for analyzing samples, for which traditional transmission way does not work quite effectively, and for analyzing surface layer structure. ATR-FTIR has been applied to every realm such as spinning and weaving, quality testing, public security and so on. At present, people are launching applied study based on specific property of ATR-FTIR. Therefore, this paper mainly introduced the present study situation and development situation of ATR-FTIR, including theoretical development for depth profiling, qualitative analysis of material surface, quantitative analysis of mixture and solution component, and the application of fiber as ATR appurtenance. In addition, some special fields were also involved, such as inspecting hollow cored fiber's structure and change of orientation, and studying effective mechanism about skin promoter.

English Abstract↗
PubMed2003

Localized aggressive periodontitis is linked to human chromosome 1q25.

Localized aggressive periodontitis (LAP; previously known as localized juvenile periodontitis) is one of the rapidly progressive periodontal diseases. Certain forms of familial LAP show a simple Mendelian pattern of transmission. However, no gene mutation has been identified to be responsible for the LAP phenotype. As an initial step to identify a gene mutation associated with LAP, we have performed genetic linkage analysis with four multigenerational families exhibiting the LAP phenotype. Affected individuals in the families were identified based on clinical and laboratory criteria in an attempt to define a homogeneous phenotype, since the clinical presentation of LAP may represent a manifestation of a heterogeneous group of diseases. The LAP phenotype is linked to a DNA marker, D1S492, with LOD score 3.48, theta=0.00. The haplotype analysis of the chromosome interval associated with D1S492 indicates that a LAP locus is located between D1S196 and D1S533 on chromosome 1, covering about 26 million DNA basepairs. We have also examined the DNA sequence of prostaglandin-endoperoxide synthase 2 (PTGS2 or cyclooxygenase 2, COX2) since prostaglandin 2 (PGE2), the product of COX2, is upregulated in LAP patients and COX2 is located between D1S196 and D1S533. No mutation in COX2 was identified in the patients.

Base Sequence↗
PubMed2003

Hydrothermal synthesis and structure of a new helical chain constructed from only molybdenum-oxide building blocks.

The compound [NH(3)(CH(2))(2)NH(2)(CH(2))(2)NH(3)](2)[Mo(9)O(30)] was synthesized at 170 degrees C via hydrothermal techniques from the starting materials of Na(2)MoO(4).H(2)O, NH(2)(CH(2))(2)NH(CH(3))(2)NH(2), and H(2)O. The compound crystallizes in the space group C2/c of the monoclinic system with a = 21.308(4) A, b = 9.234(2) A, c = 19.195(4) A, beta = 120.27(3) degrees, V = 3261.9(11)A(3), Z = 4. Two novel and symmetrically related helices coexist in the centrosymmetric solid, in which the two kinds of helices appear in the left-handed and right-handed enantiomorphs, respectively. This is the first example of a helical chain structure consisting of only molybdenum-oxide building blocks. The central axis about each helical chain is a 2-fold screw axis.

Journal Article↗
PubMed2003

A novel three-dimensional network constructed from tetramolybdate clusters linked via two types of copper complex fragments: synthesis, characterization, and magnetic behavior of [[CuII(2,2'-bpy)][CuII(IN)2][Mo4O12(OH)2]].

A novel three-dimensional copper molybdate with mixed ligands, [[Cu(II)(2,2'-bpy)][Cu(II)(IN)(2)][Mo(4)O(12)(OH)(2)]] (IN(-) = isonicotinate ion, 2,2'-bpy = 2,2'-bipyridine), 1, has been hydrothermally synthesized and structurally characterized, and this compound is built from an unprecedented tetranuclear molybdenum oxide cluster covalently bonded to two types of copper complex fragments, [Cu(II)(2,2'-bpy)](2+) and [Cu(II)(IN)(2)], via terminal oxygen atoms of [MoO(6)] octahedra. Crystal data for compound 1: monoclinic, space group C2/c, a = 16.4755 A, b = 10.3714 A, c = 17.4382 A, alpha = 90.0000 degrees, beta = 94.8098 degrees, gamma = 90.0000 degrees; V = 2969.24 A(3); Z = 2. Variable temperature magnetic susceptibility indicates that both ferromagnetic and antiferromagnetic interactions exist in 1.

Journal Article↗
PubMed2003

[Arginine vasopressin-induced nitric oxide content changes in cultured cardiac fibroblasts and its relation to nuclear factor-kappaB].

To investigate the changes in the nitric oxide (NO) contents, nitric oxide synthase (NOS) activity and inducible nitric oxide (iNOS) mRNA expression in arginine vasopressin (AVP)-induced cardiac fibroblasts (CFs) in vitro and its relation to nuclear factor-kappaB (NF-kappaB), CFs were isolated by trypsin digestion method. Nitric acid reductase method, spectrophotometry, reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence-interactive laser cytometer techniques and Western blotting were used respectively to detect NO contents, NOS activity, iNOS mRNA expression and the activation of NF-kappaB in CFs. AVP increased NO contents, NOS activity and iNOS mRNA expressions in a concentration-dependent manner; NF-kappaB was activated and mobilized from cytoplasm to nucleus in AVP-induced CFs; PDTC, one of the inhibitors of NF-kappaB, could inhibit aforementioned increments. It is suggested that the increases in NO contents, elevation of NOS activity and increment of iNOS mRNA expression may be mediated through NF-kappaB activation pathway in cultured CFs induced by AVP, and that NF-kappaB is involved in the occurrence and development of myocardial fibrosis.

Animals↗
PubMed2003

Mechanisms of H+ modulation of glycinergic response in rat sacral dorsal commissural neurons.

Many ionotropic receptors are modulated by extracellular H+. So far, few studies have directly addressed the role of such modulation at synapses. In the present study, we investigated the effects of changes in extracellular pH on glycinergic miniature inhibitory postsynaptic currents (mIPSCs) as well as glycine-evoked currents (IGly) in mechanically dissociated spinal neurons with native synaptic boutons preserved. H+ modulated both the mIPSCs and IGly biphasically, although it activated an amiloride-sensitive inward current by itself. Decreasing extracellular pH reversibly inhibited the amplitude of the mIPSCs and IGly, while increasing external pH reversibly potentiated these parameters. Blockade of acid-sensing ion channels (ASICs) with amiloride, the selective antagonist of ASICs, or decreasing intracellular pH did not alter the modulatory effect of H+ on either mIPSCs or IGly. H+ shifted the EC50 of the glycine concentration-response curve from 49.3 +/- 5.7 microM at external pH 7.4 to 131.5 +/- 8.1 microM at pH 5.5, without altering the Cl- selectivity of the glycine receptor (GlyR), the Hill coefficient and the maximal IGly, suggesting a competitive inhibition of IGly by H+. Both Zn2+ and H+ inhibited IGly. However, H+ induced no further inhibition of IGly in the presence of a saturating concentration of Zn2+. In addition, H+ significantly affected the kinetics of glycinergic mIPSCs and IGly. It is proposed that H+ and/or Zn2+ compete with glycine binding and inhibit the amplitude of glycinergic mIPSCs and IGly. Moreover, binding of H+ induces a global conformational change in GlyR, which closes the GlyR Cl- channel and results in the acceleration of the seeming desensitization of IGly as well as speeding up the decay time constant of glycinergic mIPSCs. However, the deprotonation rate is faster than the unbinding rate of glycine from the GlyR, leading to reactivation of the undesensitized GlyR after washout of agonist and the appearance of a rebound IGly. H+ also modulated the glycine cotransmitter, GABA-activated current (IGABA). Taken together, the results support a "conformational coupling" model for H+ modulation of the GlyR and suggest that H+ may act as a novel modulator for inhibitory neurotransmission in the mammalian spinal cord.

2-Amino-5-phosphonovalerate↗
PubMed2003

New vanadium phosphate ([(phen)VIVO]2(VV2O5)(HPO4))n with chiral layer architecture.

A new layered vanadium phosphate ([(phen)V(IV)O](2)(V(V)(2)O(5))(HPO(4))n has been hydrothermally synthesized and structurally characterized by elemental analysis, IR, and single-crystal X-ray diffraction. This compound crystallized in the monoclinic space group P2/c with a = 9.979(2) A, b = 9.886(2) A, c = 15.298(3) A, beta = 102.86(3) degrees, V = 1471.3(5) A(3), and Z = 4. In the structure of this compound, two nitrogen atoms of 1,10-phen are directly coordinated to the vanadium skeleton. Interestingly, the crystal structure consists of two types of chiral layers, one left-handed and the other right-handed, which lead to a racemic solid-state compound. In each layer, there coexist three distinct rings, described as a 8-membered ring [V(2)(oct)P(2)O(4)], 12-membered ring [V(2)(omicron)(ct)V(2)(tet)P(2)O(6)], and 16-membered ring [V(2)(omicron)(ct)V(4)(tet)P(2)O(8)].

Journal Article↗
PubMed2003

[Effects of chelerythrine on cell proliferation and p27 expression of cardiac fibroblasts modulated by arginine vasopressin].

OBJECTIVE: To study the effects of chelerythrine, a protein kinase C (PKC) inhibitor, on the cell proliferation and p27 expression of cardiac fibroblasts (CFs) modulated by arginine vasopressin (AVP) and to investigate the intracellular signal transduction mechanisms of AVP in CFs. METHODS: The cultured CFs of neonatal Sprague-Dawley rats were divided into 3 groups: AVP group (10(-7) mol/L AVP was added into the culture), chelerythrine group (10(-6) mol/L chelerythrine and 10(-7) mol/L AVP were added into the culture), and control group. MTT assay was used to evaluate the cell proliferation. The cultured cells were collected and propidium iodide was used to label the DNA so as to identify the cell cycle. Specific mouse-versus-rat p27 protein monoclonal antibody and fluorescein isothiocyanate-labeled secondary antibody were added into the cell suspension to label the p27 protein in the cells. Flow cytometry was used to determine the distribution of cell cycles and p27 expression. RESULTS: (1). The A value of CFs measured by MTT assay in AVP + chelerythrine group was 0.32 +/- 0.01, significantly lower than that of the AVP group (0.39 +/- 0.01, P < 0.01). (2). The percentage of CFs in S stage was 4.4% +/- 1.7% in the AVP + chelerythrine group, lower than those of the AVP group (15.5% +/- 1.4%, P < 0.01) and control group (7.5% +/- 1.0%). The PI of CFs was 20.9% +/- 1.2% in the AVP + chelerythrine group, significantly lower than that of the AVP group (31.4% +/- 1.5%, P < 0.01). The PI of the AVP group was significantly lower than that of the control group (26.0% +/- 1.0%, P < 0.01). The percentage of CFs in G(0)/G(1) stage was 79.1% +/- 1.2% in the AVP + 1 chelerythrine group, significantly higher than that in the AVP group (68.6% +/- 1.5%, P < 0.01). The percentage of CFs in G(0)/G(1) stage in the AVP group was significantly lower than that in the control group (74.0% +/- 1.0%, P < 0.01) too. (3). The expression rate of p27 protein was 91.7% +/- 2.2% in the AVP + chelerythrine group, significantly higher than that in the AVP group (63.3% +/- 1.9%, P < 0.01). CONCLUSION: PKC inhibitor remarkably reverses the CFs proliferation and p27 downregulation induced by AVP. It may be involved in the intracellular signal transduction pathway of AVP in CFs.

Alkaloids↗
PubMed2003

[Effects of atorvastatin on the proliferation and collagen synthesis of rat cardiac fibroblasts].

OBJECTIVE: To investigate the effects of atorvastatin on the proliferation and collagen synthesis of rat cardiac fibroblasts (CFs). METHODS: Isolated and cultured CFs of neonatal Sprague-Dawley (SD) rats were isolated and cultured. The DNA synthesis of CFs was measured by (3)H-TdR uptake test. CFs proliferation was measured by thiazolyl blue (MTT) assay. Cell cycle distribution was determined with flow cytometer (FCM). Collagen synthesis was measured by 3H-proline uptake test. RESULTS: (1) The (3)H-TdR uptake in the 10(-7) mol/L, 10(-6) mol/L, 10(-5) mol/L, and 10(-4) mol/L atorvastatin groups was (cpm/5,000 cells) 314 +/- 68, 253 +/- 52, 201 +/- 53, and 170 +/- 48 respectively, all significantly lower than that of the control group (378 +/- 65, all P < 0.001). (2) MTT colorimetry showed that the A(490) values were 0.288 +/- 0.008, 0.252 +/- 0.007, 0.225 +/- 0.008, and 0.216 +/- 0.013 respectively in the 10(-7) mol/L, 10(-6) mol/L, 10(-5) mol/L and 10(-4) mol/L atorvastatin groups, all significantly lower than that in the control group (0.311 +/- 0.005, all P < 0.01). (3) The percentage of cells in G(0)/G(1) phase was 54.8% +/- 2.5%, 61.4% +/- 2.7%, 70.4% +/- 3.2%, and 82.0% +/- 4.0% in the 10(-7) - 10(-4) mol/L atorvastatin groups, all significantly higher than that in the control group (46.5 +/- 2.9, all P < 0.01). The percentage of cells in S phase was 18.8% +/- 2.3%, 15.8% +/- 2.1%, 12.5% +/- 1.8%, and 7.3% +/- 2.0% in the 10(-7) - 10(-4) mol/L atorvastatin groups, all significantly lower than that in the control group (23.1% +/- 2.0%, all P < 0.01). The percentage of cells in G(2)/M phase was 26.5% +/- 0.8%, 22.8% +/- 1.2%, 17.2% +/- 1.4%, and 10.7% +/- 2.0% in the 10(-7) - 10(-4) mol/L atorvastatin groups respectively, all significantly lower than that in the control group (30.5% +/- 1.4%, all P < 0.01). The proliferation index (PI) was 45.3% +/- 2.5%, 38.6% +/- 2.7%, 29.6% +/- 3.2%, and 18.0% +/- 4.0% in the 10(-7) - 10(-4) mol/L atorvastatin groups respectively, all significantly lower than that in the control group (53.5% +/- 2.9%, all P < 0.01). (4) The (3)H-proline uptake was (cpm/5 000 cells) 422 +/- 59, 332 +/- 67, 252 +/- 53, and 184 +/- 48 in the 10(-7) mol/L, 10(-6) mol/L, 10(-5) mol/L, and 10(-4) mol/L atorvastatin groups respectively, all significantly lower than that in the control group (566 +/- 62, all P < 0.01). CONCLUSION: Atorvastatin inhibits effectively the proliferation of cultured rat CFs and the collagen synthesis therein, which may play a role in the regression of heart remodeling.

Animals↗
PubMed2003

Lead exposure through gestation-only caused long-term learning/memory deficits in young adult offspring.

Numerous observations in clinical and preclinical studies indicate that the developing brain is particular sensitive to lead (Pb)'s pernicious effects. However, the effect of gestation-only Pb exposure on cognitive functions at maturation has not been studied. We investigated the potential effects of three levels of Pb exposure (low, middle, and high Pb: 0.03%, 0.09%, and 0.27% of lead acetate-containing diets) at the gestational period on the spatial memory of young adult offspring by Morris water maze spatial learning and fixed location/visible platform tasks. Our results revealed that three levels of Pb exposure significantly impaired memory retrieval in male offspring, but only female offspring at low levels of Pb exposure showed impairment of memory retrieval. These impairments were not due to the gross disturbances in motor performance and in vision because these animals performed the fixed location/visible platform task as well as controls, indicating that the specific aspects of spatial learning/memory were impaired. These results suggest that exposure to Pb during the gestational period is sufficient to cause long-term learning/memory deficits in young adult offspring.

Animals↗
PubMed2003

The stress experience dependent long-term depression disassociated with stress effect on spatial memory task.

Behavioral stress can either block or facilitate memory and affect the induction of long-term potentiation (LTP) and long-term depression (LTD). However, the relevance of the stress experience-dependent long-term depression (SLTD) to spatial memory task is unknown. Here we have investigated the effects of acute and sub-acute elevated platform (EP) and foot shock (FS) stress on LTD induction in CA1 region of the hippocampus of anesthetized rats and spatial memory in Morris water maze. We found that LTD was facilitated by acute EP stress, but not by sub-acute EP stress that may be due to the fast adaptation of the animals to this naturalistic mild stress. However, FS stress, an inadaptable strong stress, facilitated LTD induction both in acute and sub-acute treatment. In addition, with the same stress protocols, acute EP stress impaired spatial memory but the sub-acute EP stressed animals performed the spatial memory task as well as the controls, may due to the same reason of adaptation. However, acute FS stress slightly impaired learning but sub-acute FS even enhanced memory retrieval. Our results showed that SLTD was disassociated with the effect of stress on memory task but might be related to stress experience-dependent form of aberrant memory.

Adaptation, Biological↗
PubMed2003

Significant neuroprotection against ischemic brain injury by inhibition of the MEK1 protein kinase in mice: exploration of potential mechanism associated with apoptosis.

MEK1/2 is a serine/threonine protein kinase that phosphorylates and activates extracellular signal-responsive kinase (ERK)1/2. In the present study we explored the role of MEK1/2 in ischemic brain injury using a selective MEK1/2 inhibitor, SL327, in mice. C57BL/6 mice were subjected to a 30-min occlusion of the middle cerebral artery (MCAO) followed by reperfusion. Western blot analysis demonstrated the immediate activation of MEK/ERK after reperfusion (within the first 10 min) in the ischemic brain; this activation was dose dependently blocked by SL327 (10-100 mg/kg, i.p.). A single dose of SL327 (100 mg/kg) administered 15 min before or 25 min after the onset of ischemia resulted in 63.6% (n = 18, p < 0.001) and 50.7% (n = 18, p < 0.01) reduction in infarct size, respectively, compared with vehicle-treated mice. Similarly, SL327 significantly reduced neurological deficits 1 to 3 days after reperfusion (n = 12, p < 0.01). The salutary effect of SL327-induced neuroprotection was independent of mitochondrial cytochrome c release or caspase-8-mediated apoptosis; however, SL327 markedly suppressed the levels of active caspase-3 and DNA fragmentation (as a measure of apoptosis) after ischemia/reperfusion. Our data suggest that the inhibition of MEK1/2 results in neuroprotection from reperfusion injury and that this protection may be associated with the reduction in apoptosis.

Aminoacetonitrile↗