Age at first birth is associated with the likelihood of frailty in middle-aged and older women: A population-based analysis from NHANES 1999-2018.

OBJECTIVES: This study examined whether age at first birth (AFB) is associated with the prevalence of frailty in middle-aged and older women. METHODS: The study included 10,828 women (age ≥ 45 years) from the National Health and Nutrition Examination Survey (NHANES) (1999-2018) in the United States. AFB data were collected using a standardized reproductive health questionnaire. Frailty was measured using a 53-item frailty index and was diagnosed if the score on that index was over 0.21. Survey-weighted logistic regression models were used to assess the association between AFB and the prevalence of frailty. A survey-weighted restricted cubic spline (RCS) model was used to determine the dose-response relationship between AFB and frailty. Mediation analyses were performed to estimate the mediated effects of education levels, family poverty income ratio, and parity on the association between AFB and the likelihood of frailty. Finally, sensitivity and subgroup analyses were conducted to validate the robustness of our findings. RESULTS: Among the 10,828 women, 3828 (35.4 %) had frailty. The RCS depicted a U-shaped association between AFB and frailty. Compared with the women in the reference group (AFB: 33-35 years), women in the other groups (AFB: < 18, 18-20, 21-23, and 24-26 years) had a higher likelihood of frailty, with respective odds ratios (95 % confidence intervals) of 3.02 (1.89-4.83), 2.32 (1.54-3.50), 1.83 (1.19-2.81), and 1.64 (1.07-2.53). However, no statistically significant differences were detected for women with AFB of 27-29, 30-32, or > 35 years compared with the reference group. Education levels, family poverty income ratio, and parity significantly mediated the approximately linear negative association between AFB and frailty in the subset of women with AFB of ≤32 years and the mediation proportions were 23.4 %, 32.4 %, and 18.3 %, respectively (all p < 0.001). CONCLUSIONS: Based on our results, we conclude that early AFB is associated with a higher likelihood of frailty in middle-aged and older women.

Association between the cumulative dose of glucocorticoids before the development of pneumonia and death in patients receiving long-term glucocorticoids: a secondary analysis based on a Chinese cohort study.

Background: The present study aimed to evaluate the association between the cumulative dose of glucocorticoids (GCs) and case fatality in hospitalized patients who developed pneumonia while receiving glucocorticoid therapy. Methods: This retrospective cohort study included 625 patients receiving long-term GC treatment who were hospitalized with pneumonia (322 male and 303 female). Data were obtained from the Dryad Digital Repository and were used to perform secondary analysis. Multivariable Cox proportional hazard regression model and restricted cubic splines (RCS) were used to evaluate the association between the cumulative dose of GCs and case fatality. Sensitivity analyses and subgroup analyses were performed. Results: The 30-day and 90-day death rates were 22.9 and 26.2%, respectively. After adjusting for potential confounders, compared with those in the lowest quintile (≤ 1.5 g), the Cox proportional hazard regression model analysis showed that patients with different cumulative doses of GCs (1.5 to 2.95, 2.95 to 5, 5 to 11.5, and > 11.5 g) had lower risks for 30-day death, with respective hazard ratios of 0.86 (95% CI, 0.52 to 1.42), 0.81 (0.49 to 1.33), 0.29 (0.15 to 0.55), and 0.42 (0.22 to 0.79). The multivariable-adjusted RCS analysis suggested a statistically significant N-shaped association between the cumulative dose of GCs and 30-day death. A higher cumulative dose of GC tended to first lead to an increase in 30-day death within 1.8 g, then to a statistically significant decrease until around 8 g [HR for 1 g = 0.82 (0.69 to 0.97)], and again to an increase afterward. Similar results were found in the subgroup analyses and sensitivity analyses. Conclusion: N-shaped association between the cumulative dose of GCs and case fatality was observed in patients receiving long-term GC treatment who were hospitalized with pneumonia. Our findings may help physicians manage these patients.

Neuroprotective effects of saffron on the late cerebral ischemia injury through inhibiting astrogliosis and glial scar formation in rats.

This study is to explore the neuroprotective effects and involved glial scar of saffron (Crocus sativus L.) on the late cerebral ischemia in rats. Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in Sprague Dawley rats that were randomly divided into sham group, MCAO group, edaravone group (as a positive control) and saffron groups (saffron extract 30, 100, 300 mg/kg). Saffron was administered orally at 2 h at the first day and once daily from day 2 to 42 after ischemia. Behavioral changes were detected from day 43 to 46 after ischemia to evaluate the effects of saffron. Infarct volume, survival neuron density, activated astrocyte, and the thickness of glial scar were also detected. GFAP, neurocan, phosphocan, neurofilament expressions and inflammatory cytokine contents were detected by Western-blotting and ELISA methods, respectively. Saffron improved the body weight loss, neurological deficit and spontaneous activity. It also ameliorated anxiety-like state and cognitive dysfunction, which were detected by elevated plus maze (EPM), marble burying test (MBT) and novel object recognition test (NORT). Toluidine blue staining found that saffron treatment decreased the infarct volume and increased the neuron density in cortex in the ischemic boundary zone. The activated astrocyte number and the thickness of glial scar in the penumbra zone reduced after saffron treatment. Additionally, saffron decreased the contents of IL-6 and IL-1ß, increased the content of IL-10 in the ischemic boundary zone. GFAP, neurocan, and phosphocan expressions in ischemic boundary zone and ischemic core zone all decreased after saffron treatment. Saffron exerted neuroprotective effects on late cerebral ischemia, associating with attenuating astrogliosis and glial scar formation after ischemic injury.

Huanglian-Jie-Du-Tang Extract Ameliorates Depression-Like Behaviors through BDNF-TrkB-CREB Pathway in Rats with Chronic Unpredictable Stress.

Neuroinflammation is considered as one of the common pathogeneses of depression. Huanglian-Jie-Du-Tang (HJDT) is a traditional Chinese herbal formula. The present study investigates the antidepressant-like effect of HJDT and its possible mechanism in rats. Rats were given HJDT (2, 4, and 8 g/kg, intragastrically), paroxetine (1.8 mg/kg, intragastrically), or an equivalent volume of saline for 42 days. The depression-related behaviors, including sucrose preference test (SPT), open field test (OFT), novel objective recognition task (NORT), and forced swimming test (FST), were detected. 5-Hydroxytryptamine (5-HT) and dopamine (DA) contents, microglial activation, proinflammatory cytokines, and brain derived neurotrophic factor (BDNF), tropomyosin receptor kinases B (TrkB), and cAMP-responsive element binding protein (CREB) expression were investigated. The results indicated HJDT (2 and 4 g/kg) dramatically ameliorated the depression-like behaviors. Also HJDT decreased the number of microglia and the proinflammatory cytokines in hippocampus. Western-blotting analysis displayed HJDT upregulated BDNF, TrkB, and pCREB/CREB expression in hippocampus. Particularly, pCREB DNA activity enhanced with HJDT treatment in hippocampus. But there was no difference in the 5-HT and DA contents with HJDT treatment. In conclusion, it was supposed that HJDT might be a potential Chinese medicine decoction for treating or alleviating complex symptoms of depression through BDNF-TrkB-CREB pathway.

Flavonoids from Radix Tetrastigmae improve LPS-induced acute lung injury via the TLR4/MD-2-mediated pathway.

Total flavonoids isolated from Radix Tetrastigmae (RTFs) possess immunomodulatory activity, particularly on inflammation. In mice with lipopolysaccharide (LPS)­induced acute lung injury (ALI), treatment with RTFs at 40, 80 and 160 mg/kg significantly reduced leukocyte infiltration, improved histopathological changes in lung tissues and decreased the LPS­induced production of several inflammatory mediators in the bronchoalveolar lavage fluid (BALF), which included the chemotatic factors, granulocyte colony­stimulating factor, monocyte inflammatory protein­1α and B­lymphocyte colony inflammatory cytokines, including interleukin (IL)­1ß, IL­6, IL­12p40 and tumor necrosis factor­α, in a dose­dependent manner. In addition, the expression of the Toll­like receptor 4 (TLR4)/myeloid differentiation factor­2 (MD­2) compound, the phosphorylation of p38 mitogen­activated protein kinase (p38MAPK), c­Jun N­terminal kinase (JNK) and nuclear transcription factor­κB (NF­κB), in addition to the DNA binding activity of NF­κB p65 in lung tissues, were all attenuated following RTF treatment. However, RTF treatment had no effect on extracellular signal­regulated kinase (ERK). In conclusion, RTFs contributed to the regulation of LPS­induced ALI through the TLR4/MD-2-mediated NF­κB, JNK and p38MAPK pathways. This may be a potential therapeutic option for the treatment of inflammatory diseases.

[Screening of Active Fractions from Huanglian Jiedu Decoction against Primary Neuron Injury after Oxygen-Glucose Deprivation].

OBJECTIVE: To observe the protective effect of active fractions of Huanglian Jiedu Decoction (HJD) on primary cortical neuron injury after oxygen-glucose deprivation (OGD)/reperfusion (R) injury. Methods Using macroporous resin method, HJDFE30, HJDFE50, HJDFE75, and HJDFE95 with 30%, 50%, 75%, and 95% alcohol were respectively prepared. Then the content of active components in different HJD fractions was determined with reverse phase high-performance liquid chromatography (RP-HPLC). The OGD/R injury model was induced by sodium dithionite on primary cortical neurons in neonate rats. MTT assay was used to observe the effect of four fractions (HJDFE30, HJDFE50, HJDFE75, and HJDFE95) and seven index components of HJD on the neuron viability. RESULTS: RP-HPLC showed active component(s) contained in HJDFE30 was geniposide; baicalin, palmatine, berberine, and wogonside contained in HJDFE50; baicalin, berberine, baicalein, and wogonin contained in HJDFE75. The neuron viability was decreased after OGD for 20 min and reperfusion for 1 h, (P <0. 01), and significantly increased after administered with HJD, HJDFE30, HJDFE50, and HJDFE75 (P <0. 05, P <0. 01). Geniposide, baicalin, baicalein, palmatine, wogonside, and wogonin could increase the cortical neuron viability (P <0. 05, P <0. 01). CONCLUSIONS: HJDFE30, HJDFE50, and HJDFE75, as active fractions of HJD, had protective effect on primary cortical neuron injury after OGD/R. Furthermore, geniposide, baicalin, and baicalein were main active components of HJD.

Distinct pro-apoptotic properties of Zhejiang saffron against human lung cancer via a caspase-8-9-3 cascade.

Lung cancer is the leading cause of cancer-related death worldwide. Here we investigated the antitumor effect and mechanism of Zhejiang (Huzhou and Jiande) saffron against lung cancer cell lines, A549 and H446. Using high performance liquid chromatography (HPLC), the contents of crocin I and II were determined. In vitro, MTT assay and annexin-V FITC/PI staining showed cell proliferation activity and apoptosis to be changed in a dose- and time-dependent manner. The inhibition effect of Jiande saffron was the strongest. In vivo, when mice were orally administered saffron extracts at dose of 100mg/kg/d for 28 days, xenograft tumor size was reduced, and ELISA and Western blotting analysis of caspase-3, -8 and -9 exhibited stronger expression and activity than in the control. In summary, saffron from Zhejiang has significant antitumor effects in vitro and in vivo through caspase-8-caspase-9-caspase-3 mediated cell apoptosis. It thus appears to have more potential as a therapeutic agent.

[Application of locomotor activity test to evaluate functional injury after global cerebral ischemia in C57BL/6 mice].

OBJECTIVE: To evaluate the application of locomotor activity test in functional injury after global cerebral ischemia (GCI) in C57BL/6 mice. METHODS: GCI was induced by bilateral carotid arteries occlusion for 30 min in C57BL/6 mice. Mice were divided into sham group, GCI group and minocycline group. Saline or minocycline (45 mg/kg) was i.p. injected once daily for 6 d after ischemia. At Day 6 after ischemia, locomotor activity was recorded for 1 h in open field test. Total distance, central distance, central distance ratio, periphery distance, periphery distance ratio, central time and periphery time were used to evaluate the behavior characteristics of locomotor activity in C57BL/6 mice after ischemia. The survival neuron density was detected by Nissl staining in hippocampus, cortex and striatum. RESULTS: Compared with sham group, total distance, central distance and central time increased and periphery time decreased in C57BL/6 mice after GCI (Ps<0.05). However, minocycline significantly reduced the central distance and central time and increased the periphery time (Ps<0.05). Neurons were damaged in hippocampus, cortex and striatum after GCI, which manifested by decreased neurons and the most serious damage in hippocampal CA1 region. Minocycline significantly improved the neuron appearance and increased the neuron number in hippocampus and striatum (P<0.001 or P<0.05). CONCLUSION: Locomotor activity in open field test can objectively evaluate the behavior injury after GCI in mice. Central distance and central time can be used as indexes of quantitative assessment.

[Influence of object material and inter-trial interval on novel object recognition test in mice].

OBJECTIVE: To investigate the efficacy of novel object recognition (NOR) test in assessment of learning and memory ability in ICR mice in different experimental conditions. METHODS: One hundred and thirty male ICR mice were randomly divided into 10 groups: 4 groups for different inter-trial intervals (ITI: 10 min, 90 min, 4 h, 24 h), 4 groups for different object materials (wood-wood, plastic-plastic, plastic-wood, wood-plastic) and 2 groups for repeated test (measured once a day or every 3 days, totally three times in each group). The locomotor tracks in the open field were recorded. The amount of time spent exploring the novel and familiar objects, the discrimination ratio (DR) and the discrimination index (DI) were analyzed. RESULTS: Compared with familiar object, DR and DI of novel object were both increased at ITI of 10 min and 90 min (P<0.01). Exploring time, DR and DI were greatly influenced by different object materials. DR and DI remained stable by using identical object material. NOR test could be done repeatedly in the same batch of mice. CONCLUSION: NOR test can be used to assess the learning and memory ability in mice at shorter ITI and with identical material. It can be done repeatedly.

[Comparison of behavioral effects of psychoactive drugs between two strains of mice].

OBJECTIVE: To compare the behavioral effects of psychoactive drugs between two strains of mice. METHODS: The Kunming (KM) and ICR mice were injected intraperitoneally with caffeine (3, 10, 30, 100 mg/kg), ephedrine (3, 10, 30, 100 mg/kg), diazepam (1, 3,1 0 mg/kg) and chloral hydrate (10, 30, 100 mg/kg), respectively. Ten min after injection, the locomotor activity in the open field was recorded for 2 h. The total distance, the distance ratio to total distance and the time in central region were analyzed for each drugs. Thirty min after injection, the latent time in the passive avoidance test was measured in a shuttle box. RESULTS: Caffeine and diazepam prolonged the latent time, and ephedrine and chloral hydrate decreased the latent time, but there were no differences between the two strains. The two strains of mice exhibited significant differences in the total distance after injection of ephedrine 10 mg/kg, diazepam 3 mg/kg and chloral hydrate 100 mg/kg. Compared to KM mice, ICR mice exhibited an increase in the distance ratio and the time in central region after injection of ephedrine 10-100 mg/kg, but a decrease after diazepam 3-10 mg/kg. CONCLUSION: KM and ICR mice show no differences in latent time, but significant differences in the total distance, the distance ratio and the time in central region in the locomotor activity. Therefore, selection of mouse strains is important in the study of psychoactive drugs.

[Protective effect of intranasal cilostazol administration on chronic injury after cerebral ischemia in mice].

OBJECTIVE: To investigate the protective effect of cilostazol administrated intranasally on chronic injury after focal cerebral ischemia in mice. METHODS: Focal cerebral ischemia in mice was induced by middle cerebral artery occlusion (MCAO). Cilostazol was administrated intranasally or intraperitoneally 1 h, 4 h and 7 h after the operation; then twice a day from the second day for 2 weeks. The neurological deficit scoring and the inclined board testing were performed within 35 d after ischemia. The survival rate, infarct volume and neuron density were assessed 35 d after ischemia. RESULT: Intranasal cilostazol at 0.3 mg/kg increased the survival rate. Intranasal cilostazol (0.3 mg/kg, 1 mg/kg) and intraperitoneal cilostazol (10 mg/kg) significantly attenuated neurological deficit, reduced infarct volume, and increased the survival neuron density in the border of ischemia region. CONCLUSION: Cilostazol administered intranasally demonstrates protective effects on chronic cerebral ischemia in mice.

Spatiotemporal properties of locomotor activity after administration of central nervous stimulants and sedatives in mice.

In the present study, we investigated the spatiotemporal properties of locomotor activity after administration of CNS sedatives (pentobarbital and diazepam) and stimulants (theophylline and caffeine) in an open field test. The absolute and relative distances traveled in central or peripheral regions within 2 h were analyzed. We found that both pentobarbital and diazepam increased total travel distances, especially within the initial 30 min, when traveling was mainly in the peripheral region. Pentobarbital induced this hyperactivity at higher doses (maximum at 30 mg/kg); while diazepam at higher doses (4 and 8 mg/kg) mainly decreased the traveled distance during 0-1 h but increased that in the periphery during 1-2 h. On the other hand, both theophylline and caffeine generally increased the traveled distance in the central region; this effect lasted longer with increasing dose. Caffeine increased the traveled distance at lower doses (maximum at 10 mg/kg) but decreased it at higher doses (30 and 100 mg/kg) during the initial 1 h. Theophylline exhibited a similar but smaller decrease at higher doses. Thus, we revealed the spatiotemporal properties that sedatives decrease central locomotion but induce a dose-related peripheral hyperactivity while stimulants induce central hyperactivity with a bell-shaped dose-response relation.

[Protective effects of Huanglian-Jiedu-Tang on chronic brain injury after focal cerebral ischemia in mice].

OBJECTIVE: To investigate the neuroprotective effects of Chinese herb medicine Huanglian-Jiedu-Tang (HJDT) on chronic brain injury after focal cerebral ischemia in mice. METHODS: Focal cerebral ischemia was induced by occlusion of right middle cerebral artery (MCA) for 15 min. HJDT (at dosage of 2 g/kg or 4 g/kg, qd, orally) was administered for 21 d from d 7 before ischemia until d 14 after ischemia. The sham and ischemic controls were administered with normal saline orally. The neurological deficit scoring and the inclined board testing were performed within 35 d after ischemia. The survival rate, the infarct volume and the neuron density were assessed 35 d after ischemia. RESULT: HJDT increased the survival rate at dose of 4 g/kg; significantly reduced the neurological deficits, infarct volume and cerebral atrophy at doses of 2 and 4 g/kg after ischemia; and significantly increased the neuron density in the ischemic hippocampal CA1 region, striatum and cortex at dose of 4 g/kg but only increase the density in hippocampal CA1 region at dose of 2 g/kg. CONCLUSION: Chinese herb medicine HJDT has neuroprotective effects on chronic brain injury after focal cerebral ischemia in mice.

[A skilled reaching test for evaluating long-term neurological deficits after focal cerebral ischemia in mice].

OBJECTIVE: To determine whether the skilled reaching test is an objective method for evaluating long-term neurological deficits after focal cerebral ischemia in mice. METHODS: In a reaching box, mice were trained to reach food pellets with their left forelimb through a 0.5 cm slit for 3 weeks. Then focal cerebral ischemia was induced by occluding the right middle cerebral artery, and the percentage of success in obtaining food was observed for 4 weeks. In comparison, the neurological deficit score, the holding angle in an inclined board test, and right turns in a corner test were simultaneously performed. At the end of the experiments, brain infarcts and neuron densities were determined. RESULT: After focal cerebral ischemia, the percentage of success in the reaching test was reduced, the right turns in the corner test were increased, the neurological deficit score was increased, and the holding angle in the inclined board test was reduced as well. The holding angle recovered 5 d after ischemia, whereas other 3 indicators remained abnormal until 4 weeks. At the end of the experiments, the brain infarct volumes were increased, and the neuron densities in the cortex, hippocampal CA1 region and striatum were reduced in ischemic mice. CONCLUSION: The skill reaching test is an objective and stable method for evaluating long-term neurological deficits after focal cerebral ischemia in mice.

Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic brain injuries.

Cilostazol, a selective inhibitor of phosphodiesterase 3, exerts neuroprotective effects on acute brain injury after cerebral ischemia in rats. However, it is unknown whether cilostazol affects the subacute or chronic ischemic injury. In the present study, we evaluated the dose- and time-dependent effects of cilostazol on acute ischemic brain injury and the long-lasting effect on the late (subacute/chronic) injury in mice with focal cerebral ischemia induced by transient middle cerebral artery occlusion. We found that pre-treatment of cilostazol (injected i.p. at 30 min before ischemia) significantly ameliorated the acute injury 24 h after ischemia, and the effective doses were 3-10 mg/kg. The post-treatment of cilostazol (10 mg/kg) was effective on the acute injury when it was injected 1 and 2 h after ischemia. In addition, for the late injury, post-treatment of cilostazol (10 mg/kg, i.p., for 7 consecutive days after ischemia) attenuated neurological dysfunctions, brain atrophy and infarct volume. It also inhibited astrocyte proliferation/glial scar formation and accelerated the angiogenesis in the ischemic boundary zone 7 and 28 days after ischemia. Thus, we conclude that cilostazol protects against not only the acute injury, but also the late injury in mice with focal cerebral ischemia; especially it can modify brain remodeling, astrogliosis and angiogenesis.

Cysteinyl leukotriene receptors CysLT1 and CysLT2 are upregulated in acute neuronal injury after focal cerebral ischemia in mice.

AIM: To determine whether cysteinyl leukotriene receptors (CysLT1 and CysLT2) are upregulated in acute neuronal injury after focal cerebral ischemia in mice, and to confirm CysLT1 receptor localization. METHODS: After permanent focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO), neurological deficits and neuron loss were determined at various time points within 48 h. The mRNA expressions of CysLT1 and CysLT2 receptors in the brain were analyzed by RT-PCR. CysLT1 receptor localization was detected by double immunofluorescence. RESULTS: Neurological deficits and neuron loss were found 6, 24 and 48 h after MCAO. The mRNA expressions of both CysLT1 and CysLT2 receptors were upregulated in the ischemic hemisphere 1, 24, and 48 h after MCAO with peaks at 24 h. The CysLT1 receptor was selectively localized in neurons 24 h after MCAO. CONCLUSION: CysLT1 and CysLT2 receptors are upregulated in acute neuronal injury after focal cerebral ischemia, and the CysLT1 receptor is localized in neurons after ischemia.

Caffeic acid ameliorates early and delayed brain injuries after focal cerebral ischemia in rats.

AIM: To investigate the effects of caffeic acid on early and delayed injuries after focal cerebral ischemia in rats, and the possible relation to 5-lipoxygenase inhibition. METHODS: Transient focal cerebral ischemia was induced by middle cerebral artery occlusion in Sprague-Dawley rats. Caffeic acid (10 and 50 mg/kg) was ip injected for 5 d after ischemia. The brain injuries were observed, and the levels of cysteinyl leukotrienes and leukotriene B4 in the brain tissue were measured. RESULTS: Caffeic acid (50 mg/kg) ameliorated neurological dysfunction and neuron loss, and decreased infarct volume 24 h after ischemia; it attenuated brain atrophy, infarct volume, and particularly astrocyte proliferation 14 d after ischemia. In addition, it reduced the production of leukotrienes (5-lipoxygenase metabolites) in the ischemic hemispheres 3 h and 7 d after ischemia. CONCLUSION: Caffeic acid has protective effect on both early and delayed injuries after focal cerebral ischemia in rats; and this effect may partly relate to 5-lipoxygenase inhibition.

[H2 receptor mediates the protective effect of histamine against the cellular edema and viability reduction induced by oxygen-glucose deprivation in rat hippocampal slices].

AIM: To determine the effect of histamine on ischemia-induced cellular edema and viability reduction in rat hippocampal slices, and the involved subtypes of histamine receptor in this effect. METHODS: In vitro ischemic injury of hippocampal slices was induced by oxygen-glucose deprivation (OGD). The slice injury was determined by real-timely measuring the changes of light transmittance (LT) for the cellular edema in CA1 region of the hippocampal slice, and by detecting the product of 2, 3, 5-triphenyltetrazolium chloride (TTC), formazan, for the slice viability. The effect of histamine at various concentrations on the slice injury was observed, and the blockage by antagonists of histamine receptors was also investigated. RESULTS: Histamine (0.01-10 micromol x L(-1)) inhibited the peak value of LT during OGD in hippocampal slices and improved the reduced viability after OGD. Diphenhydramine (0.1-10 micromol x L(-1)), an H1 receptor antagonist, did not affect the effect of histamine, while cimetidine (0.1-10 micromol x L(-1)), an H2 receptor antagonist, partly abolished the protective effect of histamine. CONCLUSION: Histamine protects hippocampal slices against ischemia-induced cellular edema and viability reduction; this effect might be mediated via, at least partly, H2 receptor.

Spatio-temporal properties of 5-lipoxygenase expression and activation in the brain after focal cerebral ischemia in rats.

The role of 5-lipoxygenase (5-LOX) in brain injury after cerebral ischemia has been reported; however, the spatio-temporal properties of 5-LOX expression and the enzymatic activation are unclear. To determine these properties, we observed post-ischemic 5-LOX changes from 3 h to 14 days after reperfusion in rats with transient focal cerebral ischemia induced by 30 min of middle cerebral artery occlusion. We found that the expression of 5-LOX, both mRNA and protein, was increased in the ischemic core 12-24 h after reperfusion, and in the boundary zone adjacent to the ischemic core 7-14 days after reperfusion. The increased 5-LOX was primarily localized in the neurons in the ischemic core at 24 h, but in the proliferated astrocytes in the boundary zone 14 days after reperfusion. As 5-LOX metabolites, the level of cysteinyl-leukotrienes in the ischemic brain was substantially increased 3 h to 24 h, near control at 3 days, and moderately increased again 7 days after reperfusion; whereas the level of LTB(4) was increased mildly 3 h but substantially 7-14 days after reperfusion. Thus, we conclude that 5-LOX expression and the enzymatic activity are increased after focal cerebral ischemia, and spatio-temporally involved in neuron injury in the acute phase and astrocyte proliferation in the late phase.