Opening the window: Ischemic postconditioning reduces the hyperemic response of delayed tissue plasminogen activator and extends its therapeutic time window in an embolic stroke model.

It has been reported that ischemic postconditioning (PC) changes the reperfusion pattern in permanent or transient models of stroke and confers neuroprotection. However, the effects of PC and subsequent use of tissue plasminogen activator (tPA) for the treatment of embolic stroke have not yet been investigated. Rats were subjected to stroke by injection of a preformed clot into the middle cerebral artery and randomly assigned to vehicle (saline 0.1 ml/100 g), tPA (3 mg/kg), PC only or PC+tPA (3 mg/kg). tPA was injected at 6 h after embolic stroke and PC was conducted at 6.5 h after ischemia by using five cycles of a 10 s occlusion and 30 s of reopening of the bilateral common carotid arteries. Cerebral blood flow (CBF) was monitored for 60 min from the time of tPA injection. Infarct size, blood brain barrier disruption, edema, neurological deficits, reactive oxygen species and apoptosis were measured 2 days later. PC decreased infarct volume, but PC+tPA was more neuroprotective than PC alone. While tPA alone dramatically increased CBF, conducting PC caused a gradual increase in CBF. A combination of PC+tPA reduced BBB leakage, brain edema, apoptosis and reactive oxygen species levels. Furthermore, a combination of PC+tPA improved neurological functions at 48 h after the induced stroke. In conclusion, PC hampered malignant hyperemia after reperfusion with tPA and extended its therapeutic window up to 6 h. Compared to PC alone, combination of thrombolysis and PC showed a better neuroprotection.

Ascorbic Acid Reduces the Adverse Effects of Delayed Administration of Tissue Plasminogen Activator in a Rat Stroke Model.

Delayed treatment of stroke with recombinant tissue plasminogen activator (r-tPA) induces overexpression of matrix metalloproteinase 9 (MMP-9) which leads to breakdown of the blood-brain barrier (BBB) and causes more injuries to the brain parenchyma. In this study, the effect of ascorbic acid (AA), an antioxidant agent, on the delayed administration of r-tPA in a rat model of permanent middle cerebral artery occlusion (MCAO) was investigated. Forty male rats were randomly divided into four groups: untreated control rats (ischaemic animals), AA-treated (500 mg/kg; 5 hr after stroke) rats, r-tPA-treated (5 hr after stroke 1 mg/kg) rats and rats treated with the combination of AA and r-tPA. Middle cerebral artery occlusion was induced by occluding the right middle cerebral artery (MCA). Infarct size, BBB, brain oedema and the levels of MMP-9 were measured at the end of study. Neurological deficits were evaluated at 24 and 48 hr after stroke. Compared to the control or r-tPA-treated animals, AA alone (p < 0.001) or in combination with r-tPA (p < 0.05) significantly decreased infarct volume. Ascorbic acid alone or r-tPA + AA significantly reduced BBB permeability (p < 0.05), levels of MMP-9 (p < 0.05 versus control; p < 0.01 versus r-tPA) and brain oedema (p < 0.001) when compared to either the control or the r-tPA-treated animals. Latency to the removal of sticky labels from the forepaw was also significantly decreased after the administration of AA + r-tPA (p < 0.05) at 24 or 48 hr after stroke. Based on our data, acute treatment with AA may be considered as a useful candidate to reduce the side effects of delayed application of r-tPA in stroke therapy.

Serum levels of interleukin (IL)-13, IL-17 and IL-18 in patients with ischemic heart disease.

OBJECTIVE: It has been reported that the cytokines play an important role in the pathogenesis of cardiovascular diseases. The aim of this study was to evaluate the serum levels of interleukin (IL)-13, IL-17 and IL-18 in patients with ischemic heart disease (IHD) and also to clarify their association with traditional risk factors of disease. METHODS: A total of 60 patients with IHD as having acute myocardial infarction (AMI; n=30) or unstable angina (UA; n=30) and 30 sex- and age- matched healthy subjects as a control group were enrolled to this cross-sectional, case-controlled study. Serum samples were collected from all participants (for AMI patients at 3-5 days after events and for UA at admission time) and tested for the IL-13, IL-17 and IL-18 by use of ELISA method. Statistical analysis was performed using ANOVA, Student t, Kruskal-Wallis, Mann-Whitney U and Chi-square tests as appropriate. RESULTS: The frequencies of subjects with detectable levels of IL-13 were 6.7%, 20% and 33.3% in AMI, UA and control groups, respectively. The frequency of subjects with detectable levels of IL-13 in control group was significantly higher as compared to AMI group and total group of patients with IHD (p<0.02 and p<0.05, respectively). The mean serum levels of IL-17 in AMI group (6.68+/- 1.2 pg/ml) and UA group (5.48+/- 1.01 pg/ml) were significantly higher than that observed in control group (2.07+/- 0.60 pg/ml; p<0.005 and p<0.04, respectively). Moreover, the mean serum levels of IL-18 in UA group (122.92+/- 18.16 pg/ml) were significantly higher than in control group (67.82+/- 5.98 pg/ml; p<0.03). The mean serum levels of IL-18 in IHD patients without a certain traditional risk factor including non-hypertensive patients (120.14+/- 17.04 pg/ml), non-dyslipidemic patients (131.86+/- 20.04 pg/ml), non-diabetic patients (111.96+/- 14.71 pg/ml) and non-smoker patients (113.93+/- 16.41 pg/ml) were significantly higher as compared to control group (p<0.04, p<0.004, p<0.03 and p<0.03, respectively). Although, the mean serum levels of IL-18 in patients with a certain traditional risk factor were higher in comparison to control group, but the differences were not significant. The means serum levels of IL-17 in patients with or without a certain traditional risk factor were also markedly higher as compared to healthy group. CONCLUSIONS: These results showed that the higher serum levels of IL-17 and IL-18 were associated with IHD. The presence or absence of a certain traditional risk factors of IHD may influence the serum levels of cytokines. These findings may be considered to improve the predictive or prognostic values of inflammatory cytokines for IHD and also to design possible novel therapeutic approaches.

High sensitivity C-reactive protein and immunoglobulin G against Chlamydia pneumoniae and chlamydial heat shock protein-60 in ischemic heart disease.

BACKGROUND: Inflammation and infectious agents such as Chlamydia pneumoniae have been associated with cardiovascular disease. OBJECTIVE: To evaluate the serum high sensitivity C-reactive protein (hs-CRP) and antibodies against Chlamydia pneumoniae and Chlamydial heat shock protein-60 (Cp-HSP-60) in patients with ischemic heart disease (IHD). METHODS: 62 patients with IHD having either acute myocardial infarction (AMI; n=31) or unstable angina (UA; n=31) and 31 sex- and age- matched healthy subjects as a control group were enrolled in this study. Serum samples of participants were tested for the presence of hs-CRP and antibodies against C. pneumoniae and Cp-HSP-60 using ELISA method. RESULTS: The seroprevalence of anti-C. pneumoniae antibody in AMI group (93.5%) or UA group (90.3%) was significantly higher than the control group (61.3%; p<0.001). The seroprevalence of anti-Cp-HSP60 IgG was 22.6% in healthy subjects with mean end titer of 43.1+/-6.32. The seropositive rates of anti-Cp-HSP60 were 48.4%, 54.8% and 51.6% in AMI, UA and the overall IHD groups with mean end titers of 94+/-22.86, 113.8+/-24.25 and 103.9+/-16.57, respectively. Both the seroprevalence and the mean titer of anti-Cp-HSP60 in patients groups were significantly higher than those observed in the control group (p<0.04 and p<0.03, respectively). Moreover, the mean serum hs-CRP levels was significantly higher in the IHD group as compared to the control group (21.6 microg/ml+/-3.73 vs 2.5 microg/ml+/-0.52; p<0.00001). The mean serum hs-CRP levels of AMI (30.3 microg/ml+/-6.07) or UA (12.9 microg/ml+/-3.85) groups were also significantly higher than those observed in the control group (p<0.00001 and p<0.001, respectively). Furthermore, the difference of the mean serum hs-CRP levels between AMI and UA groups was also significant (p<0.02). CONCLUSIONS: These results showed that the seroprevalence of antibodies against C. pneumoniae and Cp-HSP-60 and the serum levels of hs-CRP and anti-Cp-HSP60 IgG were higher in patients with IHD.