Dae-Il Chang

The effect of PARP inhibitor on ischaemic cell death, its related inflammation and survival signals

Poly(ADP‐ribose) polymerase (PARP) plays an important role in ischaemic cell death, and 3‐aminobenzamide (3‐AB), one of the PARP inhibitors, has a protective effect on ischaemic stroke. We investigated the neuroprotective mechanisms of 3‐AB in ischaemic stroke. The occlusion of middle cerebral artery (MCA) was made in 170 Sprague–Dawley rats, and reperfusion was performed 2 h after the occlusion. Another 10 Sprague–Dawley rats were used for sham operation. 3‐AB was administered to 85 rats 10 min before the occlusion [3‐AB group (n = 85) vs. control group without 3‐AB (n = 85)]. Infarct volume and water content were measured, brain magnetic resonance imaging, terminal deoxynucleotidyltransferase (TdT)‐mediated dUTP‐biotin nick end‐labelling (TUNEL) and Cresyl violet staining were performed, and immunoreactivities (IRs) of poly(ADP‐ribose) polymer (PAR), cleaved caspase‐3, CD11b, intercellular adhesion molecule‐1 (ICAM‐1), cyclooxygenase‐2 (COX‐2), phospho‐Akt (pAkt) and phospho‐glycogen synthase kinase‐3 (pGSK‐3) were compared in the peri‐infarcted region of the 3‐AB group and its corresponding ischaemic region of the control group at 2, 8, 24 and 72 h after the occlusion. In the 3‐AB group, the infarct volume and the water content were decreased (about 45% and 3.6%, respectively, at 24 h), the number of TUNEL‐positive cells was decreased (about 36% at 24 h), and the IRs of PAR, cleaved caspase‐3, CD11b, ICAM‐1 and COX‐2 were significantly reduced, while the IRs of pAkt and pGSK‐3 were increased. These results suggest that 3‐AB treatment could reduce the infarct volume by reducing ischaemic cell death, its related inflammation and increasing survival signals. The inhibition of PARP could be another potential neuroprotective strategy in ischaemic stroke.

Plaque Rupture is a Determinant of Vascular Events in Carotid Artery Atherosclerotic Disease: Involvement of Matrix Metalloproteinases 2 and 9

Background and Purpose Unstable carotid atherosclerotic plaques are characterized by cap rupture, leading to thromboembolism and stroke. Matrix metalloproteinases (MMPs) have been implicated in the progression of atherosclerosis and plaque rupture. The aim of this study was to assess the relationship between the expressions of MMP-2 and MMP-9 and carotid plaque instability. Methods Eighty atherosclerotic plaques were collected from 74 patients undergoing carotid endarterectomy. Clinical information was obtained from each patient, and plaque morphology was examined at the macroscopic and microscopic levels. The immunohistochemical expressions of MMPs were graded using semiquantitative scales. Results Macroscopic ulceration (84.6% versus 63.4%, p=0.042) and microscopic cap rupture (79.5% versus 51.2%, p=0.010) were more common in symptomatic than in asymptomatic patients. Immunoreactivities of MMP-2 and MMP-9 were increased in 40 and 36 atheromatous plaques, respectively. Macroscopic ulceration was strongly correlated with the expressions of MMP-2 (p<0.001) and MMP-9 (p=0.001). There were significant correlations between increased MMP-2 expression and cap rupture (p=0.002), intraplaque hemorrhage (p=0.039), and a thin fibrous cap (p=0.002), and between increased MMP-9 expression and cap rupture (p=0.010) and a large lipid core (p=0.013). Conclusions Plaque rupture was significantly associated with the development of vascular events in carotid atherosclerotic disease. MMP-2 and MMP-9 are strongly correlated with plaque instability.

Parsing brain activity associated with acupuncture treatment in Parkinson's diseases

Acupuncture, a common treatment modality within complementary and alternative medicine, has been widely used for Parkinsons disease (PD). Using functional magnetic resonance imaging (fMRI), we explored the neural mechanisms underlying the effect of specific and genuine acupuncture treatment on the motor function in patients with PD. Three fMRI scans were performed in random order in a block design, one for verum acupuncture (VA) treatment, another one for a covert placebo (CP), and the third one for an overt placebo (OP) at the motor function implicated acupoint GB34 on the left foot of 10 patients with PD. We calculated the contrast that subtracts the blood‐oxygen‐level dependent (BOLD) response for the acupuncture effect (VA vs. CP) and the placebo effect (CP vs. OP). We found a significant improvement in the motor function of the affected hand after acupuncture treatment. The putamen and the primary motor cortex were activated when patients with PD received the acupuncture treatment (VA vs. CP) and these activations correlated with individual enhanced motor function. Expectation towards acupuncture modality (CP vs. OP) elicited activation over the anterior cingulate gyrus, the superior frontal gyrus, and the superior temporal gyrus. These findings suggest that acupuncture treatment might facilitate improvement in the motor functioning of patients with PD via the basal ganglia‐thalamocortical circuit.

Inhibition of GSK-3 reduces infarct volume and improves neurobehavioral functions

In the present study, we have investigated the effects of glycogen synthase kinase-3 (GSK-3) inhibition on infarct volume and neurobehavioral functions in a focal cerebral ischemia model. To achieve our goals, GSK-3 inhibitor II or VIII was injected at several time points and in varing dosages. GSK-3 inhibitor VIII was more effective than inhibitor II, and infarct volume and water content in the VIII group were significantly decreased 24h after the onset of ischemic stroke, as compared with the control group. These protective effects were associated with reductions of TUNEL-positive cells, neutrophil infiltration, glucose levels after ischemia, and GSK-3 enzyme activity. In addition, expressions of death and inflammation-related signals decreased and those of survival-related signals increased. Lastly, neurobehavioral functions were restored to a greater extent in the VIII group than in the control group. Together, these results suggest that GSK-3 inhibition reduces infarct volume and restores neurobehavioral functions.

The advantage of high-resolution MRI in evaluating basilar plaques: A comparison study with MRA

OBJECTIVE Intracranial atherosclerosis (ICAS) is a major cause of ischemic stroke; however it is rather neglected. Vessel wall visualization by high resolution magnetic resonance imaging (HRMRI) might provide more accurate information. METHODS A total of 219 consecutive patients with acute ischemic stroke underwent MRI, MRA and proton-density weighted HRMRI. Using HRMRI, the patients were divided into 3 groups with respect to basilar plaques: no plaque (n = 85), minimal plaque (n = 72) and apparent plaque (n = 62). Demographics and characteristics were compared between the groups, and the extents of stenoses calculated from MRA versus HRMRI data were also compared. Factors potentially associated with basilar plaque were validated by multivariate analysis. RESULTS Patients with apparent plaque had higher frequencies of diabetes mellitus, lower high-density lipoprotein and higher hemoglobin A1c, erythrocyte sedimentation rate and homocysteine. Of the 62 cases of apparent plaque, severe stenosis (>50%) was observed in 10 (16%) by MRA and in 27 (43%) by HRMRI, which points to overestimation of plaques by HRMRI. In addition, no stenosis was evident on MRA in 13 patients with apparent plaque even though they had up to 72% stenosis on HRMRI. After adjusting for covariates, basilar artery apparent plaque was independently associated with old age, previous stroke, diabetes mellitus, low HDL and high levels of homocysteine. CONCLUSIONS Basilar artery stenosis with plaque is more accurately detected using HRMRI than MRA. In addition, the associated risk factors differ somewhat. The use of HRMRI for evaluating ICAS deserves more attention.

The Role of Matrix Metalloproteinase 9 in Early Neurological Worsening of Acute Lacunar Infarction

The involvement of matrix metalloproteinases (MMPs) in ischemic-stroke-induced inflammatory response has recently been suggested; however, the relationship between MMPs and stroke progression has not been evaluated. We investigated the role of MMPs in neurological worsening of acute lacunar infarction. Forty-nine consecutive patients with an acute lacunar infarction (as defined by clinical and MRI criteria within 48 h after stroke onset) were evaluated. Clinical, biochemical, rheological, inflammatory and other parameters were compared between progressive and nonprogressive groups. Among the variables, only inflammatory parameters, including MMP-9 and erythrocyte sedimentation rate, were associated with neurological worsening of acute lacunar infarction (p < 0.05). These results suggest that the inflammatory process could play an important role in early neurological worsening of acute lacunar infarction.

Microbleeds and free active MMP-9 are independent risk factors for neurological deterioration in acute lacunar stroke.

Background and purpose:  In this prospective study, we evaluated mutual relationships amongst microbleeds, matrix metalloproteinase‐9 (MMP‐9) and neurological deterioration in patients with their first acute lacunar stroke.

Efficacy of early administration of escitalopram on depressive and emotional symptoms and neurological dysfunction after stroke: a multicentre, double-blind, randomised, placebo-controlled study.

BACKGROUND Mood and emotional disturbances are common in patients with stroke, and adversely affect the clinical outcome. We aimed to evaluate the efficacy of early administration of escitalopram to reduce moderate or severe depressive symptoms and improve emotional and neurological dysfunction in patients with stroke. METHODS This was a placebo controlled, double-blind trial done at 17 centres in South Korea. Patients who had had an acute stroke within the past 21 days were randomly assigned in a 1:1 ratio to receive oral escitalopram (10 mg/day) or placebo for 3 months. Randomisation was done with permuted blocks stratified by centre, via a web-based system. The primary endpoint was the frequency of moderate or severe depressive symptoms (Montgomery-Åsberg Depression Rating Scale [MADRS] ≥16). Endpoints were assessed at 3 months after randomisation in the full analysis set (patients who took study medication and underwent assessment of primary endpoint after randomisation), in all patients who were enrolled and randomly assigned (intention to treat), and in all patients who completed the trial (per-protocol analysis). This trial is registered with ClinicalTrials.gov, number NCT01278498. FINDINGS Between Jan 27, 2011, and June 30, 2014, 478 patients were assigned to placebo (n=237) or escitalopram (n=241); 405 were included in the full analysis set (195 in the placebo group, 210 in the escitalopram group). The primary outcome did not differ by study group in the full analysis set (25 [13%] patients in the placebo group vs 27 [13%] in the escitalopram group; odds ratio [OR] 1·00, 95% CI 0·56-1·80; p>0·99) or in the intention-to-treat analysis (34 [14%] vs 35 [15%]; OR 1·01, 95% CI 0·61-1·69, p=0·96). The study medication was generally well tolerated; the most common adverse events were constipation (14 [6%] patients who received placebo vs 14 [6%] who received escitalopram), muscle pain (16 [7%] vs ten [4%]), and insomnia (12 [5%] vs 12 [5%]). Diarrhoea was more common in the escitalopram group (nine [4%] patients) than in the placebo group (two [1%] patients). INTERPRETATION Escitalopram did not significantly reduce moderate or severe depressive symptoms in patients with acute stroke. FUNDING Dong-A Pharmaceutical and Ministry for Health, Welfare, and Family Affairs, South Korea.

Amnesic syndrome in a mammillothalamic tract infarction.

It is controversial whether isolated lesions of mammillothalamic tract (MTT) produce significant amnesia. Since the MTT is small and adjacent to several important structures for memory, amnesia associated with isolated MTT infarction has been rarely reported. We report a patient who developed amnesia following an infarction of the left MTT that spared adjacent memory-related structures including the anterior thalamic nucleus. The patients memory deficit was characterized by a severe anterograde encoding deficit and retrograde amnesia with a temporal gradient. In contrast, he did not show either frontal executive dysfunction or personality change that is frequently recognized in the anterior or medial thalamic lesion. We postulate that an amnesic syndrome can develop following discrete lesions of the MTT.

Effects of Uric Acid Levels on Outcome in Severe Ischemic Stroke Patients Treated with Intravenous Recombinant Tissue Plasminogen Activator

Uric acid (UA) has been known to be a neuroprotective antioxidant because of its free radical scavenger activity. We studied the influence of UA in patients with acute ischemic stroke after thrombolytic therapy. Two hundred eighteen consecutive patients treated with intravenous thrombolysis were included in this analysis. We analyzed the relationship between serum UA levels obtained at the emergency department and clinical outcomes. Early improvement and excellent functional outcomes were measured using the National Institutes of Health Stroke Scale (NIHSS) 24 h after onset and the modified Rankin scale after 3 months. There was no significant relationship between serum UA levels and early improvement or excellent functional outcome in the total patients (p = 0.583 and p = 0.082, respectively). However, in patients with severe baseline stroke deficits (NIHSS score ≥15), higher-tertile UA levels were significantly associated with excellent functional outcomes (p = 0.003). Excellent functional outcomes in patients with severe baseline disability might have a significant association with serum UA levels particularly in men but not in women (p = 0.007 in men and p = 0.621 in women). Increased serum UA levels might be associated with better outcomes in ischemic stroke patients treated with intravenous thrombolysis, but the effectiveness of UA can differ by initial stroke severity and gender.