Neurological complications of coronary artery bypass graft surgery: six month follow-up study.

As part of a major prospective study of the neurological complications of coronary artery bypass graft surgery patients were reviewed over six months to determine the clinical course and functional impact of early postoperative complications. One hundred and ninety one out of 312 (61%) patients had developed early postoperative disorders. At six months 165 of the 191 patients with early neurological complications were reviewed. Of the 165, 85 still had detectable neurological signs, but these were often minor and of little functional importance. Only 10 patients had neurological disability at six months, and this was major in only four patients, all of whom had suffered major perioperative stroke. No patient with non-disabling neurological complications in hospital became functionally impaired on returning home. Neurological disorders are not a major cause of failure to return to work by six months after coronary artery bypass surgery. Of 139 patients who were of working age and had not returned to work by six months, only four were prevented by neurological injury related to surgery. The long term prognosis for early neurological disorders after coronary artery bypass surgery is usually favourable, except in those patients who have sustained major perioperative stroke.     

重型颅脑外伤致脑疝患者的临床救治体会

目的:探讨重型颅脑外伤致脑疝的临床救治方法并总结救治体会,以提高重型颅脑外伤致脑疝患者的临床救治水平,提高其生存率。方法:回顾性分析2006年1月～2011年12月年收治的220例重型颅脑外伤致脑疝的患者的临床资料,探讨综合性救治措施对重型颅脑外伤致脑疝患者的临床意义。结果:根据格拉斯哥预后评分(GOS)评价全组预后:45例恢复良好(20.5%),34例中残(15.5%),41例重残(18.6%),25例植物生存(11.4%),75例死亡(34.1%),其中7例术中死亡,28例术后死于感染、消化道出血及多器官功能衰竭等严重并发症,40例死于脑损伤及继发脑功能严重衰竭。结论:颅脑外伤致脑疝患者致死率高,预后差,采取术前、术中、术后的综合救治措施,可显著提高患者生存率及改善预后。     

Neurotrophin-3, TNF-alpha and IL-6 relations in serum and cerebrospinal fluid of ischemic stroke patients

Pro-inflammatory cytokines and neurotrophins in the central nervous system (CNS) have been recognized as mediators of both neurodegenerative and neuroprotective mechanisms in a number of CNS pathologies. A rapid, sustained elevation of these molecules was recently reported after traumatic and ischemic brain injury. Inflammatory mechanisms and immune activation have been hypothesized to play a role in the pathogenesis of cerebral ischemia. Stroke is the third largest cause of death next to heart disease and cancer in the world, and it is an important cause of death and disability in developed countries. Role of excitatory amino acids receptors activation, calcium overload, nitric oxide and oxidative stress in the pathogenesis of ischemic brain damage is well established. Stroke may modulate peripheral neurotrophic factors levels. In experimental animal models, neurotrophin-3 (NT-3) has been shown to be produced by glial cells as an adaptability response to hypoxia. In spite of substantial research and significant number of neuroprotective drugs that have been developed to limit ischemic brain damage and to improve the outcome for stroke patients, no specific therapy for stroke is available. The neurotrophins have been proposed as therapeutic agents for the treatment of neurodegenerative disorders and ischemic injury. In the present work, we investigated the possible correlation of NT-3 with tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the serum and cerebrospinal fluid (CSF) from patients with ischemic stroke (IS).     

CAS和CEA治疗颈内动脉重度狭窄疗效及对脑血流量、血清miR-145、IGF1R的影响

目的:探讨颈动脉支架植入术(CAS)和颈动脉内膜剥脱术(CEA)治疗颈内动脉重度狭窄疗效及对脑血流量、血清miR-145、胰岛素样生长因子1受体(IGF1R)的影响。方法:回顾性分析2018年1月至2019年12月我院收治的100例颈动脉重度狭窄患者的临床资料,按照手术方式不同分为A组和B组,每组50例,A组给予CAS治疗,B组给予CEA治疗。比较两组围术期情况、脑血流量、血清miR-145、IGF1R、简易精神状态检查表(MMSE)量表、蒙特利尔认知评估量表(MoCA)的变化,并比较术后并发症、再狭窄率及死亡率。结果:两组患者手术时间、术中失血量、术后机械通气时间、ICU停留时间、住院时间比较,差异无统计学意义(P>0.05);术后3个月时,两组脑血流量指标相对达峰时间(rTTP)、相对平均通过时间(rMTT)、相对脑血容量(rCBV)、相对脑血流量(rCBE)、血清miR-145、IGF1R、MMSE量表、MoCA量表评分比较差异均无统计学意义(P>0.05);术后30 d内,两组心动过缓、心肌酶谱升高、高灌注综合征、局部血肿、颈动脉急性闭塞比较差异无统计学意义(P>0.05),A组脑卒中、低血压发生率明显高于B组,B组高血压发生率明显高于A组(P<0.05);术后1年时,两组患者死亡率、再狭窄率比较差异无统计学意义(P>0.05)。结论:CAS和CEA治疗颈内动脉重度狭窄患者的疗效相似,均可有效改善脑血流量,调节血清miR-145、IGF1R水平的表达,促进认知功能恢复,但CAS术后脑卒中、低血压发生率更高,CEA术后高血压发生率更高。     

Mitochondrial respiratory chain and free radical generation in stroke

Being the second most common cause of death in the industrial countries and one of the major causes of death and disability, stroke has a great effect on public health and is the neurological disease which accounts for the largest number of hospitalizations. In order to develop new treatments, biochemical mechanisms involved in brain damage have been investigated. Among them, oxidant species generated during stroke have been implicated as critical mediators of neuronal injury in this condition, although neuroprotective roles have also been demonstrated. This review is focused on the role of the mitochondrial respiratory chain as both source and target of reactive oxygen and nitrogen species such as nitric oxide, superoxide and peroxynitrite produced in cerebral ischemia. The neuroprotective role of antioxidants or other molecules acting on the mitochondrial respiratory chain and ATP synthesis in the setting of cerebral ischemia is discussed.     

Metabolic characterization of neurological diseases by proton localized NMR spectroscopy of the human brain.

Proton localized Magnetic Resonance Spectroscopy (MRS) of the brain allows the non invasive detection of intracellular cerebral metabolites. Localized MRS has been performed using short stimulated-echo times in various neurological diseases including stroke, multiple sclerosis, and AIDS-related leukoencephalopathies. Principal component analysis (PCA) was used to determine the critical parameters defining the metabolic profile of normal and diseased brain. PCA clearly differentiates the demyelinating processes from ischaemic lesions and leukoencephalopathies. Localized MRS of the brain appears growingly as a tool of choice to discriminate, quantitate and assess cerebral metabolic damage in patients with neurological disorders.     

The Predictive Value of the Boston Acute Stroke Imaging Scale (BASIS) in Acute Ischemic Stroke Patients among Chinese Population

Objective

Evaluate the predictive value of Boston Acute Stroke Imaging Scale (BASIS) in acute ischemic stroke in Chinese population.

Methods

This was a retrospective study. 566 patients of acute ischemic stroke were classified as having a major stroke or minor stroke based on BASIS. We compared short-term outcome (death, occurrence of complications, admission to intensive care unit [ICU] or neurological intensive care unit [NICU]), long-term outcome (death, recurrence of stroke, myocardial infarction, modified Rankin scale) and economic index including in-hospital cost and length of hospitalization. Continuous variables were compared by using the Student t test or Kruskal-Wallis test. Categorical variables were tested with the Chisquare test. Cox regression analysis was applied to identify whether BASIS was the independent predictive variable of death.

Results

During hospitalization, 9 patients (4.6%) died in major stroke group while no patients died in minor stroke group (p<0.001), 12 patients in the major stroke group and 5 patients in minor stroke group were admitted to ICU/NICU (p = 0.001). There were more complications (cerebral hernia, pneumonia, urinary tract infection) in major stroke group than minor stroke group (p<0.05). Meanwhile, the average cost of hospitalization in major stroke group was 3,100 US$ and 1,740 US$ in minor stroke group (p<0.001); the average length of stay in major and minor stroke group was 21.3 days and 17.3 days respectively (p<0.001). Results of the follow-up showed that 52 patients (26.7%) died in major stroke group while 56 patients (15.1%) died in minor stroke group (P<0.001). 62.2% of the patients in major stroke group and 80.4% of the patients in minor stroke group were able to live independently (P = 0.002). The survival analysis showed that patients with major stroke had 80% higher of risk of death than patients with minor stroke even after adjusting traditional atherosclerotic factors and NIHSS at baseline (HR = 1.8, 95% CI: 1.1–3.1).

Conclusion

BASIS can predict in-hospital mortality, occurrence of complication, length of stay and hospitalization cost of the acute ischemic stroke patients and can also estimate the long term outcome (death and the dependency). BASIS could and should be used as a dichotomous stroke classification system in the daily practice.     

Perioperative and early postoperative neurological deficit in older patients during carotid artery thrombendarterectomy

Cerebrovascular accidents, strokes in particular, are among the most frequent causes of death today in developed countries. In the last two decades, stroke was the second most frequent cause of death in Primorsko-Goranska Region in Croatia. In older patients, individuals older than 65 years of age have an increased risk of stroke, mainly because the degree of carotid artery stenosis increases with age. The most frequent complication of the high percent stenosis of the carotid arteries is thrombosis in the area of atherosclerotic changes of blood vessels. With the increase in the age of the population, there is also an increase in the number of risk factors of cerebrovascular accident. Doppler ultrasound sonography and Multi Slice CT scans have the most prominent role in the early detection of atherosclerotic changes and in the assessment of the degree of carotid artery narrowing. Today, in Croatia as well as worldwide, thrombendarterectomy holds the most important place in stroke prevention. Between 2006 and 2009, 209 patients underwent surgical intervention at the Clinical Hospital Center in Rijeka for high degree of carotid artery narrowing. In the group younger than 65 years of age, which consisted of 53 patients, a neurological deficit was noted in 4 patients (7.54%) in the perioperative and early postoperative course. In the group of individuals older than 65 years of age, which consisted of 156 patients, a neurological deficit was noted in 9 patients (5.76%). There was no significant statistical difference in the incidence of neurological deficit, nor in the mortality in individuals older than 65 years of age during carotid arteries thrombendarterectomy.     

Neuron Specific Enolase and C-reactive Protein Levels in Stroke and Its Subtypes: Correlation with Degree of Disability

Stroke is an emergency which threatens life and third leading cause of death and long term disability in developed countries. The use of biomarkers in diagnosing stroke and assessing prognosis is an emerging and rapidly evolving field. The study aimed to investigate the predictive value of biochemical marker of brain damage neuron-specific enolase (NSE) and systemic inflammatory marker C-reactive protein (CRP) with respect to degree of disability at the time of admission and short term in stroke patients. We investigated 120 patients with cerebrovascular stroke who were admitted within 72 h of onset of stroke in the Department of Neurology at Sri Aurobindo Institute of Medical Sciences, Indore, India. NSE and CRP were analyzed by solid enzyme linked immunosorbent assay using analyzer and micro plate reader from Biorad 680. In all patients, the neurological status was evaluated by a standardized neurological examination and the National Institutes of Health Stroke Scale on admission and on day 7. Serum NSE and CRP concentration were found significantly increased in acute stroke cases as compared to control in present study (<0.05 and <0.001 respectively). The maximum serum NSE and CRP levels within 72 h of admission were significantly higher in patients with greater degree of disability at the time of admission. Both biomarkers were found significantly correlated with neurological disability and short term outcome. Our study showed that serum biomarkers NSE and CRP have high predictive value for determining severity and early neurobehavioral outcome after acute stroke.     

Ischemic stroke incidence in Santa Coloma de Gramenet (ISISCOG), Spain. A community-based study

Background

In Spain, stroke is one of the major causes of death and the main cause of severe disability in people over 65 years. We analyzed the incidence of ischemic stroke, stroke subtypes, case fatality and disability at 90 days after the event in a Spanish population.

Methods

A prospective community-based register of ischemic strokes was established in Santa Coloma de Gramenet (Barcelona) [116,220 inhabitants of all ages, according to the municipal census of December 31,2001], from January 1 to December 31, 2003.Standard definitions and case finding methods were used to identify all cases in all age groups. Every patient underwent a complete clinical evaluation and systematic tests including neuroimaging (CT/MRI) and vascular studies (carotid duplex ultrasound intra and extracranial and MR angiography).

Results

Over a one year period, 196 ischemic strokes were registered [107 men; median age = 76 years (range 39–98)], being the first event in 159 patients (81.1%) and a recurrent stroke in 37 (18.9%). After age-adjustment to the European population, the incidence of ischemic stroke per 100,000 inhabitants was 172 (95% CI, 148–196); 219 (176–261) in men and 133 (105–160) in women, with an annual incidence for first ischemic stroke of 139 (118–161); 165 (128–201) in men and 115 (89–140) in women. The incidence of stroke increased with age.Stroke subtypes (TOAST classification criteria) were lacunar in 28.8%, atherothrombotic in 18.6%, cardioembolic in 26.6% and undetermined in 26.0% of patients. At 90 days, the case-fatality was 12%, and among survivors, moderate-to-severe disability was present in 45 % at 3 months.

Conclusion

This prospective community-based study shows one of the lowest incidences of stroke in Europe, as well as one of the lowest case fatality and disability rates at 90 days after stroke.

     

Macrophage migration inhibitory factor (MIF) acetylation protects neurons from ischemic injury

Ischemia-induced neuronal death leads to serious lifelong neurological deficits in ischemic stroke patients. Histone deacetylase 6 (HDAC6) is a promising target for neuroprotection in many neurological disorders, including ischemic stroke. However, the mechanism by which HDAC6 inhibition protects neurons after ischemic stroke remains unclear. Here, we discovered that genetic ablation or pharmacological inhibition of HDAC6 reduced brain injury after ischemic stroke by increasing macrophage migration inhibitory factor (MIF) acetylation. Mass spectrum analysis and biochemical results revealed that HDAC6 inhibitor or aspirin treatment promoted MIF acetylation on the K78 residue. MIF K78 acetylation suppressed the interaction between MIF and AIF, which impaired MIF translocation to the nucleus in ischemic cortical neurons. Moreover, neuronal DNA fragmentation and neuronal death were impaired in the cortex after ischemia in MIF K78Q mutant mice. Our results indicate that the neuroprotective effect of HDAC6 inhibition and aspirin treatment results from MIF K78 acetylation; thus, MIF K78 acetylation may be a therapeutic target for ischemic stroke and other neurological diseases.Subject terms: Cell death in the nervous system, Stroke     

The lightning heart: a case report and brief review of the cardiovascular complications of lightning injury

Lightning strike is a rare natural phenomenon, which carries a risk of dramatic medical complications to multiple organ systems and a high risk of fatality. The known complications include but are not limited to: myocardial infarction, arrhythmia, cardiac contusion, stroke, cutaneous burns, respiratory disorders, neurological disorders, acute kidney injury and death. We report a case of a healthy young man who suffered a lightning injury and discuss the cardiovascular complications of lightning injury, ranging from ECG changes to death. The patient in our case, a 27-year old previously healthy male, developed a syndrome of rhabdomyolysis and symptomatic cardiogenic pulmonary edema. Electrocardiographic findings included transient T-wave inversions, late transition shift and long QT. His clinical condition improved with supportive measures.Early recognition of lightning injury syndromes and anticipation of complications may help us improve outcomes for these patients. Evaluation of patients having experienced a lightning injury should include a minimum of a detailed history and physical examination, 12-lead ECG and drawing of baseline troponins. Prolonged electrocardiographical monitoring (for monitoring of ventricular arrhythmias) and assessment for signs and symptoms of hemodynamic compromise may be warranted.     

Atrial fibrillation and stroke: prevalence in different types of stroke and influence on early and long term prognosis (Oxfordshire community stroke project)

OBJECTIVE--To determine in patients with first ever stroke whether atrial fibrillation influences clinical features, the need to perform computed tomography, and prognosis. DESIGN--Observational cohort study with maximum follow up of 6.5 years. SETTING--Primary care, based on 10 general practices in urban and rural Oxfordshire. SUBJECTS--Consecutive series of 675 patients with first ever stroke registered in the Oxfordshire community stroke project. MAIN OUTCOME MEASURES--Prevalence of atrial fibrillation by type of stroke; effect of atrial fibrillation on case fatality rate and risk of recurrent stroke, vascular death, and death from all causes. RESULTS--Prevalence of atrial fibrillation was 17% (95% confidence interval 14% to 20%) for all stroke types (115/675), 18% (15% to 21%) for cerebral infarction (97/545), 11% (4% to 11%) for primary intercerebral haemorrhage (7/66), and 0% (0 to 11%) for subarachnoid haemorrhage (0/33). For patients with cerebral infarction the 30 day case fatality rate was significantly higher with atrial fibrillation (23%) than with sinus rhythm (8%); the risk of early recurrent stroke (within 30 days) was 1% with atrial fibrillation and 4% with sinus rhythm. In patients who survived at least 30 days the average annual risk of recurrent stroke was 8.2% (5.9% to 10.9%) with sinus rhythm and 11% (6.0% to 17.3%) with atrial fibrillation. CONCLUSIONS--After a first stroke atrial fibrillation was not associated with a definite excess risk of recurrent stroke, either within 30 days or within the first few years. Survivors with and without atrial fibrillation had a clinically important absolute risk of further serious vascular events.     

微血管减压术治疗面肌痉挛术后相关并发症的临床分析

目的:总结面肌痉挛患者的术后并发症的发生情况并分析其原因。方法:回顾性分析了1548名在我院行微血管减压术治疗面肌痉挛的患者的临床资料,所有患者接受电话随访或者门诊随访,随访时间均超过2年,总结其临床疗效及术后并发症的发生情况。结果:微血管减压术后痊愈率及明显缓解率分别为92.5%及4.2%。249名(16.09%)患者出现不同的并发症,其中最常见的并发症为面瘫及术后手术区域皮肤感觉障碍,无死亡及重大并发症患者。听力损害发生率为3.5%。其他并发症包括脑脊液漏、后组颅神经损伤、外展神经损伤、颅内出血等。结论:微血管减压术是治疗面肌痉挛的安全有效操作,以手术区域感觉障碍及迟发性面瘫是主要的并发症,持久性的或者严重的并发症比较少见。     

Edaravone ameliorates oxidative stress associated cholinergic dysfunction and limits apoptotic response following focal cerebral ischemia in rat

Stroke is a life-threatening disease with major cause of mortality and morbidity worldwide. The neuronal damage following cerebral ischemia is a serious risk to stroke patients. Oxidative stress and apoptotic damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. The objective of this study was to test the hypothesis that administration of edaravone (Edv) maintains antioxidant status in brain, improves the cholinergic dysfunction and suppresses the progression of apoptosis response in rat. To test this hypothesis, male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) of 2 h followed by reperfusion for 22 h. Edv was administered (10 mg/kg bwt) intraperitoneally 30 min before the onset of ischemia and 1 h after reperfusion. After reperfusion, rats were tested for neurobehavioral activities and were sacrificed for the infarct volume, estimation of oxidative damage markers. Edv treatment significantly reduced ischemic lesion volume, improved neurological deficits, contended oxidative loads, and suppressed apoptotic damage. In conclusion, treatment with Edv ameliorated the neurological and histological outcomes with elevated endogenous anti-oxidants status as well as reduced induction of apoptotic responses in MCA occluded rat. We theorized that Edv is among the pharmacological agents that reduce free radicals and its associated cholinergic dysfunction and apoptotic damage and have been found to limit the extent of brain damage following stroke.     

Relation of anthropometric and dynamometric variables to serious postoperative complications.

Prediction of serious postoperative complications by using standard anthropometric and biochemical nutritional variables was attempted in 225 patients admitted for major abdominal surgery. In 102 of the patients hand-grip dynamometry was also measured, and this proved the most sensitive test, predicting complications in 48 of the 55 patients (87%) who developed them (p < 0.001). Arm muscle circumference and forearm muscle circumference below 85% of the standard value were also of predictive value (p < 0.02 and p < 0.01 respectively); weight for height and serum albumin concentrations were less satisfactory, while weight loss of more than 10% was not significantly related to complications. Dynamometry is a useful, rapid, and inexpensive screening test for detecting malnutrition that is likely to predispose to serious postoperative morbidity.     

Disability transitions after 30 months in three community-dwelling diagnostic groups in Spain

Background

Little is known about changes in disability over time among community-dwelling patients. Accordingly, this study sought to assess medium-term disability transitions.

Patients and Methods

300 chronic obstructive pulmonary disease (COPD), chronic heart failure and stroke patients living at home in Madrid were selected from general practitioner lists. In 2009, disability was assessed after a mean of 30 months using the World Health Organisation (WHO) Disability Assessment Schedule 2.0 (WHODAS 2.0). Follow-up was completed using death registries. Losses to follow-up were due to: death, 56; institutionalisation, 9; non-location, 18; and non-participation, 17. Changes in WHODAS 2.0 scores and life status were described and analysed using Cox and multinomial regression. Disability at end of follow-up was imputed for 56 deceased and 44 surviving patients.

Results

Mean disability scores for 200 surviving patients at end of follow-up were similar to baseline scores for the whole group, higher than their own baseline scores, and rose by 16.3% when imputed values were added. The strongest Cox predictors of death were: age over 84 years, adjusted hazard ratios with 95%CI 8.18 (3.06-21.85); severe/complete vs. no/mild disability, 5.18 (0.68-39.48); and stroke compared to COPD, 1.40 (0.67-2.91). Non-participants and institutionalised patients had higher proportions with severe/complete baseline disability. A one-point change in baseline WHODAS 2.0 score predicted independent increases in risk of 12% (8%-15%) for severe/complete disability or death.

Conclusions

A considerably high proportion of community-dwelling patients diagnosed with COPD, CHF and stroke undergo medium-term changes in disability or vital status. The main features of the emerging pattern for this group appear to be as follows: approximately two-thirds of patients continue living at home with moderately reduced functional status; 1/3 die or worsen to severe/complete disability; and 1/10 improve. Baseline disability scores, age and diagnosis are associated with disability and death in the medium term.     

Prevalence and outcome of symptomatic carotid lesions in young adults. National Research Council Study Group.

OBJECTIVE--To estimate the prevalence and outcome of symptomatic internal carotid artery lesions in young adults. DESIGN--Multicentre hospital based observational study with five year follow up. SETTING--Seven neurological departments in northern and central Italy. SUBJECTS--240 patients (115 men) aged 15-44 with a recent transient ischaemic attack or stroke in the carotid territory. MAIN OUTCOME MEASURES--(a) Prevalence of symptomatic internal carotid artery stenosis or occlusion detected by continuous wave Doppler ultrasonography at entry; (b) incidence rates of cerebral, cardiac, and non-vascular death; non-fatal stroke; and non-fatal myocardial infarction. RESULTS--Carotid stenoses of 50-99% and occlusions were found in 38 patients (15.8%). Both conditions were significantly more frequent in patients aged over 35 and in those with hypertension, diabetes mellitus, and stroke at entry. The standardised mortality ratio at five years was 10.5 (95% confidence interval 5.0 to 19.3). Survival of patients with stenoses of 0-49% and occlusions was significantly better than that of patients with stenoses of 50-99%. Carotid stenosis of 50-99% was an independent predictor of death (hazard ratio 7.9; 95% confidence interval 2.2 to 29) and non-fatal stroke (hazard ratio 7.4; 1.5 to 37.4). CONCLUSIONS--The prevalence of carotid stenosis or occlusion in young adults after a cerebrovascular event is low. Though patients with high grade symptomatic carotid stenosis are at risk of non-fetal and fetal events, patients with internal artery occlusion apparently have a benign prognosis.     

Rapamycin Treatment Improves Neuron Viability in an In Vitro Model of Stroke

Ischemic stroke is the leading cause of serious, long-term adult disability and is associated with sensorimotor and cognitive impairments due to neuronal degeneration. Currently, recombinant tissue plasminogen activator (rTPA) is the only FDA-approved medical therapy for treatment of patients with acute ischemic stroke. However, rTPA can only be given within 3 hours of symptom onset, and only 2% of patients are eligible. Therefore, there is an urgent need for novel neuroprotective treatment options for ischemic stroke. An emerging treatment for a diverse range of neurological disorders associated with neurodegeneration is rapamycin, a key modulator of the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway is the primary regulator of the cellular response to nutrient availability, changes in energy status and stress as seen following ischemia and reperfusion. However, rapamycin’s effects on mTORC1 and mTORC2 are poorly understood in neurons. In the current study we show that rapamycin can prevent the activation of both mTORC1 and mTORC2 in cortical neurons and improve cell survival following oxygen glucose deprivation (OGD), an in vitro model of ischemic stroke. This work further supports the investigation of rapamycin as a novel neuroprotectant for ischemic stroke.     

Neuroprotective effects of ONO-1924H, an inhibitor of poly ADP-ribose polymerase (PARP), on cytotoxicity of PC12 cells and ischemic cerebral damage

N-[3-(4-Oxo-3,4-dihydro-phthalazin-1-yl)phenyl]-4-(morpholin-4-yl) butanamide methanesulfonate monohydrate (ONO-1924H) is a novel inhibitor of poly ADP-ribose polymerase (PARP). In this study, we examined the effects of ONO-1924H on cytotoxicity induced by hydrogen peroxide in PC12 cells in vitro and cerebral damage and neurological deficits induced by middle cerebral artery (MCA) thrombus occlusion in vivo in rat. In the in vitro cytotoxicity assay, exposure to 0.5 mmol/L hydrogen peroxide induced cell death in differentiated PC12 cells. ONO-1924H, a PARP inhibitor (Ki=0.21 micromol/L), reduced cell death in a concentration-dependent manner that was correlated with inhibition of PARP activation. A 50% reduction in cell death (EC50) was achieved with 2.4 micromol/L ONO-1924H. In the MCA occlusion model, ONO-1924H was injected intravenously at doses of 3, 10 and 30 mg/kg/h for 3 h, and cerebral damage and neurological deficits were estimated 24 h after MCA occlusion. ONO-1924H treatment led to a significant decrease in cerebral damage in the 10 mg/kg/h-treated group (P < 0.05) and the 30 mg/kg/h-treated group (P < 0.01). Further, ONO-1924H at doses of 30 mg/kg/h significantly (P < 0.05) improved neurological deficits. These findings suggest that the novel PARP inhibitor, ONO-1924H, affords effective neuroprotection and is a useful therapeutic candidate for the treatment of ischemic stroke.