Current Neurovascular Research - Volume 12, Issue 2, 2015

This study investigated whether a low estimated glomerular filtration rate (eGFR) leads to a higher risk of stroke recurrence and a poor prognosis in hemorrhagic stroke patients. A total of 2000 stroke patients were recruited during 2000-2001 and prospectively followed up for a median of 4.5 years. The independent association of a low eGFR with stroke recurrence and poor prognosis was evaluated using Kaplan–Meier analysis and Cox regression models. Among the hemorrhagic stroke patients, the incidence rate of a low eGFR for the compound endpoints (stroke recurrence, myocardial infarction, and all-cause mortality) was greater than that of a normal eGFR (P=0.012). A similar result was observed for the incidence rate of recurrence and death caused by cardiovascular disease or stroke (Csdeath) (P=0.013, and P=0.001, respectively). After adjustment for age, sex, and other cardiovascular risk factors, a low eGFR was associated with a 2.93-fold increased risk of the compound endpoints (P=0.001, RR=2.93, 95% CI=1.58-5.43), 3.06-fold increased risk of recurrent stroke (P=0.003, RR=3.06, 95% CI=1.46-6.40), and 3.57-fold increased risk of Csdeath (P=0.005, RR=3.57, 95% CI=1.46-8.70) among hemorrhagic stroke patients. Among the hemorrhagic stroke patients, a low eGFR was a strong predictor of stroke recurrence and a poor prognosis.

No evidence is currently provided on the involvement of uric acid (UA) and Cu/Zn Superoxide Dismutase (Cu/Zn SOD) in functional recovery of stroke patients after neurorehabilitation. For this purpose, the relationship between UA and Cu/Zn SOD plasma levels and clinical and functional outcome measures were analysed in twenty-five post-acute stroke patients undergoing intensive neurorehabilitation. UA and Cu/Zn SOD plasma levels were evaluated in fifteen healthy subjects as control values. Neurorehabilitation was associated with improved scores (P<0.05) of the National Institutes of Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and the mPULSES profile. UA plasma levels were higher before neurorehabilitation, decreased after, but were still higher than control values. Conversely, Cu/Zn SOD plasma levels were lower than control values before neurorehabilitation and increased after, even though the absolute values were still lower than controls. An inverse correlation was found between variations of UA plasma levels observed before and after neurorehabilitation (Δ UA) and those of Cu/Zn SOD (Δ Cu/Zn SOD) (r= –0.386; P<0.001). No significant correlations were observed between ΔUA and the variations of the scores observed in all clinical outcome measures before and after neurorehabilitation (Δ scores of clinical outcome measures). Δ Cu/Zn SOD correlated positively with Δ NIHSS, Δ mRS and Δ mPULSES scores. Our data provide evidence of neurorehabilitation effectiveness on modulating UA and Cu/Zn SOD plasma levels and suggest that Cu/Zn SOD could assume the significance of biomarker of functional recovery, rather than UA that could be a marker of the magnitude of oxidative injury.

This study aimed to establish an experimental exudative age-related macular degeneration (AMD) model in the common marmoset (Callithrix jacchus), which is a small New World monkey. Choroidal neovascularization (CNV) was induced by laser irradiation on the left eye of each animal under anesthesia. Eight laser spots were applied around the macular area using the image-guided laser system (532 nm) attached with Micron III at 650 mW–2,000 mW power. Laser pulse duration and spot size were fixed at 100 ms and 50 µm, respectively. At 14 days after laser irradiation, fluorescein angiograms were observed. At 21 days after laser irradiation, the fluorescein angiograms were transcardially perfused to the bilateral common carotid arteries with 4% paraformaldehyde for the transverse section or with fluorescein-conjugated dextran (MW = 2,000 kDa) for the retinal pigment epithelia (RPE)-choroidal flatmount. At 14 days after laser irradiation, late hyperfluorescence and leakage within or beyond the lesion borders were observed in a laser power-dependent manner. In the RPE–choroidal flatmount, the mean size of the CNV lesions at 1,500 mW was 1.34 ± 0.49 × 105 µ;m2 (Mean ± S.D., n = 29), and the coefficient of variation for each CNV area was 36.5% (n = 29). In conclusion, we succeeded in producing an experimental exudative type of AMD model in the common marmoset. This model may be useful in elucidating the pathophysiological mechanism and screening of new candidates for exudative AMD.

Diabetes mellitus (DM) is related to an increase in the incidence of vascular dementia. Inflammation is an important cause of endothelial dysfunction and cognitive deficits. The anti -tumor necrosis factor (TNF)-α fusion protein etanercept has been reported to exhibit memory-enhancing effects and endothelial protection. We tested the effect of etanercept on the cognitive endpoints and compared it with the cognitive dysfunction in streptozotocin (STZ )- induced DM rats by using the Morris water maze test (MWMT) and passive avoidance test (PAT). Systolic blood pressure (SBP), thoracic endothelial function, endothelial nitric oxide synthase (eNOS) expression, and hippocampal brain-derived neurotrophic factor (BDNF) expression were assessed. Thirty days after the induction of DM, rats exhibited severe learning and memory deficits associated with endothelial dysfunction and decreased expression of eNOS and BDNF. Chronic treatment with etanercept (0.8 mg/kg, s.c., every week for 30 days) improved cognitive performance, endothelial function, and expression of eNOS and BDNF in DM rats. Furthermore, the memory-improving effects of etanercept were independent of hyperglycemia. These data suggest that etanercept treatment prevents changes in endothelial function, eNOS expression, and hippocampal expression of BDNF and, consequently, vascular dementia in DM rats.

Sepsis is a severe clinical syndrome in which a system-wide inflammatory response follows initial attempts to eliminate pathogens. It is not novel that in sepsis the brain is one of the first organs affected which causes an increase in morbidity and mortality and its consequences may be exacerbated when associated with a diagnosis of chronic inflammation, such as in obesity. Thus, the aim of the present study is to evaluate the susceptibility to brain damage after sepsis in obese rats. During two months, Wistar rats, 60 days, 250-300g received hypercaloric nutrition to induce obesity. Sepsis was submitted to the cecal ligation and perforation (CLP) procedure and sham-operated rats was considered control group. The experimental groups were divided into Sham + Eutrophic, Sham + Obesity, CLP + Eutrophic and CLP + Obesity. Twelve and twenty four hours after surgery the blood brain barrier (BBB) permeability, nitrite/nitrate concentration, myeloperoxidase (MPO) activity, oxidative damage to lipids and proteins and superoxide dismutase (SOD) and catalase (CAT) activities were evaluated in the hippocampus, cortex and prefrontal cortex. The data indicate that in obese rats subjected to sepsis occurs an increase of BBB permeability in different brain regions compared to eutrophic septic rats. This alteration reflected an increase of MPO activity, concentration of nitrite/nitrate, oxidative damage to lipids and proteins and an imbalance of SOD and CAT especially 24 hours after sepsis. It follows that obesity due to its pro-inflammatory phenotype can aggravate or accelerate the sepsis-induced damage in rat brain.

Ischemic stroke swiftly induces a wide spectrum of pathophysiological sequelae, particularly in the aged brain. The translational failure of experimental therapies, might partially be related to monotherapeutic approaches, not address potential counter-mechanisms sufficiently or within the best time window. For example, therapeutic effects relying on stem/progenitor cell mobilization by granulocyte-colony stimulating factor (G-CSF), require approximately a week to become manifest, which is potentially beyond the optimal timing. Here, We tested the hypothesis that treating post-stroke aged rats with the combination of bone marrow-derived mononuclear cells (BM MNC) and G-CSF improves the long term (56 days) functional outcome by compensating the delay before G-CSF effects come to full effect. 1x106 syngeneic BM MNC per kg bodyweight (BW) with G-CSF (50µg/kg, given intraperitoneal by via the jugular vein to aged Sprague- Dawley rats, six hours post-stroke. This process was repeated daily, for a 28 day period. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunohistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period. Daily G-CSF treatment led to a robust and consistent improvement of neurological function, but did not alter final infarct volumes. The combination of G-CSF and BM MNC, did not further improve post-stroke recovery. The lack of an additional benefit may be due to interaction between both approaches, and to a lesser extent, in the insensitivity of the aged brains’ regenerative mechanisms. Also considering recent findings on other tandem approaches involving G-CSF in animal models featuring relevant co-morbidities, we conclude that such combination therapies are not the optimal approach to treat the acutely injured aged brain.

Cocaine abuse remains a devastating medical problem for our society. Current concepts suggest that both hemorrhagic and ischemic stroke, particularly in young people, can result as a consequence of cocaine exposure. We provide an analysis of mechanisms of injury and a discussion of the pharmacological management of stroke following cocaine use. Preclinical research suggests that the cause of cocaine-mediated stroke is multifactorial and involves vasospasm, changes in cerebral vasculature, and platelet aggregation. We suggest that drugs able to induce vasospastic, thrombogenic, or neurotoxic effects of cocaine could be suitable as therapeutic agents. In contrast caution should be exerted when using anti-platelet and thrombolytic agents in cocaine users with stroke.

According to the World Health Organization, diabetes mellitus (DM) in the year 2030 will be ranked the seventh leading cause of death in the world. DM impacts all systems of the body with oxidant stress controlling cell fate through endoplasmic reticulum stress, mitochondrial dysfunction, alterations in uncoupling proteins, and the induction of apoptosis and autophagy. Multiple treatment approaches are being entertained for DM with Wnt1 inducible signaling pathway protein 1 (WISP1), mechanistic target of rapamycin (mTOR), and silent mating type information regulation 2 homolog) 1 (S. cerevisiae) (SIRT1) generating significant interest as target pathways that can address maintenance of glucose homeostasis as well as prevention of cellular pathology by controlling insulin resistance, stem cell proliferation, and the programmed cell death pathways of apoptosis and autophagy. WISP1, mTOR, and SIRT1 can rely upon similar pathways such as AMP activated protein kinase as well as govern cellular metabolism through cytokines such as EPO and oral hypoglycemics such as metformin. Yet, these pathways require precise biological control to exclude potentially detrimental clinical outcomes. Further elucidation of the ability to translate the roles of WISP1, mTOR, and SIRT1 into effective clinical avenues offers compelling prospects for new therapies against DM that can benefit hundreds of millions of individuals throughout the globe.

Proliferative retinopathies are the leading causes of blindness in Western societies. The development of new, more efficacious treatments that take advantage of recent advances in the fields of gene and cell therapy requires further investigations on the mechanisms underlying disease onset and progression, and adequate animal models that recapitulate the pathogenesis of human proliferative retinopathy and allow evaluation of the long-term therapeutic benefits that these therapies can offer. Unfortunately, most models of retinal neovascularization have short-term evolution and diabetic rodents show a very mild retinal phenotype, limited to non-proliferative changes, and do not develop proliferative retinopathy at all. Transgenic mice overexpressing Insulin-like Growth Factor-I (IGF-I) in the retina (TgIGF-I) constitute the only rodent model currently available that develops most of the retinal alterations observed in diabetic eyes, with a temporal evolution that resembles that of the human disease. TgIGF-I have retinal vascular alterations that progress as animals age from non-proliferative to proliferative disease, making these mice an excellent model of proliferative retinopathy that, due to its slow progression, allows long-term evaluation of novel antiangiogenic therapies. At the molecular level, transgenic retinas recapitulate a variety of changes that are also observed in diabetic retinas, which reinforces the validity of this model. In addition to vascular and glial alterations, Tg-IGF-I mice show progressive neurodegeneration that leads to blindness in old animals. Thus, TgIGF-I are a useful model for testing the long-term efficacy and safety of innovative antiangiogenic, glial-modulating and neuroprotective therapies for the treatment of diabetic retinopathy and other retinal proliferative disorders.

The dominant hypothesis in multiple sclerosis is that it is an autoimmune disease; however, there is considerable evidence that the immune attack on myelin may be secondary to a cytodegenerative event. Furthermore, the immune modulating therapies longest in clinical use, although modulating the frequency and severity of exacerbation, do not affect long-term progression towards disability. Clearly alternative perspectives on the etiology of multiple sclerosis are warranted. In this paper I outline the commonalities between idiopathic normal pressure hydrocephalus and multiple sclerosis. These include decreased intracranial compliance as evidenced by increased cerebrospinal fluid volume and velocity of cerebrospinal fluid flow through the cerebral aqueduct; increased ventricular volume; periventricular demyelination lesions; increase in size of Virchow-Robin spaces; presence of Hakim’s triad comprised of locomotory disabilities, cognitive problems and bladder control problems. Furthermore, multiple sclerosis is associated with decreased arterial compliance. These are all suggestive that there is a pulse wave encephalopathy component to multiple sclerosis. There are enough resemblances between normal pressure hydrocephalus and multiple sclerosis to warrant further investigation. Whether decreases in intracranial compliance is a consequence of multiple sclerosis or is a causal factor is unknown. Effective therapies can only be developed when the etiology of the disease is understood.