Acute cerebral ischemia triggers local and systemic immune response. The aims of this project was to assess the blood serum concentration of the markers of inflammation and markers of the blood brain barrier damage on the first day of ischemic stroke, and the mutual correlations between these marker levels. Methods Our prospective study included 138 patients with first-in-life stroke, who were analyzed according to: plasma concentration of the following markers on the first day of stroke: Il-2 and IL-6, S100B, TNF alfa, GRN, NSE, uPA, VEGF, BDNF, CRP, leucocyte and thrombocyte counts; their neurological status on the first day of stroke (NIHSS) and their functional status at 30 days following stroke (mRS). Result The study included 138 patients with mean age: 73.11 ± 11.48 [36-103]. Patients with a higher score on the NIHSS than those obtaining lower scores showed significantly higher concentrations of TNF-alpha, WBC, CRP, NSE, IL-6 and S100B. Patients with a higher score on the mRS than those obtaining lower scores showed significantly higher concentrations of WBC, CRP, GRN, IL-6, S100B. Factors with an independent influence on the neurological status on the first day of stroke were: sex, WBC, PLT, CRP, S100B and IL-6 levels. Atrial fibrillation, leukocyte count, CRP, NSA, uPA, interleukin 6 and S100B showed an independent impact on the functional status on the 30th day of stroke. Patients with symptomatic atherosclerosis of carotid/cerebral and/or coronary arteries, as compared to others, were older (p= 0.003) and had higher levels of CRP, Il-6, and S100B. In each case, the differences were statistically significant. Conclusions The concentration of Il-6 and S100B on the first day of stroke are significant for both the neurological status and the functional status in the acute period of the disease. Increased CRP and leukocyte count are associated with a worse prognosis regarding the course of acute stroke. The expression of pro-inflammatory agents and markers of blood-brain barrier damage in the acute phase of stroke is more prominent in patients with symptomatic atherosclerosis than in patients with no clinical features of atherosclerosis.
The blood–brain barrier is the structure (BBB), which isolates the central nervous system from the external environmental. During a stroke, the BBB gets damaged, which is accompanied by changes in the concentrations and distributions of claudin-5, occludin, ZO-1, and other building blocks of the BBB. The aim of this study was to assess the concentrations of selected components of the BBB—occludin, claudin-5, and zonulin (ZO-1)—and to define a potential relationship between the concentrations of these three substances and the type of stroke, the location and extent of the infarct focus, the neurological/functional status in the acute phase of the disease, and the patient’s clinical profile. Methods: In this prospective study, we qualified patients with first-in-life stroke. All patients were analyzed according to: the presence of comorbidities, type of stroke (OCSP), treatment type in the first day of hospitalization, hemorrhagic transformation of infarct focus (ECASS), neurological status on the first day of stroke (NIHSS), functional status (mRS) on the ninth day of disease. In all patients, the plasma concentrations of claudin-5, occludin, and ZO-1 on the first day of stroke were examined and next, the mean concentrations were analyzed and compared between subgroups created on the basis of demographical and clinical features. Results: The mean concentration of occludin was significantly higher in patients with partial anterior cerebral infarct (PACI) compared to patients with posterior cerebral infarct (POCI; 1.03 vs. 0.66 ng/mL; p = 0.009) and in patients with location of ischemic stroke in the carotid artery supply compared with in the vertebrobasilar supply (respectively: 1.036 vs. 0.660 ng/mL; p = 0.009). The mean concentration of claudin 5 was significantly higher in patients with PACI compared to patients with POCI (0.37 vs. 0.21 ng/mL; p = 0.011) and in patients with location of ischemic stroke in the carotid artery supply in comparison with vertebrobasilar supply (respectively: 0.373 vs. 0.249 ng/mL; p = 0.011). The differences in mean occludin and claudin 5 concentrations between female and male were statistically not significant, similarly between patients < 65 years and older. A significantly higher mean concentration of zonulin was observed in patients > 65 years of age compared to younger patients (0.59 vs. 0.48 ng/mL; p = 0.010) and in patients with arterial hypertension compared to patients without the disease (0.63 ng/mL vs. 0.26 ng/mL; p = 0.026). There were no statistically significant relationships between the concentration of occludin, claudin 5, and zonulin and the neurological status according to the NIHSS on the first day of stroke. Conclusions: The location of stroke in the anterior part of the brain’s blood supply is associated with high blood levels of occludin and claudin 5 in the acute phase of stroke. The blood concentration of occludin is significantly lower in lacunar stroke comparing to this in non-lacunar stroke. Old age and arterial hypertension correlate positively with the concentration of zonulin 1 in acute stroke. There is no relationship between the blood levels of occludin, claudin 5, and zonulin 1 on the first day of stroke and the neurological and functional status in the acute phase of the disease.
Ischemic stroke is the most common cause of adult disability and one of the leading causes of death worldwide, with a serious socio-economic impact. In the present work, we used a new thromboembolic model, recently developed in our lab, to induce focal cerebral ischemic (FCI) stroke in rats without reperfusion. We analyzed selected proteins implicated in the inflammatory response (such as the RNA-binding protein HuR, TNFα, and HSP70) via immunohistochemistry and western blotting techniques. The main goal of the study was to evaluate the beneficial effects of a single administration of minocycline at a low dose (1 mg/kg intravenously administered 10 min after FCI) on the neurons localized in the penumbra area after an ischemic stroke. Furthermore, given the importance of understanding the crosstalk between molecular parameters and motor functions following FCI, motor tests were also performed, such as the Horizontal Runway Elevated test, CatWalk™ XT, and Grip Strength test. Our results indicate that a single administration of a low dose of minocycline increased the viability of neurons and reduced the neurodegeneration caused by ischemia, resulting in a significant reduction in the infarct volume. At the molecular level, minocycline resulted in a reduction in TNFα content coupled with an increase in the levels of both HSP70 and HuR proteins in the penumbra area. Considering that both HSP70 and TNF-α transcripts are targeted by HuR, the obtained results suggest that, following FCI, this RNA-binding protein promotes a protective response by shifting its binding towards HSP70 instead of TNF-α. Most importantly, motor tests showed that reduced inflammation in the brain damaged area after minocycline treatment directly translated into a better motor performance, which is a fundamental outcome when searching for new therapeutic options for clinical practice.
The animal thromboembolic model of ischemia perfectly mimics human ischemic stroke which remains the leading cause of disability and mortality in humans. The development of new treatment strategies was therefore imperative. The purpose of this study is to improve the thromboembolic stroke model in rats in order to design experiments that use motor tests, and are in accordance with the 3R principles to prevent complications and maintain the same size of the infarct repeatedly. Tail vein dye application, a protective skull mask and a stress minimization protocol were used as additional modifications to the animal stroke model. These modifications significantly minimized the pain and stress severity of the procedures in this model. In our experimental group of Long-Evans rats, a photo-induced stroke was caused by the application of a photosensitive dye (Rose Bengal) activated with white-light irradiation, thus eliminating the need to perform a craniotomy. The animals’ neurological status was evaluated using a runway elevated test. Histological examination of the brain tissue was performed at 12, 24 and 48 h, and seven days post-stroke. Tissue examination revealed necrotic foci in the cortex and the subcortical regions of the ipsilateral hemisphere in all experimental groups. Changes in the area, width and depth of the necrotic focus were observed over time. All the experimental groups showed motor disturbances after stroke survival. In the proposed model, photochemically-induced stroke caused long-term motor deficits, showed high reproducibility and low mortality rates. Consequently, the animals could participate in motor tests which are particularly suitable for assessing the efficacy of neuro-regenerative therapies, while remaining in line with the latest trends in animal experimental design.
Neurodegenerative diseases as a group of congenital or acquired diseases of the nervous system are currently more common in the aging societies, being one of the most severe diseases faced the healthcare services. Many scientific teams are searching for a better understanding of the mechanisms of these diseases, i.e. their detection, treatment as well as putative prevention methods. Progranulin is one of the twenty-first century discoveries and is a precursor of multifunctional cysteine-rich proteins granulins, which play a crucial role in cell development, cell cycle control, wound healing, inflammatory and cancerogenic processes, neuron development, and neurodegeneration. In 2006, the first mutation in the gene encoding progranulin was discovered as the cause of frontotemporal dementia (FTLD). The human PGRN sequence was first fully characterized on the basis of mRNA isolated from bone marrow cells. Up to now, more than 75 mutations have been reported in patients with various forms of FTLD. All discovered mutations cause the disease either by loss of function of the entire progranulin protein or loss of function of one allele of the PGRN gene. Taking into account the available data regarding PGRN, we would like to collect and systematize the data about progranulin and its putative usefulness as a prognostic factor in some neurodegenerative diseases. The role of progranulin in neurodegenerative diseases is invaluable, not only as a prognostic factor in the presymptomatic stage of the disease but also as a chance for its future therapeutic application in neurodegenerative diseases. Low levels of progranulin were found to correlate with either prodromal symptoms or even asymptomatic stages in patients with established mutations in the progranulin-encoding gene. Research currently in progress provides valuable information about the possibility of this protein being used to improve the diagnosis as well as treatment of different neurodegenerative diseases.
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