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Background: Edema represents one of the earliest negative markers of survival and consecutive neurological deficit following stroke. The mixture of cellular and vasogenic edema makes treating this condition complicated, and to date, there is no pathogenically oriented drug treatment for edema, which leaves parenteral administration of a hypertonic solution as the only non-surgical alternative., Objective: New insights into water metabolism in the brain have opened the way for molecular targeted treatment, with aquaporin 4 channels (AQP4) taking center stage. We aimed here to assess the effect of inhibiting AQP4 together with the administration of a neurotropic factor (Cerebrolysin) in ischemic stroke., Methods: Using a permanent medial cerebral artery occlusion rat model, we administrated a single dose of the AQP4 inhibitor TGN-020 (100 mg/kg) at 15 minutes after ischemia followed by daily Cerebrolysin dosing (5ml/kg) for seven days. Rotarod motor testing and neuropathology examinations were next performed., Results: We showed first that the combination treatment animals have a better motor function preservation at seven days after permanent ischemia. We have also identified distinct cellular contributions that represent the bases of behavior testing, such as less astrocyte scarring and a larger neuronalsurvival phenotype rate in animals treated with both compounds than in animals treated with Cerebrolysin alone or untreated animals., Conclusion: Our data show that water diffusion inhibition and Cerebrolysin administration after focal ischemic stroke reduces infarct size, leading to a higher neuronal survival in the peri-core glial scar region., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Aquaporin-4 (AQP4) is the most abundant water channel in the brain, and its inhibition before inducing focal ischemia, using the AQP4 inhibitor TGN-020, has been showed to reduce oedema in imaging studies. Here, we aimed to evaluate, for the first time, the histopathological effects of a single dose of TGN-020 administered after the occlusion of the medial cerebral artery (MCAO). On a rat model of non-reperfusion ischemia, we have assessed vascular densities, albumin extravasation, gliosis, and apoptosis at 3 and 7 days after MCAO. TGN-020 significantly reduced oedema, glial scar, albumin effusion, and apoptosis, at both 3 and 7 days after MCAO. The area of GFAP-positive gliotic rim decreased, and 3D fractal analysis of astrocytic processes revealed a less complex architecture, possibly indicating water accumulating in the cytoplasm. Evaluation of the blood vessels revealed thicker basement membranes colocalizing with exudated albumin in the treated animals, suggesting that inhibition of AQP4 blocks fluid flow towards the parenchyma in the paravascular drainage pathways of the interstitial fluid. These findings suggest that a single dose of an AQP4 inhibitor can reduce brain oedema, even if administered after the onset of ischemia, and AQP4 agonists/antagonists might be effective modulators of the paravascular drainage flow., Competing Interests: The authors declare no conflict of interest.

Aquaporin-4 (AQP4) and glutamate transporter-1 (GLT-1) represent the major water and glutamate astrocyte buffering gateways in the brain. Utilizing perilesional ischemic human cortices, we have performed here for the first time an integrative assessment on both AQP4 and GLT-1, and on their proximity to blood vessels and neurons. Counting the relative number of AQP4±/GLT-1±/glial fibrillary acidic protein± cells showed that double-positive variants were overall most frequent, and their number tended to decrease from organized and recent perilesional cortices to controls. AQP4/GLT-1 colocalization showed higher coefficients for the perilesional cortices compared with controls, suggesting an increased water/glutamate-buffering capability. Distance frequency analysis of AQP4/GLT-1 in relationship to neurons showed that both markers were concentrated at 20-40 μm around the perikarya; with AQP4 being more abundant in close proximity, these differences were not being driven by changes in neuropil density alone. Our study suggests a dual, simultaneous astrocytic function depending on the relative distance to neurons and vessels, with increased water and glutamate-buffering capability in the mid perineuronal space, and an increased water-buffering capability in the immediate perineuronal space, even higher than around vessels. Thus, adding specific AQP4/GLT-1 modulator agents selectively depending on the acute/chronic phase of stroke might increase the efficacy of existing treatments., (© 2014 International Society of Neuropathology.)

Although already in use in several medical domains, only recently optical coherence tomography (OCT) has been applied in the study of ischemic events. In this paper, we will focus on characterizing ischemic stroke, in a rat model, by OCT. Investigations were carried on a set of 25 rats, on which ischemic stroke was inflicted by a transient occlusion of the middle cerebral artery (tMCAO). Animals were sacrificed 1, 3, 7 and 28 days after occlusion. We tested the OCT's power of detection and discrimination of stroke area compared to both normal, contralateral hemisphere and non-affected brain tissue, together with the aid of histochemical and pathological examination. Our results show a great potential of OCT to be used as a detection tool in acute and chronic phases of stroke.

Reduced cerebral blood flow beyond the compensatory mechanisms leads to cerebral hypoxia. Hypoxia causes various lesions of neurons, glial cells and cerebral blood vessels, depending on its duration and intensity. In our study, we reduced cerebral blood flow in the experience animal on average by 30%, by right internal carotid artery ligation. Fifteen days after the onset of hypoxia, by histology and immunohistochemical studies, we identified neuronal, glial and vascular damage. Lesions of nerve and glial cells ranged from changes of cytoplasmic tinting with the development of "red neurons", to neuronal and glial cytolysis with areas of focal necrosis. Vascular lesions were represented by the collapse, fragmentation and discontinuity of capillaries, always associated with a marked perivascular edema.

Background: We report a case of a 78-year-old woman with a large cerebral infarction probably due to athermanous embolism following atrial fibrillation., Case Description: The patient, known with atrial fibrillation, high blood pressure and heart failure, complained of headache and motor impairment on the left side of the body. CT imaging revealed a subacute ischemic lesion in the right fronto-occipital lobes, and an old ischemic lesion in the right fronto-parietal lobes. Anticoagulant treatment was conducted with careful monitoring of the coagulability status. After almost three weeks, suddenly the patient became comatose and died shortly after. Macroscopic and microscopic examination confirmed the cortico-subcortical ischemic lesions, but also identified a fresh hemorrhagic site in pons, distant from the initial lesion sites. An immunohistochemical study identified blood vessels in the ischemic sites completely isolated from any glial support., Conclusions: This is a rare case of a large cerebral infarction with a pontine hemorrhagic event.

We study here the histopathological changes in twenty-two cases of acute ischemic stroke. The average age of the patients was 62-year-old, and the interval from the onset of the disease to the death varied from 6 hours to 15 years. The brain lesions after acute stroke were observed in all regions. Their evolution allowed us to classify them in fourth stages. Phase one changes (1-2 days after onset) (n=2 patients) included red hypoxic and "ghost" neurons and other acute neuronal injury and spongiosis. The second phase (n=14 patients) was subdivided into: (a) a phase of acute inflammation (3-37 days after onset) (n=5 patients), where we observed especially features of acute inflammation together with coagulative necrosis, and (b) phase of chronic inflammation (10 days-53 years after the onset) (n=9 patients), in which prevail mononuclear and macrophage infiltrate, astrogliosis, spongiosis and neo-vascularization. In the third phase (26 days-23 years after the onset), we included six cases characterized by the absence of an inflammatory reaction, presence of cavitation, astrogliosis and macrophages. Our study describes the heterogeneity of brain injury after acute ischemic stroke with the participation of all brain components, and the chronology in which these lesions develop and evolve.