scholarly journals Accessing neuroinflammation sites: Monocyte/neutrophil-mediated drug delivery for cerebral ischemia

2019 ◽  
Vol 5 (7) ◽  
pp. eaau8301 ◽  
Author(s):  
Jia Hou ◽  
Xu Yang ◽  
Shiyi Li ◽  
Zhekang Cheng ◽  
Yuhua Wang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Flow ◽  
Cerebral Ischemia ◽  
Inflammatory Response ◽  
Target Cells ◽  
Ischemic Brain ◽  
Therapeutic Molecules ◽  
Cerebral Parenchyma ◽  
Cell Carriers ◽  
The Brain

Cerebral ischemia (CI) results from inadequate blood flow to the brain. The difficulty of delivering therapeutic molecules to lesions resulting from CI hinders the effective treatment of this disease. The inflammatory response following CI offers a unique opportunity for drug delivery to the ischemic brain and targeted cells because of the recruitment of leukocytes to the stroke core and penumbra. In the present study, neutrophils and monocytes were explored as cell carriers after selectively carrying cRGD liposomes, which effectively transmigrated the blood-brain barrier, infiltrated the cerebral parenchyma, and delivered therapeutic molecules to the injured sites and target cells. Our results showed the successful comigration of liposomes with neutrophils/monocytes and that both monocytes and neutrophils were important for successful delivery. Enhanced protection against ischemic injury was achieved in the CI/reperfusion model. The strategy presented here shows potential in the treatment of CI and other diseases related to inflammation.

Energy-requiring cell functions in the ischemic brain

1982 ◽  
Vol 56 (4) ◽  
pp. 482-497 ◽  
Author(s):  
Jens Astrup
Keyword(s):  
Blood Flow ◽  
Cerebral Ischemia ◽  
Global Cerebral Ischemia ◽  
Specific Inhibition ◽  
Ischemic Brain ◽  
Content Type ◽  
Cell Functions ◽  
The Brain ◽  
Fine Print

✓ The energy-requiring cell functions in the brain are described. The role of specific inhibition of these functions, and their critical low-supply levels of blood flow and oxygen are reviewed in relation to clinical management of focal and complete global cerebral ischemia.

scholarly journals New cerebrovascular agent with hypotensive activity

2019 ◽  
Vol 5 (2) ◽  
pp. 71-77
Author(s):  
Galina A. Kim ◽  
Tamara S. Gan’shina ◽  
Elena V. Kurza ◽  
Ilya N. Kurdyumov ◽  
Denis V. Maslennikov ◽  
...  
Keyword(s):  
Blood Flow ◽  
Antihypertensive Agent ◽  
Brain Injuries ◽  
Cerebrovascular Disorders ◽  
Male Rats ◽  
Hypotensive Activity ◽  
Duration Of Action ◽  
Ischemic Brain ◽  
Cerebrovascular Activity ◽  
The Brain

Introduction: In cerebrovascular disorders, special attention is paid to a hypertensive cerebrovascular crisis, which combines a vascular injury of the brain and hypertension. The paper studies the cerebrovascular properties of the calcium channel blocker of S-Amlodipine nicotinate antihypertensive agent. Materials and methods: Tests were performed on 96 nonlinear male rats, measuring local blood flow in the cerebral cortex in 36 awake animals, using a laser Doppler flowmeter. Cerebral circulation was recorded in the animals when modeling ischemic and hemorrhagic brain injuries. Results and discussion: S-Amlodipine nicotinate (0.1 mg/kg i/v) shows a pronounced cerebrovascular activity in the models of ischemic and hemorrhagic injuries of the brain. In terms of the vasodilating effect in ischemic brain injury, the drug is comparable to mexidol, nimodipine, picamilon, but is superior to nimodipine and picamilon in terms of duration of action, and in the model of hemorrhagic stroke, S-Amlodipine nicotinate is superior to nimodipine and is comparable to picamilon and mexidol. The analysis of the mechanism of action of the agent revealed the participation of GABA A-receptors in the implementation of cerebrovascular properties of the agent. Conclusion: Significant cerebrovascular activity of S-Amlodipine nicotinate (0.1 mg/kg i/v) antihypertensive agent was revealed. The presence of GABAergic mechanism on cerebral blood flow in the agent action along with blockade of slow calcium channels ensures its high efficacy in treatment of both ischemic and hemorrhagic brain injuries.

Microregional blood flow changes in experimental cerebral ischemia

1971 ◽  
Vol 35 (2) ◽  
pp. 155-166 ◽  
Author(s):  
Y. Lucas Yamamoto ◽  
Kathryne M. Phillips ◽  
Charles P. Hodge ◽  
William Feindel
Keyword(s):  
Blood Flow ◽  
Cerebral Ischemia ◽  
Fluorescein Angiography ◽  
Focal Cerebral Ischemia ◽  
Gamma Activity ◽  
Collateral Flow ◽  
Silicon Detectors ◽  
Content Type ◽  
Perfusion Flow ◽  
The Brain

✓ A branch of the middle cerebral artery on the convexity of the dog brain was occluded to produce an area of focal cerebral ischemia which could then be defined by fluorescein angiography of the brain. Repeated fluorescein angiography and measurement of microregional cerebral blood flow by xenon133 injected into the carotid artery and monitored by miniature lithium-drifted silicon detectors for gamma activity demonstrated that the ischemic zone was reduced in size by better collateral flow when the animals were allowed to breathe 5% carbon dioxide and 95% oxygen. Conversely, hyperventilation reducing the pCO2 made the ischemic zone larger by reducing collateral flow. No evidence was found to indicate that hypercapnia preferentially deprived the ischemic zone of perfusion flow. Retrograde collateral flow in the surface arteries appeared effective in terms of microcirculatory perfusion.

scholarly journals The Many Faces of Post-Ischemic Tau Protein in Brain Neurodegeneration of the Alzheimer’s Disease Type

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2213
Author(s):  
Ryszard Pluta ◽  
Stanisław J. Czuczwar ◽  
Sławomir Januszewski ◽  
Mirosław Jabłoński
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Tau Protein ◽  
Ischemia Reperfusion ◽  
Disease Type ◽  
Dependent Manner ◽  
Ischemic Brain ◽  
The Brain

Recent data suggest that post-ischemic brain neurodegeneration in humans and animals is associated with the modified tau protein in a manner typical of Alzheimer’s disease neuropathology. Pathological changes in the tau protein, at the gene and protein level due to cerebral ischemia, can lead to the development of Alzheimer’s disease-type neuropathology and dementia. Some studies have shown increased tau protein staining and gene expression in neurons following ischemia-reperfusion brain injury. Recent studies have found the tau protein to be associated with oxidative stress, apoptosis, autophagy, excitotoxicity, neuroinflammation, blood-brain barrier permeability, mitochondrial dysfunction, and impaired neuronal function. In this review, we discuss the interrelationship of these phenomena with post-ischemic changes in the tau protein in the brain. The tau protein may be at the intersection of many pathological mechanisms due to severe neuropathological changes in the brain following ischemia. The data indicate that an episode of cerebral ischemia activates the damage and death of neurons in the hippocampus in a tau protein-dependent manner, thus determining a novel and important mechanism for the survival and/or death of neuronal cells following ischemia. In this review, we update our understanding of proteomic and genomic changes in the tau protein in post-ischemic brain injury and present the relationship between the modified tau protein and post-ischemic neuropathology and present a positive correlation between the modified tau protein and a post-ischemic neuropathology that has characteristics of Alzheimer’s disease-type neurodegeneration.

scholarly journals Ghrelin reduces cerebral ischemic injury in rats by reducing M1 microglia/macrophages

2022 ◽  
Vol 66 (1) ◽  
Author(s):  
Rong Tian ◽  
Gengsheng Mao
Keyword(s):  
Cerebral Ischemia ◽  
Brain Tissue ◽  
Infarct Volume ◽  
Neurological Function ◽  
Tunel Staining ◽  
Triphenyltetrazolium Chloride ◽  
Ischemic Brain ◽  
Tnf Α ◽  
Ischemic Brain Tissue ◽  
The Brain

The purpose of this study was to investigate the effect of Ghrelin on the polarization of microglia/ macrophages after cerebral ischemia (CI) in rats. 60 wild-type SD rats were randomly divided into sham group, CI group, CI+Ghrelin group, 20 rats in each group. The modified Longa suture method was used to establish the middle cerebral artery occlusion (MCAO) model in rats. Before surgery, Ghrelin was injected subcutaneously (100μg/kg, twice a day) for 4 consecutive weeks. After modeling, neurological function scores were performed with three behavioral experiments: mNSS score, Corner test, and Rotarod test, to evaluate the recovery of neurological function after Ghrelin treatment. At the same time, the brain tissues were collected and stained with 2,3,5-triphenyltetrazolium chloride (TTC) to detect the cerebral infarct volume. RT-qPCR was used to detect the expression of TNF-α and IL-1β in the ischemic brain tissue, and the TUNEL staining was used to detect the apoptosis of brain tissue. Flow cytometry was used to detect the percentage of M1 type microglia/macrophages which were isolated by trypsin digestion of fresh cerebral cortex. Then, the Western blotting and immunofluorescence method were used to detect the phosphorylation level of AKT (P-AKT) and AKT. Compared with the CI group, the neurological function of the rats in the CI+Ghrelin group was dramatically improved, and the cerebral infarction area was dramatically reduced. At the same time, the expression of TNF-α and IL-1β in the ischemic brain tissue of rats in the CI+Ghrelin group decreased, and the apoptotic cells in the brain tissue also decreased. Compared with the CI treatment group, the activation of M1 microglia/macrophages in the cortex of the ischemic side of the infarct and the peri-infarct area in the CI+Ghrelin group was dramatically inhibited. At the same time, the ratio of P-AKT/AKT of the brain tissue in the CI+Ghrelin group was dramatically higher than that of the CI group. In the rat cerebral ischemia model, Ghrelin can promote the repair of brain damage and the recovery of neurological function after ischemia. Its mechanism may be related to activating AKT to selectively reduce M1 microglia/macrophages, reducing inflammation and cell apoptosis in brain tissue.

scholarly journals Characteristics of nervous tissue after modeling of focal cerebral ischemia in rats at different periods of reperfusion

2018 ◽  
Vol 24 (3) ◽  
pp. 58-64
Author(s):  
O.I. Savchuk ◽  
G.G. Skibo
Keyword(s):  
Cerebral Ischemia ◽  
Brain Damage ◽  
Nervous Tissue ◽  
Focal Cerebral Ischemia ◽  
Tactile Sensitivity ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Ischemic Period ◽  
The Brain ◽  
Occlusion Period

The stroke-causing problems are extremely important in Ukraine. This makes a heavy burden not only on the health care system, but also on the whole society as a whole. That's why we've studied structural and ultrastructural changes of cortical neurons and striatum of the brain and the development of delayed death of nerve cells after the modeling of the middle cerebral artery occlusion (MCAO) and post ischemic period in rats. We've analyzed the data at different terms after modeling of MCAO. The purpose of the study was to investigate the changes in the nervous tissue in the modeling of focal cerebral ischemia by monofilament occlusion of MCAO in rats at different periods of reperfusion. The statistical processing of primary digital experimental data was carried out using the software Statistica 6.0. It was confirmed that the 60-minute occlusion of the MCAO is an adequate model of focal ischemic brain damage in rats. Changes of locomotor activity and a tactile sensitivity were determined in rats after occlusion and after reperfusion during the post-period period. It was found that in the experimental group with a reperfusion period of 72 hours, a clear increase of the volume of the ischemic area of the brain, accompanied by significant neurological deficiency, was observed. Reduced research activity of the rats was revealed, which was shown in the decrease of the number of squares they crossed, the number of racks, the increase of acts of grooming and the duration of acts of frizings. Following ischemic brain damage, there was also a disbalance of somato-sensory functions, as evidenced by an increase in the time during which the animal took a test stimulus ("Sticky tape") from both the anterior paws when tested for tactile sensitivity (adhesive removal test). An electron microscopic study of the cortex showed that dark wrinkled neurons and enlightened swollen neurons were observed at 72 hours of post-occlusion period, indicating different ways of death of these cells. Changes in striatum were similar to changes in the cortex, which progressed with an increase in the post-occlusion period. The protocol of the serial evaluation of neurological disorders used after MCAO modeling allowed detecting long-term stable functional disorders in laboratory rats. The obtained data indicate significant changes in the structure of the cortex and striatum in the post-ischemic period and the progressive nature of these changes.

scholarly journals Neuroprotective and cerebrovascular effects of endogenous N-Arachidonoyl-GABA and its putative Cox-2 metabolite – GABA conjugate with Prostaglandin E2

2021 ◽  
Vol 7 (3) ◽  
pp. 49-61
Author(s):  
Narine R. Mirzoyan ◽  
Nelly G. Khostikyan ◽  
Vahe S. Meliksetyan ◽  
Arpine A. Hakobyan ◽  
Tamara S. Gan’shina ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Ischemia ◽  
Prostaglandin E2 ◽  
Brain Tissue ◽  
Brain Ischemia ◽  
Cerebral Circulation ◽  
Transient Ischemia ◽  
Cox 2 ◽  
The Brain ◽  
Rat Brain Tissue

Introduction: The aim of the study was to compare the neuroprotective and cerebrovascular effects of bioactive, endogenous lipid – N-arachidonoyl-GABA (AA-GABA) and GABA conjugate with prostaglandin E2 (PGE2-GABA) by evaluation of a morphological state of rat brain tissue and lipofuscin levels under the condition of permanent focal brain ischemia, as well as cerebral circulation under the condition of global transient ischemia. Materials and methods: The study has been implemented using the models of the left middle cerebral artery occlusion (MCAO) and global transient ischemia of the brain. A morphological examination of the brain tissue, a registration of local blood flow by laser flowmeter, and quantitative measurement of lipofuscin by fluorescence spectroscopy were used. Results and discussion: AA-GABA and the putative COX-2 metabolite PGE2-GABA showed significant neuroprotective and cerebrovascular effects in rat models of global and focal cerebral ischemia. In the MCAO model, AA-GABA and PGE2-GABA at a dose of 2 mg/kg/day administered i.p. for 6 or 12 days led to: 1) significant restoration of neurons and glial cells with intracellular regeneration of cytoplasmic and nuclear structures, 2) decrease in brain tissue edema; 3) attenuated thrombosis and stasis, and 4) absence of large necrotic foci in rat brain tissue. AA-GABA and PGE2-GABA at the same dose prevented excessive accumulation of lipofuscin in both brain hemispheres in rats with MCAO. All the studied compounds increase cerebral blood circulation in rats subjected to global transient ischemia. However, the cerebrovascular effect of PGE2-GABA was superior to the activity of AA-GABA and all other tested compounds. AA-GABA and PGE2-GABA, unlike PGE2 and nimodipine, increase the cerebral blood flow in rats with global transient brain ischemia and have no influence on the intact animals. Apparently, the GABAergic vascular system of the brain is involved in the mechanisms of the neuroprotective action of AA-GABA and PGE2-GABA. Conclusion: For the first time, we demonstrated the ability of AA-GABA and its putative metabolite COX-2 PGE2-GABA to improve cerebral circulation, attenuate structural damage and lipofuscin accumulation during cerebral ischemia. The natural origin of AA-GABA, which possesses neuroprotective and cerebrovascular activity, as well as anti-aggregatory activity, allows considering AA-GABA as one of the endogenous protective factors in ischemic brain lesions. Graphical abstract:

scholarly journals Diverse Functions of Pericytes in Cerebral Blood Flow Regulation and Ischemia

2015 ◽  
Vol 35 (6) ◽  
pp. 883-887 ◽  
Author(s):  
Francisco Fernandez-Klett ◽  
Josef Priller
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cerebral Ischemia ◽  
Brain Damage ◽  
Neuronal Activity ◽  
Flow Regulation ◽  
Functional Hyperemia ◽  
Mural Cells ◽  
Ischemic Tissue ◽  
The Brain

Pericytes are mural cells with contractile properties. Here, we provide evidence that microvascular pericytes modulate cerebral blood flow in response to neuronal activity (‘functional hyperemia’). Besides their role in neurovascular coupling, pericytes are responsive to brain damage. Cerebral ischemia is associated with constrictions and death of capillary pericytes, followed by fibrotic reorganization of the ischemic tissue. The data suggest that precapillary arterioles and capillaries are major sites of hemodynamic regulation in the brain.

scholarly journals GAPDH controls extracellular vesicle biogenesis and enhances therapeutic potential of EVs in silencing the Huntingtin gene in mice via siRNA delivery

2020 ◽  
Author(s):  
Ghulam Hassan Dar ◽  
Cláudia C. Mendes ◽  
Wei-Li Kuan ◽  
Mariana Conceição ◽  
Samir El-Andaloussi ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Therapeutic Potential ◽  
Sirna Delivery ◽  
Extracellular Vesicle ◽  
Glycolytic Enzyme ◽  
Target Cells ◽  
Binding Motif ◽  
Systemic Injection ◽  
The Brain

AbstractExtracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication and pathophysiology. Their capacity to transfer biomolecules between cells has sparked efforts to bioengineer EVs as drug delivery vehicles. However, a better understanding of EV biogenesis mechanisms and function is required to unleash their considerable therapeutic potential. Here we demonstrate a novel role for GAPDH, a glycolytic enzyme, in EV assembly and secretion, and we exploit these findings to develop a GAPDH-based methodology to load therapeutic siRNAs onto EVs for targeted drug delivery to the brain. In a series of experiments, we observe high levels of GAPDH binding to the outer surface of EVs via a phosphatidylserine binding motif, designated as G58, and discover that the tetrameric nature of GAPDH promotes extensive EV aggregation. Studies in a Drosophila EV biogenesis model demonstrate that GAPDH is absolutely required for normal generation of intraluminal vesicles in endosomal compartments and promotes vesicle clustering both inside and outside the cell. Fusing a GAPDH-derived G58 peptide to dsRNA-binding motifs permits highly efficient loading of RNA-based drugs such as siRNA onto the surface of EVs. Such vesicles efficiently deliver siRNA to target cells in vitro and into the brain of a Huntington’s disease mouse model after systemic injection, resulting in silencing of the huntingtin gene in multiple anatomical regions of the brain and modulation of phenotypic features of disease. Taken together, our study demonstrates a novel role for GAPDH in EV biogenesis, and that the presence of free GAPDH binding sites on EVs can be effectively exploited to substantially enhance the therapeutic potential of EV-mediated drug delivery to the brain.

Sign in / Sign up

Export Citation Format

Share Document