scholarly journals Paeoniflorin improves functional recovery through repressing neuroinflammation and facilitating neurogenesis in rat stroke model

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10921
Author(s):  
Hongli Tang ◽  
Leiruo Wu ◽  
Xixi Chen ◽  
Huiting Li ◽  
Baojun Huang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Neurovascular Unit ◽  
Artery Occlusion ◽  
Male Rats ◽  
Regulatory Function ◽  
Stroke Model ◽  
Paeoniae Radix ◽  
Signaling Activation ◽  
Von Willebrand

Background Microglia, neuron, and vascular cells constitute a dynamic functional neurovascular unit, which exerts the crucial role in functional recovery after ischemic stroke. Paeoniflorin, the principal active component of Paeoniae Radix, has been verified to exhibit neuroprotective roles in cerebralischemic injury. However, the mechanisms underlying the regulatory function of Paeoniflorin on neurovascular unit after cerebral ischemia are still unclear. Methods In this study, adult male rats were treated with Paeoniflorin following transient middle cerebral artery occlusion (tMCAO), and then the functional behavioral tests (Foot-fault test and modified improved neurological function score, mNSS), microglial activation, neurogenesis and vasculogenesis were assessed. Results The current study showed that Paeoniflorin treatment exhibited a sensorimotor functional recovery as suggested via the Foot-fault test and the enhancement of spatial learning as suggested by the mNSS in rat stroke model. Paeoniflorin treatment repressed microglial cell proliferation and thus resulted in a significant decrease in proinflammatory cytokines IL-1β, IL-6 and TNF-α. Compared with control, Paeoniflorin administration facilitated von Willebrand factor (an endothelia cell marker) and doublecortin (a neuroblasts marker) expression, indicating that Paeoniflorin contributed to neurogenesis and vasculogenesis in rat stroke model. Mechanistically, we verified that Paeoniflorin repressed JNK and NF-κB signaling activation. Conclusions These results demonstrate that Paeoniflorin represses neuroinflammation and facilitates neurogenesis in rat stroke model and might be a potential drug for the therapy of ischemic stroke.

scholarly journals Selective intra-carotid blood cooling in acute ischemic stroke: A safety and feasibility study in an ovine stroke model

2021 ◽  
pp. 0271678X2110249
Author(s):  
Giorgio FM Cattaneo ◽  
Andrea M Herrmann ◽  
Sebastian A Eiden ◽  
Manuela Wieser ◽  
Elias Kellner ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Carotid Artery ◽  
Acute Ischemic Stroke ◽  
Neurological Outcome ◽  
Artery Occlusion ◽  
Control Group ◽  
Stroke Model ◽  
Primary Endpoints ◽  
Neuroprotective Strategy ◽  
Vessel Patency

Selective therapeutic hypothermia (TH) showed promising preclinical results as a neuroprotective strategy in acute ischemic stroke. We aimed to assess safety and feasibility of an intracarotid cooling catheter conceived for fast and selective brain cooling during endovascular thrombectomy in an ovine stroke model. Transient middle cerebral artery occlusion (MCAO, 3 h) was performed in 20 sheep. In the hypothermia group (n = 10), selective TH was initiated 20 minutes before recanalization, and was maintained for another 3 h. In the normothermia control group (n = 10), a standard 8 French catheter was used instead. Primary endpoints were intranasal cooling performance (feasibility) plus vessel patency assessed by digital subtraction angiography and carotid artery wall integrity (histopathology, both safety). Secondary endpoints were neurological outcome and infarct volumes. Computed tomography perfusion demonstrated MCA territory hypoperfusion during MCAO in both groups. Intranasal temperature decreased by 1.1 °C/3.1 °C after 10/60 minutes in the TH group and 0.3 °C/0.4 °C in the normothermia group (p < 0.001). Carotid artery and branching vessel patency as well as carotid wall integrity was indifferent between groups. Infarct volumes (p = 0.74) and neurological outcome (p = 0.82) were similar in both groups. Selective TH was feasible and safe. However, a larger number of subjects might be required to demonstrate efficacy.

scholarly journals MLC901 Favors Angiogenesis and Associated Recovery after Ischemic Stroke in Mice

2016 ◽  
Vol 42 (1-2) ◽  
pp. 139-154 ◽  
Author(s):  
Carine Gandin ◽  
Catherine Widmann ◽  
Michel Lazdunski ◽  
Catherine Heurteaux
Keyword(s):  
Ischemic Stroke ◽  
Neurovascular Unit ◽  
Artery Occlusion ◽  
Herbal Extract ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Preventive Action ◽  
Important Player ◽  
Endothelial Growth Factor ◽  
Cerebral Artery Occlusion

Background: There is increasing evidence that angiogenesis, through new blood vessel formation, results in improved collateral circulation and may impact the long-term recovery of patients. In this study, we first investigated the preventive action of a 5-week pretreatment of MLC901, an herbal extract preparation derived from Chinese medicine, against the deleterious effects of ischemic stroke and its effects on angiogenesis in a model of focal ischemia in mice. Methods: The stroke model was induced by 60 min of middle cerebral artery occlusion followed by reperfusion. MLC901 was administered in the drinking water of animals (6 g/l) for 5 weeks before ischemia and then during reperfusion. Results: MLC901 treatment increased the survival rate, reduced the cerebral infarct area and attenuated the blood brain barrier leakage as well as the neurologic dysfunction following ischemia and reperfusion. We provide evidence that MLC901 enhances endothelial cell proliferation and angiogenesis by increasing the number of neocortical vessels in the infarcted area. MLC901 regulates the expression of hypoxic inducible factor 1α and its downstream targets such as vascular endothelial growth factor and angiopoietins 1 and 2. This work also shows that erythropoietin is an important player in the enhancement of angiogenesis by MLC901. Conclusions: These results demonstrate therapeutic properties of MLC901, in addition to those previously described, in stimulating revascularization, neuroprotection and repair of the neurovascular unit after ischemic stroke.

scholarly journals Delayed inhibition of tonic inhibition enhances functional recovery following experimental ischemic stroke

2017 ◽  
Vol 39 (6) ◽  
pp. 1005-1014 ◽  
Author(s):  
James E Orfila ◽  
Himmat Grewal ◽  
Robert M Dietz ◽  
Frank Strnad ◽  
Takeru Shimizu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Ex Vivo ◽  
Long Term Potentiation ◽  
Artery Occlusion ◽  
Memory Impairments ◽  
Time Points ◽  
Term Potentiation ◽  
Cerebral Artery Occlusion

The current study focuses on the ability to improve cognitive function after stroke with interventions administered at delayed/chronic time points. In light of recent studies demonstrating delayed GABA antagonists improve motor function, we utilized electrophysiology, biochemistry and neurobehavioral methods to investigate the role of α5 GABAA receptors on hippocampal plasticity and functional recovery following ischemic stroke. Male C57Bl/6 mice were exposed to 45 min transient middle cerebral artery occlusion and analysis of synaptic and functional deficits performed 7 or 30 days after recovery. Our findings indicate that hippocampal long-term potentiation (LTP) is impaired 7 days after stroke and remain impaired for at least 30 days. We demonstrate that ex vivo administration of L655,708 reversed ischemia-induced plasticity deficits and importantly, in vivo administration at delayed time-points reversed stroke-induced memory deficits. Western blot analysis of hippocampal tissue reveals proteins responsible for GABA synthesis are upregulated (GAD65/67 and MAOB), increasing GABA in hippocampal interneurons 30 days after stroke. Thus, our data indicate that both synaptic plasticity and memory impairments observed after stroke are caused by excessive tonic GABA activity, making inhibition of specific GABA activity at delayed timepoints a potential therapeutic approach to improve functional recovery and reverse cognitive impairments after stroke.

scholarly journals Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem®-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke

2018 ◽  
Vol 19 (12) ◽  
pp. 3782 ◽  
Author(s):  
Kristine Ravina ◽  
Denise Briggs ◽  
Sezen Kislal ◽  
Zuha Warraich ◽  
Tiffany Nguyen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Neurotrophic Factor ◽  
Infarct Volume ◽  
Brain Derived Neurotrophic Factor ◽  
Artery Occlusion ◽  
Sensorimotor Function ◽  
Neural Repair ◽  
Adhesive Removal ◽  
Cerebral Artery Occlusion

Ischemic stroke is a leading cause of death and disability worldwide. Potential therapeutics aimed at neural repair and functional recovery are limited in their blood-brain barrier permeability and may exert systemic or off-target effects. We examined the effects of brain-derived neurotrophic factor (BDNF), delivered via an extended release HyStem®-C hydrogel implant or vehicle, on sensorimotor function, infarct volume, and neuroinflammation, following permanent distal middle cerebral artery occlusion (dMCAo) in rats. Eight days following dMCAo or sham surgery, treatments were implanted directly into the infarction site. Rats received either vehicle, BDNF-only (0.167 µg/µL), hydrogel-only, hydrogel impregnated with 0.057 µg/µL of BDNF (hydrogel + BDNFLOW), or hydrogel impregnated with 0.167 µg/µL of BDNF (hydrogel + BDNFHIGH). The adhesive removal test (ART) and 28-point Neuroscore (28-PN) were used to evaluate sensorimotor function up to two months post-ischemia. The hydrogel + BDNFHIGH group showed significant improvements on the ART six to eight weeks following treatment and their behavioral performance was consistently greater on the 28-PN. Infarct volume was reduced in rats treated with hydrogel + BDNFHIGH as were levels of microglial, phagocyte, and astrocyte marker immunoexpression in the corpus striatum. These data suggest that targeted intracerebral delivery of BDNF using hydrogels may mitigate ischemic brain injury and restore functional deficits by reducing neuroinflammation.

scholarly journals JNK-IN-8, a c-Jun N-terminal kinase inhibitor, improves functional recovery through suppressing neuroinflammation in ischemic stroke

2018 ◽  
Author(s):  
Hongli Tang ◽  
Qinxue Dai ◽  
Wandong Hong ◽  
Kunyuan Han ◽  
Danyun Jia ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Functional Recovery ◽  
Kinase Inhibitor ◽  
Neurological Function ◽  
Mitogen Activated Protein Kinase ◽  
Male Rats ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Tnf Α

Abstractc-Jun N-terminal kinase (JNK), a mitogen activated protein kinase, is activated in ischemia brain injury and plays an important role in cerebral ischemic injury. Emerging studies demonstrated that JNK-IN-8 (a specific JNK inhibitor) regulates traumatic brain injury through controlling neuronal apoptosis and inflammation. However, the role of JNK-IN-8 in ischemic stroke and the underlying mechanisms of JNK-IN-8 involving neuroprotection remain poorly understood. In the present study, male rats were subjected to tMCAO (transient middle cerebral artery occlusion) followed by treatment with JNK-IN-8, and then the modified improved neurological function score (mNSS), the Foot-fault test and the level of inflammatory cytokines (IL-1β, IL-6 and TNF-α) were assessed. We found that JNK-IN-8-treated rats with MCAO exerted a significant improvement in spatial learning as measured by the improved mNSS, and showed sensorimotor functional recovery as measured by the Foot-fault test. JNK-IN-8 also exerted anti-inflammatory effects as indicated by decreased activation of microglia and the decreased expresson of IL-6, IL-1β and TNF-α. Furthermore, JNK-IN-8 suppressed the activation of JNK and subsequent activation of NF-κB signaling as indicated by the decreased level of phosphorylated JNK (p-JNK) and p65. These data suggest that JNK-IN-8 suppressed neuroinflammation and improved neurological function by inhibiting JNK/NF-κB pathway after ischemic brain injury, thus offering a new target for prevention of ischemic brain injury.

scholarly journals Differential Effects of Physical and Social Enriched Environment on Angiogenesis in Male Rats After Cerebral Ischemia/Reperfusion Injury

2021 ◽  
Vol 15 ◽  
Author(s):  
Xin Zhang ◽  
Jing-Ying Liu ◽  
Wei-Jing Liao ◽  
Xiu-Ping Chen
Keyword(s):  
Reperfusion Injury ◽  
Functional Recovery ◽  
Environmental Enrichment ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Male Rats ◽  
Immunofluorescent Staining ◽  
Housing Conditions ◽  
Adhesive Removal

Different housing conditions, including housing space and the physiological and social environment, may affect rodent behavior. Here, we examined the effects of different housing conditions on post-stroke angiogenesis and functional recovery to clarify the ambiguity about environmental enrichment and its components. Male rats in the model groups underwent right middle cerebral artery occlusion (MCAO) followed by reperfusion. The MCAO rats were divided into four groups: the physical enrichment (PE) group, the social enrichment (SE) group, the combined physical and social enrichment (PSE) group and the ischemia/reperfusion + standard conditioning (IS) group. The rats in the sham surgery (SS) group were housed under standard conditions. In a set of behavioral tests, including the modified Neurological Severity Score (mNSS), rotarod test, and adhesive removal test, we demonstrated that the animals in the enriched condition groups exhibited significantly improved neurological functions compared to those in the standard housing group. Smaller infarction volumes were observed in the animals of the PSE group by MRI detection. The enriched conditions increased the microvessel density (MVD) in the ischemic boundary zone, as revealed by CD31 immunofluorescent staining. The immunochemical and q-PCR results further showed that environmental enrichment increased the expression levels of angiogenic factors after ischemia/reperfusion injury. Our data suggest that all three enrichment conditions promoted enhanced angiogenesis and functional recovery after ischemia/reperfusion injury compared to the standard housing, while only exposure to the combination of both physical and social enrichment yielded optimal benefits.

Abstract 12: S-Nitrosylation Invokes Functional Recovery from Experimental Stroke through the Hypoxia-inducible Factor-1 alpha/Vascular Endothelial Growth Factor Pathway

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Mushfiquddin Khan ◽  
Tajinder S Dhammu ◽  
Fumiyo Matsuda ◽  
Inderjit Singh ◽  
Avtar K Singh
Keyword(s):  
Functional Recovery ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Artery Occlusion ◽  
Tube Formation ◽  
Male Rats ◽  
Experimental Stroke ◽  
Capillary Endothelial Cells ◽  
Stimulation Of

Background: In stroke patients, the stimulation of neurorepair mechanisms is necessary to reduce morbidity and disability. Our studies on brain and spinal cord trauma show that an exogenous treatment with the S-nitrosylating agent S-nitrosoglutathione (GSNO) stimulates neurorepair and aids functional recovery. Using a rat model of cerebral ischemia reperfusion (IR), we tested the hypothesis that GSNO invokes the neurorepair process and improves neurobehavioral functions through the angiogenic HIF-1α/VEGF pathway. Methods: Stroke was induced by middle cerebral artery occlusion for 60 min followed by reperfusion in adult male rats. The injured animals were treated with vehicle (IR group, n=7), GSNO (0.25 mg/kg, GSNO group, n=7), and GSNO plus the HIF-1α inhibitor 2-mthoxyestradiol (0.25 mg/kg GSNO+5.0 mg/kg ME, GSNO+ME group, n=7). The groups were studied for 14 days to determine neurorepair mechanisms and functional recovery. Brain capillary endothelial cells were used to show that GSNO promotes angiogenesis and that GSNO-mediated induction of VEGF and the stimulation of angiogenesis are dependent on HIF-1α activity. Results: GSNO treatment of IR enhanced the expression of HIF-1α, VEGF, and PECAM-1. This GSNO treatment also led to increased expression of neurorepair mediators including BDNF. Increased expression of VEGF/BDNF and the degree of tube formation (angiogenesis) by GSNO were reduced in an endothelial cell culture model after the inhibition of HIF-1α by ME. ME treatment of the GSNO group also blocked not only GSNO’s effect of reduced infarct volume (p<0.05) and enhanced expression of PECAM-1but also its improvement of motor and neurological functions (p<0.001). Conclusions: GSNO shows therapeutic promise for stroke by stimulating the process of neurorepair and aiding functional recovery through the HIF-1α/VEGF/PECAM-1 dependent pathway.

Abstract WMP37: Neurovascular Protection by Telmisartan Via Reducing Neuroinflammation in SHR-SR Brain After Ischemic Stroke

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Syoichiro Kono ◽  
Tomoko Kurata ◽  
Kota Sato ◽  
Nozomi Hishikawa ◽  
Toru Yamashita ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Low Dose ◽  
Spontaneously Hypertensive Rat ◽  
Neurovascular Unit ◽  
Artery Occlusion ◽  
Collagen Iv ◽  
Vehicle Group ◽  
High Dose ◽  
Spontaneously Hypertensive ◽  
Hypertensive Rat

Telmisartan is a highly lipid soluble angiotensin receptor blocker (ARB) which improves insulin sensitivity and reduces triglyceride levels, thus is called metabo-sartan. We examined effects of telmisartan on neurovascular unit (NAGO, collagen IV, and GFAP) and neuroinflammation (MMP-9 and inflammasome) in brain of stroke-resistant spontaneously hypertensive rat (SHR-SR). At 12 weeks of age, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 min, and were divided into the following 3 groups, i.e., vehicle group, low-dose telmisartan group (0.3 mg/kg/day), and high-dose telmisartan group (3 mg/kg/day, p.o. ). Immunohistological analysis at ages 6, 12 and 18 months showed progressive decreases of NAGO-positive endothelium and collagen IV positive basement membrane, and progressive increases of MMP-9-positive neurons, GFAP-positive astrocytes, and NLRP3-positive inflammasome in the cerebral cortex of vehicle group. Low dose telmisartan reduced such changes without lowering blood pressure (BP), and high dose telmisartan further improved such changes with lowering BP. The present findings suggest that a persistent hypertension caused a long lasting inflammation after tMCAO in SHR-SR which accelerated neurovascular disruption and emergent inflammasome, and that telmisartan greatly reduced such inflammation and protected the neurovascular unit via its pleiotropic effects in living hypertensive rat brain after ischemic stroke.

scholarly journals Middle Cerebral Artery Occlusion Model in Rodents: Methods and Potential Pitfalls

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Fudong Liu ◽  
Louise D. McCullough
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Artery Occlusion ◽  
Stroke Model ◽  
Occlusion Model ◽  
Cerebral Artery Occlusion ◽  
Paradoxical Results ◽  
Age And Sex

A variety of animal models have been developed for modeling ischemic stroke. The middle cerebral artery occlusion (MCAO) model has been utilized extensively, especially in rodents. While the MCAO model provides stroke researchers with an excellent platform to investigate the disease, controversial or even paradoxical results are occasionally seen in the literature utilizing this model. Various factors exert important effects on the outcome in this stroke model, including the age and sex of the animal examined. This paper discusses emerging information on the effects of age and sex on ischemic outcomes after MCAO, with an emphasis on mouse models of stroke.

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