Post-stroke gaseous hypothermia increases vascular density but not neurogenesis in the ischemic penumbra of aged rats

Sandu, Raluca Elena; Uzoni, Adriana; Ciobanu, Ovidiu; Moldovan, Mihai; Anghel, Andrei; Radu, Eugen; Coogan, Andrew N.; Popa‐Wagner, Aurel

doi:10.3233/rnn-150600

Cited by 17 publications

(12 citation statements)

References 46 publications

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“…Epidemiological studies have found that morbidity of human stroke positive correlate to age, and aged brain does not respond exactly to ischemia compared to the young brain ( Popa-Wagner et al, 2006 ; Buga et al, 2014 ; Sandu et al, 2016 ). Based on this we will establish MCAO model in aged rats to observe TFC neuroprotective effects and its mechanism in future study, which are closer to the clinic and more persuasive.…”

Section: Discussionmentioning

confidence: 99%

Total Flavonoids in Caragana (TFC) Promotes Angiogenesis and Enhances Cerebral Perfusion in a Rat Model of Ischemic Stroke

Liu

et al. 2018

Front. Neurosci.

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Previous studies have demonstrated that total flavonoid extracts from Caragana sinica (TFC) exert multiple therapeutic effects, promote blood flow, and exhibit anti-inflammatory and antioxidant properties. The present study aimed to investigate whether TFC promotes angiogenesis and exerts neuroprotective effects in a rat model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats were subjected to tMCAO for 1.5 h, followed by 24 h of reperfusion. TFC (15, 30, 60 mg/kg) was administered for 14 days. Evaluations of neurological function were performed following reperfusion, and infarct volumes were assessed in brain slices stained with 2,3,5-triphenyltetrazolium chloride (TTC). Our results indicated that TFC significantly attenuated cerebral infarct volume and neurological deficits following tMCAO. Laser Doppler, micro-PET/CT, and MRI analyses further demonstrated that TFC reduced infarct volume and enhanced cerebral blood flow in a dose-dependent manner, with the most significant effects occurring at a concentration of 60 mg/kg. Significant up-regulation of CD31, VEGF, Ang-1, HIF-1α, delta-like 4 (Dll4), and Notch1 expression was also observed in the experimental groups, relative to that in the vehicle group. In summary, the results of the present study indicate that TFC (15, 30, 60 mg/kg) attenuates neurological deficits, reduces infarct volume, and promotes angiogenesis following MCAO in a concentration-dependent manner, likely via increases in the expression of CD31, VEGF, Ang-1, HIF-1α, Dll4, and Notch1. Further studies are required to determine the clinical usefulness and potential mechanisms of TFC in patients with cerebral focal ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Total Flavonoids in Caragana (TFC) Promotes Angiogenesis and Enhances Cerebral Perfusion in a Rat Model of Ischemic Stroke

Liu

et al. 2018

Front. Neurosci.

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“…Age is a principal risk factor for stroke. Previous studies showed that aged brain is capable of mounting a vigorous angiogenic response after stroke; however, the vast majority of angiogenic response genes showed delayed upregulation in the aged rats [ 37 , 38 ]. The Notch pathway is an ancient intercellular signaling mechanism, which is fundamental for the development of human tissues, organs, and systems.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of the Long Non-Coding RNA Meg3 Promotes Angiogenesis After Ischemic Brain Injury by Activating Notch Signaling

et al. 2016

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Angiogenesis after ischemic brain injury contributes to the restoration of blood supply in the ischemic zone. Strategies to improve angiogenesis may facilitate the function recovery after stroke. Recent researches have demonstrated that dysfunction of long non-coding RNAs are associated with angiogenesis. We have previously reported that long non-coding RNAs (lncRNAs) are aberrantly expressed in ischemic stroke. However, little is known about long non-coding RNAs and theirs role in angiogenesis after stroke. In this study, we identified a rat lncRNAs, Meg3, and found that Meg3 was significantly decreased after ischemic stroke. Overexpression of Meg3 suppressed functional recovery and decreased capillary density after ischemic stroke. Downregulation of Meg3 ameliorated brain lesion and increased angiogenesis after ischemic stroke. Silencing of Meg3 resulted in a proangiogenic effect evidenced by increased endothelial cell migration, proliferation, sprouting, and tube formation. Mechanistically, we showed that Meg3 negatively regulated notch pathway both in vivo and in vitro. Inhibition of notch signaling in endothelial cells reversed the proangiogenic effect induced by Meg3 downregulation. This study revealed the function of Meg3 in ischemic stroke and elucidated its mechanism in angiogenesis after ischemic stroke.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-016-0270-z) contains supplementary material, which is available to authorized users.

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“…Clinical application and feasibility in stroke patients, however, have been hampered by the logistic challenges of long duration cooling in humans (24–48 h) and concerns about rebound ICP complications during rewarming (Schwab et al, 1998 , 2001 ). Few studies have investigated hypothermia after experimental stroke in aged animals, and those that have (long duration gaseous hypothermia, 24–48 h) demonstrated temporary neuroprotection (Florian et al, 2008 ; Joseph et al, 2012 ; Sandu et al, 2016 ; Vintilescu et al, 2016 ). ICP, and thus rebound elevations during rewarming, however, were not measured in these studies.…”

Section: Discussionmentioning

confidence: 99%

Intracranial Pressure Elevation 24 h after Ischemic Stroke in Aged Rats Is Prevented by Early, Short Hypothermia Treatment

Murtha

Beard

Bourke

et al. 2016

Front. Aging Neurosci.

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Stroke is predominantly a senescent disease, yet most preclinical studies investigate treatment in young animals. We recently demonstrated that short-duration hypothermia-treatment completely prevented the dramatic intracranial pressure (ICP) rise seen post-stroke in young rats. Here, our aim was to investigate whether a similar ICP rise occurs in aged rats and to determine whether short-duration hypothermia is an effective treatment in aged animals. Experimental middle cerebral artery occlusion (MCAo-3 h occlusion) was performed on male Wistar rats aged 19–20 months. At 1 h after stroke-onset, rats were randomized to 2.5 h hypothermia-treatment (32.5°C) or normothermia (37°C). ICP was monitored at baseline, for 3.5 h post-occlusion, and at 24 h post-stroke. Infarct and edema volumes were calculated from histology. Baseline pre-stroke ICP was 11.2 ± 3.3 mmHg across all animals. Twenty-four hours post-stroke, ICP was significantly higher in normothermic animals compared to hypothermia-treated animals (27.4 ± 18.2 mmHg vs. 8.0 ± 5.0 mmHg, p = 0.03). Infarct and edema volumes were not significantly different between groups. These data demonstrate ICP may also increase 24 h post-stroke in aged rats, and that short-duration hypothermia treatment has a profound and sustained preventative effect. These findings may have important implications for the use of hypothermia in clinical trials of aged stroke patients.

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Post-stroke gaseous hypothermia increases vascular density but not neurogenesis in the ischemic penumbra of aged rats

Abstract: Long-term hypothermia may be a viable clinical approach by simultaneously targeting multiple processes including better tissue preservation, enhanced vascular density and improved behavioral performance.

Cited by 17 publications

References 46 publications

Total Flavonoids in Caragana (TFC) Promotes Angiogenesis and Enhances Cerebral Perfusion in a Rat Model of Ischemic Stroke

Total Flavonoids in Caragana (TFC) Promotes Angiogenesis and Enhances Cerebral Perfusion in a Rat Model of Ischemic Stroke

Downregulation of the Long Non-Coding RNA Meg3 Promotes Angiogenesis After Ischemic Brain Injury by Activating Notch Signaling

Intracranial Pressure Elevation 24 h after Ischemic Stroke in Aged Rats Is Prevented by Early, Short Hypothermia Treatment

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