Growth differentiation factor 11 improves neurobehavioral recovery and stimulates angiogenesis in rats subjected to cerebral ischemia/reperfusion

Ma, Jue; Zhang, Lina; Niu, Tengfei; Ai, Chibo; Jia, Gongwei; Jin, Xinhao; Li, Wen; Zhang, Keming; Zhang, Qinbin; Li, Changqing

doi:10.1016/j.brainresbull.2018.02.011

Cited by 50 publications

(47 citation statements)

References 40 publications

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“…Recently, there have been conflicting results regarding the role of GDF11 in aging heart and skeletal muscle 45 – 49 . However, our initial report 11 , studies from four independent labs 50 – 53 , and work presented here consistently support the conclusion that GDF11 has a positive influence on the aging CNS. Furthermore, since multiple other circulating factors have been shown to affect CNS function in old mice, there seems to be little doubt that the CNS is a surprisingly responsive target for blood-borne factors.…”

Section: Discussionsupporting

confidence: 82%

“…Whether GDF11-treated old mice exhibit improved cognition through olfactory discrimination tasks and/or hippocampus-dependent spatial navigation tasks also needs further research. Notably, recent studies have shown improved neurocognitive behavior in rodents treated with GDF11 in stroke 50 , 53 and AD 52 models. Therefore, it is feasible that systemic GDF11 treatment also could lead to enhanced cognition in aging.…”

Section: Discussionmentioning

confidence: 99%

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Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice

Ozek

Krolewski

Buchanan

et al. 2018

Sci Rep

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Aging is the biggest risk factor for several neurodegenerative diseases. Parabiosis experiments have established that old mouse brains are improved by exposure to young mouse blood. Previously, our lab showed that delivery of Growth Differentiation Factor 11 (GDF11) to the bloodstream increases the number of neural stem cells and positively affects vasculature in the subventricular zone of old mice. Our new study demonstrates that GDF11 enhances hippocampal neurogenesis, improves vasculature and increases markers of neuronal activity and plasticity in the hippocampus and cortex of old mice. Our experiments also demonstrate that systemically delivered GDF11, rather than crossing the blood brain barrier, exerts at least some of its effects by acting on brain endothelial cells. Thus, by targeting the cerebral vasculature, GDF11 has a very different mechanism from that of previously studied circulating factors acting to improve central nervous system (CNS) function without entering the CNS.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice

Ozek

Krolewski

Buchanan

et al. 2018

Sci Rep

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“…48 A previous study effectively demonstrated the neuroprotective potential of GDF11 in stroke. 49 , 50 GDF11 functions by phosphorylating and activating Smad3, similar to TGF-β. Activation of TGF-β signaling has diverse functions, including an increase in angiogenesis and neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling

Chen

Wang

Feng

et al. 2020

Molecular Therapy - Nucleic Acids

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Circular RNAs (circRNAs) are expressed at high levels in the brain and are involved in various central nervous system diseases. However, the potential role of circRNAs in ischemic stroke-associated neuronal injury remains largely unknown. Herein, we uncovered the function and underlying mechanism of the circRNA UCK2 (circUCK2) in ischemia stroke. The oxygen-glucose deprivation model in HT-22 cells was used to mimic ischemia stroke in vitro . Neuronal viability and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assays and TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling) staining, respectively. Middle cerebral artery occlusion was conducted to evaluate the function of circUCK2 in mice. The levels of circUCK2 were significantly decreased in brain tissues from a mouse model of focal cerebral ischemia and reperfusion. Upregulated circUCK2 levels significantly decreased infarct volumes, attenuated neuronal injury, and improved neurological deficits. circUCK2 reduced oxygen glucose deprivation (OGD)-induced cell apoptosis by regulating transforming growth factor β (TGF-β)/mothers against decapentaplegic homolog 3 (Smad3) signaling. Furthermore, circUCK2 functioned as an endogenous miR-125b-5p sponge to inhibit miR-125b-5p activity, resulting in an increase in growth differentiation factor 11 (GDF11) expression and a subsequent amelioration of neuronal injury. Consequently, these findings showed that the circUCK2/miR-125b-5p/GDF11 axis is an essential signaling pathway during ischemia stroke. Thus, the circRNA circUCK2 may serve as a potential target for novel treatment in patients with ischemic stroke.

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“…Subsequently, other reports argued that GDF11 was positively associated with aging, cachexia, and inhibition of muscle regeneration in aged mice (Egerman et al, ; Harper et al, ; Jones et al, ), while different studies showed a beneficial role for GDF11 in the periphery (Poggioli et al, ; Su et al, ; Walker et al, ). In the central nervous system, GDF11 was also shown to be neuroprotective for neurovascular recovery and neurogenesis (Anqi, Ruiqi, Yanming, & Chao, ; Ma et al, ; Ozek, Krolewski, Buchanan, & Rubin, ; Schafer & LeBrasseur, ; Zhang et al, ).…”

Section: Introductionmentioning

confidence: 99%

Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction‐like phenotype in aged mice

et al. 2019

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Aging is a negative regulator of general homeostasis, tissue function, and regeneration. Changes in organismal energy levels and physiology, through systemic manipulations such as calorie restriction and young blood infusion, can regenerate tissue activity and increase lifespan in aged mice. However, whether these two systemic manipulations could be linked has never been investigated. Here, we report that systemic GDF11 triggers a calorie restriction-like phenotype without affecting appetite or GDF15 levels in the blood, restores the insulin/IGF-1 signaling pathway, and stimulates adiponectin secretion from white adipose tissue by direct action on adipocytes, while repairing neurogenesis in the aged brain. These findings suggest that GDF11 has a pleiotropic effect on an organismal level and that it could be a linking mechanism of rejuvenation between heterochronic parabiosis and calorie restriction. As such, GDF11 could be considered as an important therapeutic candidate for age-related neurodegenerative and metabolic disorders. K E Y W O R D Sadiponectin, aging, calorie restriction, GDF11, heterochronic parabiosis, rejuvenation | 9 of 11 KATSIMPARDI eT Al. GDF11 (Peprotech, was dissolved in water, further diluted according to the manufacturer's instructions, and injected at a concentration of 1 mg/kg. Control mice (young or aged) were injected with equivalent volumes of saline. Injection concentration was chosen based on a pilot study with three different concentrations (0.1, 0.5, and 1.0 mg/kg) where consistent weight loss and brain rejuvenation were observed upon 1 mg/kg GDF11 administration. The half-life of GDF11 at these concentrations was found to be of 12 hr. | GDF11 administration

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Growth differentiation factor 11 improves neurobehavioral recovery and stimulates angiogenesis in rats subjected to cerebral ischemia/reperfusion

Cited by 50 publications

References 40 publications

Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice

Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice

RETRACTED: Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling

Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction‐like phenotype in aged mice

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