Sustained Functional Improvement by Hepatocyte Growth Factor-Like Small Molecule BB3 after Focal Cerebral Ischemia in Rats and Mice

Chaparro, Rafael E; Izutsu, Miwa; Sasaki, Toshihiro; Sheng, Huaxin; Zheng, Yi; Sadeghian, Homa; Qin, Tao; Bornstädt, Daniel von; Herisson, Fanny; Duan, Bin; Li, Jingsong; Jiang, Kai; Pearlstein, Molly; Pearlstein, Robert D.; Smith, David Eugene; Goldberg, Itzhak D.; Ayata, Cenk; Warner, David S.

doi:10.1038/jcbfm.2015.23

Cited by 19 publications

(19 citation statements)

References 42 publications

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“…18 Briefly, mice were anesthetized with isoflurane, intubated, and ventilated. The rectal temperature was maintained at 37°C ± 0.2°C throughout the procedure.…”

Section: Methodsmentioning

confidence: 99%

XBP1 (X-Box–Binding Protein-1)–Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G

Jiang

Zhang

et al. 2017

Stroke

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Background and Purpose Impaired protein homeostasis induced by endoplasmic reticulum (ER) dysfunction is a key feature of a variety of age-related brain diseases including stroke. To restore ER function impaired by stress, the unfolded protein response (UPR) is activated. A key UPR pro-survival pathway is controlled by the ER stress sensor inositol-requiring enzyme-1 (IRE1), downstream X-box binding protein-1 (XBP1), and O-linked b-N-acetylglucosamine (O-GlcNAc) modification of proteins (O-GlcNAcylation). Stroke impairs ER function, which activates UPR. The rationale of this study was to explore the potentials of the IRE1/XBP1/O-GlcNAc axis as a target for neuroprotection in ischemic stroke. Methods Mice with Xbp1 loss- and gain-of-function in neurons were generated. Stroke was induced by transient or permanent occlusion of the middle cerebral artery (MCAO) in young and aged mice. Thiamet-G was used to increase O-GlcNAcylation. Results Deletion of Xbp1 worsened outcome after transient and permanent MCAO. After stroke, O-GlcNAcylation was activated in neurons of the stroke penumbra in young mice, which was largely Xbp1-dependent. This activation of O-GlcNAcylation was impaired in aged mice. Pharmacologic increase of O-GlcNAcylation before or after stroke improved outcome in both young and aged mice. Conclusions Our study indicates a critical role for the IRE1/XBP1 UPR branch in stroke outcome. O-GlcNAcylation is a pro-survival pathway that is activated in the stroke penumbra in young mice but impaired in aged mice. Boosting pro-survival pathways to counterbalance the age-related decline in the brain’s self-healing capacity could be a promising strategy to improve ischemic stroke outcome in aged brains.

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“…18 Briefly, mice were anesthetized with isoflurane, intubated, and ventilated. The rectal temperature was maintained at 37°C ± 0.2°C throughout the procedure.…”

Section: Methodsmentioning

confidence: 99%

XBP1 (X-Box–Binding Protein-1)–Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G

Jiang

Zhang

et al. 2017

Stroke

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“…Transient middle cerebral artery occlusion (MCAO) was performed as described previously with minor modifications. 18 Briefly, male mice (2–3 months old) were anesthetized with 5% isoflurane in 30% O 2 balanced with N 2 O. Mice were then endotracheally intubated and mechanically ventilated.…”

Section: Methodsmentioning

confidence: 99%

Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome

Zhang

Sheng

Liu

et al. 2016

J Cereb Blood Flow Metab

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Impaired function of the endoplasmic reticulum (ER stress) is a hallmark of many human diseases including stroke. To restore ER function in stressed cells, the unfolded protein response (UPR) is induced, which activates 3 ER stress sensor proteins including activating transcription factor 6 (ATF6). ATF6 is then cleaved by proteases to form the short-form ATF6 (sATF6), a transcription factor. To determine the extent to which activation of the ATF6 UPR branch defines the fate and function of neurons after stroke, we generated a conditional and tamoxifen-inducible sATF6 knock-in mouse. To express sATF6 in forebrain neurons, we crossed our sATF6 knock-in mouse line with Emx1-Cre mice to generate ATF6-KI mice. After the ATF6 branch was activated in ATF6-KI mice with tamoxifen, mice were subjected to transient middle cerebral artery occlusion. Forced activation of the ATF6 UPR branch reduced infarct volume and improved functional outcome at 24 h after stroke. Increased autophagic activity at early reperfusion time after stroke may contribute to the ATF6-mediated neuroprotection. We concluded that the ATF6 UPR branch is crucial to ischemic stroke outcome. Therefore, boosting UPR pro-survival pathways may be a promising therapeutic strategy for stroke.

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“…This compound crosses the BBB and does not need to be manufactured by recombinant methods at high cost compared to HGF, which represents an obvious advantage. Another BBB-crossing molecule with HGF-like activity, BB3, was employed in pre-clinical models of stroke, showing good functional improvements ( Chaparro et al, 2015 ). A small molecule enhancing MET activity (the MET agonist NDX-1017 or ATH-1017) was recently tested in AD patients (NCT03298672), resulting in positive outcomes in terms of brain network activity, even if larger studies need to be performed to show more robust and statistically significant results.…”

Section: Therapeutical Potential Of Hgf and Hgf Mimetics In Neurological Disordersmentioning

confidence: 99%

HGF and MET: From Brain Development to Neurological Disorders

Desole

Gallo

Vitacolonna

et al. 2021

Front. Cell Dev. Biol.

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Hepatocyte growth factor (HGF) and its tyrosine kinase receptor, encoded by the MET cellular proto-oncogene, are expressed in the nervous system from pre-natal development to adult life, where they are involved in neuronal growth and survival. In this review, we highlight, beyond the neurotrophic action, novel roles of HGF-MET in synaptogenesis during post-natal brain development and the connection between deregulation of MET expression and developmental disorders such as autism spectrum disorder (ASD). On the pharmacology side, HGF-induced MET activation exerts beneficial neuroprotective effects also in adulthood, specifically in neurodegenerative disease, and in preclinical models of cerebral ischemia, spinal cord injuries, and neurological pathologies, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). HGF is a key factor preventing neuronal death and promoting survival through pro-angiogenic, anti-inflammatory, and immune-modulatory mechanisms. Recent evidence suggests that HGF acts on neural stem cells to enhance neuroregeneration. The possible therapeutic application of HGF and HGF mimetics for the treatment of neurological disorders is discussed.

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Sustained Functional Improvement by Hepatocyte Growth Factor-Like Small Molecule BB3 after Focal Cerebral Ischemia in Rats and Mice

Cited by 19 publications

References 42 publications

XBP1 (X-Box–Binding Protein-1)–Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G

XBP1 (X-Box–Binding Protein-1)–Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G

Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome

HGF and MET: From Brain Development to Neurological Disorders

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