Retinoic acid ameliorates blood–brain barrier disruption following ischemic stroke in rats

Kong, Liang; Wang, Yue; Wang, Xiaojing; Wang, Xiaotong; Zhao, Yan; Wang, Limei; Chen, Zhe-Yu

doi:10.1016/j.phrs.2015.05.014

Cited by 55 publications

(36 citation statements)

References 66 publications

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“…Zhu found that RA reduced infarct size and cardiomyocyte apoptosis in myocardial ischemia/reperfusion (I/R) injury [ 33 ]. Kong suggested that RA may serve as a new therapeutic approach to prevent blood brain barrier (BBB) dysfunction and tPA-induced rat ICH in ischemic stroke, and the protective effect of RA on the BBB was dependent on RARα [ 34 ]. The hippocampal TUNEL test demonstrated that VAN decreased the apoptosis in the CA1, CA3, and DG regions at the acute stage of HIBD.…”

Section: Discussionmentioning

confidence: 99%

Vitamin A bio-modulates apoptosis via the mitochondrial pathway after hypoxic-ischemic brain damage

et al. 2018

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Our previous studies demonstrated that vitamin A deficiency (VAD) can impair the postnatal cognitive function of rats by damaging the hippocampus. The present study examined the effects of retinoic acid (RA) on apoptosis induced by hypoxic-ischemic damage in vivo and in vitro, and investigated the possible signaling pathway involved in the neuroprotective anti-apoptotic effects of RA. Flow cytometry, immunofluorescence staining and behavioral tests were used to evaluate the neuroprotective and anti-apoptotic effects of RA. The protein and mRNA levels of RARα, PI3K, Akt, Bad, caspase-3, caspase-8, Bcl-2, Bax, and Bid were measured with western blotting and real-time PCR, respectively. We found impairments in learning and spatial memory in VAD group compared with vitamin A normal (VAN) and vitamin A supplemented (VAS) group. Additionally, we showed that hippocampal apoptosis was weaker in the VAN group than that in VAD group. Relative to the VAD group, the VAN group also had increased mRNA and protein levels of RARα and PI3K, and upregulated phosphorylated Akt/Bad levels in vivo. In vitro, excessively low or high RA signaling promoted apoptosis. Furthermore, the effects on apoptosis involved the mitochondrial membrane potential (MMP). These data support the idea that sustained VAD following hypoxic-ischemic brain damage (HIBD) inhibits RARα, which downregulates the PI3K/Akt/Bad and Bcl-2/Bax pathways and upregulates the caspase-8/Bid pathway to influence the MMP, ultimately producing deficits in learning and spatial memory in adolescence. This suggests that clinical interventions for HIBD should include suitable doses of VA.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0360-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Vitamin A bio-modulates apoptosis via the mitochondrial pathway after hypoxic-ischemic brain damage

et al. 2018

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“…Reports in the stroke literature regarding the effect of exogenous treatment of RA on focal ischemic injury generally conclude that RA is beneficial though different stroke models and exogenous RA treatment regimens were used. Exogenous RA results in a smaller lesion [ 6 , 24 ], improved blood brain barrier integrity [ 24 ], reduced neuroinflammatory response accompanied by decreased hippocampal cell death and improved behavioral recovery [ 22 ], and increased neurogenesis and improved neurobehavioral outcomes when coupled with environmental enrichment [ 42 ]. Possibly, endogenous RA synthesis mediated by PSCs and macrophages that we describe here has similar effects as reported for exogenous RA in the post-stroke environment.…”

Section: Discussionmentioning

confidence: 99%

Col1a1+ perivascular cells in the brain are a source of retinoic acid following stroke

et al. 2016

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BackgroundPerivascular stromal cells (PSCs) are a recently identified cell type that comprises a small percentage of the platelet derived growth factor receptor-β+ cells within the CNS perivascular space. PSCs are activated following injury to the brain or spinal cord, expand in number and contribute to fibrotic scar formation within the injury site. Beyond fibrosis, their high density in the lesion core makes them a potential significant source of signals that act on neural cells adjacent to the lesion site.ResultsOur developmental analysis of PSCs, defined by expression of Collagen1a1 in the maturing brain, revealed that PSCs first appear postnatally and may originate from the meninges. PSCs express many of the same markers as meningeal fibroblasts, including expression of the retinoic acid (RA) synthesis proteins Raldh1 and Raldh2. Using a focal brain ischemia injury model to induce PSC activation and expansion, we show a substantial increase in Raldh1+/Raldh2+ PSCs and Raldh1+ activated macrophages in the lesion core. We find that RA levels are significantly elevated in the ischemic hemisphere and induce signaling in astrocytes and neurons in the peri-infarct region.ConclusionsThis study highlights a dual role for activated, non-neural cells where PSCs deposit fibrotic ECM proteins and, along with macrophages, act as a potentially important source of RA, a potent signaling molecule that could influence recovery events in a neuroprotective fashion following brain injury.

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“…While endothelial tight junctions are formed by proteins such as claudin, occludin and zonula occluden (ZO), the basal lamina forms the basement membrane of ECM and includes laminin, collagen, and fibronectin [177,178]. Astrocyte-derived factors including angiopoietin-1 (ANG-1) [179][180][181], sonic hedgehog (SHH) [182][183][184][185], glial-derived neurotrophic factor (GDNF) [186][187][188], retinoic acid (RA) [189][190][191], and IGF-1 [192,193] have been demonstrated to promote recovery of the BBB by protecting endothelial cells and/or enhancing tight junction reassembly, via signaling mediated by their receptors, tie-2, patched-1, GDNF receptor alpha-1 and alpha-2, nuclear RA receptor, and IGF-1 receptor, respectively [78,79] (Table. 1).…”

Section: The Bbb Integrity-promoting Effects Of Astrocytesmentioning

confidence: 99%

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

et al. 2020

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Traumatic brain injury (TBI) is one of the leading causes of fatality and disability worldwide. Despite its high prevalence, effective treatment strategies for TBI are limited. Traumatic brain injury induces structural and functional alterations of astrocytes, the most abundant cell type in the brain. As a way of coping with the trauma, astrocytes respond in diverse mechanisms that result in reactive astrogliosis. Astrocytes are involved in the physiopathologic mechanisms of TBI in an extensive and sophisticated manner. Notably, astrocytes have dual roles in TBI, and some astrocyte-derived factors have double and opposite properties. Thus, the suppression or promotion of reactive astrogliosis does not have a substantial curative effect. In contrast, selective stimulation of the beneficial astrocytederived molecules and simultaneous attenuation of the deleterious factors based on the spatiotemporalenvironment can provide a promising astrocyte-targeting therapeutic strategy. In the current review, we describe for the first time the specific dual roles of astrocytes in neuronal plasticity and reconstruction, including neurogenesis, synaptogenesis, angiogenesis, repair of the blood-brain barrier, and glial scar formation after TBI. We have also classified astrocyte-derived factors depending on their neuroprotective and neurotoxic roles to design more appropriate targeted therapies.

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Retinoic acid ameliorates blood–brain barrier disruption following ischemic stroke in rats

Cited by 55 publications

References 66 publications

Vitamin A bio-modulates apoptosis via the mitochondrial pathway after hypoxic-ischemic brain damage

Vitamin A bio-modulates apoptosis via the mitochondrial pathway after hypoxic-ischemic brain damage

Col1a1+ perivascular cells in the brain are a source of retinoic acid following stroke

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

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