Minocycline ameliorates hypoxia-induced blood–brain barrier damage by inhibition of HIF-1α through SIRT-3/PHD-2 degradation pathway

Yang, Fang; Zhou, Lingsha; Wang, D.; Wang, Z.; Huang, Qianyi

doi:10.1016/j.neuroscience.2015.07.051

Cited by 55 publications

(33 citation statements)

References 36 publications

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“…Mitochondrial dysfunction is identified as a major contributor to the early brain injury of SAH [22,23].Herein, we explored the role of SIRT3, which is a NAD + -dependent deacetylase located in mitochondria, in SAH-induced brain injury. Previous researches indicated that SIRT3 protected against brain injury by inhibiting the activation of HIF1a and ROS-mediated oxidative damage [24]. In this experiment, we found the protein level and deacetylation function of SIRT3 were significantly decreased after SAH.…”

Section: Discussionmentioning

confidence: 48%

SIRT3 protects against early brain injury following subarachnoid hemorrhage via promoting mitochondrial fusion in an AMPK dependent manner

Luo

Liu

et al. 2020

Chin Neurosurg Jl

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Background: Subarachnoid hemorrhage (SAH), an acute cerebrovascular accident, features with its high death and disability rate. Sirtuin3 (SIRT3) is a NAD+ dependent deacetylase which mainly located in mitochondria. Reduced SIRT3 function was indicated to involve in many disorders of central nervous system. Herein, we aimed to explore the neuroprotective effects of SIRT3 on SAH and to furtherly explore the underlying mechanisms. Methods: Adult C57BL/6 J male mice (8-10 weeks) were used to establish SAH models. The pharmacological agonist of SIRT3, Honokiol (HKL), was injected in an intraperitoneal manner (10 mg/kg) immediately after the operation. Brain edema and neurobehavioral score were assessed. Nissl staining and FJC staining were used to evaluate the extent of neuronal damage. The changes of mitochondria morphology were observed with transmission electron microscopy. Western blot was used for analyzing the protein level of SIRT3 and the downstream signaling molecules. Result: SIRT3 was downregulated after SAH, and additional treatment of SIRT3 agonist HKL alleviated brain edema and neurobehavioral deficits after SAH. Additionally, electron microscopy showed that HKL significantly alleviated the morphological damage of mitochondria induced by SAH. Further studies showed that HKL could increase the level of mitochondrial fusion protein Mfn1 and Mfn2, thus maintaining (mitochondrial morphology), protecting mitochondrial function and promoting neural survival. While, additional Compound C (CC) treatment, a selective AMPK inhibitor, abolished these protective effects. Conclusions: Activation of SIRT3 protects against SAH injury through improving mitochondrial fusion in an AMPK dependent manner.

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Section: Discussionmentioning

confidence: 48%

SIRT3 protects against early brain injury following subarachnoid hemorrhage via promoting mitochondrial fusion in an AMPK dependent manner

Luo

Liu

et al. 2020

Chin Neurosurg Jl

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“…To test whether there was a causal relation between increased microglia and impaired white matter function after cerebral hypoperfusion we investigated the effect of minocycline. This drug, can readily penetrate the blood brain barrier, and it has been shown to improve white matter structure (Jalal et al, ; Yang et al, ; Yrjänheikki et al, ). The current study provided new information to show that minocycline has beneficial effects both restoring the functional impairment induced by hypoperfusion and reducing microglia number.…”

Section: Discussionmentioning

confidence: 99%

Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease

Manso

Holland

Kitamura

et al. 2017

Glia

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Chronic cerebral hypoperfusion is a key mechanism associated with white matter disruption in cerebral vascular disease and dementia. In a mouse model relevant to studying cerebral vascular disease, we have previously shown that cerebral hypoperfusion disrupts axon-glial integrity and the distribution of key paranodal and internodal proteins in subcortical myelinated axons. This disruption of myelinated axons is accompanied by increased microglia and cognitive decline. The aim of the present study was to investigate whether hypoperfusion impairs the functional integrity of white matter, its relation with axon-glial integrity and microglial number, and whether by targeting microglia these effects can be improved. We show that in response to increasing durations of hypoperfusion, the conduction velocity of myelinated fibres in the corpus callosum is progressively reduced and that paranodal and internodal axon-glial integrity is disrupted. The number of microglial cells increases in response to hypoperfusion and correlates with disrupted paranodal and internodal integrity and reduced conduction velocities. Further minocycline, a proposed antiinflammatory and microglia inhibitor, restores white matter function related to a reduction in the number of microglia. The study suggests that microglial activation contributes to the structural and functional alterations of myelinated axons induced by cerebral hypoperfusion and that dampening microglia numbers/proliferation should be further investigated as potential therapeutic benefit in cerebral vascular disease. K E Y W O R D Sblood flow, conduction velocity, microglia, minocycline, white matter integrity

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“…For example, minocycline has been demonstrated to reduce hemorrhage frequency and increase endothelial tight junction and basement membrane proteins in aged 5xFAD/ APOE4 transgenic mice [201]. Furthermore, recent studies showed that minocycline significantly reduced the infarct size, prevented tissue loss, improved perfusion, reduced BBB permeability, and increased tight junction protein levels in spontaneously hypertensive stroke-prone rats [205,206]. Future studies should determine the benefit of CypA and MMP-9 inhibitors on vascular dysfunction in AD and APOE transgenic mouse models.…”

Section: Vasculoprotective Approachesmentioning

confidence: 99%

Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease

Nelson

Sweeney

Sagare

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

418

414

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Vascular insults can initiate a cascade of molecular events leading to neurodegeneration, cognitive impairment and dementia. Here, we review the cellular and molecular mechanisms in cerebral blood vessels and the pathophysiological events leading to cerebral blood flow dysregulation and disruption of the neurovascular unit and the blood-brain barrier, which all may contribute to the onset and progression of dementia and Alzheimer’s disease (AD). Particularly, we examine the link between neurovascular dysfunction and neurodegeneration including the effects of AD genetic risk factors on cerebrovascular functions and clearance of Alzheimer’s amyloid-β peptide toxin, and the impact of vascular risk factors, environment and lifestyle on cerebral blood vessels, which in turn may affect synaptic, neuronal and cognitive functions. Finally, we examine potential experimental treatments for dementia and AD based on the neurovascular model, and discuss some critical questions to be addressed by future studies.

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Minocycline ameliorates hypoxia-induced blood–brain barrier damage by inhibition of HIF-1α through SIRT-3/PHD-2 degradation pathway

Cited by 55 publications

References 36 publications

SIRT3 protects against early brain injury following subarachnoid hemorrhage via promoting mitochondrial fusion in an AMPK dependent manner

SIRT3 protects against early brain injury following subarachnoid hemorrhage via promoting mitochondrial fusion in an AMPK dependent manner

Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease

Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease

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