Glial Scar Formation Occurs in the Human Brain after Ischemic Stroke

Huang, Lizhen; Wu, Zhe Bao; Zhuge, Qichuan; Zheng, Wei; Shao, Baiqi; Wang, Brian; Sun, Feng-Yan; Jin, Kunlin

doi:10.7150/ijms.8140

Cited by 136 publications

(95 citation statements)

References 14 publications

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“…Our data suggest that SB505124 be considered as a potential therapeutic either alone, or after pre-clinical evaluation, as an adjunct to hypothermia to improve neurologic outcome. Since delayed inflammation and glial scar formation are also critical events in other forms of developmental brain injuries as well as for injuries sustained by adults such as stroke, spinal cord injury and traumatic brain injury, 58,59 SB505124 should be evaluated in animal models of these pathologies as well.…”

Section: Discussionmentioning

confidence: 99%

Delayed ALK5 inhibition improves functional recovery in neonatal brain injury

Clausi

Levison

2016

J Cereb Blood Flow Metab

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Neuroinflammation subsequent to developmental brain injury contributes to a wave of secondary neurodegeneration and to reactive astrogliosis that can inhibit oligodendrocyte progenitor differentiation and subsequent myelination. Here we evaluated the therapeutic efficacy of a small molecule antagonist for a TGFß receptor in a model of moderate perinatal hypoxia-ischemia (H-I). Osmotic pumps containing SB505124, an antagonist of the type 1 TGFß1 receptor ALK5, or vehicle, were implanted three days after H-I induced at postnatal day 6. Perinatal H-I induced selective neuronal death, ventriculomegaly, elevated CNS levels of IL-6 and IL-1a, astrogliosis, and fewer proliferating oligodendrocyte progenitors. Myelination was reduced by $50%. Anterograde tracing revealed extensive axonal loss in the corticospinal tract. These alterations correlated with functional impairments across a battery of behavioral tests. All of these parameters were brought back towards normal levels with SB505124 treatment. Notably, SB505124 preserved neurons in the hippocampus and thalamus. Our results indicate that inhibiting ALK5 signaling, even as late as three days after injury, creates an environment that is more permissive for oligodendrocyte maturation and myelination producing significant improvements in neurological outcome. This new therapeutic would be especially appropriate for moderately preterm asphyxiated infants, for whom there is presently no FDA approved neuroprotective therapeutic.

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Section: Discussionmentioning

confidence: 99%

Delayed ALK5 inhibition improves functional recovery in neonatal brain injury

Clausi

Levison

2016

J Cereb Blood Flow Metab

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“…It has been earlier shown that the concentration of MT is generally down-regulated [11 -13] and that of GFAP is up-regulated [2,31,32] under various harmful conditions, while under those same conditions, changes in vimentin and GFAP levels are simultaneous [2]. All of these are changes that occur under the processes of the major pathological role played by astrocytes in the brain and spinal cord [2].…”

Section: Resultsmentioning

confidence: 91%

Corvitin restores metallothionein and glial fibrillary acidic protein levels in rat brain affected by pituitrin-izadrin

Shiyntum¹,

Dovban²,

Kovalchuk³

et al. 2017

Ukr.Biochem.J.

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In this research, we investigated the effect of pituitrin-izadrin induced injury on the levels of metallothionein (MT) and soluble and filament forms of glial fibrillary acidic protein (GFAP) in the hippocampusA strocytes are amongst the earliest and prominent to express changes under attacks [1]. They are the most numerous nonneuronal cell types in the central nervous system (CNS) and make up about 50% of the volume of the human brain [1,2]. Their functions are known to be critical, such as scavenge transmitters released during synaptic activity, control ion and water homeostasis, release neurotrophic factors, shuttle metabolite, and waste products, and to participate in the formation of the blood-brain-barrier [3,4]. Failure of any of these supportive functions of astrocytes will constitute a threat to neuronal survival. Astrocytes are home to a number of essential proteins of the CNS, including metallothionein and glial fibrillary acidic protein, which presumably carry out some astrocyte functions.Metallothioneins (MTs) are cysteine-rich, low molecular weight, heat stable proteins firstly described by Margoshes [5]. They are largely synthesized in the liver and the kidney in humans but are found at a number of other sites. In the CNS, MT-I and MT-II are conspicuously absent from neuronal populations, yet abundant in fibrous and protoplasmic astrocytes. MT is detectable in the extracellular fluid of the injured brain and astrocytes are capable of secreting MT in a regulatable manner [6].MTs have been implicated as regulatory molecules in gene expression, homeostatic control of cellular metabolism of metals, and cellular adaptation to stress. Thus, they fulfill a regulatory capacity and influence transcription, replication, protein synthesis, metabolism, as well as other zinc-dependent biological processes [7]. It has been shown that the ability of animals to recover from CNS injuries or degenerative diseases depends on the deficiency or excess availability of MT-I/-II [7][8][9][10][11]. MT has equally been demonstrated to be down-regulated in cases of induced intoxication [12] and infection [13] but its correlated effect to other astrocyte proteins has yet to be tested.GFAP is expressed in mature astrocytes in the CNS [14]. It is a member of the family of cytoskeletal proteins and is the primary intermediate filament with a size of 8-9 nm, highly specific to the CNS. However, it has been found outside the CNS in relatively low amounts [15]. It has two physicochemical GFAP forms: water-soluble (sGFAP) and filament (fGFAP) [16]. The sGFAP is unevenly distributed in various brain regions, with the maximum con-

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“…The major contributor to injuries following reperfusion is the reactive oxygen species (ROS) generated both from inflammatory cells and damaged mitochondria (Manzanero et al 2013). Pathologically, similar to the microscopic changes observed in animal models of stroke, evidence of reactive gliosis has been reported in human subjects after ischemic stroke including increased numbers of glial fibrillary acidic protein (GFAP)-positive reactive astrocytes and ED1-positive activated microglia as well as enhanced expression of chondroitin sulphate proteoglycans (CSPG) in the cortical penumbra regions (Huang et al 2014). Hence, stroke involves a series of pathological changes that require a number of corresponding measures for the subsequent repairing.…”

Section: Therapeutic Actions Of Adsc Implicated In Pathophysiologicalmentioning

confidence: 79%

Transplantation of Adipose-Derived Stem Cells in Stroke

Sun

2014

Cellular Therapy for Stroke and CNS Injuries

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Glial Scar Formation Occurs in the Human Brain after Ischemic Stroke

Cited by 136 publications

References 14 publications

Delayed ALK5 inhibition improves functional recovery in neonatal brain injury

Delayed ALK5 inhibition improves functional recovery in neonatal brain injury

Corvitin restores metallothionein and glial fibrillary acidic protein levels in rat brain affected by pituitrin-izadrin

Transplantation of Adipose-Derived Stem Cells in Stroke

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