Gliotoxicity and Glioprotection: the Dual Role of Glial Cells

Quincozes‐Santos, André; Santos, Camila Leite; Almeida, Rômulo Rodrigo de Souza; Silva, Amanda da; Thomaz, Natalie K.; Costa, Naithan Ludian Fernandes; Weber, Fernanda Becker; Schmitz, Izaviany; Medeiros, Lara Scopel; Medeiros, L.; Dotto, Bethina Segabinazzi; Dias, Filipe Renato Pereira; Sovrani, Vanessa; Bobermin, Larissa Daniele

doi:10.1007/s12035-021-02574-9

Cited by 24 publications

(25 citation statements)

References 204 publications

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“…In line with this, there is now emerging evidence that both the progression and clinical outcomes of Zika infection are closely associated with glial cells (Greenhalgh et al, 2020;Quincozes-Santos et al, 2021). Glial cells are essential for brain development and homeostasis (Greenhalgh et al, 2020).…”

Section: Immune and Inflammatory Mechanismsmentioning

confidence: 89%

Neurodevelopment in Children Exposed to Zika in utero: Clinical and Molecular Aspects

et al. 2022

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Five years after the identification of Zika virus as a human teratogen, we reviewed the early clinical manifestations, collectively called congenital Zika syndrome (CZS). Children with CZS have a very poor prognosis with extremely low performance in motor, cognitive, and language development domains, and practically all feature severe forms of cerebral palsy. However, these manifestations are the tip of the iceberg, with some children presenting milder forms of deficits. Additionally, neurodevelopment can be in the normal range in the majority of the non-microcephalic children born without brain or eye abnormalities. Vertical transmission and the resulting disruption in development of the brain are much less frequent when maternal infection occurs in the second half of the pregnancy. Experimental studies have alerted to the possibility of other behavioral outcomes both in prenatally infected children and in postnatal and adult infections. Cofactors play a vital role in the development of CZS and involve genetic, environmental, nutritional, and social determinants leading to the asymmetric distribution of cases. Some of these social variables also limit access to multidisciplinary professional treatment.

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Section: Immune and Inflammatory Mechanismsmentioning

confidence: 89%

Neurodevelopment in Children Exposed to Zika in utero: Clinical and Molecular Aspects

et al. 2022

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“…Several studies have shown that, despite causing injury, inflammation also maintains the balance of physiological responses in the body [ 61 ]. In addition, while certain neuroinflammatory pathways are destructive, they can also repair cerebral ischemic damage [ 62 ]. After I/R injury, inflammation typically occurs in three phases: i.e., acute, subacute, and chronic phases.…”

Section: Discussionmentioning

confidence: 99%

A short peptide exerts neuroprotective effects on cerebral ischemia–reperfusion injury by reducing inflammation via the miR-6328/IKKβ/NF-κB axis

Jin²,

Liu

et al. 2023

J Neuroinflammation

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Background Despite considerable efforts, ischemic stroke (IS) remains a challenging clinical problem. Therefore, the discovery of effective therapeutic and targeted drugs based on the underlying molecular mechanism is crucial for effective IS treatment. Methods A cDNA-encoding peptide was cloned from RNA extracted from Rana limnocharis skin, and the mature amino acid sequence was predicted and synthesized. Hemolysis and acute toxicity of the peptide were tested. Furthermore, its neuroprotective properties were evaluated using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats and an oxygen–glucose deprivation/reperfusion (OGD/R) model in neuron-like PC12 cells. The underlying molecular mechanisms were explored using microRNA (miRNA) sequencing, quantitative real-time polymerase chain reaction, dual-luciferase reporter gene assay, and western blotting. Results A new peptide (NP1) with an amino acid sequence of ‘FLPAAICLVIKTC’ was identified. NP1 showed no obvious toxicities in vivo and in vitro and was able to cross the blood–brain barrier. Intraperitoneal administration of NP1 (10 nmol/kg) effectively reduced the volume of cerebral infarction and relieved neurological dysfunction in MCAO/R model rats. Moreover, NP1 significantly alleviated the decrease in viability and increase in apoptosis of neuron-like PC12 cells induced by OGD/R. NP1 effectively suppressed inflammation by reducing interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels in vitro and in vivo. Furthermore, NP1 up-regulated the expression of miR-6328, which, in turn, down-regulated kappa B kinase β (IKKβ). IKKβ reduced the phosphorylation of nuclear factor-kappa B p65 (NF-κB p65) and inhibitor of NF-κB (I-κB), thereby inhibiting activation of the NF-κB pathway. Conclusions The newly discovered non-toxic peptide NP1 (‘FLPAAICLVIKTC’) exerted neuroprotective effects on cerebral ischemia–reperfusion injury by reducing inflammation via the miR-6328/IKKβ/NF-κB axis. Our findings not only provide an exogenous peptide drug candidate and endogenous small nucleic acid drug candidate but also a new drug target for the treatment of IS. This study highlights the importance of peptides in the development of new drugs, elucidation of pathological mechanisms, and discovery of new drug targets.

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“…Microglia are motile cells that investigate the brain environment. Upon brain invasion or insult, microglia quickly develop into different functionally overlapping phenotypes to exert neuroprotective and neurotoxic effects [54]. Phagocytic microglia are the first cells activated upon bilirubin insult [17,46,55], in an attempt to protect neurons from injury by suppressing the inflammatory response, clearing harmful substances and removing cellular debris.…”

Section: Yin-yang Properties Of Neuroinflammation In Bilirubin Neurot...mentioning

confidence: 99%

Neuroinflammation in Bilirubin Neurotoxicity

Zhang¹,

Chen²,

Jiang³

2023

J. Integr. Neurosci.

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Bilirubin neurotoxicity is a serious consequence of hyperbilirubinemia, which is the most common disease of the neonatal period. Clinically, bilirubin neurotoxicity can result in motor deficit, auditory dysfunction, cerebral palsy, seizure and neurodevelopmental diseases, amongst others. Bilirubin neurotoxicity is one of the major worldwide causes of neonatal brain injury, especially in poorer developing countries. However, the mechanisms of bilirubin neurotoxicity are still unclear. After the failure of attempts targeting neurons in many neurodegenerative disorders, neuroinflammation has become a significant target of research. Here, recent advances concerning neuroinflammation in bilirubin neurotoxicity are reported with a focus on the clinical characteristics of bilirubin neurotoxicity, including age-dependency, region-specificity and its yin-yang properties. Effects of neuroinflammation on blood brain interfaces and treatments targeting neuroinflammation in bilirubin neurotoxicity are also reviewed, which may promote the precision of future treatment of bilirubin neurotoxicity.

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Gliotoxicity and Glioprotection: the Dual Role of Glial Cells

Cited by 24 publications

References 204 publications

Neurodevelopment in Children Exposed to Zika in utero: Clinical and Molecular Aspects

Neurodevelopment in Children Exposed to Zika in utero: Clinical and Molecular Aspects

A short peptide exerts neuroprotective effects on cerebral ischemia–reperfusion injury by reducing inflammation via the miR-6328/IKKβ/NF-κB axis

Neuroinflammation in Bilirubin Neurotoxicity

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