Impairment of the autophagic flux in astrocytes intoxicated by trimethyltin

Fabrizi, Cinzia; Pompili, Elena; Vito, Stefania De; Somma, Francesca; Catizone, Angela; Ricci, Giulia; Lenzi, Paola; Fornai, Francesco; Fumagalli, Laura

doi:10.1016/j.neuro.2015.10.004

Cited by 18 publications

(18 citation statements)

References 44 publications

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“…Autophagy impairment has been reported in other neurodegenerative processes. In fact, upon neurotoxin intoxication, astrocytes undergo autophagic flux block that can be rescued by rapamycin or by GSK-3 β inhibition [ 69 ]. GSK3 overactivity has been reported to occur in sporadic Alzheimer's disease (AD) cases and therefore may play an important role in disease progression.…”

Section: Role Of Gsk3 In Autophagymentioning

confidence: 99%

Multifaceted Roles of GSK‐3 in Cancer and Autophagy‐Related Diseases

Mancinelli

Carpino

Petrungaro

et al. 2017

Oxidative Medicine and Cellular Longevity

187

131

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GSK-3 is a ubiquitously expressed serine/threonine kinase existing as GSK-3α and GSK-3β isoforms, both active under basal conditions and inactivated upon phosphorylation by different upstream kinases. Initially discovered as a regulator of glycogen synthesis, GSK-3 is also involved in several signaling pathways controlling many different key functions. Here, we discuss recent advances regarding (i) GSK-3 structure, function, regulation, and involvement in several cancers, including hepatocarcinoma, cholangiocarcinoma, breast cancer, prostate cancer, leukemia, and melanoma (active GSK-3 has been shown to induce apoptosis in some cases or inhibit apoptosis in other cases and to induce cancer progression or inhibit tumor cell proliferation, suggesting that different GSK-3 modulators may address different specific targets); (ii) GSK-3 involvement in autophagy modulation, reviewing signaling pathways involved in neurodegenerative and liver diseases; (iii) GSK-3 role in oxidative stress and autophagic cell death, focusing on liver injury; (iv) GSK-3 as a possible therapeutic target of natural substances and synthetic inhibitors in many diseases; and (v) GSK-3 role as modulator of mammalian aging, related to metabolic alterations characterizing senescent cells and age-related diseases. Studies summarized here underline the GSK-3 multifaceted role and indicate such kinase as a molecular target in different pathologies, including diseases associated with autophagy dysregulation.

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Section: Role Of Gsk3 In Autophagymentioning

confidence: 99%

Multifaceted Roles of GSK‐3 in Cancer and Autophagy‐Related Diseases

Mancinelli

Carpino

Petrungaro

et al. 2017

Oxidative Medicine and Cellular Longevity

187

131

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“…The accentuated increase of interleukin IL-1β, IL-6, and tumor necrosis factor TNF-α levels in mice hippocampus, as well as iNOS, arginase-1, IL-1β, TNF-α, and IL-6 levels in cultured astrocytes, follows TMT exposure ( 23 ). It is also reported that the TMT exposure is capable of impairing the late stages of autophagic flux in primary cultured astrocytes, leading the accumulation of protein aggregates in the cell ( 24 ). Genes involved in neuronal differentiation and astrocyte activity, inflammatory response, and apoptosis are overexpressed in the dentate gyrus region of the hippocampus, while such upregulation is not found in the cornu ammonis regions ( 25 ), adding evidence to the suggestion that TMT intoxication causes specific neuronal damage ( 26 ).…”

Section: Trimethyltin (Tmt) Neurotoxicitymentioning

confidence: 99%

Organotins in Neuronal Damage, Brain Function, and Behavior: A Short Review

et al. 2018

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The consequences of exposure to environmental contaminants have shown significant effects on brain function and behavior in different experimental models. The endocrine-disrupting chemicals (EDC) present various classes of pollutants with potential neurotoxic actions, such as organotins (OTs). OTs have received special attention due to their toxic effects on the central nervous system, leading to abnormal mammalian neuroendocrine axis function. OTs are organometallic pollutants with a tin atom bound to one or more carbon atoms. OT exposure may occur through the food chain and/or contaminated water, since they have multiple applications in industry and agriculture. In addition, OTs have been used with few legal restrictions in the last decades, despite being highly toxic. In addition to their action as EDC, OTs can also cross the blood–brain barrier and show relevant neurotoxic effects, as observed in several animal model studies specifically involving the development of neurodegenerative processes, neuroinflammation, and oxidative stress. Thus, the aim of this short review is to summarize the toxic effects of the most common OT compounds, such as trimethyltin, tributyltin, triethyltin, and triphenyltin, on the brain with a focus on neuronal damage as a result of oxidative stress and neuroinflammation. We also aim to present evidence for the disruption of behavioral functions, neurotransmitters, and neuroendocrine pathways caused by OTs.

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“…TMT-treated animals show neuronal death and glial activation in the hippocampus (Fiedorowicz et al, 2001; Kim et al, 2014b). They also exhibit cognitive deficits and behavioral changes, including memory loss, learning impairment, hyperactivity, aggression, and seizures (Besser et al, 1987; Fabrizi et al, 2015; Kim et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Involvement of BDNF/ERK signaling in spontaneous recovery from trimethyltin-induced hippocampal neurotoxicity in mice

Lee

Yang

Kim

et al. 2016

Brain Research Bulletin

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Trimethyltin (TMT) toxicity causes histopathological damage in the hippocampus and induces seizure behaviors in mice. The lesions and symptoms recover spontaneously over time; however, little is known about the precise mechanisms underlying this recovery from TMT toxicity. We investigated changes in the brain-derived neurotrophic factor/extracellular signal-regulated kinases (BDNF/ERK) signaling pathways in the mouse hippocampus following TMT toxicity. Mice (7 weeks old, C57BL/6) administered TMT (2.6 mg/kg intraperitoneally) showed acute and severe neurodegeneration with increased TUNEL-positive cells in the dentate gyrus (DG) of the hippocampus. The mRNA and protein levels of BDNF in the hippocampus were elevated by TMT treatment. Immunohistochemical analysis showed that TMT treatment markedly increased phosphorylated ERK1/2 expression in the mouse hippocampus 1-4 days after TMT treatment, although the intensity of ERK immunoreactivity in mossy fiber decreased at 1-8 days post-treatment. In addition, ERK-immunopositive cells were localized predominantly in doublecortin-positive immature progenitor neurons in the DG. In primary cultured immature hippocampal neurons (4 days in vitro), BDNF treatment alleviated TMT-induced neurotoxicity, via activation of the ERK signaling pathway. Thus, we suggest that BDNF/ERK signaling pathways may be associated with cell differentiation and survival of immature progenitor neurons, and will eventually lead to spontaneous recovery in TMT-induced hippocampal neurodegeneration.

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Impairment of the autophagic flux in astrocytes intoxicated by trimethyltin

Cited by 18 publications

References 44 publications

Multifaceted Roles of GSK‐3 in Cancer and Autophagy‐Related Diseases

Multifaceted Roles of GSK‐3 in Cancer and Autophagy‐Related Diseases

Organotins in Neuronal Damage, Brain Function, and Behavior: A Short Review

Involvement of BDNF/ERK signaling in spontaneous recovery from trimethyltin-induced hippocampal neurotoxicity in mice

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