ER stress and ER stress-mediated apoptosis are involved in manganese-induced neurotoxicity in the rat striatum in vivo

Wang, Ting; Li, Xuehui; Dong-xu, Yang; Zhang, Hongtao; Zhao, Peng; Fu, Junjie; Yao, Biyun; Zhou, Zhenming

doi:10.1016/j.neuro.2015.02.007

Cited by 53 publications

(36 citation statements)

References 59 publications

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“…The striatum and cerebral cortex parts were chosen because Mn affects more severely the striatum and cortex regions than any other region of the CNS [33]. Exposure of Mn caused histopathological alterations in the striatum.…”

Section: Discussionmentioning

confidence: 99%

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Polyphenolic Extract of Euphorbia supina Attenuates Manganese-Induced Neurotoxicity by Enhancing Antioxidant Activity through Regulation of ER Stress and ER Stress-Mediated Apoptosis

Bahar

Lee

Bhattarai

et al. 2017

IJMS

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Manganese (Mn) is an important trace element present in human body, which acts as an enzyme co-factor or activator in various metabolic reactions. While essential in trace amounts, excess levels of Mn in human brain can produce neurotoxicity, including idiopathic Parkinson’s disease (PD)-like extrapyramidal manganism symptoms. This study aimed to investigate the protective role of polyphenolic extract of Euphorbia supina (PPEES) on Mn-induced neurotoxicity and the underlying mechanism in human neuroblastoma SKNMC cells and Sprague-Dawley (SD) male rat brain. PPEES possessed significant amount of total phenolic and flavonoid contents. PPEES also showed significant antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and reducing power capacity (RPC) assays. Our results showed that Mn treatment significantly reduced cell viability and increased lactate dehydrogenase (LDH) level, which was attenuated by PPEES pretreatment at 100 and 200 µg/mL. Additionally, PPEES pretreatment markedly attenuated Mn-induced antioxidant status alteration by resolving the ROS, MDA and GSH levels and SOD and CAT activities. PPEES pretreatment also significantly attenuated Mn-induced mitochondrial membrane potential (ΔΨm) and apoptosis. Meanwhile, PPEES pretreatment significantly reversed the Mn-induced alteration in the GRP78, GADD34, XBP-1, CHOP, Bcl-2, Bax and caspase-3 activities. Furthermore, administration of PPEES (100 and 200 mg/kg) to Mn exposed rats showed improvement of histopathological alteration in comparison to Mn-treated rats. Moreover, administration of PPEES to Mn exposed rats showed significant reduction of 8-OHdG and Bax immunoreactivity. The results suggest that PPEES treatment reduces Mn-induced oxidative stress and neuronal cell loss in SKNMC cells and in the rat brain. Therefore, PPEES may be considered as potential treat-ment in Mn-intoxicated patients.

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Section: Discussionmentioning

confidence: 99%

“…Mn can induce protease activation and apoptotic cell death [31,32]. Recently, involvement of ER stress and ER stress-mediated apoptosis has been found in Mn-induced neurotoxicity in the rat striatum in vivo [33]. …”

Section: Introductionmentioning

confidence: 99%

Polyphenolic Extract of Euphorbia supina Attenuates Manganese-Induced Neurotoxicity by Enhancing Antioxidant Activity through Regulation of ER Stress and ER Stress-Mediated Apoptosis

Bahar

Lee

Bhattarai

et al. 2017

IJMS

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“…Specifically, the pro-apoptotic proteins BAX and BAK not only regulate the Ca 2+ levels in the ER but also modulate the activity of the UPR ER sensor IRE1 via physical interaction, thus performing essential roles in the induction of mitochondrial apoptosis following ER stress-induced UPR ER [78]. While BCL2 proteins can modulate IRE1 activity, IRE1 self-activation also activates the MAPK/JNK pathway, which in turn, activates BH3-only proteins, including BIM, and suppresses the anti-apoptotic activity of BCL2 [99, 100]. Augmenting this effect, CHOP induces BIM transcription while simultaneously suppressing BCL-2 induction, linking the ER stress response to mitochondrial apoptosis [97, 98, 101].…”

Section: Cross Talk Between Uprer and Mitochondrial Apoptosismentioning

confidence: 99%

Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer

Bhat

Chaudhary

Kumar

et al. 2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

104

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Abrogation of endoplasmic reticulum (ER) protein folding triggered by exogenous or endogenous factors, stimulates a cellular stress response, termed ER stress. ER stress reestablishes ER homeostasis through integrated signaling termed the ER-unfolded protein response (UPRER). In the presence of severe toxic or prolonged ER stress, the pro-survival function of UPRER is transformed into a lethal signal transmitted to and executed through mitochondria. Mitochondria are key for both apoptotic and autophagic cell death. Thus ER is vital in sensing and coordinating stress pathways to maintain overall physiological homeostasis. However, this function is deregulated in cancer, resulting in resistance to apoptosis induction in response to various stressors including therapeutic agents. Here we review the connections between ER stress and mitochondrial apoptosis, describing potential cancer therapeutic targets.

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“…Of particular interest, Mn-induced p53 phosphorylation, as well as upregulation of p53 levels, have been shown to be important events in cellular response to Mn exposure both in vivo and in vitro, possibly contributing to neuronal apoptosis [31, 45–47]. Endoplasmic reticulum (ER) stress is another factor that may lead to Mn-induced apoptosis [48]. …”

Section: Introductionmentioning

confidence: 99%

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

Peres

Schettinger

Chen

et al. 2016

BMC Pharmacol Toxicol

280

183

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Manganese (Mn) is an essential heavy metal. However, Mn’s nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson’s disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.

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ER stress and ER stress-mediated apoptosis are involved in manganese-induced neurotoxicity in the rat striatum in vivo

Cited by 53 publications

References 59 publications

Polyphenolic Extract of Euphorbia supina Attenuates Manganese-Induced Neurotoxicity by Enhancing Antioxidant Activity through Regulation of ER Stress and ER Stress-Mediated Apoptosis

Polyphenolic Extract of Euphorbia supina Attenuates Manganese-Induced Neurotoxicity by Enhancing Antioxidant Activity through Regulation of ER Stress and ER Stress-Mediated Apoptosis

Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

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