Glutathione Depletion Promotes Aluminum-Mediated Cell Death of PC12 Cells

Satoh, Eiko; Okada, Morihiro; Takadera, Tsuneo; Ohyashiki, Takao

doi:10.1248/bpb.28.941

Cited by 24 publications

(17 citation statements)

References 40 publications

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“…Regardless of the host, the route of administration, and the chemical speciation, Al has been found to be a potent neurotoxicant 8) . Al has also been proposed to be one of the critical environmental factors related to several serious neurodegenerative diseases, such as Alzheimer's disease (AD) 3,[9][10][11][12] . AD is the most common form of dementia, and with increasing life expectancy across the world, AD is a rapidly growing socioeconomic and medical problem 13) .…”

Section: Introductionmentioning

confidence: 99%

Aluminium-Maltolate-induced Impairment of Learning, Memory and Hippocampal Long-term Potentiation in Rats

Liang

Wang

et al. 2012

Ind Health

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Recently, aluminium (Al) has been proposed to be one of the environmental factors responsible for cause Alzheimer's disease (AD). However, the relationship between Al and AD is controversial. To investigate the effects of subchronic Aluminium-maltolate (Al (mal) 3 ) exposure on the behavioral, electrophysiological functions. Forty Sprague-Dawley (SD) rats were randomly distributed into five groups. Over two months, rats in the saline group received daily intraperitoneal (i.p.) injections 0.9% saline, rats in the maltolate group received 7.56 mg/kg maltolate, and rats in the 0.27, 0.54, 1.08 mg/kg Al (mal) 3 groups received i.p. administrations of these three doses, respectively. Neural behavior was assessed in Morris water maze. Long-term potentiation (LTP) in hippocampus was recorded. Al content in the neocortex was determined using a graphite furnace atomic absorption spectrophotometer. Our studies indicate that subchronic Al (mal) 3 exposure significantly impaired spatial learning and memory abilities, suppressed the LTP in the CA1 hippocampal area, and elevated Al levels in cerebral cortex in a dose-dependent fashion. In conclusion, low doses of Al (mal) 3 can still lead to dramatic Al accumulation in the brain, severely impair learning and memory capacities, and hippocampal LTP.

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Section: Introductionmentioning

confidence: 99%

Aluminium-Maltolate-induced Impairment of Learning, Memory and Hippocampal Long-term Potentiation in Rats

Liang

Wang

et al. 2012

Ind Health

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“…Recently, we have reported that the treatment of PC12 cells with Al(maltol) 3 causes a decrease in the levels of the intracellular reduced glutathione depending on the amount of Al(maltol) 3 accumulated in the cells. 11) These findings strongly suggested that Al accumulation in tissues is closely related to the development of neurodegenerative disorders although a causal relationship between Al and neurodegenerative disorders remains unclear.…”

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confidence: 97%

Involvement of NO Generation in Aluminum-Induced Cell Death

Satoh

Yasuda

Yamada

et al. 2007

Biological & Pharmaceutical Bulletin

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Aluminum (Al) is the third most abundant element in the earth's crust and has been implicated as an etiologic factor in neurological disorders including Alzheimer's disease, 1,2) Parkinson's dementia syndrome, and dialysis encephalopathy syndrome. 3,4) In fact, some evidence supports the selective accumulation of Al within neurons containing neurofibrillay tangles in patients with Alzheimer's disease and within the aging human brain. 1,5) Meiri et al., have also reported that brain Al concentrations reach submilimolar levels in some encephalopathies.6) Several lines of research that use cultured cells and the aluminum-maltolate complex (Al(maltol) 3 ), which is a membrane permeable, lipophilic complex of Al, also showed that the exposure of cells such as the Neuro-2a murine neuroblastoma cells, 7) human NT2 neuroblastoma cells, 8) and PC12 cells 9,10) to the Al complex results in a decrease in cell viability via the apoptotic cell death pathway. Recently, we have reported that the treatment of PC12 cells with Al(maltol) 3 causes a decrease in the levels of the intracellular reduced glutathione depending on the amount of Al(maltol) 3 accumulated in the cells. 11) These findings strongly suggested that Al accumulation in tissues is closely related to the development of neurodegenerative disorders although a causal relationship between Al and neurodegenerative disorders remains unclear.NO is considered to be a modulator and a simple and diffusible free radical.12) It is believed to play an important role in physiological and pathophysiological events in many cellular systems. [13][14][15] Furthermore, it has also been reported that NO concentration increased in the brain during the course of ischemia, Alzheimer's disease, and other degenerative conditions. [16][17][18] Numerous studies in several cell systems have demonstrated that NO is closely related to cell death mechanisms and plays the role of a mediator. [19][20][21][22][23] A recent study has reported that NO is produced in the mitochondria via Ca 2ϩ -dependent mitochondrial NO synthases (mtNOS). [24][25][26] The NO produced in the mitochondria by mtNOS plays the role of a modulator of mitochondrial oxygen consumption and transmembrane potential via a reversible reaction with cytochrome c oxidase. It is well-known that NO rapidly reacts with superoxide anion radicals to form peroxynitrite, which is an oxidant substance producing cytotoxic effects in many cells. 14,20) Previously, we have reported that accumulation of Al(maltol) 3 in PC12 cells results in apoptotic cell death depending on the intracellular generation of reactive oxygen species (ROS).10) Therefore, it would be interesting to determine if intracellular NO generation is involved in the onset mechanism of Al-mediated-cytotoxicity. Therefore, in the present study, we examined the effects of a NO generator and NO synthase inhibitors on Al(maltol) 3 -induced cell death. Our results suggest that intracellular NO generation may play an important role in the development of cell toxicity associated wit...

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“…Exposure of rat PC12 cells to aluminum maltolate resulted in depletion of glutathione, resulting in release of lactate dehydrogenase (LDH) from the cell and generation of reactive oxygen species. These effects were reversed by pretreatment with N-acetylcysteine [33]. Treatment of Neuro2a cells with Al maltolate for 24 h dose -dependently increased cell death by a combination of apoptosis and necrosis.…”

Section: Discussionmentioning

confidence: 92%

“…Indeed, TNF induces the hyperphosphorylation of kinesin light chains which effectively inhibits transport [9]. Interestingly, one consequence of tau over-expression is peri-nuclear clustering of mitochondria and the failure of normal kinesin dependent transport [10,33,43].…”

Section: Introductionmentioning

confidence: 99%

Peri-nuclear clustering of mitochondria is triggered during aluminum maltolate induced apoptosis

DeWitt

Hurd

Fox

et al. 2006

JAD

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Synapse loss and neuronal death are key features of Alzheimer's disease pathology. Disrupted axonal transport of mitochondria is a potential mechanism that could contribute to both. As the major producer of ATP in the cell, transport of mitochondria to the synapse is required for synapse maintenance. However, mitochondria also play an important role in the regulation of apoptosis. Investigation of aluminum (Al) maltolate induced apoptosis in human NT2 cells led us to explore the relationship between apoptosis related changes and the disruption of mitochondrial transport. Similar to that observed with tau over expression, NT2 cells exhibit peri-nuclear clustering of mitochondria following treatment with Al maltolate. Neuritic processes largely lacked mitochondria, except in axonal swellings. Similar, but more rapid results were observed following staurosporine administration, indicating that the clustering effect was not specific to Al maltolate. Organelle clustering and transport disruption preceded apoptosis. Incubation with the caspase inhibitor zVAD-FMK effectively blocked apoptosis, however failed to prevent organelle clustering. Thus, transport disruption is associated with the initiation, but not necessarily the completion of apoptosis. These results, together with observed transport defects and apoptosis related changes in Alzheimer disease brain suggest that mitochondrial transport disruption may play a significant role in synapse loss and thus the pathogenesis or Alzheimer's disease.

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Glutathione Depletion Promotes Aluminum-Mediated Cell Death of PC12 Cells

Cited by 24 publications

References 40 publications

Aluminium-Maltolate-induced Impairment of Learning, Memory and Hippocampal Long-term Potentiation in Rats

Aluminium-Maltolate-induced Impairment of Learning, Memory and Hippocampal Long-term Potentiation in Rats

Involvement of NO Generation in Aluminum-Induced Cell Death

Peri-nuclear clustering of mitochondria is triggered during aluminum maltolate induced apoptosis

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