Metallothionein isoforms (I + II and III) and interleukin-6 in the hippocampus of old rats: May their concomitant increments lead to neurodegeneration?

Eugenio Mocchegiani, Robertina Giacconi, Patrizia Fattoretti, Tiziana Casoli, Catia Cipriano, Elisa Muti, Marco Malavolta, Giuseppina DiStefano, Carlo Bertoni-Freddari

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Abstract

Metallothionein (MT)-III isoform is a brain metal-binding protein that, like the MT-I+II isoform, binds zinc with high affinity. In the young-adult age, MT-III isoform increases during transient stress while MT-I+II isoform decreases, suggesting compensatory phenomena between the two isoforms and a protective role of MT-III against oxidative damage. This role may be questioned during ageing, because the stress-like condition is chronic in ageing due to high persistent levels of interleukin-6. In the present study, high expression of MT-III and MT-I+II genes (examined by RT-PCR and in situ hybridisation) was found in the hippocampus of old rats. These results indicate that a large amount of free zinc ions can be sequestered by MT isoforms, leading to impaired zinc-dependent functions in the ageing brain. In addition, zinc (tested with the Timm's method) was found to be low in mossy fibres from the old hippocampus. As this method tests bound and unbound zinc, we also investigated free zinc ion bioavailability based on the ratio active thymulin/total thymulin. We found that zinc ion bioavailability was low in old rats, together with increased interleukin-6 mRNA, high expression of both MT isoforms and reduced number of synapses whose function is zinc-dependent, in the old hippocampus. The results indicate that concomitant increments of both MT isoforms may provoke detrimental synergistic effects leading to reduced free zinc ion bioavailability for synapses. As a consequence, compensatory phenomena between MT isoforms may not occur in the old hippocampus due to chronic stress-like condition elicited by high persistent levels of interleukin-6.

Original languageEnglish
Pages (from-to)133-142
Number of pages10
JournalBrain Research Bulletin
Volume63
Issue number2
DOIs
Publication statusPublished - Mar 15 2004

Fingerprint

Metallothionein
Interleukin-6
Hippocampus
Protein Isoforms
Zinc
Circulating Thymic Factor
Ions
Biological Availability
Synapses
Brain
In Situ Hybridization
Young Adult
Carrier Proteins
Metals
Polymerase Chain Reaction
Messenger RNA
growth inhibitory factor

Keywords

  • Ageing
  • Cytokines
  • Inflammation
  • Neuroprotection
  • Zinc

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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title = "Metallothionein isoforms (I + II and III) and interleukin-6 in the hippocampus of old rats: May their concomitant increments lead to neurodegeneration?",
abstract = "Metallothionein (MT)-III isoform is a brain metal-binding protein that, like the MT-I+II isoform, binds zinc with high affinity. In the young-adult age, MT-III isoform increases during transient stress while MT-I+II isoform decreases, suggesting compensatory phenomena between the two isoforms and a protective role of MT-III against oxidative damage. This role may be questioned during ageing, because the stress-like condition is chronic in ageing due to high persistent levels of interleukin-6. In the present study, high expression of MT-III and MT-I+II genes (examined by RT-PCR and in situ hybridisation) was found in the hippocampus of old rats. These results indicate that a large amount of free zinc ions can be sequestered by MT isoforms, leading to impaired zinc-dependent functions in the ageing brain. In addition, zinc (tested with the Timm's method) was found to be low in mossy fibres from the old hippocampus. As this method tests bound and unbound zinc, we also investigated free zinc ion bioavailability based on the ratio active thymulin/total thymulin. We found that zinc ion bioavailability was low in old rats, together with increased interleukin-6 mRNA, high expression of both MT isoforms and reduced number of synapses whose function is zinc-dependent, in the old hippocampus. The results indicate that concomitant increments of both MT isoforms may provoke detrimental synergistic effects leading to reduced free zinc ion bioavailability for synapses. As a consequence, compensatory phenomena between MT isoforms may not occur in the old hippocampus due to chronic stress-like condition elicited by high persistent levels of interleukin-6.",
keywords = "Ageing, Cytokines, Inflammation, Neuroprotection, Zinc",
author = "Eugenio Mocchegiani and Robertina Giacconi and Patrizia Fattoretti and Tiziana Casoli and Catia Cipriano and Elisa Muti and Marco Malavolta and Giuseppina DiStefano and Carlo Bertoni-Freddari",
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T1 - Metallothionein isoforms (I + II and III) and interleukin-6 in the hippocampus of old rats

T2 - May their concomitant increments lead to neurodegeneration?

AU - Mocchegiani, Eugenio

AU - Giacconi, Robertina

AU - Fattoretti, Patrizia

AU - Casoli, Tiziana

AU - Cipriano, Catia

AU - Muti, Elisa

AU - Malavolta, Marco

AU - DiStefano, Giuseppina

AU - Bertoni-Freddari, Carlo

PY - 2004/3/15

Y1 - 2004/3/15

N2 - Metallothionein (MT)-III isoform is a brain metal-binding protein that, like the MT-I+II isoform, binds zinc with high affinity. In the young-adult age, MT-III isoform increases during transient stress while MT-I+II isoform decreases, suggesting compensatory phenomena between the two isoforms and a protective role of MT-III against oxidative damage. This role may be questioned during ageing, because the stress-like condition is chronic in ageing due to high persistent levels of interleukin-6. In the present study, high expression of MT-III and MT-I+II genes (examined by RT-PCR and in situ hybridisation) was found in the hippocampus of old rats. These results indicate that a large amount of free zinc ions can be sequestered by MT isoforms, leading to impaired zinc-dependent functions in the ageing brain. In addition, zinc (tested with the Timm's method) was found to be low in mossy fibres from the old hippocampus. As this method tests bound and unbound zinc, we also investigated free zinc ion bioavailability based on the ratio active thymulin/total thymulin. We found that zinc ion bioavailability was low in old rats, together with increased interleukin-6 mRNA, high expression of both MT isoforms and reduced number of synapses whose function is zinc-dependent, in the old hippocampus. The results indicate that concomitant increments of both MT isoforms may provoke detrimental synergistic effects leading to reduced free zinc ion bioavailability for synapses. As a consequence, compensatory phenomena between MT isoforms may not occur in the old hippocampus due to chronic stress-like condition elicited by high persistent levels of interleukin-6.

AB - Metallothionein (MT)-III isoform is a brain metal-binding protein that, like the MT-I+II isoform, binds zinc with high affinity. In the young-adult age, MT-III isoform increases during transient stress while MT-I+II isoform decreases, suggesting compensatory phenomena between the two isoforms and a protective role of MT-III against oxidative damage. This role may be questioned during ageing, because the stress-like condition is chronic in ageing due to high persistent levels of interleukin-6. In the present study, high expression of MT-III and MT-I+II genes (examined by RT-PCR and in situ hybridisation) was found in the hippocampus of old rats. These results indicate that a large amount of free zinc ions can be sequestered by MT isoforms, leading to impaired zinc-dependent functions in the ageing brain. In addition, zinc (tested with the Timm's method) was found to be low in mossy fibres from the old hippocampus. As this method tests bound and unbound zinc, we also investigated free zinc ion bioavailability based on the ratio active thymulin/total thymulin. We found that zinc ion bioavailability was low in old rats, together with increased interleukin-6 mRNA, high expression of both MT isoforms and reduced number of synapses whose function is zinc-dependent, in the old hippocampus. The results indicate that concomitant increments of both MT isoforms may provoke detrimental synergistic effects leading to reduced free zinc ion bioavailability for synapses. As a consequence, compensatory phenomena between MT isoforms may not occur in the old hippocampus due to chronic stress-like condition elicited by high persistent levels of interleukin-6.

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