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Sublethal dose of 4-hydroxynonenal reduces intracellular calcium in surviving motor neurons in vivo

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Abstract

4-Hydroxynonenal (4-HNE), a major lipid peroxidation product, induces oxidative stress, acts as an autonomous effector of cell death in motor neuron hybrid cell cultures, and is elevated in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). Elevation of the total intracellular calcium has also been demonstrated in motor axon terminals of ALS patients as well as in spinal motor neurons of animal models of familial and sporadic ALS. Since the association of intracellular calcium and oxidative stress has been suggested in ALS, the in vivo effect of intrathecally administered 4-HNE on the motor neuronal calcium level was examined in the spinal cord of rats. After 12 days of treatment, total intracellular calcium was assayed by electron microscopic histochemistry using the oxalate-pyroantimonate method. Morphology of spinal motor neurons was characterized by light and electron microscopy. In rats, 4-HNE treatment induced a mild impairment of gait, elevation of 4-HNE in the CSF, loss of spinal motor neurons, and reduction of total calcium in the surviving, structurally intact motor neurons. 4-HNE could only cause a lesion if glutathione synthesis was concomitantly inhibited in the animals. The results suggest that upstream components of the oxidative injury in relation to lipid peroxidation are necessary to compromise the glutathione system in ALS, allowing an increase of 4-HNE in the CSF, which further aggravates the primary oxidative lesion. The reduced intracellular calcium in the surviving motor neurons with no morphological features of degeneration may reflect an impaired ionic homeostasis, which may indicate a residual damage of an incomplete degenerative process.

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Acknowledgements

Part of the results has been presented at the 52nd Annual Meeting of the American Academy of Neurology, San Diego, 29 April–6 May 2000. This work was supported by grants from OTKA (T/034314, T/042858, M/036252), ETT (33/2003) and MDA. The valuable help of Dr. David Beers in editing the manuscript is greatly appreciated.

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Authors and Affiliations

  1. Institute of Biophysics, Biological Research Center, P.O. Box 521, 6701, Szeged, Hungary

    Lóránd Vigh & László Siklós

  2. Department of Neurology, Baylor College of Medicine, Houston, Texas, USA

    Stanley H. Appel

  3. Department of Neurology, University of Szeged, Szeged, Hungary

    Judit Soós & József I. Engelhardt

  4. Department of Neurology, School of Medicine, The University of Texas Medical Branch, Galveston, Texas, USA

    R. Glenn Smith

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  1. Lóránd Vigh
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  2. R. Glenn Smith
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  3. Judit Soós
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  5. Stanley H. Appel
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  6. László Siklós
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Correspondence to László Siklós.

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Vigh, L., Smith, R.G., Soós, J. et al. Sublethal dose of 4-hydroxynonenal reduces intracellular calcium in surviving motor neurons in vivo. Acta Neuropathol 109, 567–575 (2005). https://doi.org/10.1007/s00401-004-0977-1

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  • DOI: https://doi.org/10.1007/s00401-004-0977-1

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