Elsevier

Neuropharmacology

Volume 35, Issue 3, March 1996, Pages 369-375
Neuropharmacology

Neuroprotective effects of α-lipoic acid and its enantiomers demonstrated in rodent models of focal cerebral ischemia

https://doi.org/10.1016/0028-3908(95)00172-7Get rights and content

Abstract

The purpose of this study was to investigate whether α-lipoic acid (LA), the oxidized form of the radical scavenger dihydrolipoic acid (DLA), protected brain tissue against ischemic damage and whether there were differences in the neuroprotective potencies between its enantiomers. We used the models of focal cerebral ischemia in mice and rats. The infarct area on the mouse brain surface and the infarct volume of the rat brain were determined by means of an image analyzing system. The LA was capable of reducing the infarct area only when it was administered subcutaneously, but not when it was administered intraperitoneally or into the cisterna magna. Both the R- and the S-enantiomer of LA protected brain tissue against ischemic damage, but their protective activities seemed to be related to the time period of pretreatment. In mice, both enantiomers revealed a similar neuroprotective potency when they were administered subcutaneously 1 or 2 hr before occlusion of the middle cerebral artery (MCA), whereas a longer time period of pretreatment (4 or 6 hr) failed to exert neuroprotection. In rats, subcutaneous pretreatment with R- or S-LA for 2hr before ischemia significantly diminished the infarct volume. We assume that LA has to be reduced to DLA which finally causes neuroprotection.

References (38)

  • M. Oubidar et al.

    Ischemia-induced brain iron delocalization: effects of iron chelators

    Free Rad. Biol. Med.

    (1994)
  • J. Peinado et al.

    Hepatic lipoate uptake

    Arch. Biochem. Biophys.

    (1989)
  • H. Scholich et al.

    Antioxidant activity of dihydrolipoate against microsomal lipid peroxidation and its dependence on α-tocopherol

    Biochim. Biophys. Acta

    (1989)
  • L. Tang et al.

    Allosteric modulation of the NMDA receptor by dihydrolipoic acid and lipoic acid in rat cortical neurons in vitro

    Neuron

    (1993)
  • S.R. Whittemore et al.

    The expression, localization and functional significance of β-nerve growth factor in the central nervous system

    Brain Res. Rev.

    (1987)
  • J. Astrup et al.

    Thresholds in cerebral ischemia: the ischemic penumbra

    Stroke

    (1981)
  • H. Benveniste et al.

    Elevation of extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis

    J. Neurochem.

    (1984)
  • C. Bromont et al.

    Increased lipid peroxidation in vulnerable brain regions after transient forebrain ischemia

    Stroke

    (1989)
  • P.H. Chan

    Oxygen radicals in focal cerebral ischemia

    Brain Pathol.

    (1994)
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