Azulenyl Nitrone Spin Traps Protect against MPTP Neurotoxicity

doi:10.1006/exnr.1998.6824

Experimental Neurology

Volume 152, Issue 1, July 1998, Pages 163-166

https://doi.org/10.1006/exnr.1998.6824 Get rights and content

Abstract

Azulenyl nitrones are a unique class of free radical spin-trapping compounds. We administered both a water-soluble and a lipid-soluble azulenyl nitrone to mice prior to administration of MPTP. Both compounds produced significant neuroprotection against depletions of dopamine and its metabolites measured 1 week after MPTP administration. There were no effects on MPP⁺levels. These findings provide further evidence that free radical scavengers can produce significant neuroprotection against MPTP neurotoxicity.

References (37)

J.S. Althaus et al.
Azulenyl nitrones: Colorimetric detection of oxyradical endproducts and neuroprotection in the gerbil transient forebrain ischemia/reperfusion model
Free Radical Biol. Med.
(1998)
B.R. Bloem et al.
The MPTP model: Versatile contributions to the treatment of idiopathic Parkinson's disease
J. Neurol. Sci.
(1990)
G.R. Buettner
The pecking order of free radicals and antioxidants: Lipid peroxidation, alpha-tocopherol, and ascorbate
Arch. Biochem. Biophys.
(1993)
X. Cao et al.
α-Phenyl-tert
Brain Res.
(1994)
C.C. Chiueh et al.
Intracranial microdialysis of salicylic acid to detect hydroxyl radical generation through dopamine autooxidation in the caudate nucleus: Effects of MPP⁺
Free Radical Biol. Med.
(1992)
R. Edamatsu et al.
The spin-trapN-tert
Biochem. Biophys. Res. Commun.
(1995)
E. Hasegawa et al.
1-Methyl-4-phenylpyridinium (MPP⁺
Biochem. Biophys. Res. Commun.
(1990)
K.T. Knecht et al.
In vivo
Arch. Biochem. Biophys.
(1993)
M.C. Krishna et al.
Do nitroxide antioxidants act as scavengers of O · ₂
J. Biol. Chem.
(1996)
S. Kuroda et al.
Delayed treatment with α-phenyl-N-tert
Neurobiol. Dis.
(1996)

T. Miyajima et al.

Optimal time and dosage of phenylN-tert

Free Radical Biol. Med.

(1997)

E. Monti et al.

Protective effect of the nitroxide tempol against the cardiotoxicity of adriamycin

Free Radical Biol. Med.

(1996)

J.W. Phillis et al.

Protection from cerebral ischemic injury in gerbils with the spin trap agentN-tert

Neurosci. Lett.

(1990)

C.A. Sack et al.

Antioxidant treatment with phenyl-α-tert

Neurosci. Lett.

(1996)

J.B. Schulz et al.

Coenzyme Q₁₀

Exp. Neurol.

(1995)

K. Sriram et al.

Evidence for generation of oxidative stress in brain by MPTP: In vitro and in vivo studies in mice

Brain Res.

(1997)

T.L. Yue et al.

Neuroprotective effects of phenyl-t-butyl nitrone in gerbil global brain ischemia and in cultured rat cerebellar neurons

Brain Res.

(1992)

M.F. Beal et al.

Kynurenine pathway measurements in Huntington's disease striatum: Evidence for reduced formation of kynurenic acid

J. Neurochem.

(1990)

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Oxidative stress plays an important role in neuronal death in neurodegenerative disorders such as Parkinson's disease (PD) and Huntington's disease (HD). Animal models of PD or HD, produced by administration of the mitochondrial toxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 3-nitropropionic acid (3NP), respectively, show increased free radical generation. Free radicals generated in biological systems can react with spin-trapping compounds, such as nitrones, to form stable adducts. In recent years, the utility of nitrones has moved beyond analytical applications and into the realm of neuroprotection as antioxidants in both brain ischemia and models of neurodegenerative diseases. In the present study, we administered a new nitrone antioxidant, stilbazulenyl nitrone (STAZN), with either MPTP or 3NP. STAZN attenuated MPTP-induced striatal dopamine depletion by 40% and showed a tendency to dose-dependent neuroprotection. STAZN dose-dependently protected against loss of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta. STAZN reduced the striatal lesion volume caused by systemic 3NP administration from 44 ± 9 to 20 ± 6 mm³. The lipid peroxidation marker, malondialdehyde(MDA), was significantly increased in the striatum, cortex, and cerebellum of rats after administration of 3NP. These increases were blocked by co-injection of STAZN. Our data provide further evidence that STAZN is a neuroprotective free radical spin trap, and suggest that the development of new antioxidants will broaden our therapeutic strategies for neurodegenerative diseases.
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To study the mechanism of the protective effect of the spin-trapping agent α-phenyl-N-tert-butyl nitrone (PBN) against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity hydroxyl radicals and functional parameters of neuroprotection were determined. C57BL/6 mice received PBN (100 mg/kg IP) over a time period of 15 days and on day 8 MPTP (40 mg/kg SC). On day 15 striatal levels of dopamine, serotonin, and metabolites were analyzed. For radical determination mice received a single injection of salicylic acid (SA) (100 mg/kg IP) in the time period of 0.5 h before to 72 h after MPTP injection. In vivo maximum hydroxyl radical levels indicated by 2,3-dihydroxybenzoic acid/SA ratios were obtained 4 h after MPTP injection, and were not affected by PBN treatment. However, the MPTP-induced mortality, reduction of locomotor activity, continuous loss of body weight, and striatal dopamine depletion were significantly less pronounced in PBN-treated animals. These results elucidate the time course of hydroxyl free radical formation in MPTP toxicity. PBN improved the functional parameters of neuroprotection against MPTP toxicity, but there is no evidence for hydroxyl radical scavenging properties to this effect.
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Our main conclusion is that neuronal survival requires the maintenance of the redox status near an optimal set-point. “Reductive stress” may be as dangerous as oxidative stress.
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^☆: T. Hudlicky

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Brief CommunicationAzulenyl Nitrone Spin Traps Protect against MPTP Neurotoxicity☆

Abstract

Free Radical Biol. Med.

J. Neurol. Sci.

Arch. Biochem. Biophys.

Brain Res.

Free Radical Biol. Med.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

J. Biol. Chem.

Neurobiol. Dis.

Free Radical Biol. Med.

Free Radical Biol. Med.

Neurosci. Lett.

Neurosci. Lett.

Exp. Neurol.

Brain Res.

Brain Res.

Kynurenine pathway measurements in Huntington's disease striatum: Evidence for reduced formation of kynurenic acid

J. Neurochem.

Brief Communication
Azulenyl Nitrone Spin Traps Protect against MPTP Neurotoxicity☆