Enhancement of peroxynitrite-evoked acetylcholine release by hydroxyl radical scavengers from mouse cerebral cortical neurons

doi:10.1016/S0024-3205(98)00339-7

Life Sciences

Volume 63, Issue 10, 31 July 1998, Pages 827-833

https://doi.org/10.1016/S0024-3205(98)00339-7 Get rights and content

Abstract

We investigated the effects of hydroxyl radical scavengers on peroxynitrite (OONO⁻)-evoked acetylcholine (ACh) release from mouse cerebral cortical neurons. N,N′-dimethylthiourea, a hydroxyl radical scavenger, dose-dependently increased OONO-evoked ACh release. Other hydroxyl radical scavengers such as uric acid and mannitol, also enhanced OONO-evoked ACh release, although these enhancing effects were not found in the absence of OONO⁻. In addition, OONO⁻-induced [⁴⁵Ca²⁺]influx was significantly facilitated by the scavengers, whereas no effects of the scavengers on [⁴⁵Ca²⁺]influx was observed in the absence of OONO⁻. These results indicate that hydroxyl radical scavengers enhance OONO⁻ -evoked ACh release via the facilitation of OONO -induced [⁴⁵Ca²⁺]influx.

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Citation Excerpt :
In this report we communicate that endogenous NGF is being targeted by peroxynitrite, an important mediator of oxidative damage. This would be consistent with observations that peroxynitrite alters acetylcholine synthesis and ChAT activity (Guermonprez et al., 2001; Ohkuma et al., 1995) as well as acetylcholine release (Hara et al., 1998; Tran et al., 2003). Moreover, peroxynitrite can directly inactivate Mn–SOD and Cu/Zn–SOD; the main antioxidant enzymes in the brain by tyrosine nitration mechanisms (Aoyama et al., 2000; Bayir et al., 2007; Demicheli et al., 2007; Filipović et al., 2007; Yamakura et al., 1998).
Basal forebrain cholinergic neurons (BFCN), a system involved in learning and memory processes, are highly dependent on a continuous supply of biologically active nerve growth factor (NGF). Age-related cholinergic atrophy and cell loss in normal brains is apparently not complemented by reductions in the levels of NGF as could be expected. In the present work, cortical proNGF/NGF were immunoprecipitated from cortical brain homogenates from young and aged and behaviorally characterized rats and resolved with antinitrotyrosine antibodies to reveal nitration of tyrosine residues in proteins. Cortical proNGF in aged and cognitively impaired rats was found to be a target for peroxynitrite-mediated oxidative damage with correlative impact on decrease in choline acetyltransferase activity. These studies provide evidence for oxidative stress damage of NGF molecules in the cerebral cortex of cognitively impaired aged rats as previously shown in AD human brains.
Suppression of Ca<sup>2+</sup> influx through L-type voltage-dependent calcium channels by hydroxyl radical in mouse cerebral cortical neurons
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In the present study, we investigated the effect of hydroxyl radical (·OH) produced by the Fenton reaction with FeSO₄ to H₂O₂ on Ca²⁺ influx by measuring [⁴⁵Ca²⁺] influx into mouse cerebral cortical neurons in primary culture. ·OH formed from 3 μM FeSO₄ and 0.01 μM H₂O₂ significantly reduced 30 mM KCl-induced [⁴⁵Ca²⁺] influx and this reduction was abolished by ·OH scavengers such as N,N′-dimethylthiourea and mannitol. Nifedipine (1 μM), an inhibitor for L-type voltage-dependent Ca²⁺ channels (VDCCs) showed no additive effect on the reduction of the 30 mM KCl-induced [⁴⁵Ca²⁺] influx, while the inhibitors for P/Q- and N-type VDCCs showed further suppression of the KCl-induced [⁴⁵Ca²⁺] influx even in the presence of ·OH. Bay k 8644, an activator of L-type VDCCs, dose-dependently stimulated [⁴⁵Ca²⁺] influx, and this stimulation disappeared in the presence of nifedipine. Similarly, ·OH also suppressed significantly [⁴⁵Ca²⁺] influx induced by Bay k 8644. These inhibitory actions of ·OH on the KCl- and Bay k 8644-induced [⁴⁵Ca²⁺] influx were completely abolished by ·OH scavengers. These results indicate that ·OH has the activity to suppress Ca²⁺ influx through L-type VDCCs.
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This review summarizes the stimulatory potentials of NO and peroxynitrite (OONO⁻) on neurotransmitter release in the central nervous system. Exogenous and endogenous NO stimulates to release neurotransmitter. NO synthesized intracellularly diffuses out through neuronal membrane and acts on the outer side of membrane to depolarize neuronal membrane, which triggers neurotransmitter release. NO-induced release of neurotransmitters is mediated by Ca²⁺-dependent and -independent processes. The latter process is operated by reverse process of the Na⁺-dependent carrier-mediated neurotransmitter uptake system or by unknown mechanisms. Ca²⁺-dependent release of neurotransmitter occurs in part subsequent to increase in Ca²⁺ influx via VDCCs, although N-type VDCCs may not involve in this action of NO because of suppression of Ca²⁺ influx through N-type VDCCs by NO. Participation of cGMP formation by NO on neurotransmitter release is controversial. A superoxide scavenger, Cu²⁺, Zn²⁺-superoxide dismutase, abolishes NO-induced neurotransmitter release and synthesized OONO⁻ induces neurotransmitter release, indicating that OONO⁻ participates in NO-evoked neurotransmitter release.
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Enhancement of peroxynitrite-evoked acetylcholine release by hydroxyl radical scavengers from mouse cerebral cortical neurons

Abstract

J. Neurol. Sci.

J. Biol. Chem.

Mol. Brain Res.

Mol. Brain Res.

Neurosci. Lett.

Free Radical Biol. Med.

Jpn. J. Pharmacol.

Mol. Brain Res.

J. Biol. Chem.

Eur. J. Pharmacol.

Japan. J. Pharmacol.

Biochim. Biophys. Acta