Nicotine protects rat brain mitochondria against experimental injuries

Cormier, Anne; Morin, Christophe; Zini, Roland; Tillement, Jean‐Paul; Lagrue, G

doi:10.1016/s0028-3908(03)00041-8

Cited by 78 publications

(57 citation statements)

References 42 publications

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“…We posit that nicotine, besides its previously known inhibition of complex I and decreased ROS generation mode (19), inhibits neurotoxin-induced CsA-sensitive mitochondria swelling and cytochrome c release through inhibition of the mPTP.…”

Section: Discussionmentioning

confidence: 95%

Investigating the Receptor-independent Neuroprotective Mechanisms of Nicotine in Mitochondria

Xie

Bézard

Zhao

2005

Journal of Biological Chemistry

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Although nicotine has been associated with a decreased risk of developing Parkinson disease, the underlying mechanisms are still unclear. By using isolated brain mitochondria, we found that nicotine inhibited N-methyl-4-phenylpyridine (MPP ؉ ) and calcium-induced mitochondria high amplitude swelling and cytochrome c release from intact mitochondria. Intra-mitochondria redox state was also maintained by nicotine, which could be attributed to an attenuation of mitochondria permeability transition. Further investigation revealed that nicotine did not prevent MPP ؉ -or calciuminduced mitochondria membrane potential loss, but instead decreased the electron leak at the site of respiratory chain complex I. In the presence of mecamylamine hydrochloride, a nonselective nicotinic acetylcholine receptor inhibitor, nicotine significantly postponed mitochondria swelling and cytochrome c release induced by a mixture of neurotoxins (MPP ؉ and 6-hydroxydopamine) in SH-SY5Y cells, suggesting that there is a receptor-independent nicotine-mediated neuroprotective effect of nicotine. These results show that interaction of nicotine with mitochondria respiratory chain together with its antioxidant effects should be considered in the neuroprotective effects of nicotine.Nicotine intake, mostly through cigarette smoking, has been associated with a decreased risk of developing Parkinson disease (PD) 2 (1, 2), a common neurodegenerative disorder caused by the death of the dopamine neurons in the substantia nigra pars compacta that project to the striatum (3). Although the mechanisms of neuroprotection by nicotine are not fully understood, and there are still some conflicting reports (4, 5), it is accepted that nicotine usually acts as a nicotinic acetylcholine receptor (nAChRs) agonist. Although nigrostriatal damage reduces expression of specific nAChRs subtypes (6), stimulation of these receptors has been proved to be neuroprotective (7). Besides its agonistic properties, nicotine has several receptor independent effects whereby it could protect neurons against toxins (8). Linert et al. (9) found that nicotine could strongly affect the course of the Fenton reaction by inhibiting the oxidation of 6-OHDA in the presence of Fe(II, III) ions. Our previous work also indicated that nicotine acts as an effective reactive oxygen species (ROS) scavenger in the gas phase of cigarette smoking (10). Recently, Cormier et al. (11) showed that nicotine was an effective NADH competitor that inhibited the mitochondria NADHubiquinone reductase (NQR) activity and significantly decreased brain mitochondrial respiratory control ratio. They also found that nicotine significantly decreased superoxide anion generation in brain mitochondria, suggesting a possible direct role of nicotine on mitochondria respiratory chain independent of its receptor.Complex I inhibition or deficiency is thought to play a major role in PD etiology (12)(13)(14), and nicotine was reported to protect neurons against pro-parkinsonian neurotoxins such as N-methyl-4-phenylpyridinium i...

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Section: Discussionmentioning

confidence: 95%

Investigating the Receptor-independent Neuroprotective Mechanisms of Nicotine in Mitochondria

Xie

Bézard

Zhao

2005

Journal of Biological Chemistry

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“…These include a direct antioxidant effect possibly through lipid peroxidation and/or by scavenging reactive oxygen species such as superoxides (Soto-Otero et al, 2002;Cormier et al, 2003). Nicotine also appears to compete with NADH to attenuate mitochondrial respiratory control (Cormier et al, 2003), and to reduce mitochondrial swelling and cytochrome c release from mitochondria in the presence of nAChR blockers . In addition, liver metabolizing enzymes such as cytochrome P450 are induced by nicotine (Tyndale, 2003;Hukkanen et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Chronic Oral Nicotine Normalizes Dopaminergic Function and Synaptic Plasticity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Primates

Quik

Chen²,

Parameswaran³

et al. 2006

J. Neurosci.

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Our recent studies show that chronic oral nicotine partially protects against striatal damage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates. To identify the cellular changes associated with this protective action, we investigated the effects of nicotine treatment on stimulus-evoked dopamine release, dopamine turnover, and synaptic plasticity in striatum from lesioned and unlesioned animals. Monkeys were chronically (6 months) treated with nicotine in the drinking water and subsequently lesioned with the dopaminergic neurotoxin MPTP (6 months) while nicotine was continued. Nigrostriatal damage increased nicotinic acetylcholine receptor (nAChR)-mediated fractional dopamine release from residual terminals, primarily through changes in ␣3*/␣6* nAChRs. In contrast, fractional receptor-evoked dopamine release was similar to control in unlesioned and lesioned animals with chronic oral nicotine. Long-term nicotine administration also attenuated the enhanced K ϩ -evoked fractional dopamine release from synaptosomes of MPTP-lesioned animals, suggesting that nicotine treatment had a generalized effect on dopaminergic function. This premise was further supported by experiments showing that nicotine dosing decreased the elevated dopamine turnover that occurs after nigrostriatal damage. We next investigated changes in synaptic plasticity with lesioning and nicotine treatment. Nicotine treatment alone enhanced synaptic plasticity by lowering the threshold for long-term depression (LTD) in the corticostriatal pathway. MPTP lesioning led to a loss of LTD, a measure of short-term synaptic plasticity. In contrast, LTD was preserved in nicotine-treated lesioned animals. Thus, the present data show that the disruptions in striatal dopaminergic function after nigrostriatal damage were attenuated with chronic nicotine administration. These cellular alterations may underlie the ability of nicotine to maintain/restore normal function with nigrostriatal damage.

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“…Preparation of Intact Rat Brain Mitochondria-The procedure as reported (32) was essentially a combination of differential centrifugation (33) and purification by Percoll density gradient centrifugation (34). Routinely, two adult Wistar rats of about 150 g each were killed by cervical dislocation, followed by decapitation.…”

Section: Methodsmentioning

confidence: 99%

A Mechanism of Sulfite Neurotoxicity

Zhang

Vincent

Halliwell

et al. 2004

Journal of Biological Chemistry

123

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Exposure of Neuro-2a and PC12 cells to micromolar concentrations of sulfite caused an increase in reactive oxygen species and a decrease in ATP. Likewise, the biosynthesis of ATP in intact rat brain mitochondria from the oxidation of glutamate was inhibited by micromolar sulfite. Glutamate-driven respiration increased the mitochondrial membrane potential (MMP), and this was abolished by sulfite but the MMP generated by oxidation of malate and succinate was not affected. The increased rate of production of NADH from exogenous NAD ؉ and glutamate added to rat brain mitochondrial extracts was inhibited by sulfite, and mitochondria preincubated with sulfite failed to reduce NAD ؉ . Glutamate dehydrogenase (GDH) in rat brain mitochondrial extract was inhibited dose-dependently by sulfite as was the activity of a purified enzyme. An increase in the K m (glutamate) and a decrease in V max resulting in an attenuation in V max /K m (glutamate) at 100 M sulfite suggest a mixed type of inhibition. However, uncompetitive inhibition was noted with decreases in both K m (NAD ؉ ) and V max , whereas V max /K m (NAD ؉ ) remained relatively constant. We propose that GDH is one target of action of sulfite, leading to a decrease in ␣-ketoglutarate and a diminished flux through the tricarboxylic acid cycle accompanied by a decrease in NADH through the mitochondrial electron transport chain, a decreased MMP, and a decrease in ATP synthesis. Because glutamate is a major metabolite in the brain, inhibition of GDH by sulfite could contribute to the severe phenotype of sulfite oxidase deficiency in human infants.

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Nicotine protects rat brain mitochondria against experimental injuries

Cited by 78 publications

References 42 publications

Investigating the Receptor-independent Neuroprotective Mechanisms of Nicotine in Mitochondria

Investigating the Receptor-independent Neuroprotective Mechanisms of Nicotine in Mitochondria

Chronic Oral Nicotine Normalizes Dopaminergic Function and Synaptic Plasticity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Primates

A Mechanism of Sulfite Neurotoxicity

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