7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced ATP loss in the mouse striatum

Royland, Joyce E.; Delfani, Kioumars; Langston, J. William; Janson, Ann Marie; Monte, Donato A. Di

doi:10.1016/s0006-8993(99)01689-3

Cited by 29 publications

(17 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ATP depletion has also been observed as a primary consequence of MPP ϩ toxicity in hepatocytes (35), brain mitochondria (36), and mouse striatum (37,38), and providing metabolites of glycolysis attenuates it (39). Similarly, supplementation with D-␤-hydroxybutyrate, as well as glucose, protects neurons from MPP ϩ toxicity in vitro and in vivo (34,40,41).…”

Section: Discussionmentioning

confidence: 99%

Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells

Kweon¹,

Marks²,

Krencik³

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The pathogenesis underlying the selective degeneration of dopaminergic neurons in Parkinson's disease (PD) 1 is not fully defined, but multiple lines of evidence implicate mitochondrial dysfunction. Thus, defects in complex I of the mitochondrial respiratory chain in the substantia nigra and evidence of oxidative stress have been noted in the brains of PD patients (1, 2). PD is also associated with exposure to pesticides (3, 4), many of which are either oxidants or mitochondrial toxins. Rapid onset of Parkinsonism in young adults following injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (5) occurs through its active metabolite, 1-methyl-4-phenylpyridinium, an inhibitor of mitochondrial complex I (6), potentially by depleting energy stores and inducing oxidative stress (7,8).Complex I is specifically and irreversibly inhibited by the neurotoxin rotenone, a hydrophobic pesticide epidemiologically linked to PD. Continuous, systemic, in vivo infusion of 2-3 mg/kg/day rotenone in rats over weeks produces relatively selective nigrostriatal dopaminergic neurodegeneration, with formation of ubiquitin-and ␣-synuclein-positive inclusions (9, 10). This low dose paradigm results in about 75% inhibition of complex I activity, and corresponds to a brain concentration of 20 -30 nM (9, 10). However, although these studies establish the principle that complex I dysfunction leads to degeneration in dopaminergic neurons, consistent levels of functional deficits related to complex I dysfunction have been difficult to reproduce (11). Accordingly, this in vivo model has not lent itself easily to the study of the mechanism of rotenone toxicity (12). Similarly, the use of primary cultures of dopaminergic neurons to study mechanisms of rotenone-induced neurodegeneration has been limited: short term, nanomolar rotenone administration in primary cultures of dopaminergic neurons does not produce selective dopaminergic damage (13). In addition, primary cultures contain a mixture of dopaminergic and nondopaminergic neurons and therefore do not lend themselves to molecular and biochemical analyses. The use of existing cell lines to study the effects of chronic rotenone exposure (14) also has shortcomings. Most cell lines do not exhibit robust dopaminergic phenotypes. In addition, the high rate of proliferation that characterize these cell lines confound the assessment of cellular susceptibility to rotenone, because proliferating cells may replace those that have succumbed to rotenone, and chronic exposure may lead to the selection of cells that become resistant to rotenone toxicity.To study the cellular mechanisms of rotenone-induced dopaminergic neuronal degeneration, we therefore developed a novel cellular model derived from immortalized midbrain MN9D cells (15), a dopaminergic neuronal cell line that has been extensively characterized as a model of dopaminergic neurons (16 -19). Using sodium butyrate (NaBu) (20) to differentiate MN9D cells and cells from a related, immortalized, non-dopaminergic midbrain neuronal cell line (MN9X ...

show abstract

Section: Discussionmentioning

confidence: 99%

Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells

Kweon¹,

Marks²,

Krencik³

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The selective nNOS inhibitor 7-nitroindazole is not an alternative to L-NAME in this respect, because of its monoamine oxidase (MAO)-B inhibitory effects (Castagnoli et al, 1997;Royland et al, 1999). MAO inhibitors were shown to have anxiolytic-like properties in the elevated plus-maze (Griebel et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of P2Y1 Receptors Causes Anxiolytic-like Effects in the Rat Elevated Plus-maze: Implications for the Involvement of P2Y1 Receptor-Mediated Nitric Oxide Production

Kittner

Franke

Fischer

et al. 2002

Neuropsychopharmacol

View full text Add to dashboard Cite

(ADPbS), the P2X 1,3 receptor agonist a,b-methylene ATP (a,bmeATP), the unspecific P2 receptor antagonist pyridoxalphosphate-6-azopheny l-2 0 ,4 0 -disulfonic acid (PPADS), and the specific P2Y 1 receptor antagonist N 6 -methyl-2 0 -deoxyadenosine-3 0 ,5 0 -bisphosphate (MRS 2179) on the elevated plus-maze behavior of the rat were investigated. All tested compounds were given intracerebroventricularly (0.5 ml). ADPbS (50 and 500 fmol) produced an anxiolytic-like behavioral profile reflected by an increase of the open arm exploration. The anxiolytic-like effects were antagonized by pretreatment with PPADS (5 pmol) or MRS 2179 (5 pmol). Both compounds caused anxiogenic-like effects when given alone. Furthermore, the anxiolytic-like effects of ADPbS could be antagonized by pretreatment with the nitric oxide synthase (NOS) inhibitor N w -nitro-L-arginine methyl ester (L-NAME). In addition, the anxiogenic-like effects of PPADS were reversed by the pretreatment with L-arginine (500 pmol), which is the natural substrate for NOS, but not by D-arginine (500 pmol), which is not. Immunofluorescence staining revealed the presence of P2Y 1 receptors on neurons in different brain regions such as hypothalamus, amygdala, hippocampus and the periaqueductal gray. Furthermore, the colocalization of P2Y 1 receptors and neuronal NOS (nNOS) on some neurons in these regions could be demonstrated. The highest density of P2Y 1 -and nNOS-immunoreactivity was detected in the dorsomedial hypothalamic nucleus. Taken together, the present results suggest that P2Y 1 receptors are involved in the modulation of anxiety in the rat. The anxiolytic-like effects after stimulation of P2Y 1 receptors seem to be in close connection with the related nitric oxide production.

show abstract

“…Although the precise mechanism and neuronal pathways mediating circling behavior in this model remain to be established, it may reflect an imbalance between dopaminergic mechanisms (Costall et al, 1976;Royland et al, 1999). After unilateral DA damage the homologous contralateral anatomical sites would become dominant, with turning behavior developing contralateral to the dominant side.…”

Section: Nitric Oxide System and Experimental Parkinson'smentioning

confidence: 98%

Role of Nitric Oxide on Motor Behavior

et al. 2005

View full text Add to dashboard Cite

The present review paper describes results indicating the influence of nitric oxide (NO) on motor control. Our last studies showed that systemic injections of low doses of inhibitors of NO synthase (NOS), the enzyme responsible for NO formation, induce anxiolytic effects in the elevated plus maze whereas higher doses decrease maze exploration. Also, NOS inhibitors decrease locomotion and rearing in an open field arena. These results may involve motor effects of this compounds, since inhibitors of NOS, NG-nitro-L-arginine (L-NOARG), N(G)-nitro-L-arginine methylester (L-NAME), N(G)-monomethyl-L-arginine (L-NMMA), and 7-Nitroindazole (7-NIO), induced catalepsy in mice. This effect was also found in rats after systemic, intracebroventricular or intrastriatal administration. Acute administration of L-NOARG has an additive cataleptic effect with haloperidol, a dopamine D2 antagonist. The catalepsy is also potentiated by WAY 100135 (5-HT1a receptor antagonist), ketanserin (5HT2a and alfal adrenergic receptor antagonist), and ritanserin (5-HT2a and 5HT2c receptor antagonist). Atropine sulfate and biperiden, antimuscarinic drugs, block L-NOARG-induced catalepsy in mice. L-NOARG subchronic administration in mice induces rapid tolerance (3 days) to its cataleptic effects. It also produces cross-tolerance to haloperidol-induced catalepsy. After subchronic L-NOARG treatment there is an increase in the density NADPH-d positive neurons in the dorsal part of nucleus caudate-putamen, nucleus accumbens, and tegmental pedunculupontinus nucleus. In contrast, this treatment decreases NADPH-d neuronal number in the substantia nigra compacta. Considering these results we suggest that (i) NO may modulate motor behavior, probably by interfering with dopaminergic, serotonergic, and cholinergic neurotransmission in the striatum; (ii) Subchronic NO synthesis inhibition induces plastic changes in NO-producing neurons in brain areas related to motor control and causes cross-tolerance to the cataleptic effect of haloperidol, raising the possibility that such treatments could decrease motor side effects associated with antipsychotic medications. Finally, recent studies using experimental Parkinson's disease models suggest an interaction between NO system and neurodegenerative processes in the nigrostriatal pathway. It provides evidence of a protective role of NO. Together, our results indicate that NO may be a key participant on physiological and pathophysiological processes in the nigrostriatal system.

show abstract

7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced ATP loss in the mouse striatum

Cited by 29 publications

References 28 publications

Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells

Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells

Stimulation of P2Y1 Receptors Causes Anxiolytic-like Effects in the Rat Elevated Plus-maze: Implications for the Involvement of P2Y1 Receptor-Mediated Nitric Oxide Production

Role of Nitric Oxide on Motor Behavior

Contact Info

Product

Resources

About