Signaling pathways in the nitric oxide and iron-induced dopamine release in the striatum of freely moving rats: Role of extracellular Ca2+ and L-type Ca2+ channels

Department of Pharmacology, University of Sassari, viale S.Pietro 43B, 07100 Sassari, Italy.
Brain Research (Impact Factor: 2.84). 07/2005; 1047(1):18-29. DOI: 10.1016/j.brainres.2005.04.008
Source: PubMed


We showed previously that exogenous iron potentiated nitric oxide (NO) donor-induced release of striatal dopamine (DA) in freely moving rats, using microdialysis. In this study, the increase in dialysate DA induced by intrastriatal infusion of the NO-donor 3-morpholinosydnonimine (SIN-1, 1.0 mM for 180 min) was scarcely affected by Ca2+ omission. N-methyl-d-glucamine dithiocarbamate (MGD) is a thiol compound whose NO trapping activity is potentiated by iron(II). Intrastriatal co-infusion of MGD either alone or associated with iron(II), however, potentiated SIN-1-induced increases in dialysate DA. In contrast, co-infusion of the NO trapper 4-(carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide (carboxy-PTIO) significantly attenuated the increase in dialysate DA induced by SIN-1 (5.0 mM for 180 min). SIN-1+MGD+iron(II)-induced increases in dialysate DA were inhibited by Ca2+ omission or co-infusion of either deferoxamine or the L-type (Ca(v) 1.1-1.3) Ca2+ channel inhibitor nifedipine; in contrast, the increase was scarcely affected by co-infusion of the N-type (Ca(v) 2.2) Ca2+ channel inhibitor omega-conotoxin GVIA. These results demonstrate that exogenous NO-induced release of striatal DA is independent on extracellular Ca2+; however, in presence of the NO trapper MGD, NO may preferentially react with either endogenous or exogenous iron to form a complex which releases striatal DA with an extracellular Ca2+-dependent and nifedipine-sensitive mechanism.

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    • "The composition of the endogenous environment in which NO is generated seems to regulate its biological actions (Wink and Mitchell 1998). DA-mediated release by exogenous NO, both in vivo (West and Galloway 1998) and in vitro (Rocchitta et al. 2005), appears to be dependent on external Ca 2? . "
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    ABSTRACT: Previous research has shown that nitric oxide (NO) synthase inhibitors prevent rodents' sensorimotor gating impairments induced by dopamine releasing drugs, such as amphetamine (Amph) and methylphenidate. The mechanisms of this effect have not been entirely understood. In the present work, we investigated some possible mechanisms by which the NO donor, NOC-12 (3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene), influence spontaneous and Amph-induced dopamine release, using rat mesencephalic primary cultured neurons preparations. Our results showed that NOC-12 increased dopamine release in a concentration-dependent manner and potentiated the Amph-induced one. Dopamine release induced by NOC-12 was disrupted by N-acetyl-L-cystein (NAC-a free radical scavenger) and MK-801, a NMDA (N-methyl-D-aspartate) non-competitive antagonist, and was concentration dependently affected by oxadiazolo[4,3]quinoxalin-1-one, an inhibitor of the soluble guanylate cyclase (sGC). In contrast, dopamine released by Amph was facilitated by NAC and by MK-801 and not affected by nifedipine (a L-type-Ca(+2) channel blocker), which enhanced NOC-12-induced dopamine release. The present work demonstrates that DA release induced by NOC-12 is partially dependent on sGC and on NMDA activation, and is modulated by L-type Ca(+2) channel and the antioxidant NAC. This mechanism differs from the Amph-induced one, which appears not to depend on L-type Ca(+2) channel and seems to be facilitated by NMDA channel blocking and by NAC. These results suggest that Amph and NOC-12 induce dopamine release through complementary pathways, which may explain the potentiation of Amph-induced dopamine release by NOC-12. These findings contribute to understand the involvement of NO in dopamine-related neuropsychiatric and neurodegenerative diseases.
    Neurotoxicity Research 09/2015; DOI:10.1007/s12640-015-9562-8 · 3.54 Impact Factor
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    • "It should be recalled, that NO signaling plays an important role in the functioning of the CNS, and activation of soluble guanylate cuclase (sGC) represent one important effect of NO. Of note, physiological release of low concentrations of NO by constitutive neuronal NOS is recognized to modulate extracellular levels of dopamine in the striatum and to critically participate in striatal DAergic homeostasis [98]. The NO/sGC/cGMP signal transduction system is also considered to be important for modulating synaptic transmission and plasticity in brain regions such as the hippocampus, cerebral cortex, and cerebellum, and further studies are required to unravel potential involvement of these pathways in DAergic neuroprotection afforded by HCT1026. "
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    ABSTRACT: Current evidence suggests a role of neuroinflammation in the pathogenesis of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of basal ganglia injury. Reportedly, nonsteroidal anti-inflammatory drugs (NSAIDs) mitigate DAergic neurotoxicity in rodent models of PD. Consistent with these findings, epidemiological analysis indicated that certain NSAIDs may prevent or delay the progression of PD. However, a serious impediment of chronic NSAID therapy, particularly in the elderly, is gastric, renal and cardiac toxicity. Nitric oxide (NO)-donating NSAIDs, have a safer profile while maintaining anti-inflammatory activity of parent compounds. We have investigated the oral activity of the NO-donating derivative of flurbiprofen, [2-fluoro-α-methyl (1,1'-biphenyl)-4-acetic-4-(nitrooxy)butyl ester], HCT1026 (30 mg kg(-1) daily in rodent chow) in mice exposed to the parkinsonian neurotoxin MPTP. Ageing mice were fed with a control, flurbiprofen, or HCT1026 diet starting ten days before MPTP administration and continuing for all the experimental period. Striatal high affinity synaptosomal dopamine up-take, motor coordination assessed with the rotarod, tyrosine hydroxylase (TH)- and dopamine transporter (DAT) fiber staining, stereological cell counts, immunoblotting and gene expression analyses were used to assess MPTP-induced nigrostriatal DAergic toxicity and glial activation 1-40 days post-MPTP. HCT1026 was well tolerated and did not cause any measurable toxic effect, whereas flurbiprofen fed mice showed severe gastrointestinal side-effects. HCT1026 efficiently counteracted motor impairment and reversed MPTP-induced decreased synaptosomal [3H]dopamine uptake, TH- and DAT-stained fibers in striatum and TH+ neuron loss in substantia nigra pars compacta (SNpc), as opposed to age-matched mice fed with a control diet. These effects were associated to a significant decrease in reactive macrophage antigen-1 (Mac-1)-positive microglial cells within the striatum and ventral midbrain, decreased expression of iNOS, Mac-1 and NADPH oxidase (PHOX), and downregulation of 3-Nitrotyrosine, a peroxynitrite finger print, in SNpc DAergic neurons. Oral treatment with HCT1026 has a safe profile and a significant efficacy in counteracting MPTP-induced dopaminergic (DAergic) neurotoxicity, motor impairment and microglia activation in ageing mice. HCT1026 provides a novel promising approach towards the development of effective pharmacological neuroprotective strategies against PD.
    Journal of Neuroinflammation 11/2010; 7(1):83. DOI:10.1186/1742-2094-7-83 · 5.41 Impact Factor
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    • "Following nifedipine administration the binding of Ca 2+ to troponin and calmodulin in the cell is limited . It prevents the increase of intracellular Ca 2+ ions increase and finally inhibits such effects as muscle contraction, hormone and neurotransmitter release, neuronal migration, activation of Ca-dependent signaling cascades and synaptic input integration (Bhaukaurally et al., 2005; Rocchita et al., 2005). Nifedipine was the first drug of this growing class of VGCCs blockers being dihydropyrimidine derivates. "
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    ABSTRACT: Present study examined the effect of VGCC L-type blocker - nifedipine given i.c.v. (0.25, 0.5, 1 and/or 2mg in toto) on the development of nociceptive behavior, clinical symptoms, plasma catecholamin concentration and reticulo-rumen motility following 5 min lasting mechanical duodenal distension (DD) in sheep. After 24h of fasting, all animals received i.m. ketamine analgesia (20 mg kg(-1)B.W) and anesthetized with pentobarbital (20 mg kg(-1)B.W., i.v. infusion) The permanent stainless steel cannula 29 mm in length and 2mm in diameter was inserted into the lateral cerebral ventricle (controlled by cerebro-spinal efflux) 10mm above the bregma and 5mm laterally from the midline sutures using stereotaxic method. Under the same general anesthesia/analgesia a T-shaped silicon cannula (inside diameter of 21 mm), was inserted into the duodenum (12 cm from pylorus). Second identical cannule was inserted into the dorsal sac of the rumen, a previously described. After surgery each animal was kept in individual boxes for 10 days prior to experiment and was treated i.m. with benzyl procaine penicillin 30,000 I.U kg(-1)B.W.)+dihydrostreptomycine sulfate (10 g kg(-1)B.W.)+prednisolone acetate (1.2 mg kg(-1)B.W.) combination and i.m. ketamine (20 mg kg(-1)B.W.) every day by seven consecutive days. Experimental DD was conducted by insertion and then distension of rubber balloon (containing 40 ml of warm water) inserted into sheep duodenum. Duodenal distension produced a significant increase in behavioral pain manifestations, tachycardia, hyperventilation, inhibition of reticulo-ruminal contractions rate (from 87.2 to 38.0% during 15-20 min), an increase of plasma catecholamine concentration (over 6.4-fold increase of epinephrine during 2h following DD, 2-times norepinephrine and 84% increase of dopamine). Nifedipine infusion administered 10 min prior to DD decreased intensity of visceral pain manifestations such as: behavioral changes, hyperventilation, reticulo-rumen motility and efficiently prevent appearance of catecholamine release. These data demonstrated that the development and persistence of duodenal hyperalgesia depends on the activation of Ca(2+) ion flux leading to neurotransmitters release and modulation of membrane excitability. It seems that nifedipine given i.c.v. 10 min prior to DD (as a source of visceral pain), inhibited specific receptors 1 subunits of VGCCs in target tissues, prevented depolarization of cell membranes and release of neurotransmitters responsible for pain sensitivity in sheep. The observed antinociceptive action of VGCCs type L blockers suggest that these channels play a crucial role in the modulation of acute visceral hyperalgesia in sheep.
    Research in Veterinary Science 10/2008; 86(2):285-92. DOI:10.1016/j.rvsc.2008.04.010 · 1.41 Impact Factor
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