Tranylcypromine, but not moclobemide, prolongs the inhibitory action of dopamine on midbrain dopaminergic neurons: An in vitro electrophysiological study

Mercuri, Nicola Biagio; Federici, Mauro; Marinelli, Silvia; Bernardi, Giorgio

doi:10.1002/1098-2396(20000901)37:3<216::aid-syn5>3.0.co;2-3

Cited by 8 publications

(6 citation statements)

References 35 publications

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“…see Sciaccaluga et al, 2020), this effect was significantly less pronounced than that of TCP, another well-known MAO blocker, which instead produces a prolonged inhibition of neuronal firing in response to DA, in analogy with previous observations (Mercuri et al, 2000).…”

Section: Discussionsupporting

confidence: 87%

“…By performing electrophysiological recordings of SNpc neurons in midbrain slices, we have shown that SAF, a selective and reversible monoamine oxidase-B inhibitor (Benedetti et al,1994; Caccia et al, 2006; Binda et al, 2007; Onofrj et al, 2008) mildly prolongs the DA signal, measured by the extent of firing inhibition of SNpc DAergic neurons in response to DA. Despite the saturating concentration of SAF used (30 μM; see Sciaccaluga et al, 2020), this effect was significantly less pronounced than that of TCP, another well-known MAO blocker, which instead produces a prolonged inhibition of neuronal firing in response to DA, in analogy with previous observations (Mercuri et al, 2000).…”

Section: Discussionsupporting

confidence: 75%

“…In particular, by exploiting as experimental readout the D 2 receptor (D 2 R)-mediated firing inhibition that characterizes these neurons (Lacey et al, 1987), we used the degree of prolongation of DA-induced firing inhibition in response to preexposure to various MAO inhibitors, as a powerful and subtle index of their potency (Mercuri et al, 1996). Therefore, to elucidate the functional efficacy of safinamide as MAO inhibitor, we compared its ability to prolog the DA signal, with that of another irreversible MAO inhibitor, tranylcypromine, (Coutts et al, 1987; Ulrich et al, 2017), whose efficacy has been characterized in our laboratories (Mercuri et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Functional efficacy of the MAO-B inhibitor safinamide in murine substantia nigrapars compactadopaminergic neuronsin vitro: a comparative study with tranylcypromine

Zarrilli,

Giacomet,

Cossa

et al. 2024

Preprint

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Safinamide (SAF) is currently used to treat Parkinson’s disease (PD) symptoms based on its theoretical ability to potentiate the dopamine (DA) signal, blocking monoamine oxidase (MAO) B. The present work aims to highlight the functional relevance of SAF as an enhancer of the DA signal, by evaluating its ability to prolong recovery from DA-mediated firing inhibition of DAergic neurons of the substantia nigra pars compacta (SNpc), compared to another MAO antagonist, tranylcypromine (TCP). Using multielectrode array (MEA) and single electrode extracellular recordings of spontaneous spikes from presumed SNpc DAergic cellsin vitro, we show that SAF (30 µM) mildly prolongs the DA-mediated firing inhibition, as opposed to the profound effect of TCP (10 µM). In patch-clamp recordings, we found that SAF (30 µM) significantly reduced the number of spikes evoked by depolarizing currents in SNpc DAergic neurons, in a sulpiride (1 µM) independent manner. According to our results, SAF marginally potentiates the DA signal in SNpc DAergic neurons, while exerting an inhibitory effect on the postsynaptic excitability acting on membrane conductances. Thus, we propose that the therapeutic effects of SAF in PD patients partially depends on MAO inhibition, while other MAO-independent sites of action could be more relevant.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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Functional efficacy of the MAO-B inhibitor safinamide in murine substantia nigrapars compactadopaminergic neuronsin vitro: a comparative study with tranylcypromine

Zarrilli,

Giacomet,

Cossa

et al. 2024

Preprint

Self Cite

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“…DFO showed anticipated effects on the regulation of iron genes, whereas iron, which was used at lower dosages as in other cellular systems and published reports (Dichtl et al, 2018), caused only small effects. Tranylcypromine was added to all treatments to prevent endogenous dopamine degradation, and an untreated condition was included to evaluate the basal expression of the investigated genes (Dichtl et al, 2019; Dichtl et al, 2018; Mercuri et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

“…Tranylcypromine was added to all treatments to prevent endogenous dopamine degradation, and an untreated condition was included to evaluate the basal expression of the investigated genes (Dichtl et al, 2019;Dichtl et al, 2018;Mercuri et al, 2000).…”

Section: Dopamine Affects Iron Metabolism In Sh-sy5y Cellsmentioning

confidence: 99%

Dopamine-iron homeostasis interaction rescues mitochondrial fitness in Parkinson’s disease

Buoso,

Seifert,

Lang

et al. 2023

Preprint

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Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson’s disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment affected the expression of transmembrane iron transporters and cellular iron accumulation. Furthermore, dopamine supplementation led to decreased mitochondrial respiration and reduced mitochondrial fitness, including reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenousSNCAmutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of these PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore this disturbed regulatory network in PD cells.

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Relaxant effect of oxime derivatives in isolated rat aorta: role of nitric oxide (NO) formation in smooth muscle

Chalupský

Lobysheva

Nepveu

et al. 2004

Biochemical Pharmacology

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Tranylcypromine, but not moclobemide, prolongs the inhibitory action of dopamine on midbrain dopaminergic neurons: An in vitro electrophysiological study

Cited by 8 publications

References 35 publications

Functional efficacy of the MAO-B inhibitor safinamide in murine substantia nigrapars compactadopaminergic neuronsin vitro: a comparative study with tranylcypromine

Functional efficacy of the MAO-B inhibitor safinamide in murine substantia nigrapars compactadopaminergic neuronsin vitro: a comparative study with tranylcypromine

Dopamine-iron homeostasis interaction rescues mitochondrial fitness in Parkinson’s disease

Relaxant effect of oxime derivatives in isolated rat aorta: role of nitric oxide (NO) formation in smooth muscle

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