A novel multi-target ligand (JM-20) protects mitochondrial integrity, inhibits brain excitatory amino acid release and reduces cerebral ischemia injury in vitro and in vivo

Nuñez-Figueredo, Yanier; Ramírez-Sánchez, Jeney; Hansel, Gisele; Pires, Elisa Nicoloso Simões; Merino, Nelsón; Valdés, Odalys; Hernández, René Delgado; Parra, Alicia Lagarto; Ochoa-Rodríguez, Estael; Verdecia-Reyes, Yamila; Salbego, Christianne Gazzana; Costa, Sílvia Lima; Souza, Diogo O.; Pardo-Andreu, Gilberto L.

doi:10.1016/j.neuropharm.2014.06.009

Cited by 44 publications

(31 citation statements)

References 58 publications

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“…In this work we have observed that JM-20 inhibited glutamate uptake by synaptic vesicles in association with an inhibition of V-ATPase activity and a dissipation of ΔpH. These related effects may contribute to the reduction of glutamate quantal size, thus reducing the glutamate released into the synapses, and could partly explain the anti-excitotoxic effect we recently observed in vivo (Nuñez-Figueredo et al, 2014b).…”

Section: Discussionsupporting

confidence: 57%

“…We observed here that JM-20 enhanced glutamate uptake in astrocyte culture alone at very low micromolar concentrations, but it did not, in cortical neurons. Because the astrocytic glutamate transport plays a major role in maintaining extracellular glutamate concentrations below neurotoxic levels (Anderson and Swanson, 2000;Danbolt, 2001), and the neurotransmitter uptake by astrocytes can be stimulated by several neuroprotective compounds (Beller et al, 2011;Karki et al, 2014;Wu et al, 2008), the above mentioned effects of JM-20 may contribute to explain its anti-excitotoxic actions in vitro (Nuñez-Figueredo et al, 2014a) and in vivo (Nuñez-Figueredo et al, 2014b).…”

Section: Discussionmentioning

confidence: 99%

“…It is expected that both the electrochemical driving force and VGLUT activity affect vesicular glutamate content and subsequent glutamatergic signaling and release (Juge et al, 2010). We have recently observed that [1,5]benzodiazepine) given 1 h after reperfusion at the neuroprotective dose of 8 mg/kg significantly reduced the glutamate concentration in cerebrospinal fluid from rats subjected to 90 min middle cerebral artery occlusion, compared with vehicletreated rats (5.5 ± 1.55 μM versus 14.4 ± 3.48 μM) (Nuñez-Figueredo et al, 2014b). The glutamate levels in JM-20-treated rats were equivalent to normal values because no difference was observed when compared to those from a sham-operated group (4.5 ± 1.2 μM).…”

Section: Introductionmentioning

confidence: 99%

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The effects of JM-20 on the glutamatergic system in synaptic vesicles, synaptosomes and neural cells cultured from rat brain

Nuñez-Figueredo

Pardo-Andreu

Loureiro

et al. 2015

Neurochemistry International

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JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido[2,3-b][1,5]benzodiazepine) is a novel benzodiazepine dihydropyridine hybrid molecule, which has been shown to be a neuroprotective agent in brain disorders involving glutamate receptors. However, the effect of JM-20 on the functionality of the glutamatergic system has not been investigated. In this study, by using different in vitro preparations, we investigated the effects of JM-20 on (i) rat brain synaptic vesicles (L-[(3)H]-glutamate uptake, proton gradient built-up and bafilomycin-sensitive H(+)-ATPase activity), (ii) rat brain synaptosomes (glutamate release) and (iii) primary cultures of rat cortical neurons, astrocytes and astrocyte-neuron co-cultures (L-[(3)H]-glutamate uptake and glutamate release). We observed here that JM-20 impairs H(+)-ATPase activity and consequently reduces vesicular glutamate uptake. This molecule also inhibits glutamate release from brain synaptosomes and markedly increases glutamate uptake in astrocytes alone, and co-cultured neurons and astrocytes. The impairment of vesicular glutamate uptake by inhibition of the H(+)-ATPase caused by JM-20 could decrease the amount of the transmitter stored in synaptic vesicles, increase the cytosolic levels of glutamate, and will thus down-regulate neurotransmitter release. Together, these results contribute to explain the anti-excitotoxic effect of JM-20 and its strong neuroprotective effect observed in different in vitro and in vivo models of brain ischemia.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The effects of JM-20 on the glutamatergic system in synaptic vesicles, synaptosomes and neural cells cultured from rat brain

Nuñez-Figueredo

Pardo-Andreu

Loureiro

et al. 2015

Neurochemistry International

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“…In vivo, JM-20 treatment (4 and 8 mg/kg) significantly decreased neurological deficit scores, edema formation, total infarct volumes and histological alterations in different brain regions 13 . Rapamycin could improve brain edema progression after reperfusion injury through maintaining blood-brain barrier integrity and inhibiting metalloproteinase 9 and aquaporin 4 (AQP4) expression 14 .…”

Section: Red Neuron Countingmentioning

confidence: 90%

“…Similar findings were seen in rats submitted to short term (1h) IR (Figure 4). In vitro, a novel multi-target ligand (JM-20 -1 and 10 μM) administered during reperfusion significantly reduced cell death in hippocampal slices subjected to oxygen and glucose deprivation 13 .…”

Section: Red Neuron Countingmentioning

confidence: 97%

Preconditioning with L-alanyl-glutamine upon cerebral edema and hypocampus red neurons counting in rats subjected to brain ischemia /reperfusion injury

Vasconcelos

Guimarães²,

Campelo³

et al. 2015

Acta Cir. Bras.

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Conception, design, intellectual and scientific content of the study, critical revision, final approval. ABSTRACT PURPOSE:To evaluate the effects of the dipeptide L-alanyl-glutamine (L-Ala-Gln) as a preconditioning agent to potentially promote reduction in the intensity of lesion or induction of resilience in rats subjected to global cerebral ischemia/reperfusion (I/R) injury. METHODS:Thirty-six male Wistar rats weighing 280-300g were randomly assigned to six groups (n=6). Groups Sham 1h and 24hwere treated with saline and spared of further interventions. The remaining groups were submitted to clamping of the common carotid arteries for 30 minutes (ischemia) and treated with saline (SS) or L-Ala-Gln. Brain reperfusion was allowed for 1or 24 h. L-Ala-Gln was administered intravenously (0.75g/kg) 30 minutes before sham procedure or induction of global brain I/R injury. Brain edema and red neuron counting were determined. Results were expressed as Mean±SD for normal results and Median±Percentile for non parametric data. Significance was established at p<0.05. RESULTS:Global I/R injury promoted an increase in brain edema at 24 h after reperfusion, whereas preconditioning with L-Ala-Gln induced no change in edema. On the other hand, L-Ala-Gln preconditioning decreased significantly red neurons counting both at 1h and 24h post reperfusion (p<0.05). CONCLUSION:There was a significant preconditioning effect with L-Ala-Gln decreasing cell death (red neurons counting) at early (1h) and late reperfusion (24h) in the cerebral tissue.

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Effects of l-theanine on anxiety-like behavior, cerebrospinal fluid amino acid profile, and hippocampal activity in Wistar Kyoto rats

et al. 2017

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A novel multi-target ligand (JM-20) protects mitochondrial integrity, inhibits brain excitatory amino acid release and reduces cerebral ischemia injury in vitro and in vivo

Cited by 44 publications

References 58 publications

The effects of JM-20 on the glutamatergic system in synaptic vesicles, synaptosomes and neural cells cultured from rat brain

The effects of JM-20 on the glutamatergic system in synaptic vesicles, synaptosomes and neural cells cultured from rat brain

Preconditioning with L-alanyl-glutamine upon cerebral edema and hypocampus red neurons counting in rats subjected to brain ischemia /reperfusion injury

Effects of l-theanine on anxiety-like behavior, cerebrospinal fluid amino acid profile, and hippocampal activity in Wistar Kyoto rats

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