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1.
Artigo em Inglês | MEDLINE | ID: mdl-38859788

RESUMO

BACKGROUND: Neurotrophins are essential factors for neural growth and function; they play a crucial role in neurodegenerative diseases where their expression levels are altered. Our previous research has demonstrated changes in synaptic plasticity and neurotrophin expression levels in a pharmacological model of Huntington's disease induced by 3-nitropropionic acid (3-NP). In the 3- NP-induced HD model, corticostriatal Long Term Depression (LTD) was impaired, but neurotrophin-3 (NT-3) restored striatal LTD. This study delves into the NT-3-induced signaling pathways involved in modulating and restoring striatal synaptic plasticity in cerebral slices from 3-NPinduced striatal degeneration in mice in vivo. METHODS: Phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways activated by NT-3 were analyzed by means of field electrophysiological recordings in brain slices from control and 3-NP treated in the presence of specific inhibitors of the signaling pathways. RESULTS: Using specific inhibitors, PLC, PI3K, and MEK/ERK signaling pathways contribute to NT3-mediated plasticity modulation in striatal tissue slices recorded from control animals. However, in the neurodegeneration model induced by 3-NP, the recovery of striatal LTD induced by NT-3 was prevented only by the PLC inhibitor. Moreover, the PLC signaling pathway appeared to trigger downstream activation of the endocannabinoid system, evidenced by AM 251, an inhibitor of the CB1 receptor, also hindered NT-3 plasticity recovery. CONCLUSION: Our finding highlights the specific involvement of the PLC pathway in the neuroprotective effects of NT-3 in mitigating synaptic dysfunction under neurodegenerative conditions.

2.
Brain Sci ; 8(12)2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30563250

RESUMO

Huntington's Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium spiny neurons (MSNs) from excitotoxic damage. This study evaluates whether mitochondrial inhibition with 3-NP that mimics the early stages of HD, modifies the kinetics and pharmacology of GABA receptors in patch clamp recorded dissociated MSNs cells. The results show that MSNs from mice treated with 3-NP exhibited differences in GABA-induced dose-response currents and pharmacological responses that suggests the presence of GABAC receptors in MSNs. Furthermore, there was a reduction in the effect of the GABAC antagonist that demonstrates a lessening of this GABA receptor subtype activity as a result of mitochondria inhibition.

3.
Neural Plast ; 2017: 3143428, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28352478

RESUMO

[This corrects the article DOI: 10.1155/2015/789502.].

4.
Neural Plast ; 2015: 789502, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26294980

RESUMO

Dopamine (DA) modulates glutamatergic synaptic transmission and its plasticity in the striatum; however it is not well known how DA modulates long-term plasticity of striatal GABAergic inhibitory synapses. This work focused on the analysis of both dopaminergic modulation of inhibitory synapses and the synaptic plasticity established between GABAergic afferents to medium spiny neurons (MSNs). Our results showed that low and high DA concentrations mainly reduced the amplitude of inhibitory synaptic response; however detailed analysis of the D1 and D2 participation in this modulation displayed a wide variability in synaptic response. Analyzing DA participation in striatal GABAergic plasticity we observed that high frequency stimulation (HFS) of GABAergic interneurons in the presence of DA at a low concentration (200 nM) favored the expression of inhibitory striatal LTD, whereas higher concentration of DA (20 µM) primarily induced LTP. Interestingly, the plasticity induced in an animal model of striatal degeneration mimicked that induced in the presence of DA at a high concentration, which was not abolished with D2 antagonist but was prevented by PKA blocker.


Assuntos
Dopamina/fisiologia , Potenciação de Longa Duração/fisiologia , Neostriado/fisiologia , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/fisiologia , Animais , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Estimulação Elétrica , Fenômenos Eletrofisiológicos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Aferentes/fisiologia , Inibidores de Proteínas Quinases , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/fisiologia , Sinapses/fisiologia , Ácido gama-Aminobutírico/fisiologia
5.
ASN Neuro ; 6(2)2014 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-24555476

RESUMO

In corticostriatal synapses, LTD (long-term depression) and LTP (long-term potentiation) are modulated by the activation of DA (dopamine) receptors, with LTD being the most common type of long-term plasticity induced using the standard stimulation protocols. In particular, activation of the D1 signaling pathway increases cAMP/PKA (protein kinase A) phosphorylation activity and promotes an increase in the amplitude of glutamatergic corticostriatal synapses. However, if the Cdk5 (cyclin-dependent kinase 5) phosphorylates the DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) at Thr75, DARPP-32 becomes a strong inhibitor of PKA activity. Roscovitine is a potent Cdk5 inhibitor; it has been previously shown that acute application of Roscovitine increases striatal transmission via Cdk5/DARPP-32. Since DARPP-32 controls long-term plasticity in the striatum, we wondered whether switching off CdK5 activity with Roscovitine contributes to the induction of LTP in corticostriatal synapses. For this purpose, excitatory population spikes and whole cell EPSC (excitatory postsynaptic currents) were recorded in striatal slices from C57/BL6 mice. Experiments were carried out in the presence of Roscovitine (20 µM) in the recording bath. Roscovitine increased the amplitude of excitatory population spikes and the percentage of population spikes that exhibited LTP after HFS (high-frequency stimulation; 100Hz). Results obtained showed that the mechanisms responsible for LTP induction after Cdk5 inhibition involved the PKA pathway, DA and NMDA (N-methyl-D-aspartate) receptor activation, L-type calcium channels activation and the presynaptic modulation of neurotransmitter release.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Potenciação de Longa Duração/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Animais , Canais de Cálcio Tipo L/metabolismo , Córtex Cerebral/fisiologia , Corpo Estriado/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Quinase 5 Dependente de Ciclina/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Roscovitina , Transmissão Sináptica/efeitos dos fármacos
6.
J Org Chem ; 70(11): 4538-41, 2005 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-15903342

RESUMO

The electrochemical oxidation ((+)Pt-Ni(-)/NH(4)Br/MeOH) of the natural product hispanolone (1a) produced, in high yield (>95%), spiro-tetracyclic compounds 7a-7d as a result of the intramolecular addition of the C-9 hydroxyl group into the C-16 position with the simultaneous addition of a CH(3)O group at the C-15 position of the hispanolone furan moiety. After the electrochemical oxidation, an acid-catalyzed slow secondary reaction occurred producing the previously undescribed alpha-butenolide derivative, iso-Leopersin G (9). An anti-inflammatory study with the electro-synthesized compounds showed that 1a has higher anti-inflammatory properties with very low cytotoxicity (e.g., the inhibition of TPA-induced ear edema assay IC(50) = 1.05 microM/ear, positive control indomethacin IC(50) = 0.27 microM/ear).


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Antineoplásicos/síntese química , Diterpenos/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Oxirredução
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