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1.
Transl Stroke Res ; 13(1): 12-24, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34292517

RESUMO

Ischemic stroke is the third leading cause of death and disability worldwide, with no available satisfactory prevention or treatment approach. The current treatment is limited to the use of "reperfusion methods," i.e., an intravenous or intra-arterial infusion of a fibrinolytic agent, mechanical removal of the clot by thrombectomy, or a combination of both methods. It should be stressed, however, that only approximately 5% of all acute strokes are eligible for fibrinolytic treatment and fewer than 10% for thrombectomy. Despite the tremendous progress in understanding of the pathomechanisms of cerebral ischemia, the promising results of basic research on neuroprotection are not currently transferable to human stroke. A possible explanation for this failure is that experiments on in vivo animal models involve healthy young animals, and the experimental protocols seldom consider the importance of protecting the whole neurovascular unit (NVU), which ensures intracranial homeostasis and is seriously damaged by ischemia/reperfusion. One of the endogenous protective systems activated during ischemia and in neurodegenerative diseases is represented by neuropeptide Y (NPY). It has been demonstrated that activation of NPY Y2 receptors (Y2R) by a specific ligand decreases the volume of the postischemic infarction and improves performance in functional tests of rats with arterial hypertension subjected to middle cerebral artery occlusion/reperfusion. This functional improvement suggests the protection of the NVU. In this review, we focus on NPY and discuss the potential, multidirectional protective effects of Y2R agonists against acute focal ischemia/reperfusion injury, with special reference to the NVU.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/tratamento farmacológico , Humanos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Isquemia , Ligantes , Neuropeptídeo Y/farmacologia , Neuropeptídeo Y/uso terapêutico , Ratos , Reperfusão
2.
Front Immunol ; 12: 782569, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868060

RESUMO

Despite the enormous progress in the understanding of the course of the ischemic stroke over the last few decades, a therapy that effectively protects neurovascular units (NVUs) and significantly improves neurological functions in stroke patients has still not been achieved. The reasons for this state are unclear, but it is obvious that the cerebral ischemia and reperfusion cascade is a highly complex phenomenon, which includes the intense neuroinflammatory processes, and comorbid stroke risk factors strongly worsen stroke outcomes and likely make a substantial contribution to the pathophysiology of the ischemia/reperfusion, enhancing difficulties in searching of successful treatment. Common concomitant stroke risk factors (arterial hypertension, diabetes mellitus and hyperlipidemia) strongly drive inflammatory processes during cerebral ischemia/reperfusion; because these factors are often present for a long time before a stroke, causing low-grade background inflammation in the brain, and already initially disrupting the proper functions of NVUs. Broad consideration of this situation in basic research may prove to be crucial for the success of future clinical trials of neuroprotection, vasculoprotection and immunomodulation in stroke. This review focuses on the mechanism by which coexisting common risk factors for stroke intertwine in cerebral ischemic/reperfusion cascade and the dysfunction and disintegration of NVUs through inflammatory processes, principally activation of pattern recognition receptors, alterations in the expression of adhesion molecules and the subsequent pathophysiological consequences.


Assuntos
Isquemia Encefálica/epidemiologia , AVC Isquêmico/epidemiologia , AVC Isquêmico/etiologia , Doenças Neuroinflamatórias/epidemiologia , Traumatismo por Reperfusão/epidemiologia , Animais , Biomarcadores , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Comorbidade , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , AVC Isquêmico/diagnóstico , AVC Isquêmico/metabolismo , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/metabolismo , Estresse Oxidativo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais
3.
Neuropharmacology ; 135: 139-150, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29481916

RESUMO

Parkinson's disease (PD) is one of the most severe neurodegenerative diseases with unknown pathogenesis and currently unsuccessful therapies. Recently, neuroprotection via sphingosine-1-phosphate (S1P)-dependent signalling has become a promising target for the treatment of neurodegenerative disorders. Our previous study demonstrated down-regulation and inhibition of the S1P-synthesizing enzyme sphingosine kinase 1 (SPHK1) in a PD cellular model. Moreover, we have previously identified a neuroprotective effect of fingolimod (FTY720), a first S1P receptor modulator utilized in the clinic. This study focused on the effects of FTY720 and the dopamine D2/D3 receptor agonist pramipexole (PPX) in a PD mouse model, induced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Administration of FTY720, similar to PPX, abolished an observed loss of tyrosine hydroxylase (TH) immunoreactivity in MPTP-lesioned brain regions. Moreover, significant changes in SPHK1 expression/activity in MPTP-lesioned mouse midbrain were identified. PPX, but not FTY720 treatment, significantly protected against these alterations. Both drugs activate another pro-survival enzyme, Akt kinase, which is a crucial protein downstream of S1PR(s). FTY720 increased BAD protein phosphorylation and in this way may protect mitochondria against the BAD-induced apoptotic signalling pathway. Both FTY720 and PPX enhanced the locomotor activity of PD mice in the rotarod tests. Our data suggest a neuroprotective role for FTY720 related to the S1PR/Akt kinase signalling pathways as a beneficial treatment target in planning new PD therapeutic options. Moreover, our findings have shed new light on a neuroprotective mechanism of PPX action associated with SPHK1 activation, which provides an opportunity for evaluating multi-target (SPHK1/S1P/S1PR) effects in the context of PD.


Assuntos
Cloridrato de Fingolimode/farmacologia , Intoxicação por MPTP/prevenção & controle , Neuroproteção/efeitos dos fármacos , Doença de Parkinson/enzimologia , Doença de Parkinson/prevenção & controle , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pramipexol/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Encéfalo/metabolismo , Intoxicação por MPTP/metabolismo , Masculino , Camundongos , Fosforilação , Teste de Desempenho do Rota-Rod , Tirosina 3-Mono-Oxigenase/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismo
4.
Prog Neuropsychopharmacol Biol Psychiatry ; 84(Pt A): 93-101, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29438731

RESUMO

Our previous studies have shown that ACPT-I [(1S, 3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid], a blood-brain barrier permeable agonist of group III metabotropic glutamate (mGlu) receptors, was neuroprotective against middle cerebral artery occlusion/reperfusion (MCAO/R) in normotensive rats. Preclinical studies are typically performed on healthy animals, whereas stroke patients predominately exhibit comorbidities, such as hypertension; therefore, in the present study, we investigated the effect of ACPT-I in spontaneously hypertensive rats (SHR) after MCAO/R. We examined the potential neuroprotective action of ACPT-I (30 mg/kg) when administered during occlusion or reperfusion via the assessment of not only the brain infarction volume but also motor (CatWalk gait analysis and open field test) and sensorimotor (vibrissae-evoked forelimb-placing test) functions following MCAO/R. We determined that ACPT-I not only reduced the cortico-striatal infarction but also improved several gait parameters (run speed, run and stand durations, swing speed and stride length) and mobility when administered 30 min after the start of the occlusion or 30 min after the start of reperfusion. Moreover, the sensorimotor function was improved in hypertensive rats treated with ACPT-I during occlusion. In conclusion, the current findings provide further evidence for the neuroprotective effects of ACPT-I against ischemic damage. These findings may have clinical implications because hypertension is an important risk factor for ischemic stroke.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Ciclopentanos/farmacologia , Hipertensão Essencial/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Ácidos Tricarboxílicos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Hipertensão Essencial/complicações , Hipertensão Essencial/patologia , Marcha/efeitos dos fármacos , Masculino , Distribuição Aleatória , Ratos Endogâmicos SHR , Receptores de Glutamato Metabotrópico/agonistas , Sensação/efeitos dos fármacos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia
5.
Neuroscience ; 344: 305-325, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28057538

RESUMO

It was postulated that neuropeptide Y (NPY)-ergic system could be involved in the ischemic pathophysiology, however, the role of particular subtypes of NPY receptors (YRs) in neuroprotection against ischemia is still not well known. Therefore, we investigated the effect of NPY and YR ligands using in vitro and in vivo experimental ischemic stroke models. Our in vitro findings showed that NPY (0.5-1µM) and specific agonists of Y2R (0.1-1µM) and Y5R (0.5-1µM) but not that of Y1R produced neuroprotective effects against oxygen-glucose deprivation (OGD)-induced neuronal cell death, being also effective when given 30min after the end of OGD. The neuroprotective effects of Y2R and Y5R agonists were reversed by appropriate antagonists. Neuroprotection mediated by NPY, Y2R and Y5R agonists was accompanied by the inhibition of both OGD-induced calpain activation and glutamate release. Data from in vivo studies demonstrated that Y2R agonist (10µg/6µl; i.c.v.) not only diminished the infarct volume in rats subjected to transient middle cerebral artery occlusion (MCAO) but also improved selected gait parameters in CatWalk behavioral test, being also effective after delayed treatment. Moreover, we found that a Y5R agonist (10µg/6µl; i.c.v.) did not reduce MCAO-evoked brain damage but improved stride length, when it was given 30min after starting the occlusion. In conclusion, our studies indicate that Y5 and especially Y2 receptors may be promising targets for neuroprotection against ischemic damage.


Assuntos
Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores de Neuropeptídeo Y/agonistas , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Calpaína/metabolismo , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Marcha/efeitos dos fármacos , Marcha/fisiologia , Glucose/deficiência , Ácido Glutâmico/metabolismo , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/metabolismo , Ataque Isquêmico Transitório/patologia , Masculino , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Neuroproteção/efeitos dos fármacos , Neuroproteção/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/metabolismo
6.
Neuropharmacology ; 102: 276-94, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26647070

RESUMO

In the present study, we investigated the effect of ACPT-I [(1S, 3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid], a blood-brain-barrier permeable agonist of group III mGlu receptor, against oxygen-glucose deprivation (OGD)-evoked neuronal cell death in primary neuronal cell cultures and in the model of transient middle cerebral artery occlusion (MCAO) in rats. We found that ACPT-I (1-200 µM) in a concentration- and time-dependent way attenuated the OGD-induced neuronal cell damage, being also effective after a delayed application (30 min after OGD). The neuroprotective effects of ACPT-I were blocked by the group III mGlu receptor antagonist, (RS)-alpha-cyclopropyl-4-phosphonophenyl glycine (CPPG), and by the activator of cAMP-dependent PKA, 8-Bromo-cAMP, but not by an inhibitor of PI-3-K signaling pathway. Moreover, ACPT-I attenuated the OGD-induced calpain activity and glutamate release. In the in vitro study, we also demonstrated the neuroprotective potential of mGluR4 positive allosteric modulators (PAMs), PHCCC (30 µM) and VU0155041 (10 and 30 µM) and synergism in neuroprotective action of low concentrations of ACPT-I and mGluR4 PAMs suggesting an important role of mGluR4 activation in prevention of ischemic neuronal cell death. In the rat MCAO model, we demonstrated that ACPT-I (30 mg/kg) injected intraperitoneally either 30 min after starting MCAO or 30 min after beginning reperfusion not only diminished the infarction volume by about 30%, but also improved selected gait parameters (CatWalk analysis) and the mobility of animals in the open field test. In conclusion, our results indicate that ACPT-I may be not only neuroprotective against ischemic neuronal damage but may also diminish the postischemic functional deficits.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Ciclopentanos/uso terapêutico , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Receptores de Glutamato Metabotrópico/agonistas , Acidente Vascular Cerebral/tratamento farmacológico , Ácidos Tricarboxílicos/uso terapêutico , Animais , Isquemia Encefálica/metabolismo , Células Cultivadas , Ciclopentanos/farmacologia , Modelos Animais de Doenças , Agonistas de Aminoácidos Excitatórios/farmacologia , L-Lactato Desidrogenase/metabolismo , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/metabolismo , Ácidos Tricarboxílicos/farmacologia
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