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1.
J Neuroinflammation ; 11: 27, 2014 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-24490798

RESUMO

BACKGROUND: Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide. METHODS: We investigated the binding of Ilantide to IL-1 receptor type I (IL-1RI) using surface plasmon resonance, the inhibition of Il-1ß-induced activation of nuclear factor κB (NF-κB) in HEK-Blue cells that contained an IL-1ß-sensitive reporter, the secretion of TNF-α in macrophages, protection against IL-1-induced apoptosis in neonatal pancreatic islets, and the penetration of Ilantide through the blood-brain barrier using competitive enzyme-linked immunosorbent assay (ELISA). We studied the effects of the peptide on social behavior and memory in rat models of lipopolysaccharide (LPS)- and amyloid-induced neuroinflammation, respectively, and its effect in a rat model of experimental autoimmune enchephalomyelitis. RESULTS: Ilantide bound IL-1RI, inhibited the IL-1ß-induced activation of NF-κB, and inhibited the secretion of TNF-α in vitro. Ilantide protected pancreatic islets from apoptosis in vitro and reduced inflammation in an animal model of arthritis. The peptide penetrated the blood-brain barrier. It reduced the deficits in social activity and memory in LPS- and amyloid-treated animals and delayed the development of experimental autoimmune enchephalomyelitis. CONCLUSIONS: These findings indicate that Ilantide is a novel and potent IL-1RI antagonist that is able to reduce inflammatory damage in the central nervous system and pancreatic islets.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite/tratamento farmacológico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Animais , Animais Recém-Nascidos , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Artrite/induzido quimicamente , Células Cultivadas , Cerebelo/citologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Humanos , Proteína Antagonista do Receptor de Interleucina 1/química , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Lipopolissacarídeos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Wistar , Comportamento Social , Transfecção , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
2.
Cytokine ; 64(1): 112-21, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23972727

RESUMO

Interleukin-4 (IL-4) is a potent antiinflammatory cytokine. However its use in the clinic is hampered by side effects. We here describe the identification of a novel synthetic peptide, termed Ph8, derived from α-helix C of IL-4, which interacts with IL-4 receptor α (IL-4Rα). Employing various cultured genetically engineered cell lines and primary lymphocytes, surface plasmon resonance, qPCR, ELISA and immunoblotting techniques we found that Ph8 bound IL-4Rα and mimicked the anti-inflammatory effects of IL-4 by inhibiting TNF-α production by macrophages in vitro. It induced phosphorylation of STAT6 65kD but inhibited phosphorylation of STAT6 110 kD induced by IL-4 in a B-cell line that expressed the type I receptor. It also inhibited the IL-4-stimulated expression of a STAT6-inducible reporter gene in cells that expressed the type II receptor. Ph8 inhibited the proliferation of Th1/2 cells and downregulated the production of IFN-γ in stimulated Th1 cells. Moreover, Ph8 did not induce any shift in Th1/Th2 profile. This is a favorable effect and it is indicating that Ph8 could block general T cell activation and inflammatory responses without further inducing the side effects generally associated with IL-4 signaling. These data collectively show that Ph8 is only a partial agonist of IL-4 mimicking its desirable properties. In agreement, Ph8 treatment of rats with collagen-induced arthritis, a Th1- and antibody- mediated disease of joint, delayed the manifestation of chronic inflammation and reduced acute inflammation in carrageenan-induced edema. Our findings indicate that Ph8 is a promising potential drug candidate for the treatment of inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Interleucina-4/farmacologia , Fragmentos de Peptídeos/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Edema/tratamento farmacológico , Células HEK293 , Humanos , Interferon gama/metabolismo , Interleucina-4/análogos & derivados , Interleucina-4/química , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/química , Fosforilação/efeitos dos fármacos , Ligação Proteica , Ratos , Ratos Wistar , Fator de Transcrição STAT6/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
3.
Neurochem Res ; 38(6): 1278-84, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23579388

RESUMO

Protein BASP1 was discovered in brains of mammals and birds. In presynaptic area of synapses, BASP1 is attached to plasma membrane owing to N-terminal myristoylation as well as to the positively charged "effecter domain". BASP1 interactions with other proteins as well as with lipids contribute to membrane traffic, axon outgrowth and synaptic plasticity. BASP1 is present also in other tissues, where it was found not only in cytoplasm, but also in nucleus. Nuclear BASP1 suppresses activity of transcription factor WT1 and acts as tumor suppressor. BASP1 deficiency in a cell leads to its transformation. Previously it was shown that in BASP1 samples prepared from different animals and different tissues, six BASP1 N-end myristoylated fragments (BNEMFs) are present. Together, they amount to 30 % of the whole molecules. BNEMFs presence in different species and tissues demonstrates their physiological significance. However BNEMFs remain unexplored. In this paper, the time of appearance and dynamics of both BASP1 and BNEMFs during rat development from embryo to adult animals were determined. In rat brain, the amounts of all BASP1 forms per cell systematically increase during development and remain at the highest levels in adult animals. BNEMFs appear during embryogenesis non-simultaneously and accumulate with different dynamics. These results say for formation of six BNEMFs in the course of different processes and, possibly, using different mechanisms.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteínas de Ligação a Calmodulina/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/metabolismo , Animais , Encéfalo/embriologia , Proteínas de Ligação a Calmodulina/genética , Proteínas do Citoesqueleto/genética , Feminino , Proteínas do Tecido Nervoso/genética , Gravidez , Ratos , Ratos Wistar
4.
Neurobiol Dis ; 48(3): 533-45, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22842016

RESUMO

The fibroblast growth factor receptor (FGFR) plays a vital role in the development of the nervous system regulating a multitude of cellular processes. One of the interaction partners of the FGFR is the neural cell adhesion molecule (NCAM), which is known to play an important role in neuronal development, regeneration and synaptic plasticity. Thus, simultaneous activation of FGFR- and NCAM-mediated signaling pathways may be expected to affect processes underlying neurodegenerative diseases. We here report the identification of a peptide compound, Enreptin, capable of interacting with both FGFR and NCAM. We demonstrate that this dual specificity agonist induces phosphorylation of FGFR and differentiation and survival of primary neurons in vitro, and that these effects are inhibited by abrogation of both NCAM and FGFR signaling pathways. Furthermore, Enreptin crosses the blood-brain barrier after subcutaneous administration, enhances long-term memory in normal mice and ameliorates memory deficit in mice with induced brain inflammation. Moreover, Enreptin reduces cognitive impairment and neuronal death induced by Aß25-35 in a rat model of Alzheimer's disease, and reduces the mortality rate and clinical signs of experimental autoimmune encephalomyelitis in rats. Thus, Enreptin is an attractive candidate for the treatment of neurological diseases.


Assuntos
Memória/efeitos dos fármacos , Moléculas de Adesão de Célula Nervosa/agonistas , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/agonistas , Animais , Comportamento Animal/efeitos dos fármacos , Encefalopatias/patologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/citologia , Ratos , Ratos Wistar , Ressonância de Plasmônio de Superfície
5.
Neuropharmacology ; 52(3): 764-78, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17095022

RESUMO

2-n-Pentyl-4-pentynoic acid (PE-4-yn-VPA) is a derivative of the antiepileptic and mood-stabilizing drug valproic acid (VPA). PE-4-yn-VPA exists as R- and S-enantiomers, the latter being more teratogenic. PE-4-yn-VPA also possesses antiepileptic, antiproliferative, and cell-differentiating properties. Moreover, the less teratogenic enantiomer, R-PE-4-yn-VPA, was recently shown to improve learning and memory. We here present a detailed investigation of the enantioselective properties of PE-4-yn-VPA using a range of in vitro and in vivo assays including measurements of cellular growth and migration, neuronal differentiation and survival, intracellular signal transduction, synaptic plasticity and maturation, and short-term memory as determined by the social recognition test. The results show that the enantiomers of PE-4-yn-VPA largely had similar effects in vitro. However, in all in vitro experiments the more teratogenic enantiomer, S-PE-4-yn-VPA, exhibited a stronger potency than R-PE-4-yn-VPA, and only S-PE-4-yn-VPA had a detrimental effect on cell survival. Interestingly, both the R- and S-enantiomer improved learning and memory. In contrast, the beneficial effect of S-PE-4-yn-VPA on memory was lost by time, whereas the effect of R-PE-4-yn-VPA administration was longer lasting, suggesting that the beneficial effect of the S-enantiomer on memory formation may be counteracted by its detrimental effect on neuronal cell survival.


Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Memória de Curto Prazo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ácido Valproico/análogos & derivados , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura/métodos , Proteína 4 Homóloga a Disks-Large , Relação Dose-Resposta a Droga , Hipocampo/citologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Neuritos/efeitos dos fármacos , Neurônios/citologia , Ratos , Ratos Wistar , Estereoisomerismo , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Sinaptofisina/metabolismo , Fatores de Tempo , Ácido Valproico/química , Ácido Valproico/farmacologia
6.
Int J Dev Neurosci ; 20(7): 527-36, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12485621

RESUMO

The neural cell adhesion molecule, NCAM, not only plays an important role in neuronal migration, differentiation and formation of connections in the developing nervous system, but also in the condensation of the mesodermal mesenchyme of the limb bud. Therefore, NCAM may be regarded as a target molecule for preventive strategies aimed at minimizing the effects of teratogens affecting the prenatal development of the nervous system and the skeleton. Treatment of fetuses with the teratogen pyrimethamine results in a reduced body weight, microcephaly and malformations of the hind limbs and forelimbs, e.g. micromelia, brachydactyly and adactyly. We here show that a peptide agonist of NCAM, C3, partly prevented the defects induced by this treatment. Although intra-amniotic administration of C3 at gestational day 14 had no effect on the pyrimethamine-induced reduction in body weight, it rescued the deficit in brain weight (microcephaly), partly reversed a decrease in thickness of the cortical plate, and significantly reduced the number of malformed fetuses. In vitro, C3 promoted survival of PC12-E2 cells treated with pyrimethamine. Since C3 is a peptide mimetic of NCAM, our data strongly suggest that stimulating of NCAM results in neuroprotection in vivo and in vitro.


Assuntos
Anormalidades Múltiplas/tratamento farmacológico , Encéfalo/anormalidades , Encéfalo/efeitos dos fármacos , Moléculas de Adesão Celular Neuronais/administração & dosagem , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Moléculas de Adesão de Célula Nervosa/agonistas , Anormalidades Múltiplas/induzido quimicamente , Animais , Animais Recém-Nascidos , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Peso Fetal/efeitos dos fármacos , Injeções , Tamanho do Órgão , Células PC12 , Peptídeos , Gravidez , Resultado da Gravidez , Pirimetamina , Ratos , Ratos Wistar , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Teratogênicos/toxicidade
7.
Exp Toxicol Pathol ; 65(5): 591-3, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22727564

RESUMO

Metabolites of the commonly used imidazole fungicide prochloraz are androgen receptor antagonists. They have been shown to block androgen-driven development and compromise reproductive function. We tested the effect of prochloraz on cognitive behavior following exposure to this fungicide during the perinatal period. Pregnant Wistar rats were administered a 200 mg/kg dose of prochloraz on gestational day (GD) 7, GD11, and GD15. The social recognition test (SRT) was performed on 7-week-old male rat offspring. We found an increase in pregnancy length and a significantly reduced pup weight on PND15 and PND40 but no effect of prenatal prochloraz exposure on social investigation or acquisition of social-olfactory memory.


Assuntos
Peso Corporal/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Imidazóis/toxicidade , Memória/efeitos dos fármacos , Gravidez Prolongada/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Comportamento Social , Animais , Animais Recém-Nascidos , Peso ao Nascer/efeitos dos fármacos , Feminino , Idade Gestacional , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos
8.
PLoS One ; 8(8): e71479, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23951173

RESUMO

Increased levels of neurotoxic amyloid-beta in the brain are a prominent feature of Alzheimer's disease. FG-Loop (FGL), a neural cell adhesion molecule-derived peptide that corresponds to its second fibronectin type III module, has been shown to provide neuroprotection against a range of cellular insults. In the present study impairments in social recognition memory were seen 24 days after a 5 mg/15 µl amyloid-beta(25-35) injection into the right lateral ventricle of the young adult rat brain. This impairment was prevented if the animal was given a systemic treatment of FGL. Unbiased stereology was used to investigate the ability of FGL to alleviate the deleterious effects on CA1 pyramidal cells of the amyloid-beta(25-35) injection. NeuN, a neuronal marker (for nuclear staining) was used to identify pyramidal cells, and immunocytochemistry was also used to identify inactive glycogen synthase kinase 3beta (GSK3ß) and to determine the effects of amyloid-beta(25-35) and FGL on the activation state of GSK3ß, since active GSK3ß has been shown to cause a range of AD pathologies. The cognitive deficits were not due to hippocampal atrophy as volume estimations of the entire hippocampus and its regions showed no significant loss, but amyloid-beta caused a 40% loss of pyramidal cells in the dorsal CA1 which was alleviated partially by FGL. However, FGL treatment without amyloid-beta was also found to cause a 40% decrease in CA1 pyramidal cells. The action of FGL may be due to inactivation of GSK3ß, as an increased proportion of CA1 pyramidal neurons contained inactive GSK3ß after FGL treatment. These data suggest that FGL, although potentially disruptive in non-pathological conditions, can be neuroprotective in disease-like conditions.


Assuntos
Peptídeos beta-Amiloides/efeitos adversos , Região CA1 Hipocampal/efeitos dos fármacos , Memória/efeitos dos fármacos , Moléculas de Adesão de Célula Nervosa/farmacologia , Fragmentos de Peptídeos/efeitos adversos , Células Piramidais/efeitos dos fármacos , Peptídeos beta-Amiloides/administração & dosagem , Animais , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Contagem de Células , Expressão Gênica/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Injeções Intravenosas , Injeções Intraventriculares , Masculino , Memória/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Células Piramidais/citologia , Células Piramidais/metabolismo , Ratos , Ratos Wistar
9.
Eur J Neurosci ; 22(7): 1589-96, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16197499

RESUMO

There is a major unmet need for development of innovative strategies for neuroprotection against ischemic brain injury. Here we show that FGL, a neural cell adhesion molecule (NCAM)-derived peptide binding to and inducing phosphorylation of the fibroblast growth factor receptor (FGFR), acts neuroprotectively after an ischemic insult both in vitro and in vivo. The neuroprotective activity of FGL was tested in vitro on dissociated rat hippocampal neurons and hippocampal slice cultures, using a protocol of oxygen-glucose deprivation (OGD). FGL protected hippocampal neurons from damage and maintained or restored their metabolic and presynaptic activity, both if employed as a pretreatment alone to OGD, and if only applied after the insult. In vivo 24 h pretreatment with a single suboccipital injection of FGL significantly protected hippocampal CA1 neurons from death in a transient global ischemia model in the gerbil. We conclude that FGL promotes neuronal survival after ischemic brain injury.


Assuntos
Isquemia Encefálica/prevenção & controle , Hipocampo/citologia , Moléculas de Adesão de Célula Nervosa/administração & dosagem , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Animais , Animais Recém-Nascidos , Contagem de Células/métodos , Células Cultivadas , Interações Medicamentosas , Glucose/deficiência , Hipóxia , Moléculas de Adesão de Célula Nervosa/síntese química , Fármacos Neuroprotetores/síntese química , Técnicas de Cultura de Órgãos , Fosforilação/efeitos dos fármacos , Propídio , Compostos de Piridínio/metabolismo , Pirróis/farmacologia , Compostos de Amônio Quaternário/metabolismo , Ratos , Ratos Wistar , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Sinapses/patologia , Sais de Tetrazólio/metabolismo , Tiazóis/metabolismo , Fatores de Tempo
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