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1.
Rheumatology (Oxford) ; 45(6): 685-93, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16399842

RESUMEN

OBJECTIVE: To identify and characterize rheumatoid factor (RF)-producing B-cells and cryoprecipitate immunoglobulin (Ig) M in hepatitis C virus (HCV)-positive patients. METHODS: We purified and characterized, by peptide mass fingerprinting integrated with an NCBI IgBlast data bank search, the IgM component of cryoprecipitate and analysed the VDJ pattern of bone marrow B-cells by gene scan analysis of 17 HCV-positive patients with type II mixed-cryoglobulinaemia. RESULTS: IgM purified from all of the patients presented an RF specificity. In three of these patients a high and predominant B-cell clone (>or=30%) was found in the bone marrow. B-cell-receptor sequences were determined and immunophenotyping of these clones was performed. Peptide masses originating after tryptic digestion of the B-cell-receptor combinatory regions and those originating by tryptic digestion of the cryoprecipitated IgM from the same patient were comparable. In the remaining patients an oligoclonal/polyclonality was found. However, in some of these patients we were able to find peptides that matched with the B-cell-receptor sequences of overexpanded B cells, indicating that, even in the absence of a clear monoclonal expansion, a fraction of total cryoprecipated IgM may derive from overexpanded B-cell clones found in patients' bone marrow. CONCLUSIONS: In the majority of mixed cryoglobulinaemia-HCV-positive patients, both in the serum and in B cells from the bone marrow, an oligoclonal pattern is the main molecular picture. When a monoclonal B-cell clone is found, its B-cell-receptor shows an antigen-binding fragment identical to that of cryoprecipitable RF-IgM. Phenotypically, B cells are CD20-positive but CD5-negative, suggesting that the B-1 B-cell subset is not likely to produce high-affinity IgM-RF molecules.


Asunto(s)
Linfocitos B/inmunología , Crioglobulinemia/inmunología , Adulto , Anciano , Secuencia de Aminoácidos , Linfocitos B/patología , Células de la Médula Ósea/inmunología , Células Clonales/inmunología , Células Clonales/patología , Crioglobulinemia/genética , Crioglobulinemia/virología , Femenino , Genes de Inmunoglobulinas , Hepatitis C/complicaciones , Hepatitis C/inmunología , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Ligeras de Inmunoglobulina/genética , Inmunoglobulina M/genética , Inmunoglobulina M/inmunología , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Factor Reumatoide/inmunología , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
2.
Tissue Antigens ; 66(3): 246-7, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16101838

RESUMEN

Herein, we report on a novel DRB1 allele (DRB1*1368) identified during sequence-based HLA-DRB typing. This new DRB1 allele is identical to DRB1*1301 at exon 2 except for a single-nucleotide substitution at codon 37, changing the amino acid Asn to Asp.


Asunto(s)
Alelos , Antígenos HLA-DR/genética , Secuencia de Bases , Exones , Femenino , Cadenas HLA-DRB1 , Prueba de Histocompatibilidad , Humanos , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido Nucleico
4.
Blood ; 96(10): 3578-84, 2000 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-11071657

RESUMEN

Analysis of the immunoglobulin receptor (IGR) variable heavy- and light-chain sequences on 17 hepatitis C virus (HCV)-associated non-Hodgkin lymphomas (NHLs) (9 patients also had type II mixed cryoglobulinemia [MC] syndrome and 8 had NHL unrelated to MC) and analysis of intraclonal diversity on 8 of them suggest that such malignant lymphoproliferations derive from an antigen-driven pathologic process, with a selective pressure for the maintenance of a functional IgR and a negative pressure for additional amino acid mutations in the framework regions (FRs). For almost all NHLs, both heavy- and light-chain complementarity-determining regions (CDR3) showed the highest similarity to antibodies with rheumatoid factor (RF) activity that have been found in the MC syndrome, thus suggesting that a common antigenic stimulus is involved in MC syndrome and in HCV-associated lymphomagenesis. Moreover, because HCV is the recognized pathologic agent of MC and the CDR3 amino acid sequences of some HCV-associated NHLs also present a high homology for antibody specific for the E2 protein of HCV, it may be reasonable to speculate that HCV E2 protein is one of the chronic antigenic stimuli involved in the lymphomagenetic process. Finally, the use of specific segments, in particular the D segment, in assembling the IgH chain of IgR seems to confer B-cell disorders with the property to produce antibody with RF activity, which may contribute to the manifestation of an overt MC syndrome.


Asunto(s)
Crioglobulinemia/complicaciones , Hepacivirus/inmunología , Linfoma no Hodgkin/etiología , Linfoma no Hodgkin/inmunología , Análisis de Secuencia de Proteína , Anciano , Secuencia de Bases , Linaje de la Célula/inmunología , Células Clonales , Regiones Determinantes de Complementariedad/química , Regiones Determinantes de Complementariedad/genética , Crioglobulinemia/metabolismo , Crioglobulinemia/patología , Femenino , Reordenamiento Génico , Humanos , Cadenas Pesadas de Inmunoglobulina/química , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Ligeras de Inmunoglobulina/química , Cadenas Ligeras de Inmunoglobulina/genética , Cadenas kappa de Inmunoglobulina/química , Cadenas kappa de Inmunoglobulina/genética , Linfoma no Hodgkin/patología , Linfoma no Hodgkin/virología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Proteínas de Neoplasias/química , Proteínas de Neoplasias/inmunología , Receptores de Antígenos de Linfocitos B/química , Receptores de Antígenos de Linfocitos B/genética , Receptores Fc/química , Receptores Fc/genética , Factor Reumatoide/metabolismo
5.
Nucleosides Nucleotides Nucleic Acids ; 19(8): 1311-26, 2000 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11097061

RESUMEN

The cytotoxicity of several Co(II), Ni(II), Cu(II) and Zn(II) complexes with various molecular structures and geometries, has been tested on LoVo and 2008 cells at 1-100 microM concentration for 24 h exposure. On the basis of 24 h results, the exposure time was prolonged to 48 and to 72 hours. The most potent complexes result [Cu(tren)(H2O)]2+ 2Cl-, E, [CoCl3(H2Meppz)], G, and [CoCl3(HMe2ppz)], H, (tren=tris(2-aminoethyl)amine, H2Meppz=1-methylpiperazin-1-ium, HMe2ppz=1,4-dimethylpiperazin-1-ium cations). Nevertheless, these complexes are able to induce cell growth reduction of about 50% at highest doses tested (1-100 microM ) and after 72 h exposure.


Asunto(s)
Antineoplásicos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Organometálicos/síntesis química , Piperazinas/síntesis química , Adenocarcinoma/patología , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias del Colon/patología , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Estructura Molecular , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Neoplasias Ováricas/patología , Oxidación-Reducción , Piperazinas/química , Piperazinas/farmacología , Relación Estructura-Actividad , Células Tumorales Cultivadas/efectos de los fármacos
6.
Int J Cancer ; 87(2): 211-6, 2000 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-10861476

RESUMEN

Type II mixed cryoglobulinemia (MC) is a systemic vasculitis characterized by the presence in the serum of a monoclonal cryoprecipitable IgM with rheumatoid factor (RF) activity. Hepatitis C virus (HCV) has been recognized as its major etiologic factor. Because MC frequently evolves into overt B-cell non-Hodgkin's lymphoma (NHL), chronic HCV infection is hypothesized to lead to both benign and malignant lymphoproliferative disease. In this study, we investigated mutations in the V(H) and V(K) genes of the B-cell clone originating the overt B-cell lymphoma in a subject with MC. Mutational patterns were analyzed longitudinally in two bone marrow biopsies obtained at the stage of MC, as well as in multiple involved tissues (bone marrow, liver, and peripheral blood cells) at the stage of overt NHL. Hybridization of variable-diversity-joining (VDJ) PCR products with a probe specific for the neoplastic clone indicated that the lymphoma originated from one of the clones over-stimulated during MC. This clone producing an IgM highly homologous to a protein with RF specificity may explain the MC syndrome in the patient. Moreover, the presence of an IgH ongoing mutation process and the expression of an Ig antigen receptor significantly homologous to an anti-HCV protein support the hypothesis that the MC syndrome and the subsequent evolution to NHL are antigen-driven lymphoproliferative processes possibly sustained by HCV. Furthermore, the marked reduction in intra-clonal diversity in the last bone marrow biopsy obtained at the stage of overt NHL points out a minor dependence of the cells on the antigen-driven mechanism, although an intrinsic propensity of the neoplastic cell to undergo replacement mutations cannot be excluded.


Asunto(s)
Crioglobulinemia/patología , Crioglobulinemia/virología , Hepacivirus , Leucemia Linfocítica Crónica de Células B/etiología , Secuencia de Aminoácidos , Especificidad de Anticuerpos , Médula Ósea/patología , Crioglobulinemia/genética , Genes de Inmunoglobulinas , Humanos , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Hígado/patología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Homología de Secuencia de Aminoácido
7.
Hepatology ; 31(1): 182-9, 2000 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10613744

RESUMEN

The hepatitis C virus (HCV) has been linked to B-cell lymphoproliferation and autoimmunity, and has been localized in several tissues. The clinical observation of an HCV-infected patient with Sjögren's syndrome (SS) and Helicobacter pylori (HP) positive gastric low-grade B-cell non-Hodgkin's lymphoma (NHL), which did not regress after HP eradication, led us to investigate the possible localization of HVC in the gastric microenvironment. HCV genome and antigens were searched in gastric biopsy specimens from the previously mentioned case, as well as from 9 additional HCV-infected patients (8 with chronic gastritis and 1 with gastric low-grade B-cell NHL). HCV-specific polymerase chain reaction (PCR) and immunohistochemistry procedures were used. The gastric B-cell NHL from the patient with SS was characterized by molecular analyses of B-cell clonality. HCV RNA was detected in both the gastric low-grade B-cell NHL and in 3 out of 6 gastric samples from the remaining cases. HCV antigens were detected in the residual glandular cells within the gastric B-cell NHL lesions, in glandular cells from 2 of the 3 additional gastric lesions that were HCV positive by PCR, and in 1 additional chronic gastritis sample in which HCV-RNA studies could not be performed. By molecular analyses, of immunoglobulin genes, the B-cell NHL from the patient with SS was confirmed to be a primary gastric lymphoma, subjected to ongoing antigenic stimulation and showing a significant similarity with rheumatoid factor (RF) and anti-HCV- antibody sequences. Our results show that HCV can localize in the gastric mucosa.


Asunto(s)
Enfermedades Autoinmunes/virología , Mucosa Gástrica/virología , Gastritis/virología , Hepacivirus/aislamiento & purificación , Linfoma de Células B/virología , Neoplasias Gástricas/virología , Anciano , Secuencia de Aminoácidos , Secuencia de Bases , Femenino , Infecciones por Helicobacter/complicaciones , Hepacivirus/genética , Hepacivirus/inmunología , Hepatitis C/complicaciones , Antígenos de la Hepatitis C/análisis , Humanos , Cadenas Pesadas de Inmunoglobulina/química , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/química , Región Variable de Inmunoglobulina/genética , Linfoma de Células B/inmunología , Linfoma de Células B/microbiología , Datos de Secuencia Molecular , ARN Viral/análisis , Síndrome de Sjögren/virología , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/microbiología
8.
J Rheumatol ; 26(5): 1101-9, 1999 May.
Artículo en Inglés | MEDLINE | ID: mdl-10332975

RESUMEN

OBJECTIVE: Studies have analyzed T cell receptor (TCR)-Vbeta in benign, minor salivary or lacrimal gland, or kidney lesions in Sjögren's syndrome (SS). We investigated SS related lymphoproliferative lesions. METHODS: By "family" reverse transcriptase polymerase chain reaction, we studied the expression of 20 different TCR-Vbeta families in parotid lymphoproliferative lesions and peripheral blood lymphocytes (PBL) from 7 patients with primary SS, in PBL from 6 primary SS patients with no associated lymphoproliferative disorder, and in activated PBL from 2 healthy controls. T cell clonal expansion was investigated in 10 Vbeta families (i.e., the most expanded ones and those previously implicated in SS pathogenesis) by single strand conformation polymorphism (SSCP) analysis. Frozen sections from parotid gland specimens were tested by immunohistochemistry for the expansion of selected Vbeta families. Viral infection within the parotid lesions and serum autoantibody response were also studied. RESULTS: An unrestricted Vbeta pattern was observed. The most widely expressed Vbeta family in parotid lesions was Vbeta2, and Vbeta immunohistochemistry results were concordant with Vbeta mRNA findings. A similar pattern was observed in PBL, although the Vbeta2 family was expressed at lower levels. The parotid/PBL ratio was occasionally > 1.8-2.0 (indicative of local Vbeta overexpression) in different Vbeta families. T cell expansion proved to be largely polyclonal by SSCP analysis, and scattered T cell clonotypes were detected within different Vbeta families, with a different pattern from patient to patient. CONCLUSION: Our observations in SS related lymphoproliferative lesions largely reflect previous evidence in fully benign lesions. The pathogenetic events involved in autoimmune benign lesions in SS may then persist and play a role in SS related lymphoproliferative disorders. The link between the observed TCR-Vbeta repertoire and specific local triggering (auto)antigens remains to be elucidated.


Asunto(s)
Trastornos Linfoproliferativos/inmunología , Enfermedades de las Parótidas/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/análisis , Síndrome de Sjögren/inmunología , Adulto , Anciano , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/patología , Femenino , Humanos , Inmunohistoquímica , Linfoma/etiología , Linfoma/patología , Persona de Mediana Edad , Enfermedades de las Parótidas/etiología , Enfermedades de las Parótidas/patología , Enfermedades de las Parótidas/virología , Reacción en Cadena de la Polimerasa , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/patología , Síndrome de Sjögren/virología , Linfocitos T/inmunología , Linfocitos T/patología , Virosis/etiología , Virosis/virología
9.
Arthritis Rheum ; 40(2): 318-31, 1997 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9041944

RESUMEN

OBJECTIVE: To determine whether the prelymphomatous stages of B cell lymphoproliferation in Sjögren's syndrome (SS) may be better characterized by the integration of clinical, pathologic, and molecular data, the latter focusing on the expansion, persistence, and dissemination of clonal B cells in the course of the disease. METHODS: Multiple tissue lesions (synchronous from different tissues and metachronous from the same tissue) were evaluated in biopsy specimens obtained from 6 consecutive patients with SS who had an associated lymphoproliferative disorder. Fully benign gastric lesions were evaluated in tissue from an additional 11 patients with SS who had no associated lymphoproliferative disorder. Multiple and complementary molecular analyses of B cell clonality were used: Southern blot, polymerase chain reaction, single-strand conformation polymorphism, DNA sequencing, and hybridization with clonospecific oligoprobes. All the patients were then strictly followed up for the appearance of lymphoma. RESULTS: Different scenarios of SS-associated B cell lymphoproliferation were identified: 1) the ongoing expansion of the same dominant clone, localized or disseminated, in tissue from 2 patients, 1 of whom later developed an overt B cell lymphoma; 2) different dominant clones in different synchronous or metachronous tissues from the remaining 4 patients with an associated lymphoproliferative disorder; and 3) small oligoclonal expansions in 7 of the 11 benign gastric lymphoid infiltrates. CONCLUSION: Prelymphomatous B cell lymphoproliferation in SS was better characterized following integration of the findings. The different types of B cell clonal expansion (oligoclonal or monoclonal, smaller or larger in size, fluctuating or established, localized or disseminated) may imply a different risk of lymphoma progression. An accurate clinical, histopathologic, and molecular characterization may therefore be crucial in future studies aimed at clarifying the pathobiology of SS-associated lymphoproliferation.


Asunto(s)
Linfocitos B/inmunología , Trastornos Linfoproliferativos/complicaciones , Trastornos Linfoproliferativos/patología , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/patología , Adulto , Biopsia , Southern Blotting , Células Clonales/química , Células Clonales/inmunología , ADN/análisis , Femenino , Humanos , Ganglios Linfáticos/patología , Activación de Linfocitos , Linfoma de Células B/patología , Linfoma no Hodgkin/patología , Persona de Mediana Edad , Glándula Parótida/patología , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Conformacional Retorcido-Simple , Análisis de Secuencia de ADN
10.
Clin Exp Rheumatol ; 14 Suppl 14: S21-9, 1996.
Artículo en Inglés | MEDLINE | ID: mdl-8722196

RESUMEN

While the simple detection of B-cell clonality does not imply B-cell malignancy, comprehensive analyses of B-cell clonality are crucial to investigate the pathobiology of B-cell lymphoproliferative disorders. Our recent studies in patients with Sjögren's syndrome have highlighted how multiple molecular analyses of B-cell clonality (Southern blot, polymerase chain reaction, single strand conformation polymorphism, and DNA sequence analysis) in prelymphomatous lesions may be of great value in helping to define the stages of progression towards low-grade malignancy. The study of T-cell expansion may also be important in investigations of the pathobiology of the different stages of B-cell lymphoproliferation (fully benign, pseudolymphomatous, or definitely malignant), which may still be T-cell-and antigen/ autoantigen-dependent.


Asunto(s)
Linfocitos B/inmunología , Linfoma de Células B/inmunología , Linfocitos T/inmunología , Células Clonales , Progresión de la Enfermedad , Técnicas Genéticas , Humanos , Linfoma de Células B/fisiopatología , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/fisiopatología
11.
Tumori ; 81(6): 405-9, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-8804464

RESUMEN

AIMS AND BACKGROUND: The detection of immunoglobulin heavy chain variable (VH)-diversity (DH)-joining (JH) region gene rearrangement by polymerase chain reaction (VDJ PCR) has been recently proposed as a rapid approach to assess B-cell clonality in lymphoproliferative disorders. The aim of the present study was to determine the efficacy of VDJ PCR in a wide spectrum of lymphoproliferative disorders previously characterized by immunohistochemistry and Southern blot (SB). METHODS: 83 SB-rearranged B-cell non-Hodgkin's lymphomas (NHL) of different histotype, 22 cases of SB-unrearranged classical Hodgkin's disease (HD), 18 cases of HIV-related reactive lymphadenopathy, and 4 frankly pre-lymphomatous lesions (MESA) in the course of Sjögren's syndrome were investigated by 2 different VDJ PCR protocols (FR3, FR2). RESULTS: The detection rate in NHL was 64% and 71% using the protocols FR3 and FR2, respectively. However, the overall VDJ PCR efficacy increased to 81% by combining the results of both protocols. In addition, differences in the combined, as well as in the single FR3 or FR2 protocol efficacy, were noted in the different NHL subgroups. B-cell clonality was also detected in 4/22 (18%) SB-unrearranged classical HD cases and in 2/18 (11%) reactive lymphadenopathy cases, whereas it was demonstrated in all the MESA lesions, 2 of them being SB-negative. CONCLUSIONS: VDJ PCR represents a useful and rapid technique to detect B-cell clonality in NHL, although with some differences depending on the NHL histotype and the panel of primers employed. The technique may also be of value to investigate the possible progression of early B-cell clonal expansion into frankly B-cell malignancy and to contribute to the controversy about the clonal lineage origin of the putative HD malignant cells.


Asunto(s)
Linfocitos B/fisiología , Reordenamiento Génico/genética , Genes de Inmunoglobulinas/genética , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Linfoma no Hodgkin/genética , Trastornos Linfoproliferativos/genética , Reacción en Cadena de la Polimerasa , Complejo Relacionado con el SIDA/genética , Diversidad de Anticuerpos , Secuencia de Bases , Southern Blotting , Células Clonales/fisiología , Cartilla de ADN , ADN de Neoplasias/genética , Enfermedad de Hodgkin/genética , Humanos , Linfoma no Hodgkin/patología , Trastornos Linfoproliferativos/patología , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa/métodos , Síndrome de Sjögren/genética
13.
Int J Cancer ; 54(1): 53-9, 1993 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-8386709

RESUMEN

A series of selected lymphoid malignancies (LMs) occurring in Italian HIV-1-infected (HIV+) patients, principally intravenous drug users, was investigated. In addition to small non-cleaved-cell (SNCC) and large-cell immunoblastic (LCI) non-Hodgkin's lymphomas (NHLs), a relatively high occurrence of anaplastic large-cell Ki-I-positive (ALC Ki-I+) lymphomas and Hodgkin's disease (HD) was observed, at variance with other reported series of HIV+ patients. Combined results of in situ hybridization and Southern-blot analyses, in conjunction with immunohistochemical detection of Epstein-Barr virus (EBV)-encoded latent membrane protein-I (LMP-I), showed an almost complete association of ALC Ki-I+ lymphomas and HD cases with EBV. The neoplastic cells of both these LMs also showed common immunophenotypic features such as frequent absence of B- and T-cell differentiation markers and expression of the Ki-I activation marker, while SNCC and LCI lymphomas were mainly of mature B-cell origin and Ki-I-. The concomitant high incidence of ALC Ki-I+ lymphomas and HD in a specific group of HIV+ patients, their almost complete association with EBV in clonal and episomal form and the great similarity in differentiation, activation and virological markers which they display suggest that these LMs are pathological variants of a continuous spectrum of HIV-I-associated disorders etiopathologically linked to EBV.


Asunto(s)
ADN de Neoplasias/análisis , Seropositividad para VIH/complicaciones , Herpesvirus Humano 4/genética , Enfermedad de Hodgkin/microbiología , Linfoma de Células B Grandes Difuso/microbiología , Antígenos CD/análisis , Antígenos de Neoplasias/análisis , Antígenos Virales/análisis , Proteínas de Unión al ADN/análisis , Antígenos Nucleares del Virus de Epstein-Barr , Reordenamiento Génico de Cadena Pesada de Linfocito B , Reordenamiento Génico de Cadena Ligera de Linfocito B , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T/genética , Genes de Inmunoglobulinas , Herpesvirus Humano 4/inmunología , Enfermedad de Hodgkin/complicaciones , Humanos , Inmunofenotipificación , Hibridación in Situ , Antígeno Ki-1 , Linfoma de Células B Grandes Difuso/complicaciones , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Proteínas de la Matriz Viral/análisis
14.
Arch Int Pharmacodyn Ther ; 235(1): 73-85, 1978 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-736693

RESUMEN

The gamma-NH2 function of GABA was blocked with either benzoyl group (BG1) or a pivaloyl (timethylacetyl) group (PG2). The two derivatives of GABA obtained by the synthetic procedure were chemically pure and fully characterized. Both 14C-BG1 and 14C-PG2, unlike 14-C-GABA, are able to penetrate the blood-brain barrier in rats after subcutaneous injection. BG1 reached its highest concentration in brain 5 min after injection and PG2 after 30 min. This difference appears to be related to the different hydrophobic character of the two compounds, measured after experiments of partition in a water ethylacetate system, and to the different rate of diffusion following subcutaneous administration. BG1 abolished pentetrazole- and bicuculine-induced convulsions in rat when injected 5 min before the administration of the convulsants and PG2 had similar effects when injected 30 min before convulsants. BG1 and PG2 had a slight inhibitory effect on GAD and both BG1 and PG2 acted as substrates for the action of proteolytic enzymes that convert the two compounds back to GABA. Toxicity of both BG1 and PG2 was practically undetectable in rat following administration of the compounds up to 1 g/kg. Glutamate oxidation by rat brain mitochondria was not affected by either BG1 or PG2.


Asunto(s)
Bicuculina/antagonistas & inhibidores , Isoquinolinas/antagonistas & inhibidores , Pentilenotetrazol/antagonistas & inhibidores , Convulsiones/inducido químicamente , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Encéfalo/metabolismo , Fenómenos Químicos , Química Física , Femenino , Masculino , Mitocondrias/metabolismo , Pentilenotetrazol/toxicidad , Ratas , Ácido gamma-Aminobutírico/farmacología , Ácido gamma-Aminobutírico/toxicidad
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