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1.
EBioMedicine ; 13: 262-273, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27745900

RESUMO

Chronic kidney disease (CKD) is a global health problem, and novel therapies to treat CKD are urgently needed. Here, we show that inhibition of G0/G1 switch 2 (G0s2) ameliorates renal inflammation in a mouse model of CKD. Renal expression of chemokine (C-C motif) ligand 2 (Ccl2) was increased in response to p65 activation in the kidneys of wild-type 5/6 nephrectomy (5/6Nx) mice. Moreover, 5/6Nx Clk/Clk mice, which carry homozygous mutations in the gene encoding circadian locomotor output cycles kaput (CLOCK), did not exhibit aggravation of apoptosis or induction of F4/80-positive cells. The renal expression of G0s2 in wild-type 5/6Nx mice was important for the transactivation of Ccl2 by p65. These pathologies were ameliorated by G0s2 knockdown. Furthermore, a novel small-molecule inhibitor of G0s2 expression was identified by high-throughput chemical screening, and the inhibitor suppressed renal inflammation in 5/6Nx mice. These findings indicated that G0s2 inhibitors may have applications in the treatment of CKD.


Assuntos
Proteínas de Ciclo Celular/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Animais , Sítios de Ligação , Proteínas CLOCK/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Quimiocina CCL2/genética , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , Ligação Proteica , RNA Interferente Pequeno/genética , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Transcrição Gênica
2.
J Biol Chem ; 291(10): 4913-27, 2016 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-26728457

RESUMO

Chronic kidney disease (CKD) is associated with an increase in serum retinol; however, the underlying mechanisms of this disorder are poorly characterized. Here, we found that the alteration of hepatic metabolism induced the accumulation of serum retinol in 5/6 nephrectomy (5/6Nx) mice. The liver is the major organ responsible for retinol metabolism; accordingly, microarray analysis revealed that the hepatic expression of most CYP genes was changed in 5/6Nx mice. In addition, D-box-binding protein (DBP), which controls the expression of several CYP genes, was significantly decreased in these mice. Cyp3a11 and Cyp26a1, encoding key proteins in retinol metabolism, showed the greatest decrease in expression in 5/6Nx mice, a process mediated by the decreased expression of DBP. Furthermore, an increase of plasma transforming growth factor-ß1 (TGF-ß1) in 5/6Nx mice led to the decreased expression of the Dbp gene. Consistent with these findings, the alterations of retinol metabolism and renal dysfunction in 5/6Nx mice were ameliorated by administration of an anti-TGF-ß1 antibody. We also show that the accumulation of serum retinol induced renal apoptosis in 5/6Nx mice fed a normal diet, whereas renal dysfunction was reduced in mice fed a retinol-free diet. These findings indicate that constitutive Dbp expression plays an important role in mediating hepatic dysfunction under CKD. Thus, the aggravation of renal dysfunction in patients with CKD might be prevented by a recovery of hepatic function, potentially through therapies targeting DBP and retinol.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Fígado/metabolismo , Insuficiência Renal Crônica/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose , Células Cultivadas , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Proteínas de Ligação a DNA/genética , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Insuficiência Renal Crônica/patologia , Ácido Retinoico 4 Hidroxilase , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta1/metabolismo , Vitamina A/sangue
3.
Biol Pharm Bull ; 37(2): 331-4, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24492731

RESUMO

Few studies have examined xanthocidin, a biotic isolated from Streptomyces xanthocidicus in 1966, because its supply is limited. Based on its chemical structure, xanthocidin has the potential to become a lead compound in the production of agrochemicals and anti-cancer drugs; however, it is unstable under both basic and acidic conditions. We recently established the total synthesis of xanthocidin using the FeCl3-mediated Nazarov reaction, and obtained two stable derivatives (#1 and #2). The results of the present study demonstrated that these derivatives exhibited the inhibitory activity of topoisomerase IIα, known as a molecular target for cancer chemotherapy, and this was attributed to the respective exo-methylene ketone group without DNA intercalation. The results obtained also suggest that these derivatives may have value as lead compounds in the synthesis of topoisomerase IIα inhibitors.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Ciclopentanos/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Streptomyces/química , Inibidores da Topoisomerase II/farmacologia , Antígenos de Neoplasias , Antineoplásicos/síntese química , DNA Topoisomerases Tipo II , Humanos , Estrutura Molecular , Inibidores da Topoisomerase II/síntese química
4.
Mod Rheumatol ; 24(3): 511-6, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24252023

RESUMO

OBJECTIVES: To evaluate humoral immune response to influenza vaccine and polysaccharide pneumococcal vaccine in patients with rheumatoid arthritis (RA) or Castleman's disease (CD) during tocilizumab therapy. METHODS: Thirty-eight patients (28 RA and 10 CD) receiving tocilizumab and 39 RA patients receiving TNF inhibitors and/or synthetic DMARDs subcutaneously received a single dose of a split-virion inactivated influenza vaccine containing A(New Caledonia (NC):H1N1), A(Hiroshima (HIR):H3N2) and B(Malaysia (MAL)) strains. Twenty-one RA patients using tocilizumab also received 23-valent polysaccharide pneumococcal vaccine. Antibody titers were measured every 4 weeks for a total of 12 weeks after vaccination. RESULTS: In the tocilizumab group, seroprotective titers (40-fold or more) were obtained in 36/38(95%) for A(NC), 35/38(92%) for A(HIR) and 32/38(84%) for B(MAL). In the patients with baseline antibody titer < 40-fold, 11/11(100%), 7/8(88%) and 18/20(90%) patients showed four-fold or more increase in the titer from baseline to A(NC), A(HIR) and B(MAL), respectively. Patients using TNF inhibitors and/or DMARDs showed similar responses. Pneumococcal antibody titers increased at least two-fold in more than 9 of 12 serotypes, which continued for longer than 12 weeks in all the patients. CONCLUSION: Interleukin-6 (IL-6) blocking therapy with tocilizumab did not affect the humoral immune response to both influenza and pneumococcal vaccines.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Imunidade Humoral , Vacinas contra Influenza/imunologia , Vacinas Pneumocócicas/imunologia , Adulto , Idoso , Artrite Reumatoide/imunologia , Hiperplasia do Linfonodo Gigante/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vacinação
5.
J Toxicol Sci ; 38(4): 547-57, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23824011

RESUMO

We reported that (-)-xanthatin, a xanthanolide sesquiterpene lactone present in the Cocklebur plant, exhibited potent anti-proliferative effects on human breast cancer cells, in which GADD45γ, a novel tumor suppressor gene, was induced. Mechanistically, topoisomerase IIα (Topo IIα) inhibition by (-)-xanthatin was shown to be the upstream trigger that stimulated the expression of GADD45γ mRNA and concomitantly produced reactive oxygen species (ROS) to maintain this expression. Since the anti-cancer drug etoposide, a selective Topo IIα inhibitor, has also been shown to induce intracellular ROS, (-)-xanthatin may exert its anti-proliferative effects on cancer cells in a similar manner to those of etoposide. In the present study, to generalize its applicability to cancer therapy, we further investigated the biological activities of (-)-xanthatin by comparing its activities to those of the established anti-cancer drug etoposide. After the exposure of breast cancer cells to (-)-xanthatin or etoposide, a prolonged and marked up-regulation in the expression of c-fos, a proapoptotic molecule, was detected together with GADD45γ; and the expression of these molecules was stabilized by ROS and abrogated by the pretreatment with N-acetyl-L-cysteine (NAC), a potent ROS scavenger. (-)-Xanthatin in particular exhibited stronger anti-proliferative potential than that of etoposide, which underlies the marked induction of c-fos/GADD45γ and ROS production.


Assuntos
Acetilcisteína/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Divisão Celular/genética , Sequestradores de Radicais Livres/farmacologia , Furanos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Supressores de Tumor/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Antígenos de Neoplasias , Neoplasias da Mama/metabolismo , DNA Topoisomerases Tipo II , Proteínas de Ligação a DNA/antagonistas & inibidores , Etoposídeo/farmacologia , Feminino , Humanos , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Células Tumorais Cultivadas , Regulação para Cima , Proteínas GADD45
6.
Chem Res Toxicol ; 26(7): 1073-9, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23718638

RESUMO

Δ(9)-Tetrahydrocannabinol (Δ(9)-THC) has been reported as possessing antiestrogenic activity, although the mechanisms underlying these effects are poorly delineated. In this study, we used the estrogen receptor α (ERα)-positive human breast cancer cell line, MCF-7, as an experimental model and showed that Δ(9)-THC exposures markedly suppresses 17ß-estradiol (E2)- induced MCF-7 cell proliferation. We demonstrate that these effects result from Δ(9)-THC's ability to inhibit E2-liganded ERα activation. Mechanistically, the data obtained from biochemical analyses revealed that (i) Δ(9)-THC up-regulates ERß, a repressor of ERα, inhibiting the expression of E2/ERα-regulated genes that promote cell growth and that (ii) Δ(9)-THC induction of ERß modulates E2/ERα signaling in the absence of direct interaction with the E2 ligand binding site. Therefore, the data presented support the concept that Δ(9)-THC's antiestrogenic activities are mediated by the ERß disruption of E2/ERα signaling.


Assuntos
Dronabinol/farmacologia , Receptor beta de Estrogênio/metabolismo , Estrogênios/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dronabinol/química , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/biossíntese , Humanos , Ligantes , Células MCF-7 , Relação Estrutura-Atividade , Células Tumorais Cultivadas
7.
J Toxicol Sci ; 38(2): 305-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23535410

RESUMO

To investigate gene(s) being regulated by ∆(9)-tetrahydrocannabinol (∆(9)-THC), we performed DNA microarray analysis of human breast cancer MDA-MB-231 cells, which are poorly differentiated breast cancer cells, treated with ∆(9)-THC for 48 hr at an IC50 concentration of approximately 25 µM. Among the highly up-regulated genes (> 10-fold) observed, fatty acid 2-hydroxylase (FA2H) was significantly induced (17.8-fold). Although the physiological role of FA2H has not yet been fully understood, FA2H has been shown to modulate cell differentiation. The results of Oil Red O staining after ∆(9)-THC exposure showed the distribution of lipid droplets (a sign of the differentiated phenotype) in cells. Taken together, the results obtained here indicate that FA2H is a novel ∆(9)-THC-regulated gene, and that ∆(9)-THC induces differentiation signal(s) in poorly differentiated MDA-MB-231 cells.


Assuntos
Neoplasias da Mama/genética , Dronabinol/farmacologia , Oxigenases de Função Mista/genética , RNA Mensageiro/metabolismo , Ativação Transcricional/efeitos dos fármacos , Neoplasias da Mama/patologia , Diferenciação Celular/efeitos dos fármacos , Feminino , Humanos , Oxigenases de Função Mista/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , PPAR alfa/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Regulação para Cima
8.
Toxicology ; 305: 1-9, 2013 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-23313378

RESUMO

Previously, we reported that (-)-xanthatin, a naturally occurring xanthanolide present in the Cocklebur plant, exhibits potent anti-proliferative effects on human breast cancer cells, accompanied by an induction of the growth arrest and DNA damage-inducible gene 45γ (GADD45γ), recognized recently as a novel tumor suppressor gene. However, the mechanisms mediating this activation were unknown. Topoisomerase IIα (Topo IIα) inhibition has been reported to produce a cell death response accompanied by an atypical DNA laddering fragmentation profile, similar to that noted previously for (-)-xanthatin. Therefore we hypothesized that (-)-xanthatin's GADD45γ activation was mediated through the Topo IIα pathway. Here, we identify that (-)-xanthatin does function as a catalytic inhibitor of Topo IIα, promoting DNA damage. In addition, reactive oxygen species (ROS) were elevated in cells treated with this agent. Mechanistically, it was determined that the induced levels of GADD45γ mRNA resulting from (-)-xanthatin exposures were stabilized by coordinately produced ROS, and that the consequent induction of GADD45γ mRNA, GADD45γ protein and ROS generation were abrogated by co-treatment with N-acetyl-l-cysteine. Taken together, the data support the concept that Topo IIα inhibition by (-)-xanthatin is a trigger that stimulates expression of DNA damage-inducible GADD45γ mRNA and that concomitantly produced ROS act downstream to further enhance the GADD45γ mRNA/GADD45γ protein induction process, resulting in breast cancer cell death.


Assuntos
Antígenos de Neoplasias/fisiologia , DNA Topoisomerases Tipo II/fisiologia , Proteínas de Ligação a DNA/fisiologia , Furanos/farmacologia , Inseticidas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Inibidores da Topoisomerase II , Acetilcisteína/farmacologia , Antígenos de Neoplasias/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Dano ao DNA , DNA Topoisomerases Tipo II/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Proteínas de Ligação a DNA/efeitos dos fármacos , Feminino , Sequestradores de Radicais Livres/farmacologia , Glutationa/metabolismo , Meia-Vida , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Regulação para Cima/efeitos dos fármacos , Proteínas GADD45
9.
Toxicol Lett ; 214(3): 314-9, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22963825

RESUMO

Cannabidiol (CBD), a major non-psychotropic constituent of fiber-type cannabis plant, has been reported to possess diverse biological activities, including anti-proliferative effect on cancer cells. Although CBD is obtained from non-enzymatic decarboxylation of its parent molecule, cannabidiolic acid (CBDA), few studies have investigated whether CBDA itself is biologically active. Results of the current investigation revealed that CBDA inhibits migration of the highly invasive MDA-MB-231 human breast cancer cells, apparently through a mechanism involving inhibition of cAMP-dependent protein kinase A, coupled with an activation of the small GTPase, RhoA. It is established that activation of the RhoA signaling pathway leads to inhibition of the mobility of various cancer cells, including MDA-MB-231 cells. The data presented in this report suggest for the first time that as an active component in the cannabis plant, CBDA offers potential therapeutic modality in the abrogation of cancer cell migration, including aggressive breast cancers.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Canabinoides/farmacologia , Inibidores Enzimáticos/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Transdução de Sinais , Quinases Associadas a rho/biossíntese
10.
Biol Pharm Bull ; 34(8): 1252-6, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21804214

RESUMO

15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein (ox-LDL), a major causal factor for atherosclerosis. Both enzymatic (15-LOX) and non-enzymatic (Cu(2+)) mechanisms have been proposed for the production of ox-LDL. We have recently reported that cannabidiol-2',6'-dimethyl ether (CBDD) is a selective and potent inhibitor of 15-LOX-catalyzed linoleic acid oxygenation (Takeda et al., Drug Metab. Dispos., 37, 1733-1737 (2009)). In the LDL, linoleic acid is present as cholesteryl linoleate, the major fatty acid esterified to cholesterol, and is susceptible to oxidative modification by 15-LOX or Cu(2+). In this investigation, we examined the efficacy of CBDD on i) 15-LOX-catalyzed oxygenation of cholesteryl linoleate, and ii) ox-LDL formation catalyzed by 15-LOX versus Cu(2+)-mediated non-enzymatic generation of this important mediator. The results obtained demonstrate that CBDD is a potent and selective inhibitor of ox-LDL formation generated by the 15-LOX pathway. These studies establish CBDD as both an important experimental tool for characterizing 15-LOX-mediated ox-LDL formation, and as a potentially useful therapeutic agent for treatment of atherosclerosis.


Assuntos
Antioxidantes/farmacologia , Araquidonato 15-Lipoxigenase/metabolismo , Canabidiol/análogos & derivados , Ésteres do Colesterol/metabolismo , LDL-Colesterol/metabolismo , Cobre/metabolismo , Lipoproteínas LDL/biossíntese , Antioxidantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Humanos , Oxirredução
11.
Chem Res Toxicol ; 24(6): 855-65, 2011 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-21568272

RESUMO

exo-Methylene lactone group-containing compounds, such as (--)-xanthatin, are present in a large variety of biologically active natural products, including extracts of Xanthium strumarium (Cocklebur). These substances are reported to possess diverse functional activities, exhibiting anti-inflammatory, antimalarial, and anticancer potential. In this study, we synthesized six structurally related xanthanolides containing exo-methylene lactone moieties, including (--)-xanthatin and (+)-8-epi-xanthatin, and examined the effects of these chemically defined substances on the highly aggressive and farnesyltransferase inhibitor (FTI)-resistant MDA-MB-231 cancer cell line. The results obtained demonstrate that (--)-xanthatin was a highly effective inhibitor of MDA-MB-231 cell growth, inducing caspase-independent cell death, and that these effects were independent of FTase inhibition. Further, our results show that among the GADD45 isoforms, GADD45γ was selectively induced by (--)-xanthatin and that GADD45γ-primed JNK and p38 signaling pathways are, at least in part, involved in mediating the growth inhibition and potential anticancer activities of this agent. Given that GADD45γ is becoming increasingly recognized for its tumor suppressor function, the results presented here suggest the novel possibility that (--)-xanthatin may have therapeutic value as a selective inducer of GADD45γ in human cancer cells, in particular in FTI-resistant aggressive breast cancers.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Furanos/química , Furanos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Xanthium/química , Antineoplásicos Fitogênicos/síntese química , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Feminino , Furanos/síntese química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Humanos , Interleucina-18/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteínas GADD45
12.
J Pharm Sci ; 100(3): 1206-11, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20891010

RESUMO

15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein, a major causal factor for atherosclerosis. Δ(9)-Tetrahydrocannabinol (Δ(9)-THC), a major component of marijuana, has suggested to suppress atherosclerosis. Although Δ(9)-THC seems to be attractive for the prevention of atherosclerosis, there is no information about whether or not 15-LOX isoform can be inhibited by Δ(9)-THC. In the present study, Δ(9)-THC was found to be a direct inhibitor for 15-LOX with an IC(50) (50% inhibition concentration) value of 2.42 µM. Furthermore, Δ(9)-THC-11-oic acid, a major and nonpsychoactive metabolite of Δ(9) -THC, but not another Δ(9)-THC metabolite 11-OH-Δ(9)-THC (psychoactive), was revealed to inhibit 15-LOX. Taken together, it is suggested that Δ(9) -THC can abrogate atherosclerosis via direct inhibition of 15-LOX, and that Δ(9)-THC-11-oic acid is shown to be an "active metabolite" of Δ(9) -THC in this case.


Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Aterosclerose/prevenção & controle , Dronabinol/análogos & derivados , Dronabinol/farmacologia , Inibidores de Lipoxigenase/farmacologia , Dronabinol/metabolismo , Humanos , Terapia de Alvo Molecular , Receptor CB2 de Canabinoide/metabolismo
13.
Brain Res Mol Brain Res ; 111(1-2): 175-81, 2003 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-12654517

RESUMO

Prolonged dietary restriction has been reported to suppress age-induced phenomena. In order to investigate how prolonged caloric restriction reduces age-related deterioration of hippocampal synaptic transmission, we compared the levels of major hippocampal polyunsaturated fatty acids, arachidonic acid and docosahexaenoic acid between 4- and 26-month-old rats. The Ca(2+) responses upon perfusion of NMDA or 30 mM K(+) between 4- and 26-month-old rats with prolonged dietary restriction were also compared using the fluorescent probe Fura-2. A decrease in membrane arachidonic acid is thought to be a major causal factor in the age-related impairment of long-term potentiation. Long-term caloric restriction seems to increase arachidonic acid levels regardless of age. However, there is no significant difference of hippocampal arachidonic acid levels between in freely feeding 4- and 26-month-old rats. Similar results were obtained from the measurement of hippocampal docosahexaenoic acid levels. Under caloric restriction, the 500 microM N-methyl-D-aspartate-induced Ca(2+) response was greatly reduced by aging, while the 30 mM K(+)-induced Ca(2+) response was not affected. In our preliminary data, the amplitude of the population spike after tetanic stimulation did not differ between 4- and 26-month-old rats under caloric restriction, while 50 microM of 2-amino-5-phosphonovaleric acid, a N-methyl-D-aspartate antagonist, markedly inhibited a potentiation of the population spike in 4-month-old rats, but with negligible inhibition in 26-month-old rats. From these results, an age-related impairment of hippocampal excitatory synaptic transmission may not be solely due to the reduction of membrane arachidonic acid. Caloric restriction might prevent age-related reduction in hippocampal synaptic transmission by enhancing non-N-methyl-D-aspartate mechanisms.


Assuntos
Envelhecimento/metabolismo , Restrição Calórica , Privação de Alimentos/fisiologia , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Vias Neurais/metabolismo , Neurônios/metabolismo , Valina/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Ácido Araquidônico/metabolismo , Cálcio/metabolismo , Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Ácidos Docosa-Hexaenoicos/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácidos Graxos Insaturados/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Lipídeos de Membrana/metabolismo , N-Metilaspartato/farmacologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiopatologia , Neurônios/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Valina/farmacologia
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