RESUMEN

Neonatal immune activation (NIA) through exposure to lipopolysaccharide (LPS) induces adult behavioral changes in rodents that resemble symptoms of developmental disorders, such as autism spectrum disorder. The neonatal timing of LPS exposure appears to play a crucial role in determining the nature and extent of long-term changes. This study aims to explore whether a 3-day LPS-NIA triggers sex- and age-related changes in gut function, potentially linking LPS-NIA to gastrointestinal dysfunction. Male and female Swiss mice received intraperitoneal injections of LPS or saline on postnatal days (PN) 3, 5, and 7. At PN35 (juvenile) and PN70 (adult), gut inflammation and oxidative stress were evaluated in addition to assessments of working memory, depressive-like symptoms, sociability, and repetitive behavior. Gut examination showed elevated C-X-C motif chemokine receptor 3 (CXCR3) in LPS-NIA mice, while MyD88 and Zonulin expressions were significantly higher only in adult LPS-NIA females. Interleukin (IL)-23 expression increased in juvenile and adult male and juvenile female LPS-NIA mice. Oxidative changes included decreased duodenal reduced glutathione (GSH) in juvenile females and ileal GSH in adult females exposed to LPS-NIA. Regarding behavioral alterations, adult LPS-NIA females exhibited depressive-like behavior. Working memory deficits were observed across all LPS-NIA groups. Only juvenile LPS-NIA females increased grooming, while rearing was higher in adult LPS-NIA mice of both sexes. The findings imply that LPS-NIA impacts intestinal barrier function and causes gut inflammatory alterations that are sex- and age-specific. These findings pave the way for exploring potential mechanisms that could contribute to LPS-induced gastrointestinal disturbances among individuals with ASD.

Asunto(s)

Animales Recién Nacidos , Lipopolisacáridos , Caracteres Sexuales , Animales , Lipopolisacáridos/toxicidad , Femenino , Ratones , Masculino , Factores de Edad , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Envejecimiento/inmunología , Envejecimiento/fisiología

RESUMEN

Evidence has demonstrated the hippocampal cholinergic system and the mammalian target of rapamycin (mTOR) participation during the memory formation of aversive events. This study assessed the role of these systems in the hippocampus for the extinction memory process by submitting male Wistar rats to fear-motivated step-down inhibitory avoidance (IA). The post-extinction session administration of the nicotinic and muscarinic cholinergic receptor antagonists, mecamylamine and scopolamine, respectively, both at doses of 2 µg/µl/side, and rapamycin, an mTOR inhibitor (0.02 µg/µl/side), into the CA1 region of the dorsal hippocampus, impaired the IA extinction memory. Furthermore, the nicotinic and muscarinic cholinergic receptor agonists, nicotine and muscarine, respectively, had a dose-dependent effect on the IA extinction memory when administered intra-CA1, immediately after the extinction session. Nicotine (0.6 µg/µl/side) and muscarine (0.02 µg/µl/side), respectively, had no effect, while the higher doses (6 and 2 µg/µl/side, respectively) impaired the IA extinction memory. Interestingly, the co-administration of muscarine at the lower dose blocked the impairment that was induced by rapamycin. This effect was not observed when nicotine at the lower dose was co-administered. These results have demonstrated the participation of the cholinergic receptors and mTOR in the hippocampus for IA extinction, and that the cholinergic agonists had a dose-dependent effect on the IA extinction memory. This study provides insights related to the behavioural aspects and the neurobiological properties underlying the early stage of fear-motivated IA extinction memory consolidation and suggests that there is hippocampal muscarinic receptor participation independent of mTOR in this memory process.

Asunto(s)

Reacción de Prevención , Extinción Psicológica , Miedo , Hipocampo , Memoria , Receptores Colinérgicos , Serina-Treonina Quinasas TOR , Animales , Masculino , Ratas , Reacción de Prevención/fisiología , Miedo/fisiología , Hipocampo/metabolismo , Muscarina/farmacología , Antagonistas Muscarínicos/farmacología , Nicotina/farmacología , Ratas Wistar , Receptores Colinérgicos/metabolismo , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Extinción Psicológica/fisiología , Memoria/fisiología

RESUMEN

The hippocampus, basolateral amygdala and ventromedial prefrontal cortex participate in the extinction of inhibitory avoidance and contextual fear conditioning. We studied the effect of drugs acting on receptors involved in synaptic modulation on extinction of both tasks. The drugs were given bilaterally right after the first of two sessions of extinction in each task through cannulae implanted into the mentioned areas. The doses used are known to influence memory consolidation of the original tasks. Their effects were evaluated on a second extinction session 24h later, and assumed to result from influences on the consolidation of extinction. The glutamate NMDA receptor stimulant d-serine (50 µg/side) and the histamine methyl-transferase inhibitor SKF9188 (12.5 µg/side) enhanced, and the NMDA antagonist amino-phosphonopentanoate (5 µg/side) and the H2 histamine receptor antagonist ranitidine (17.5 µg/side) inhibited, extinction of both tasks regardless of the region into which they were administered. Thus, glutamate NMDA receptors are involved in the consolidation of extinction of both tasks, and histamine H2 receptors modulate that process in all areas studied. Norepinephrine (1 µg/side), the ß-adrenoceptor antagonist timolol (1 µg/side), the D1 dopamine receptor agonist SKF38393 (12.5 µg/side) and the D1 antagonist SCH23390 (1.5 µg/side) also affected extinction of both tasks, but their effects varied with the task and with the site of infusion, suggesting that extinction modulation by ß- and D1 receptors is more complex. In conclusion, extinction of two different aversive tasks is modulatable by various systems, which bears upon the behavioral and pharmacological treatment of fear-motivated brain disorders.

Asunto(s)

Amígdala del Cerebelo/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Miedo/psicología , Hipocampo/efectos de los fármacos , Motivación/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , 2-Amino-5-fosfonovalerato/administración & dosificación , 2-Amino-5-fosfonovalerato/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Benzazepinas/administración & dosificación , Benzazepinas/farmacología , Región CA1 Hipocampal/fisiología , Cateterismo , Antagonistas de Dopamina/administración & dosificación , Antagonistas de Dopamina/farmacología , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacología , Miedo/efectos de los fármacos , Antagonistas de los Receptores H2 de la Histamina/administración & dosificación , Antagonistas de los Receptores H2 de la Histamina/farmacología , Masculino , Microinyecciones , Ranitidina/efectos adversos , Ranitidina/farmacología , Ratas , Ratas Wistar , Timolol/farmacología

RESUMEN

The creatine (Cr) and phosphocreatine (PCr) system is essential for the buffering and transport of high-energy phosphates. Although achievements made over the last years have highlighted the important role of creatine in several neurological diseases, the adaptive processes elicited by this guanidino compound in hippocampus are poorly understood. In the present study, we showed that creatine (0.5-25mM) gradually increases the amplitude of first population spike (PS) and elicits secondary PS in stratum radiatum of the CA1 region, in hippocampal slices. Creatine also decreased the intensity of the stimulus to induce PS, when compared with hippocampal slices perfused with artificial cerebrospinal fluid (ACSF). The competitive NMDA receptor antagonist, 2-amino-5-phosphonopentanoic acid (AP5; 100microM) attenuated creatine-induced increase of amplitude of PS and appearance of secondary PS, providing pharmacological evidence of the involvement of NMDA receptors in the electrophysiological effects of creatine. Accordingly, creatine (0.01-1mM) increased [3H]MK-801 binding to hippocampal membranes by 55%, further indicating that this compound modulates NMDA receptor function. These results implicate the NMDA receptor in amplitude and population spike increase elicited by creatine in hippocampus. Furthermore, these data suggest that this guanidino compound may also play a putative role as a neuromodulator in the brain, and that at least some of its effects may be mediated by an increase in glutamatergic function.

Asunto(s)

Potenciales de Acción/efectos de los fármacos , Creatina/farmacología , Hipocampo/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Animales , Membrana Celular/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Electrofisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Espacio Extracelular/efectos de los fármacos , Técnicas In Vitro , Masculino , Potenciales de la Membrana/efectos de los fármacos , Ratas , Ratas Wistar

RESUMEN

Cyclooxygenases (COXs) are rate-limiting enzymes in the metabolic pathways in which arachidonic acid is converted to prostaglandins. COX-2 is the isoform induced at injury/inflammation sites and expressed constitutively in a few tissues, such as the central nervous system, and plays a role in neurodegenerative diseases associated with increased excitatory activity. However, the role of COX-2 and its main product, prostaglandin E(2) (PGE(2)), in the convulsive states is not fully established. In this study we showed that the selective COX-2 inhibitor, celecoxib (at the dose of 2mg/kg, but not at the doses of 0.2 or 20mg/kg, p.o.), protects against the seizures induced by pentylenetetrazol (PTZ, 60 mg/kg, i.p.). The role of PGE(2) in the convulsions induced by PTZ was further investigated by administering anti-PGE(2) antibodies (4 microg/2 microl, i.c.v.), and assessing electroencephalographic changes induced by PTZ (PTZ, 60 mg/kg, i.p.). Anti-PGE(2) antibodies attenuated PTZ-induced seizures in rats. In addition, combining PGE(2) (100 ng/2 microl, i.c.v.) with a subconvulsant dose of PTZ (20mg/kg, i.p.) caused seizures, further supporting a role for this prostaglandin in the convulsions induced by PTZ. Finally, we showed that the anticonvulsant action of celecoxib (2mg/kg, p.o.) was reversed by the intracerebroventricular administration of PGE(2) (10 ng/2 microl, i.c.v.). These data constitute strong converging pharmacological evidence supporting a facilitatory role for the COX-2/PGE(2) pathway in the seizures induced by PTZ. However, whether selective COX-2 inhibitors are safer anti-inflammatory drugs for epileptic patients than nonspecific inhibitors remains to be determined.

Asunto(s)

Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Pentilenotetrazol , Convulsiones/fisiopatología , Transducción de Señal/fisiología , Análisis de Varianza , Animales , Anticuerpos/farmacología , Celecoxib , Inhibidores de la Ciclooxigenasa/farmacología , Dinoprostona/inmunología , Relación Dosis-Respuesta a Droga , Electroencefalografía/métodos , Masculino , Pirazoles/farmacología , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacología

RESUMEN

Achievements made over the last years have highlighted the important role of creatine in health and disease. However, studies of its effect on cognition function have been limited. In the present study, we investigated the effect of creatine on early consolidation of the spatial learning in rats. Statistical analysis showed that intrahippocampal administration of creatine (2.5 and 7.5 nmol/hippocampus) (post-training) decreased the latency for scape and mean number of errors in Barnes maze test. The involvement of polyamine binding site at NMDA receptor in creatine-induced spatial learning enhancement was investigated by co-administration of arcaine (0.02 nmol/hippocampus) or spermidine (0.02 nmol/hippocampus) with creatine (2.5 nmol/hippocampus) (post-training). Statistical analysis revealed that creatine-induced spatial learning enhancement was reverted by co-administration of arcaine (0.02 nmol/hippocampus) and intensified by spermidine (0.02 nmol/hippocampus). These results provide evidence that creatine not only seem to be involved in energy metabolism but may also play an important role in early consolidation of spatial learning in hippocampus which participation of polyamines binding site at the NMDA receptor.

Asunto(s)

Creatina/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Poliaminas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Percepción Espacial/efectos de los fármacos , Animales , Biguanidas/farmacología , Sitios de Unión , Creatina/administración & dosificación , Creatina/antagonistas & inhibidores , Hipocampo/fisiología , Masculino , Microinyecciones , Ratas , Espermidina/farmacología , Estimulación Química

RESUMEN

Glutaric acidemia type I (GA-I) is an inherited metabolic disease characterized by striatal degeneration, seizures, and accumulation of glutaric acid (GA). Considering that GA impairs energy metabolism and induces reactive species generation, we investigated whether the acute administration of creatine, an amino acid with antioxidant and ergogenic properties, protects against the seizures and neurochemical alterations (inhibition of Na(+),K(+)-ATPase and increased protein carbonylation) induced by the intrastriatal injection of GA (4 micromol/striatum). We also investigated whether creatine protected against the GA-induced inhibition of glutamate uptake in vitro. Creatine administration (300 mg/kg, p.o.) decreased seizures (evidenced by electrographic changes), protein carbonylation and Na(+),K(+)-ATPase inhibition induced by GA. However, creatine, at a dose capable of fully preventing GA-induced protein carbonylation (50 and 150 mg/kg, p.o.), did not prevent convulsions and Na(+),K(+)-ATPase inhibition, suggesting that the anticonvulsant activity of creatine in this experimental model is not related to its antioxidant action. Creatine also protected against the GA-induced inhibition of l-[(3)H]glutamate uptake in synaptosomes, suggesting that creatine may reduce the deleterious effects of GA by maintaining glutamate uptake in the synaptic cleft. Therefore, considering that creatine significantly attenuates the deleterious effects of GA assessed by behavioral and neurochemical measures, it is plausible to propose the use of this amino acid as an adjuvant therapy in the management of glutaric acidemia.

Asunto(s)

Anticonvulsivantes/uso terapéutico , Química Encefálica/efectos de los fármacos , Creatina/uso terapéutico , Glutaratos , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Estimulación Eléctrica/efectos adversos , Electroencefalografía/métodos , Masculino , Carbonilación Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Convulsiones/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo

RESUMEN

Monosialoganglioside (GM1) is a glycosphingolipid present in most cell membranes that displays antioxidant and neuroprotective properties. GM1 increases catalase activity in cerebral cortices in vivo, but the mechanisms underlying this effect of GM1 are not known. In the current study we investigated the effect of GM1 (50 mg/kg, ip) on the content of hemoglobin and catalase activity of hippocampus, cortex, and striatum of rats. GM1 administration increased catalase activity and hemoglobin content in brain samples after 30 min, but had no effect on blood catalase activity. GM1-induced increase in catalase activity was abolished by brain perfusion with heparinized saline. Brain catalase activity in the absence of blood, estimated by regression analysis of data from perfused and nonperfused animals, was not altered by the systemic injection of GM1. Moreover, the addition of GM1 (30 or 100 microM) did not increase catalase activity in slices of cerebral cortex in situ, further suggesting that blood circulation is required for this effect. The GM1-induced vasodilation was confirmed in vivo, because the systemic injection of GM1 (50 mg/kg, ip) increased (1.2-1.6 times) the width of pial vessels.

Asunto(s)

Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Catalasa/metabolismo , Gangliósido G(M1)/farmacología , Vasodilatación , Animales , Encéfalo/enzimología , Catalasa/análisis , Hemoglobinas/análisis , Hemoglobinas/metabolismo , Masculino , Ratas , Ratas Wistar

RESUMEN

Methylene blue (MB) is a thiazine dye with cationic and lipophilic properties that acts as an electron transfer mediator in the mitochondria. Due to this metabolic improving activity and free radicals scavenging effects, MB has been used in the treatment of methemoglobinemia and ifosfamide-induced encephalopathy. Considering that methylmalonic acidemia consists of a group of inherited metabolic disorders biochemically characterized by impaired mitochondrial oxidative metabolism and reactive species production, we decided to investigate whether MB, protects against the behavioral and neurochemical alterations elicited by the intrastriatal injection of methylmalonate (MMA). In the present study we showed that intrastriatal injection of MB (0.015-1.5nmol/0.5microl) protected against seizures (evidenced by electrographic recording), protein carbonylation and Na(+),K(+)-ATPase inhibition ex vivo induced by MMA (4.5micromol/1.5microl). Furthermore, we investigated whether convulsions elicited by intrastriatal MMA administration are accompanied by striatal protein carbonyl content increase and changes in Na(+),K(+)-ATPase activity in rat striatum. The effect of MB (0.015-1.5nmol/0.5microl) and MMA (4.5micromol/0.5microl) on striatal NO(x) (NO(2) plus NO(3)) content was also evaluated. Statistical analysis revealed that the MMA-induced NO(x) content increase was attenuated by intrastriatal injection of MB and the duration of convulsive episodes correlated with Na(+),K(+)-ATPase inhibition, but not with MMA-induced total protein carbonylation. In view of that MB decreases MMA-induced neurotoxicity assessed by behavioral and neurochemical parameters, the authors suggest that MB may be of value to attenuate neurological deficits of methylmalonic acidemic patients.

Asunto(s)

Cuerpo Estriado/efectos de los fármacos , Azul de Metileno/farmacología , Ácido Metilmalónico/toxicidad , Estrés Oxidativo , Convulsiones/prevención & control , Animales , Cuerpo Estriado/enzimología , Cuerpo Estriado/metabolismo , Electroencefalografía , Masculino , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , ATPasa Intercambiadora de Sodio-Potasio/metabolismo

RESUMEN

Methylmalonic acidemias consist of a group of inherited metabolic disorders caused by deficiency of methylmalonyl-CoA mutase activity and biochemically characterized by methylmalonate (MMA) accumulation, impairment mitochondrial oxidative metabolism and reactive species production. Preliminary studies with nitric oxide synthase (NOS) inhibitors have suggested that nitric oxide (NO) plays a role in the convulsant effect of MMA. However, definitive biochemical and electrophysiological evidence of the involvement of NO in the convulsions induced by MMA are lacking. In this study, we investigated whether the inhibition of NOS by 7-nitroindazole (7-NI, 3-60mg/kg, i.p.) altered the convulsions, protein oxidative damage, NO(x) (NO(2) plus NO(3)) production and Na(+),K(+)-ATPase activity inhibition induced by MMA. 7-NI decreased striatal NO(x) content, but increased seizures and protein carbonylation induced by MMA (6mumol/striatum). The intrastriatal injection of l-arginine (50nmol/0.5mul), but not of d-arginine (50nmol/0.5mul), increased striatal NO(x) content and protected against MMA-induced electroencephalographic seizures, striatal protein carbonylation and Na(+),K(+)-ATPase inhibition. Furthermore, l-arginine (50nmol/0.5mul) and MMA had no additive effect on NO(x) increase. These results are experimental evidence that endogenous NO plays a protective role in the convulsions and acute neurochemical alterations induced by this organic acid.

Asunto(s)

Anticonvulsivantes/farmacología , Indazoles/farmacología , Ácido Metilmalónico/efectos adversos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico/fisiología , Estrés Oxidativo/efectos de los fármacos , Convulsiones/fisiopatología , Animales , Anticonvulsivantes/uso terapéutico , Arginina/farmacología , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Electroencefalografía/efectos de los fármacos , Indazoles/uso terapéutico , Masculino , Ácido Metilmalónico/administración & dosificación , Premedicación , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , ATPasa Intercambiadora de Sodio-Potasio/efectos de los fármacos

RESUMEN

Monosialoganglioside (GM1) is a glycosphingolipid that protects against some neurological conditions, such as seizures and ischemia. Glutaric acidemia type I (GA-I) is an inherited disease characterized by striatal degeneration, seizures, and accumulation of glutaric acid (GA). In this study, we show that GA inhibits Na+,K+-ATPase activity and increases oxidative damage markers (total protein carbonylation and thiobarbituric acid-reactive substances-TBARS) production in striatal homogenates from rats in vitro and ex vivo. It is also shown that GM1 (50 mg/kg, i.p., twice) protects against GA-induced (4 micromol/striatum) seizures, protein carbonylation, TBARS increase, and inhibition of Na+,K+-ATPase activity ex vivo. Convulsive episodes induced by GA strongly correlated with Na+,K+-ATPase activity inhibition in the injected striatum but not with oxidative stress marker measures. Muscimol (46 pmol/striatum), but not MK-801 (3 nmol/striatum) and DNQX (8 nmol/striatum) prevented GA-induced convulsions, increase of TBARS and protein carbonylation and inhibition of Na+,K+-ATPase activity. The protection of GM1 and muscimol against GA-induced seizures strongly correlated with Na+,K+-ATPase activity maintenance ex vivo. In addition, GM1 (50-200 microM) protected against Na+,K+-ATPase inhibition induced by GA (6 mM) but not against oxidative damage in vitro. GM1 also decreased pentylenetetrazole (PTZ)-induced (1.8 micromol/striatum) seizures, Na+,K+-ATPase inhibition, and increase of TBARS and protein carbonyl in the striatum. These data suggest that Na+,K+-ATPase and GABA(A) receptor-mediated mechanisms may play important roles in GA-induced seizures and in their prevention by GM1.

Asunto(s)

Convulsivantes/toxicidad , Gangliósido G(M1)/farmacología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Convulsiones/prevención & control , ATPasa Intercambiadora de Sodio-Potasio/efectos de los fármacos , Animales , Maleato de Dizocilpina/farmacología , Electroencefalografía , Antagonistas de Aminoácidos Excitadores/farmacología , Agonistas del GABA/farmacología , Glutaratos/administración & dosificación , Glutaratos/toxicidad , Inyecciones Intraventriculares , Masculino , Muscimol/farmacología , Pentilenotetrazol/toxicidad , Carbonilación Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de GABA-A/efectos de los fármacos , Convulsiones/inducido químicamente , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo

RESUMEN

Methylmalonic acidemias are metabolic disorders caused by a severe deficiency of methylmalonyl CoA mutase activity, which are characterized by neurological dysfunction, including convulsions. It has been reported that methylmalonic acid (MMA) accumulation inhibits succinate dehydrogenase (SDH) and beta-hydroxybutyrate dehydrogenase activity and respiratory chain complexes in vitro, leading to decreased CO2 production, O2 consumption and increased lactate production. Acute intrastriatal administration of MMA also induces convulsions and reactive species production. Though creatine has been reported to decrease MMA-induced convulsions and lactate production, it is not known whether it also protects against MMA-induced oxidative damage. In the present study we investigated the effects of creatine (1.2-12 mg/kg, i.p.) and MK-801 (3 nmol/striatum) on the convulsions, striatal content of thiobarbituric acid reactive substances (TBARS) and on protein carbonylation induced by MMA. Moreover, we investigated the effect of creatine (12 mg/kg, i.p.) on the MMA-induced striatal creatine and phosphocreatine depletion. Low doses of creatine (1.2 and 3.6 mg/kg) protected against MMA-induced oxidative damage, but did not protect against MMA-induced convulsions. A high dose of creatine (12 mg/kg, i.p.) and MK-801 (3 nmol/striatum) protected against MMA-induced seizures (evidenced by electrographic recording), protein carbonylation and TBARS production ex vivo. Furthermore, acute creatine administration increased the striatal creatine and phosphocreatine content and protected against MMA-induced creatine and phosphocreatine depletion. Our results suggest that an increase of the striatal high-energy phosphates elicited by creatine protects not only against MMA-induced convulsions, but also against MMA-induced oxidative damage. Therefore, since NMDA antagonists are limited value in the clinics, the present results indicate that creatine may be useful as an adjuvant therapy for methylmalonic acidemic patients.

Asunto(s)

Creatina/farmacología , Malonatos/antagonistas & inhibidores , Malonatos/toxicidad , Estrés Oxidativo/fisiología , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Animales , Conducta Animal/efectos de los fármacos , Creatina/administración & dosificación , Creatina/metabolismo , Maleato de Dizocilpina/farmacología , Electrodos Implantados , Electroencefalografía/efectos de los fármacos , Masculino , Malonatos/administración & dosificación , Microinyecciones , Neostriado , Proteínas del Tejido Nervioso/metabolismo , Fármacos Neuroprotectores/farmacología , Fosfocreatina/metabolismo , Ratas , Ratas Wistar , Convulsiones/fisiopatología , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo

RESUMEN

Acute intrastriatal administration of methylmalonic acid (MMA) induces convulsions through NMDA receptor-mediated mechanisms and increases production of end products of oxidative damage. Although it has been demonstrated that nitric oxide (NO) production increases with NMDA receptor stimulation and contributes to the oxidative damage observed in several neurodegenerative disorders, the role of NO in MMA-induced convulsions has not been investigated to date. In the present study we investigated the effects of the intrastriatal injection of N(omega)-nitro-L-arginine methyl ester (L-NAME: 10(-4) to 10(0) nmol/0.5 microl) on the convulsions and striatal protein carbonylation induced by the intrastriatal injection of MMA (4.5 micromol/1.5 microl). l-NAME (10(-3) to 10(-1)nmol) protected against MMA-induced convulsions and protein carbonylation ex vivo. These results suggest the involvement of NO in the convulsive behavior and protein carbonylation elicited by MMA.

Asunto(s)

Ácido Metilmalónico/administración & dosificación , Óxido Nítrico/metabolismo , Estrés Oxidativo/fisiología , Convulsiones/inducido químicamente , Animales , Inhibidores Enzimáticos/farmacología , Inyecciones Intraventriculares , Masculino , NG-Nitroarginina Metil Éster/farmacología , Ratas , Ratas Wistar