RESUMEN
OBJECTIVE: There is an urge to identify new molecules which can modulate process of epileptogenesis, since currently available drugs act symptomatically and one-third of the patients remain refractory to the disease. Hence, the present study was conducted to evaluate the effects of Resveratrol (RESV) on epileptogenesis in pentylenetetrazole (PTZ)-induced kindling in mice. METHOD: Swiss albino mice were administered RESV (10, 20 and 40â mg/kg,p.o) in acute study. On the seventh day animals were subjected to various neurological and neurobehavioral tests viz, Increasing Current Electroshock Test (ICES), PTZ-induced seizures, passive avoidance response, and elevated plus maze test. For the development of kindling PTZ was administered in a dose of 25â mg/kg, i.p. on every alternate day and RESV in all the three doses was administered daily. Seizure score was continuously monitored till the development of kindling and cognition tests were performed in the end of the study. The animals were sacrificed and levels of inflammatory biomarkers viz., IL-1ß, interleukin-1 receptor antagonist (IL1-Ra), IL-6, and TNF-α were assessed in the hippocampus and cortex of the kindled animals. RESULTS: RESV in all three doses increased the seizure threshold to hind limb extension in the ICES test. RESV in all the tested doses suppressed the development of kindling and reduced the levels of IL-1ß, IL1-Ra, IL-6, and TNF-α in kindled mice. CONCLUSION: RESV suppressed the development of kindling in mice and decreased the levels of inflammatory biomarkers in their hippocampus. RESV modified brain inflammation during epileptogenesis and found to possess nootropic activity in the kindled mice.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Corteza Cerebral/metabolismo , Suplementos Dietéticos , Hipocampo/metabolismo , Convulsiones/prevención & control , Estilbenos/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Anticonvulsivantes/administración & dosificación , Antioxidantes/administración & dosificación , Antioxidantes/uso terapéutico , Reacción de Prevención/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/inmunología , Convulsivantes/antagonistas & inhibidores , Convulsivantes/toxicidad , Encefalitis/inducido químicamente , Encefalitis/inmunología , Encefalitis/metabolismo , Encefalitis/prevención & control , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Excitación Neurológica/efectos de los fármacos , Excitación Neurológica/inmunología , Excitación Neurológica/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/uso terapéutico , Pentilenotetrazol/antagonistas & inhibidores , Pentilenotetrazol/toxicidad , Distribución Aleatoria , Resveratrol , Convulsiones/inducido químicamente , Convulsiones/inmunología , Convulsiones/metabolismo , Estilbenos/administración & dosificaciónRESUMEN
Inflammation is one of the mechanisms involved in seizure induction. In this study, the effect of minocycline, an anti-inflammatory drug, was investigated on kindling acquisition. Chemical kindling was induced by injection of a subthreshold dose of pentylenetetrazol (PTZ; 37.5 mg/kg) in mice on every other day. Two groups of animals received minocycline (25 mg/kg) at 1 h before or 1 h after PTZ injection. Following the last PTZ injection, the changes in gene expression of TNF-α receptor, γ2 subunit of GABAA receptor and NR2A subunit of NMDA receptor were assessed in the hippocampus and piriform cortex. Injection of minocycline before PTZ increased the latency to stage 4 seizure, and decreased the duration of stages 4 and 5 seizure. It also prevented the increase in the mRNA of NR2A subunit of NMDA receptor in the hippocampus and removed the PTZ-induced increase in mRNA of γ2 subunit of GABAA receptor in piriform cortex of PTZ kindled mice. Minocycline also prevented the increase in TNF-α receptor gene expression in both hippocampus and piriform cortex. Injection of minocycline after PTZ had no significant effect on measured parameters. Therefore, it can be concluded that minocycline may exert an anticonvulsant effect through preventing the increase in GABAA and NMDA receptor subunits. These effects are accompanied by a reduction in an important inflammation index, TNF-α receptor.
Asunto(s)
Anticonvulsivantes/farmacología , Hipocampo/efectos de los fármacos , Excitación Neurológica/efectos de los fármacos , Minociclina/farmacología , Corteza Piriforme/efectos de los fármacos , Convulsiones/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Expresión Génica/fisiología , Hipocampo/patología , Hipocampo/fisiopatología , Excitación Neurológica/inmunología , Masculino , Ratones , Pentilenotetrazol , Corteza Piriforme/patología , Corteza Piriforme/fisiopatología , ARN Mensajero/metabolismo , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Convulsiones/inmunología , Convulsiones/patologíaRESUMEN
PURPOSE: Temporal lobe epilepsy is associated with the inflammatory process related to the basic mechanisms that lead to seizure susceptibility and brain damage. Platelet-activating factor (PAF), a potent, short-lived phospholipid mediator of inflammation, participates in physiologic signaling in the brain. However, after seizures, PAF accumulates in the brain and activates intracellular signaling related with inflammation-mediated excitotoxicity and hippocampal hyperexcitability. The objective of this study is to evaluate the effect of PAF antagonism on hippocampal hyperexcitability, seizure susceptibility, and neuroprotection using the kindling paradigm and pilocarpine-induced seizure damage models. METHODS: The PAF antagonist, LAU-0901 (60 mg/kg, i.p.), or vehicle, was administrated each day of kindling or daily during the 4 weeks after status epilepticus (SE). We analyzed seizure severity, electrical activity, cellular damage, and inflammation in the hippocampi of both treated groups. KEY FINDINGS: LAU-0901 limits the progression of kindling and attenuates seizure susceptibility 1 week after the kindling procedure. In addition, under the seizure-damage conditions studied here, we observed that LAU-0901 induces hippocampal neuroprotection and limits somatostatin interneuronal cell loss and inflammation. SIGNIFICANCE: Our results indicate that modulation of PAF overactivity attenuates seizure susceptibility, hippocampal hyperexcitability, and neuroinflammation.
Asunto(s)
Citocinas/metabolismo , Dihidropiridinas/farmacología , Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal/inmunología , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Excitación Neurológica/efectos de los fármacos , Excitación Neurológica/inmunología , Fármacos Neuroprotectores/farmacología , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Muerte Celular/efectos de los fármacos , Dinoprostona/metabolismo , Epilepsia del Lóbulo Temporal/patología , Hipocampo/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de Activación Plaquetaria/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/inmunología , Células Piramidales/patología , Ratas , Ratas WistarRESUMEN
The aim of the present review is to discuss the evidence supporting the hypothesis that inflammation and neurogenesis play an important role in temporal lobe epilepsy (TLE) and to examine whether possible strategies that involve the pharmacological manipulation of inflammation/neurogenesis can lead to the development of novel approaches for the treatment of epilepsy. Since it is not yet clear whether the neuron-glia response obtained in this pathology is a secondary effect of an aggressive inflammation or if it is somehow related to the cause of the epileptic condition, with the present review we guide the readers through the complex and ambiguous crosstalk between neuroimmunology and epilepsy.
Asunto(s)
Diferenciación Celular/inmunología , Citocinas/inmunología , Epilepsia del Lóbulo Temporal/inmunología , Excitación Neurológica/inmunología , Neuronas/patología , Animales , Quimiocinas/inmunología , Epilepsia del Lóbulo Temporal/patología , Hipocampo/inmunología , Hipocampo/patología , Humanos , Inflamación/inmunología , Interleucina-1/inmunología , Interleucina-6/inmunología , Excitación Neurológica/patología , Neuronas/inmunología , Estado Epiléptico/inmunología , Estado Epiléptico/patología , Células Madre/citología , Células Madre/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
The effects of kindled seizures elicited from sites in the left and right temporal lobes on mitogen-induced proliferation (LPS, Con A, PHA) and induction of representative TH1 (IFN-gamma) and TH2 (IL-10, IL-4) cytokines were determined in activated rat splenocytes. With reference to cell proliferation, the changes depended on the hemispheric side and location of kindling. Kindling of the left side mediated significant increase in cell proliferation by LPS. Left side kindling resulted in decreased cell proliferation by PHA. Although right side kindling showed no change when taken together, further analysis showed that the reduced proliferation by PHA was mediated when the pyriform cortex was kindled with no change from amygdaloid nuclei. Similar hemispheric polarization was observed in the production of IL-10 and IFN-gamma by Con A-stimulated splenocytes in left side kindled rats. Hence, kindled temporal lobe seizures induced changes in specific immune functions. These effects are not only lateralized but are also specific with respect to the particular region kindled. Since epileptic patients have altered immune functions, this report contributes to our understanding of this complex immune-brain cross-talk in epilepsy.
Asunto(s)
Epilepsia del Lóbulo Temporal/inmunología , Lateralidad Funcional/fisiología , Excitación Neurológica/inmunología , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/inmunología , Animales , División Celular/efectos de los fármacos , División Celular/inmunología , Femenino , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Interleucina-4/biosíntesis , Lipopolisacáridos/farmacología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Mitógenos/farmacología , Ratas , Ratas Sprague-Dawley , Bazo/citología , Bazo/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Lóbulo Temporal/citología , Lóbulo Temporal/inmunologíaRESUMEN
A somatostatin-specific antibody (Ab) (1:250) was continuously infused into the stimulated dorsal hippocampus of rats from 4 days before to 26 days after the beginning of kindling or until the first stage 5. Controls received boiled Ab. The number of stimulations to the first stage 5 were reduced by 41 +/- 4% (P < 0.01, Student's t-test) in animals infused with the Ab compared to controls. The cumulative after-discharge in the stimulated hippocampus was slightly, although not significantly, reduced. Kindling was not affected when the Ab was infused only during the first 10 stimulations (stage 2). Histological analysis showed no neurotoxic effects in the hippocampus as a consequence of Ab infusion.