RESUMO
Epilepsy is known to cause alterations in neural networks. However, many details of these changes remain poorly understood. The objective of this study was to investigate changes in the properties of hippocampal CA1 pyramidal neurons and their synaptic inputs in a rat lithium-pilocarpine model of epilepsy. In the chronic phase of the model, we found a marked loss of pyramidal neurons in the CA1 area. However, the membrane properties of the neurons remained essentially unaltered. The results of the electrophysiological and morphological studies indicate that the direct pathway from the entorhinal cortex to CA1 neurons is reinforced in epileptic animals, whereas the inputs to them from CA3 are either unaltered or even diminished. In particular, the dendritic spine density in the str. lacunosum moleculare, where the direct pathway from the entorhinal cortex terminates, was found to be 2.5 times higher in epileptic rats than in control rats. Furthermore, the summation of responses upon stimulation of the temporoammonic pathway was enhanced by approximately twofold in epileptic rats. This enhancement is believed to be a significant contributing factor to the heightened epileptic activity observed in the entorhinal cortex of epileptic rats using an ex vivo 4-aminopyridine model.
Assuntos
Região CA1 Hipocampal , Modelos Animais de Doenças , Epilepsia , Lítio , Pilocarpina , Células Piramidais , Animais , Células Piramidais/patologia , Células Piramidais/metabolismo , Ratos , Epilepsia/induzido quimicamente , Epilepsia/patologia , Epilepsia/fisiopatologia , Masculino , Região CA1 Hipocampal/patologia , Lítio/toxicidade , Lítio/farmacologia , Córtex Entorrinal/patologia , Ratos WistarRESUMO
Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.
Assuntos
Epilepsia do Lobo Temporal , Ratos , Animais , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/patologia , Pilocarpina/efeitos adversos , Lamotrigina/efeitos adversos , Lítio/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Anticonvulsivantes/efeitos adversos , Convulsões/tratamento farmacológico , Hipocampo , Modelos Animais de DoençasRESUMO
Status epilepticus (SE) triggers many not yet fully understood pathological changes in the nervous system that can lead to the development of epilepsy. In this work, we studied the effects of SE on the properties of excitatory glutamatergic transmission in the hippocampus in the lithium-pilocarpine model of temporal lobe epilepsy in rats. The studies were performed 1 day (acute phase), 3 and 7 days (latent phase), and 30 to 80 days (chronic phase) after SE. According to RT-qPCR data, expression of the genes coding for the AMPA receptor subunits GluA1 and GluA2 was downregulated in the latent phase, which may lead to the increased proportion of calcium-permeable AMPA receptors that play an essential role in the pathogenesis of many CNS diseases. The efficiency of excitatory synaptic neurotransmission in acute brain slices was decreased in all phases of the model, as determined by recording field responses in the CA1 region of the hippocampus in response to the stimulation of Schaffer collaterals by electric current of different strengths. However, the frequency of spontaneous excitatory postsynaptic potentials increased in the chronic phase, indicating an increased background activity of the glutamatergic system in epilepsy. This was also evidenced by a decrease in the threshold current causing hindlimb extension in the maximal electroshock seizure threshold test in rats with temporal lobe epilepsy compared to the control animals. The results suggest a series of functional changes in the properties of glutamatergic system associated with the epilepsy development and can be used to develop the antiepileptogenic therapy.
Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Estado Epiléptico , Ratos , Animais , Pilocarpina/toxicidade , Pilocarpina/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Lítio/farmacologia , Lítio/metabolismo , Hipocampo/metabolismo , Epilepsia/metabolismo , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Modelos Animais de DoençasRESUMO
Status epilepticus (SE) causes persistent abnormalities in the functioning of neuronal networks, often resulting in worsening epileptic seizures. Many details of cellular and molecular mechanisms of seizure-induced changes are still unknown. The lithium-pilocarpine model of epilepsy in rats reproduces many features of human temporal lobe epilepsy. In this work, using the lithium-pilocarpine model in three-week-old rats, we examined the morphological and electrophysiological changes in the hippocampus within a week following pilocarpine-induced seizures. We found that almost a third of the neurons in the hippocampus and dentate gyrus died on the first day, but this was not accompanied by impaired synaptic plasticity at that time. A diminished long-term potentiation (LTP) was observed following three days, and the negative effect of SE on plasticity increased one week later, being accompanied by astrogliosis. The attenuation of LTP was caused by the weakening of N-methyl-D-aspartate receptor (NMDAR)-dependent signaling. NMDAR-current was more than two-fold weaker during high-frequency stimulation in the post-SE rats than in the control group. Application of glial transmitter D-serine, a coagonist of NMDARs, allows the enhancement of the NMDAR-dependent current and the restoration of LTP. These results suggest that the disorder of neuron-astrocyte interactions plays a critical role in the impairment of synaptic plasticity.