Systemic injections of kainic acid (KA) cause epileptic seizures with delayed neuronal damage in the limbic system, particularly in the hippocampus. KA excitotoxicity activates complex signal transduction events that trigger apoptotic cell death. The c-Jun N-terminal kinase (JNK) pathway plays an important role in cell death, and the peptide D-JNKI1, a competitive JNK inhibitor, is a potent neuroprotective agent. To analyse the role of JNK and the effects of D-JNKI1 administration on excitotoxic neuronal death, we induced epileptic seizures by intraperitoneal (i.p.) injection of KA in adult male Sprague-Dawley rats; a group of rats received i.p. D-JNKI1 2 h after KA. KA caused massive cell death in the hippocampus: in Nissl-stained sections, stereological counts showed a significant decrease in neuronal density in all CA fields, both at 1 and 5 days after seizures, which was partially prevented by D-JNKI1 treatment. These results were confirmed by counts of degenerating neurons in CA3 in FluoroJade B-stained sections. Seizure activity also induced marked gliosis as observed with glial fibrillary acidic protein (GFAP) immunohistochemistry. We also analysed c-Jun activation as a target of JNK and central transcriptional effector in the adult rat brain following KA injection. Phospho-c-Jun immunoreactivity was absent in the hippocampus of untreated animals, whereas strong nuclear neuronal labeling could be observed, starting from 3 h after KA administration, in microtubule-associated protein-2-positive neurons but not in GFAP-positive astrocytes. D-JNKI1 treatment also reduced the positivity for phospho-c-Jun in the hippocampus, thus confirming the specificity of the peptide in blocking JNK. Therefore, JNK is a promising target for blocking seizure-induced cell death.
c-Jun N-terminal kinase signaling pathway in excitotoxic cell death following kainic acid-induced status epilepticus
VERONESI, Carlo;
2010
Abstract
Systemic injections of kainic acid (KA) cause epileptic seizures with delayed neuronal damage in the limbic system, particularly in the hippocampus. KA excitotoxicity activates complex signal transduction events that trigger apoptotic cell death. The c-Jun N-terminal kinase (JNK) pathway plays an important role in cell death, and the peptide D-JNKI1, a competitive JNK inhibitor, is a potent neuroprotective agent. To analyse the role of JNK and the effects of D-JNKI1 administration on excitotoxic neuronal death, we induced epileptic seizures by intraperitoneal (i.p.) injection of KA in adult male Sprague-Dawley rats; a group of rats received i.p. D-JNKI1 2 h after KA. KA caused massive cell death in the hippocampus: in Nissl-stained sections, stereological counts showed a significant decrease in neuronal density in all CA fields, both at 1 and 5 days after seizures, which was partially prevented by D-JNKI1 treatment. These results were confirmed by counts of degenerating neurons in CA3 in FluoroJade B-stained sections. Seizure activity also induced marked gliosis as observed with glial fibrillary acidic protein (GFAP) immunohistochemistry. We also analysed c-Jun activation as a target of JNK and central transcriptional effector in the adult rat brain following KA injection. Phospho-c-Jun immunoreactivity was absent in the hippocampus of untreated animals, whereas strong nuclear neuronal labeling could be observed, starting from 3 h after KA administration, in microtubule-associated protein-2-positive neurons but not in GFAP-positive astrocytes. D-JNKI1 treatment also reduced the positivity for phospho-c-Jun in the hippocampus, thus confirming the specificity of the peptide in blocking JNK. Therefore, JNK is a promising target for blocking seizure-induced cell death.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
