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 DJNKI1, a competitive JNK inhibitor, represents a potent neuroprotective agent. To analyze the role of JNK and the effects of DJNKI1 administration on excitotoxic neuronal death we induced epileptic seizures on adult male Sprague-Dawley rats by i.p. injection of KA (15 mg/kg) with or without DJNKI1 i.p. administration, 2h after KA treatment. KA caused massive cell death in the hippocampus, which could be quantified in Cresyl violet stained sections. In fact, stereological counts showed a significant decrease in neuronal density in all CA fields, but not in the dentate gyrus, both at one and five days after seizures, which was partially prevented by DJNKI1 treatment. We excluded that this effect might be due to an artefact secondary to prevention of brain oedema by D-JNKI1 administration, since estimation of hippocampal volume by the Neurolucida Software showed no differences among the experimental groups. Evaluation of neuronal degeneration showed that DJNKI1 treatment prevented the appearance of Fluoro-Jade B positive-profiles in all CA fields. Seizure activity also induced marked gliosis as observed with GFAP immunohistochemistry. The peptide reduced the size of damaged area in the entorhinal cortex. We also analyzed c-Jun activation as target of JNK and central trascriptional effector in the adult rat brain following KA injection. Phospho-c-Jun immunoreactivity was absent in the limbic system of untreated animals, whereas a strong nuclear neuronal labeling could be observed starting from 3h after KA. DJNKI1 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.
Neuroprotection by DJNKI1 following seizure activity.
VERONESI, Carlo;
2008
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 DJNKI1, a competitive JNK inhibitor, represents a potent neuroprotective agent. To analyze the role of JNK and the effects of DJNKI1 administration on excitotoxic neuronal death we induced epileptic seizures on adult male Sprague-Dawley rats by i.p. injection of KA (15 mg/kg) with or without DJNKI1 i.p. administration, 2h after KA treatment. KA caused massive cell death in the hippocampus, which could be quantified in Cresyl violet stained sections. In fact, stereological counts showed a significant decrease in neuronal density in all CA fields, but not in the dentate gyrus, both at one and five days after seizures, which was partially prevented by DJNKI1 treatment. We excluded that this effect might be due to an artefact secondary to prevention of brain oedema by D-JNKI1 administration, since estimation of hippocampal volume by the Neurolucida Software showed no differences among the experimental groups. Evaluation of neuronal degeneration showed that DJNKI1 treatment prevented the appearance of Fluoro-Jade B positive-profiles in all CA fields. Seizure activity also induced marked gliosis as observed with GFAP immunohistochemistry. The peptide reduced the size of damaged area in the entorhinal cortex. We also analyzed c-Jun activation as target of JNK and central trascriptional effector in the adult rat brain following KA injection. Phospho-c-Jun immunoreactivity was absent in the limbic system of untreated animals, whereas a strong nuclear neuronal labeling could be observed starting from 3h after KA. DJNKI1 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.
