Continuous neurodegeneration and death pathway activation in neurons and glia in an experimental model of severe chronic epilepsy.
Whether seizures might determine the activation of cell death pathways and what could be the relevance of seizure-induced cell death in epilepsy are still highly debated issues. We recently developed an experimental model of acquired focal cortical dysplasia (the MAM-pilocarpine or MP rat) in which the occurrence of status epilepticus--SE--and subsequent seizures induced progressive cellular/molecular abnormalities and neocortical/hippocampal atrophy. Here, we exploited the same model to verify when, where, and how cell death occurred in neurons and glia during epilepsy course. We analyzed Fluoro Jade (FJ) staining and the activation of c-Jun- and caspase-3-dependent pathways during epilepsy, from few hours post-SE up to six months of spontaneous recurrent seizures. FJ staining revealed that cell injury in MP rats was not temporally restricted to SE, but extended throughout the different epileptic stages. The region-specific pattern of FJ staining changed during epilepsy, and FJ(+) neurons became more prominent in the dorsal and ventral hippocampal CA at chronic epilepsy stages. Phospho-c-Jun- and caspase-3-dependent pathways were selectively activated respectively in neurons and glia, at early but even more conspicuously at late chronic stages. Phospho-c-Jun activation was associated with increased cytochrome-c staining, particularly at chronic stages, and the staining pattern of cytochrome-c was suggestive of its release from the mitochondria. Taken together, these data support the content that at least in the MP rat model the recurrence of seizures can also sustain cell death mechanisms, thus continuously contributing to the pathologic process triggered by the occurrence of SE.
Molecular Neuroanatomy and Pathogenesis Unit, IRCCS Foundation Neurological Institute "Carlo Besta", Via Temolo 4, 20126 Milan, Italy.
Paola
P
Nobili
Molecular Neuroanatomy and Pathogenesis Unit, IRCCS Foundation Neurological Institute "Carlo Besta", Via Temolo 4, 20126 Milan, Italy.
Francesca
F
Colciaghi
Molecular Neuroanatomy and Pathogenesis Unit, IRCCS Foundation Neurological Institute "Carlo Besta", Via Temolo 4, 20126 Milan, Italy.
Adele
A
Finardi
Molecular Neuroanatomy and Pathogenesis Unit, IRCCS Foundation Neurological Institute "Carlo Besta", Via Temolo 4, 20126 Milan, Italy.
Sara
S
Zambon
Molecular Neuroanatomy and Pathogenesis Unit, IRCCS Foundation Neurological Institute "Carlo Besta", Via Temolo 4, 20126 Milan, Italy.
Denise
D
Locatelli
Molecular Neuroanatomy and Pathogenesis Unit, IRCCS Foundation Neurological Institute "Carlo Besta", Via Temolo 4, 20126 Milan, Italy. Electronic address: giorgio.battaglia@istituto-besta.it.
Giorgio Stefano
GS
Battaglia
D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D054220:Malformations of Cortical Development / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013226:Status Epilepticus / Q000378:metabolism* / Q000473:pathology*
D016755:Proto-Oncogene Proteins c-jun; C505410:Casp3 protein, rat; D053148:Caspase 3
Acquired focal cortical dysplasia; Caspase-3; Cell injury; Cytochrome-c; Fluoro Jade; Phospho-c-Jun; Seizures; Status epilepticus