Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy

Abstract

To identify the upstream signals of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy (TLE), we evaluated by immunohistochemistry and confocal microscopy brain tissues of 13 TLE patients and 5 control patients regarding expression of chemokines and cell-cycle proteins. The chemokine RANTES (CCR5) and other CC-chemokines and apoptotic markers (caspase-3, -8, -9) were expressed in lateral temporal cortical and hippocampal neurons of TLE patients, but not in neurons of control cases. The chemokine RANTES is usually found in cytoplasmic and extracellular locations. However, in TLE neurons, RANTES was displayed in an unusual location, the neuronal nuclei. In addition, the cell-cycle regulatory transcription factor E2F1 was found in an abnormal location in neuronal cytoplasm. The pro-inflammatory enzyme cyclooxygenase-2 and cytokine interleukin-1β were expressed both in neurons of patients suffering from temporal lobe epilepsy and from cerebral trauma. The vessels showed fibrin leakage, perivascular macrophages and expression of IL-6 on endothelial cells. In conclusion, the cytoplasmic effects of E2F1 and nuclear effects of RANTES might have novel roles in neuronal apoptosis of TLE neurons and indicate a need to develop new medical and/or surgical neuroprotective strategies against apoptotic signaling by these molecules. Both RANTES and E2F1 signaling are upstream from caspase activation, thus the antagonists of RANTES and/or E2F1 blockade might be neuroprotective for patients with medically intractable temporal lobe epilepsy. The results have implications for the development of new medical and surgical therapies based on inhibition of chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy.

Acute Encephalitis Syndrome in Adults and Its Correlation with Cytokine Levels in the Serum and Cerebrospinal Fluid

“…Fiala et al evaluated RANTES expression in temporal lobe epilepsies (TLE). They found RANTES to be unusually expressed in TLE neurons, and this abnormal expression was responsible for seizures (26). Whether similar expression occurs in symptomatic seizures in AES needs further elaboration.…”

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

“…37 This suggests that this event is not specific only to the neuronal populations intrinsically vulnerable to heritableor aging-related neurodegenerative disorders, but may be a direct result of excitotoxicity in neurons. Indeed, we show that administration of KA in vivo leads to incorporation of BrdU in the principal neurons of the hippocampal CA fields and is associated with nuclear localization of Notch1.…”

Cortical gene expression correlates of temporal lobe epileptogenicity

“…An increase in HS3ST3A1 is associated with an increase in the placental chemokine co-receptor 5 gene (CCR5) which is observed with an increase in maternal HIV viral load [73]. As previously noted, temporal lobe epilepsy apoptotic markers, caspase-3, −8, −9, and the upstream caspase signal chemokine, RANTES (CCR5), are expressed in lateral temporal cortical and hippocampal neurons [37].…”

“…The study suggests that down regulation of a cohort of microglial genes could contribute to decreased chemotactic and anti-inflammatory capability of the cells of the central nervous system and could act in concert with other up-regulated genes to amplify inflammation-mediated neuronal damage [36]. TLE is known to be an inflammatory disease involving several of the same chemotactic and mitogenic stimuli associated with microglial activation in other neurodegenerative diseases [36,37]. Failure to down-regulate microglial activation and proliferation contributes to chronic neuronal hyper-excitability through chronic inflammatory pathways [38].…”

“…Neuronal apoptosis has also been detected in medically intractable human temporal lobe epilepsy (TLE). TLE apoptotic markers, caspase-3, −8, −9, and the upstream caspase signal chemokine, RANTES (CCR5), are expressed in lateral temporal cortical and hippocampal neurons [37].…”