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. 2013 Feb;20(1):59-69.
doi: 10.1016/j.pathophys.2012.02.003. Epub 2012 Mar 22.

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

Affiliations

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

Milan Fiala et al. Pathophysiology. 2013 Feb.

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.

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Conflict of interest statement

The authors report no financial interest in any product or service mentioned in this article.

Figures

Figure 1
Figure 1. Expression of CC and CXC chemokines and chemokine receptors in MIE (medically intractable temporal lobe epilepsy) and trauma
Immunohistochemistry or confocal microscopy of temporal lobe (TL) and hippocampus (H) using the following antibodies: (A) RANTES (TL, 40X); (B) RANTES/NeuN (TL, 100x); (C) RANTES green /DAPI (TL, confocal microscopy 100x) (D) RANTES/GFAP (H, 40x); (E) MIP -1 β (40x); (F) MIP-1α(40x); (G) RANTES (Trauma cortex, 20x); (H) SDF-1(H,40x); (I) CCR5 (20x); (J) CCR1 (40x); (K) CXCR4 (40x); (L) CCR5 (Trauma cortex, 40x). Note RANTES expression in neuronal nuclei (A-D) but cytoplasmic expression of MIP-1α and MIP-1β extending into the neuropil (E, F).
Figure 2
Figure 2. Expression of COX-2 and cytokines in MIE (medically intractable temporal lobe epilepsy) and trauma
Immunohistochemistry of temporal lobe (TL) and hippocampus (H) using the following antibodies: (A) COX-2 (Case 2,TL, 40x); (B) COX-2 (Case 7,TL, 40x/100x); (C) COX-2 (cortex, trauma case, 20x); (D) IL-6 (40x); (E) IL-1β/COX 2 (40x); (F) IL-1β (40x/100x); (G) IL-1β/GFAP (H, 40x); (H) IL-1β (cortex, tumor case, 40x).
Figure 3
Figure 3. Expression of apoptotic markers and cell cycle proteins in MIE (medically intractable temporal lobe epilepsy) and trauma
TUNEL reaction or immunohistochemistry of temporal lobe (TL) and hippocampus (H) using the following antibodies (A) TUNEL (TL, 40x); (B) Caspase 3 (AR-55) (TL,40x) (C) TL Caspase 9 (AR-57) (40x); (D) Caspase 8 (AR-17) (TL, 40x); (E) E2F-1 (TL, 100x); (F) E2F-1 (H,100x); (G) E2F-1 (Trauma cortex, 10x); (H) P-Rb (H, 20x).
Figure 4
Figure 4. CD 68 and fibrinogen expression in MIE (medically intractable temporal lobe epilepsy) and trauma
Perivascular infiltration and blood brain barrier leakage were demonstrated by immunohistochemical staining of the temporal lobe and hippocampus using anti-CD 68 in TL (A, 40X) and H (B, 40X) of MIE, TL of trauma (C,40X), as well as fibrinogen staining in TL (D, 20x).

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