Investigation of hypoxia-inducible factor-1α in hippocampal sclerosis: a postmortem study.
OBJECTIVE
Hypoxia-inducible factor-1α (HIF-1α) is involved in critical aspects of cell survival in response to hypoxia and regulates vascular endothelial growth factor (VEGF) expression. Previous experimental and human studies in epilepsy show up-regulation of VEGF following seizures, although expression of HIF-1α as its potential regulator has not been explored. We used a postmortem (PM) series from patients with epilepsy and hippocampal sclerosis (HS) to investigate patterns of expression of HIF-1α and VEGF and their potential contribution to neuroprotection.


METHODS
In 33 PMs (17 cases with unilateral HS, 3 with bilateral HS, 3 with No-HS, and 10 controls), we quantified neuronal immunolabeling for HIF-1α and VEGF in hippocampal subfields.


RESULTS
HIF-1α- and VEGF-immunopositive hippocampal neurones were observed in HS, No-HS, and also in control cases; there was no significant difference in overall labeling between epilepsy cases and controls. In positive cases, HIF-1α and VEGF neuronal labeling localized primarily in CA1, CA4, and CA3 subfields in all groups; significantly more positive neurons were seen in the entorhinal cortex in epilepsy cases (p < 0.05). Labeling lateralized to the side of sclerosis in unilateral HS cases, with significant differences between hemispheres (p < 0.05). There was a trend for high HIF-1α labeling scores in patients with Dravet syndrome without HS and sudden unexpected death in epilepsy (SUDEP) cases, and lower scores with long seizure-free periods prior to death. Hippocampal HIF-1α and VEGF labeling showed a significant correlation. There was neuronal colocalization of HIF-1α and VEGF.


CONCLUSIONS
Regional expression patterns are in keeping with seizure-related activation of HIF-1α and VEGF. The prominent expression in non-HS cases could support an overall neuroprotective effect. Correlation between HIF-1α and VEGF neuronal immunolabeling supports HIF-1α-mediated induction of VEGF in epilepsy.
Departments of Clinical and Experimental Epilepsy             Neuropathology             Neurology, UCL, Institute of Neurology, Queen Square, London, United Kingdom.
Alexandra
A
Feast
Lillian
L
Martinian
Joan
J
Liu
Claudia B
CB
Catarino
Maria
M
Thom
Sanjay M
SM
Sisodiya
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D004827:Epilepsy / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000737:chemistry / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D012598:Sclerosis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000502:physiology; D055815:Young Adult
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A