Vascular changes in epilepsy: functional consequences and association with network plasticity in pilocarpine-induced experimental epilepsy.
Angiogenesis and blood-brain-barrier (BBB) damage have been proposed to contribute to epileptogenesis and/or ictogenesis in experimental and human epilepsy. We tested a hypothesis that after brain injury angiogenesis occurs in the most damaged hippocampal areas with the highest need of tissue repair, and associates with formation of epileptogenic neuronal networks. We induced status epilepticus (SE) with pilocarpine in adult rats, and investigated endothelial cell proliferation (BrdU and rat endothelial cell antigen-1 (RECA-1) double-labeling), vessel length (unbiased stereology), thrombocyte aggregation (thrombocyte immunostaining), neurodegeneration (Nissl staining), neurogenesis (doublecortin (DCX) immunohistochemistry), and mossy fiber sprouting (Timm staining) in the hippocampus at different time points post-SE. As functional measures we determined BBB leakage (quantified immunoglobulin G (IgG) immunostaining), and hippocampal blood volume (CBV) and flow (CBF) in vivo (magnetic resonance imaging, MRI). The total length of hippocampal blood vessels was decreased by 17% at 2 d after status epilepticus (SE) induced by pilocarpine in adult rats (P<0.05 as compared to controls) which was not accompanied by alterations in hippocampal blood volume (BV) and flow (BF). Number of proliferating endothelial cells peaked at 4 d post-SE and correlated with an increase in vessel length (r=0.900, P<0.05). Vessels length had recovered to control level or even higher at 2 wk post-SE, angiogenesis being most prominent in the CA3 (128% as compared to that in controls, P<0.05), and was associated with increased BV (178% as compared to that in controls, P<0.05). Enlargement of vessel diameter in the hippocampal fissure was associated with thrombocyte aggregation in distal capillaries. BBB was most leaky during the first 4 d post-SE and increased IgG extravasation was observed for 60 d. Our data show that magnitude of endothelial cell proliferation is not associated with severity of acute post-SE neurodegeneration or formation of abnormal neuronal network. This encourages identification of molecular targets that initiate and maintain specific aspects of tissue reorganization, including preservation and proliferation of endothelial cells to reduce the risk of epileptogenesis and enhance recovery after brain injury.
Ndode-Ekane
X E
XE
Epilepsy Research Laboratory, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland.
Hayward
N
N
Gröhn
O
O
Pitkänen
A
A
D000818:Animals; D000941:Antigens / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000473:pathology / Q000503:physiopathology; D002196:Capillaries / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D006624:Hippocampus / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009415:Nerve Net / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D055495:Neurogenesis / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology
D000941:Antigens; D003292:Convulsants; C000714328:DCX protein, human; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D007074:Immunoglobulin G; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D010862:Pilocarpine