Abstracts

SELECTIVE VEGF INHIBITION USING PTK787 DECREASES SPONTANEOUS SEIZURE EXPRESSION IN THE EPILEPTIC RAT BRAIN

Abstract number : 3.361
Submission category : 13. Neuropathology of Epilepsy
Year : 2009
Submission ID : 10440
Source : www.aesnet.org
Presentation date : 12/4/2009 12:00:00 AM
Published date : Aug 26, 2009, 08:12 AM

Authors :
Kenneth Jenrow, C. Liccardello, K. Lapanowski, D. Evans and K. Elisevich

Rationale: Ongoing investigations in our laboratory have implicated vascular pathologies and the abnormal leakage of plasma proteins (and/or other solutes) across the blood-brain barrier (BBB) in the development and maintenance of epileptic foci in the spontaneously epileptic rat brain. We previously reported that expression of vascular endothelial growth factor (VEGF) remains chronically upregulated among reactive astrocytes in the kainic acid model of spontaneous epilepsy, coinciding with pathological microvessels within limbic and paralimbic structures. The persistence of pathological microvessels in other contexts has been shown to be selectively dependent upon elevated VEGF expression. We hypothesized that pathological microvessels in the spontaneously epileptic rat brain might be similarly VEGF-dependent, and that depriving them of VEGF might result in their selective deterioration. To test this hypothesis, we administered a selective small molecule inhibitor of VEGF tyrosine kinases, PTK787 (Novartis), and measured the effects of this compound on seizure expression, vascular pathology, and vascular permeability. Methods: Status epilepticus (SE) was induced in male wistar rats (250g - 350 g) by systemic kainic acid injection (10 mg/kg, i.v.), and was terminated four hours after its onset by injection of pentobarbital (25 mg/kg, i.p.). Spontaneous behavioral seizures were monitored in these rats for 6 months (8 hours/day, 5 days/week) prior to initiating therapy with PTK787, and subsequently during two months of PTK787 administration. PTK787 (20 mg/ml, PEG, 100 mg/kg) was administered BID, 7 days/week, by oral injection , whereas vehicle control epileptic rats received PEG injections according to the same schedule. Rats were sacrificed upon completion therapy and their brain tissues were harvested and immunohistochemically stained for vonWillebrand factor (vWF), albumin, glial fibrillary acidic protein (GFAP), and VEGF. Results: PTK787 administration produced a significant decrease in the frequency of spontaneous seizures relative to established baselines for spontaneous seizure frequency, and relative to vehicle control epileptic rats. Seizure severity was not affected by PTK787 therapy. Analysis of immunohistochemical staining revealed a degradation of pathological microvessels, accompanied by enhanced tissue loss in parahippocampal structures, in rats receiving PTK787 relative to vehicle control epileptic rats. Reactive astrocytes expressing GFAP and/or VEGF were not noticeably affected by PTK787 therapy. Conclusions: Our results generally confirm that persistent abnormal leakage of plasma proteins (and/or other solutes) across the BBB promotes spontaneous seizures in the chronically epileptic rat brain. The success of our PTK787 dose regimen at reducing pathological microvessels and spontaneous seizures suggests that aggressive anti-VEGF therapy may have caused an effective microresection within the putative epileptic foci. This therapeutic approach may be clinically useful for treating patients with established epileptic foci with associated with vascular pathologies.
Neuropathology of Epilepsy