Abstracts

Rationale: Understanding the micro-environmental changes characterizing the epileptic brain tissue is essential for development of novel therapeutic tools. Accumulating evidence point at alterations in nutrient balance in epilepsy, but little is known about the changes in the expression of nutrients' uptake carriers. The aim of the current work was to study the effect of chronic epilepsy on cerebral uptake carriers for the key nutrient folate - the reduced folate carrier (RFC) and folate receptor α (FRα), and on folate concentrations in the brain. Methods: Experiments were conducted using the rat lithium-pilocarpine model of temporal lobe epilepsy. Brains were harvested 8-10 weeks after pilocarpine injection, when rats develop spontaneous recurrent seizures (SRS). The expression of FRα and RFC was evaluated through immunofluorescence and quantitative RT-PCR. Folate concentrations in plasma and brain tissue were evaluated using a chemiluminescence-based analytical method. Results: The emission intensity of both RFC and FRα was elevated 8- and 4-fold (P < 0.01, n=5), respectively, in the hippocampal CA1 of rats with SRS compared with naïve controls, with no significant alterations in other brain areas. The expression of both carriers was primarily upregulated in neurons. Seizures did not affect carriers' mRNA levels. The brain folate concentration in SRS rats was preserved, despite significantly reduced plasma folate concentration in the SRS compared to the naïve rats (P < 0.05, n=5-6).  Conclusions: If corroborated by complementary research in humans, the findings of this study may be utilized clinically for supplemental therapy treatment planning, in imaging the epileptic focus, and for drug delivery into the epileptic brain. Further studies are required for better understanding the alterations in folate distribution and metabolism in the epileptic brain and their clinical and mechanistic significance. Funding: This work was supported by a grant from the National Institute for Psychobiology in Israel (AM, SE, DE) and by Prusiner-Abramsky Award in Basic Clinical Neuroscience (DE). We thank Prof. Higazi Abd Al-Roof and Mr. Awad Sror from the Biochemistry Laboratory, Hadassah Medical Center, Jerusalem, Israel, for their assistance in conducting the folate concentration assays.Sara Eyal is affiliated with the David R. Bloom Centre for Pharmacy and Dr. Adolf and Klara Brettler Centre for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel.