Abstracts

Rationale: 2-Deoxy-D-glucose (2DG), an inhibitor of glycolysis, exerts anticonvulsant and antiepileptic actions in experimental epilepsy models. The novel mechanism of action against seizure progression and plasticity is related to the ability of 2DG to reduce BDNF (brain derived neurotrophic factor) and its receptor trkB by transcriptional regulation involving NRSF (neuron-restrictive silencing factor), its metabolic sensor CtBP (C-terminal binding protein) and chromatin modification (Nat Neurosci 9:1382-7, 2006). To determine if 2DG at clinically effective doses has adverse effects on behavior and cognition, we tested adult rats in the Morris water maze (MWM, a measure of hippocampus-dependent spatial learning and memory) and the open field (OF, a measure of exploratory behavior and anxiety).Methods: MWM: Adult male Sprague-Dawley rats were divided into a control group and two experimental groups. For 14 consecutive days, control rats (n=6) received saline i.p and the experimental groups received 2DG 250 or 1000 mg/kg i.p. (n=8 each) twice daily. Rats were then tested in the MWM using standard procedures. After one day of habituation to the test apparatus, rats underwent 4 days of acquisition training with 4 trials per day using the hidden platform version, followed by a one day probe trial with the platform removed. OF: Using a crossover design, rats received either saline or 2DG (250 mg/kg i.p.) 30 min prior to testing in the OF (3 trials per day separated by 8 min, over 4 consecutive days). Exploratory activity was assessed by the number of squares traversed in an open field consisting of 64 squares (each 23 x 23 cm). After a 3 day washout, the saline-treated rats were given 2DG (250 mg/kg) and rats initially treated with 2DG received saline for 4 consecutive days according the same protocol. Results: MWM: All groups learned the location of the hidden platform (acquisition learning) during the 4 days of testing as indicated by shorter latencies to platform on day 4 than day 1 (p<0.001). There were no significant differences in the effect of treatment (controls vs 2DG-treated groups) on escape latency (p=0.24) or any treatment x day effect (p=0.074), but time to escape onto the platform was longer on day 1 in 2DG-treated rats compared to controls (p<0.05). There were no differences in memory for the platform location as assessed by a probe trial between controls and 2DG-treated groups on 2 separate measures: percent time spent swimming in the previous platform quadrant (p=0.081) or crossings over prior platform position (p=0.56). OF: The crossover design trial revealed that rats receiving 2DG at a dose of 250 mg/kg had a ~2-fold reduction in open field activity compared to periods of saline treatment (p< 0.001). Conclusions: 2DG, a potential anticonvulsant agent with novel mechanisms of action, did not affect spatial learning and memory in rats, but reversibly reduced open field locomotor activity at a clinically effective dose. Supported by NIH RO1-25020 (TPS) and The Charlie Foundation (CES).