Biomedicine Select

This Biomedicine Select explores a cluster of recent papers that highlight traditional and new approaches to treating a variety of diseases—from a small-molecule inhibitor to treat temporal lobe epilepsy to cell replacement therapy for diabetes to a unique way to generate tumor-specific antigens. Epilepsy affects more than 50 million people worldwide and about 40% of those with the disease continue to have seizures despite treatment with antiepileptic medications or surgery. Some of these individuals are able to reduce the number of seizures by adopting a ketogenic diet (in which no carbohydrates are consumed, only fats and proteins), suggesting that the glycolytic pathway may somehow be involved in epilepsy. Using a rat (''kindling'') model of severe temporal lobe epilepsy, Garriga-Canut and colleagues (2006) investigate the link between glycolysis and epilepsy using 2-deoxy-D-glucose (2DG), a synthetic glucose analog that blocks glycolysis. Treatment of the ''kindling'' rats with 2DG increased the threshold for seizures induced by electrical stimuli and reduced the severity of subsequent seizures. 2DG treatment also resulted in decreased expression of genes encoding the neurotrophin BDNF and its receptor TrkB, which are usually upregulated during seizures. This downregulation is mediated by the transcription factor NRSF (neural-restrictive silencing factor), which recruits the corepressor CtBP in an NADH-labile manner resulting in histone modifications that repress transcription. The authors propose that a 2DG-mediated decrease in glycolysis may reduce NADH levels such that interactions between NRSF and CtBP are strengthened leading to enhanced repression of BDNF signaling. 2DG is known to be well tolerated in humans having been tested in clinical trials for other purposes. Although it is early days therapeutically speaking, the authors propose that 2DG could be the founding member of a new class of antiepileptic drug whose therapeutic effect is mediated by targeting energy metabolism. Focusing on a much rarer form of epilepsy, MERFF (myoclonic epilepsy with ragged red fibers), Mahata et al. (2006) turn to the protozoan parasite Leishmania to circumvent a mitochondrial mutation that causes this disorder. The mu-tation—an A to G nucleotide switch at position 8344—in a mitochondrially encoded transfer RNA (tRNA Lys) leads to reduced translation of mitochondrial mRNAs and accumulation of aberrant translation products, resulting in disease pathology. Leishmania has evolved a specialized RNA import protein complex (RIC) in its mitochondrial inner membrane that imports nuclear-encoded tRNAs into the parasite mitochondria. In their new work, Mahata and colleagues use cultured cybrids (enucleated cells from MERFF patients fused …