2DG (2-deoxy-D-glucose) is a chemical analogue of sugar, which is currently in preclinical development as a novel anticonvulsant and antiepileptic compound for treatment of epilepsy. 2DG differs from normal glucose only by removal of a single oxygen atom. As a close chemical analogue of sugar, 2DG is taken up into cells by normal glucose transport mechanisms, but unlike normal sugar it cannot undergo metabolism and acts as an inhibitor of glucose metabolism (glycolysis).
Studies at the University of Wisconsin have revealed that 2DG has novel acute and chronic anticonvulsant properties that are unlike any drugs currently available for treatment of epilepsy. 2DG acutely suppresses epileptic discharges in multiple experimental models of epilepsy, and has seizure-suppressing effects in a unique spectrum of animal models of epilepsy compared to currently marketed drugs. In addition to suppressing seizures, 2DG prevents the progression of the effects of seizures, which can include susceptibility to additional seizures, memory loss, and cognitive dysfunction. At the present time there are no anticonvulsant drugs on the market with disease-modifying properties that can favorably alter the consequences and prognosis for patients with epilepsy.
Conventional anticonvulsant medications exert their therapeutic actions primarily by reducing the excitability of ion channels and synapses of neurons in the brain that can prevent or suppress seizures. In patients who fail to respond to conventional anticonvulsants, the ketogenic diet (replacement of carbohydrates with fats and proteins) sometimes produces improvement. The discovery of the therapeutic effects of 2DG was a result of efforts to investigate whether restriction of sugar and carbohydrate in this diet contributed to its actions. By blocking glycolytic metabolism of sugar, 2DG suppresses excitability in the brain leading to seizures, and also favorably modifies expression of neural genes in the brain contributing to the adverse consequences of seizures and long-term dysfunction associated with epilepsy. Because regions of the brain producing seizures have increased needs for energy and metabolic demand for sugar, 2DG preferentially accumulates in these regions during seizures. The trapping of 2DG after uptake into cells has allowed it to be used safely for decades as a metabolic tracer for glucose utilization in human PET imaging and scanning. Preliminary toxicity studies in animals also demonstrate that 2DG is well tolerated at doses that have therapeutic effects against seizures and TBI.
Work on the therapeutic effects of 2DG in TBI is being conducted at the University of Wisconsin by NGX Founder Dr. Thomas Sutula with support of the Department of Defense. This work in rodents has demonstrated that brief treatment with 2DG (~2 weeks) at the time of injury reduces the progression of structural brain damage as long as six months after TBI. A patent application has been filed by the Wisconsin Alumni Research Foundation (WARF) with the US Patent and Trade Office for use of 2DG as a neuroprotective agent in head trauma. Additional work is underway to determine if 2DG at the time of injury can prevent long-term adverse consequence of head injury.