Preclinical toxicity studies supporting 2DG for treatment of status epilepticus.

2-deoxy-D-glucose (2DG) has been proposed as a potential antiseizure treatment based on seizure suppressive actions in multiple acute and chronic seizure models, including models of status epilepticus (SE). Here we summarize recently completed preclinical toxicological studies of single doses of an intravenous formulation of 2DG supporting potential safety of 2DG for acute treatment of SE and acute repetitive seizures (ARS).

2-Deoxy-D-glucose administration after seizures has disease-modifying effects on kindling progression.

2-deoxy-D-glucose (2DG) is a glucose analog and reversible inhibitor of glycolysis with anticonvulsant and antiepileptic effects in multiple seizure models. 2DG at a dose of 250 mg/kg intraperitoneally (IP) delays progression of repeated seizures evoked by kindling in rats when administered 30 min prior to twice daily kindling stimulation. As toxicological studies have demonstrated that repeated daily oral administration of 2DG at doses of 60-375 mg/kg/day in rats induces dose-dependent, reversible cardiac myocyte vacuolation, it was of interest to determine if 2DG also slowed kindling progression when administered at or below doses causing cardiac toxicity and at various time points after evoked seizures.

2DG and glycolysis as therapeutic targets for status epilepticus.

2-deoxy-D-glucose (2DG) is a glucose analog differing from glucose only by removal of an oxygen atom at the 2 position, which prevents the isomerization of glucose-6-phosphate to fructose-6-phosphate, and thereby reversibly inhibits glycolysis. PET studies of regional brain glucose utilization positron-emitting 18F-2DG demonstrate that brain regions generating seizures have diminished glucose utilization during interictal conditions, but rapidly transition to markedly increased glucose delivery and utilization during seizures, particularly in status epilepticus (SE). 2-deoxy-D-glucose has acute antiseizure actions in multiple in vivo and in vitro seizure models, including models of SE induced by the chemo convulsants pilocarpine and kainic acid, suggesting that focal enhanced delivery of 2DG to ictal brain circuits is a potential novel anticonvulsant intervention for the treatment of SE.

Experimental Neurotherapeutics: Surfing the Tidal Wave of New Opportunities.

The subspecialty of experimental neurotherapeutics trains neurologists in discovering and developing new treatments for neurologic diseases. Based on development of exciting new treatments for genetic and inflammatory diseases, we predict that there will be many other breakthroughs. The job market has expanded rapidly in academia, the pharmaceutical industry, government, and not-for-profit sectors; many new opportunities can be anticipated.

Diffusion Tensor Orientation as a Microstructural MRI Marker of Mossy Fiber Sprouting After TBI in Rats.

Diffusion tensor imaging (DTI) metrics are highly sensitive to microstructural brain alterations and are potentially useful imaging biomarkers for underlying neuropathologic changes after experimental and human traumatic brain injury (TBI). As potential imaging biomarkers require direct correlation with neuropathologic alterations for validation and interpretation, this study systematically examined neuropathologic abnormalities underlying alterations in DTI metrics in the hippocampus and cortex following controlled cortical impact (CCI) in rats. Ex vivo DTI metrics were directly compared with a comprehensive histologic battery for neurodegeneration, microgliosis, astrocytosis, and mossy fiber sprouting by Timm histochemistry at carefully matched locations immediately, 48 hours, and 4 weeks after injury.

Genetic Background Influences Acute Response to TBI in Kindling-Susceptible, Kindling-Resistant, and Outbred Rats.

We hypothesized that the acute response to traumatic brain injury (TBI) shares mechanisms with brain plasticity in the kindling model. Utilizing two unique, complementary strains of inbred rats, selected to be either susceptible or resistant to seizure-induced plasticity evoked by kindling of the perforant path, we examined acute electrophysiological alterations and differences in brain-derived neurotrophic factor (BDNF) protein concentrations after a moderate-to-severe brain injury. At baseline, limited strain-dependent differences in acute electrophysiological activity were found, and no differences in BDNF.

Epilepsy and aging.

The intersection of epilepsy and aging has broad, significant implications. Substantial increases in seizures occur both in the elderly population, who are at a higher risk of developing new-onset epilepsy, and in those with chronic epilepsy who become aged. There are notable gaps in our understanding of aging and epilepsy at the basic and practical levels, which have important consequences.

2-Deoxy-d-glucose reduces epileptiform activity by presynaptic mechanisms.

2-Deoxy-d-glucose (2DG), a glucose analog that inhibits glycolysis, has acute and chronic antiepileptic effects. We evaluated 2DG's acute effects on synaptic and membrane properties of CA3 pyramidal neurons in vitro. 2DG (10 mM) had no effects on spontaneously occurring postsynaptic currents (PSCs) in 3.

Distinct behavioral phenotypes in novel "fast" kindling-susceptible and "slow" kindling-resistant rat strains selected by stimulation of the hippocampal perforant path.

Kindling is a phenomenon of activity-dependent neural circuit plasticity induced by repeated seizures that results in progressive permanent increases in susceptibility to epilepsy. As the permanent structural and functional modifications induced by kindling include a diverse range of molecular, cellular, and functional alterations in neural circuits, it is of interest to determine if genetic background associated with seizure-induced plasticity might also influence plasticity in neural circuitry underlying other behaviors. Outbred Sprague-Dawley (SD) rats were selected and bred for ~15 generations for "fast' or "slow" rates of kindling development in response to stimulation of the perforant path input to the hippocampus.

Environmental enrichment: evidence for an unexpected therapeutic influence.

Environmental enrichment produces wide-ranging effects in the brain at molecular, cellular, network, and behavioral levels. The changes in neuronal plasticity are driven by changes in neurotransmitters, neurotrophic factors, neuronal morphology, neurogenesis, network properties of the brain, and behavioral correlates of learning and memory. Exposure to an enriched environment has also demonstrated intriguing possibilities for treatment of a variety of neurodegenerative diseases including Huntington's disease, Alzheimer's disease, and Parkinson's disease.

Behavioral, cognitive, and safety profile of 2-deoxy-2-glucose (2DG) in adult rats.

2-Deoxy-D-glucose (2DG), a glucose analog that transiently inhibits glycolysis, has anticonvulsant and antiepileptic disease-modifying properties in experimental in vivo models of seizures and epilepsy. Here we evaluated the effects of 2DG across the range of doses (50-500mg/kg i.p.

Fisher statistics for analysis of diffusion tensor directional information.

A statistical approach is presented for the quantitative analysis of diffusion tensor imaging (DTI) directional information using Fisher statistics, which were originally developed for the analysis of vectors in the field of paleomagnetism. In this framework, descriptive and inferential statistics have been formulated based on the Fisher probability density function, a spherical analogue of the normal distribution. The Fisher approach was evaluated for investigation of rat brain DTI maps to characterize tissue orientation in the corpus callosum, fornix, and hilus of the dorsal hippocampal dentate gyrus, and to compare directional properties in these regions following status epilepticus (SE) or traumatic brain injury (TBI) with values in healthy brains.

Time-frequency analysis using damped-oscillator pseudo-wavelets: Application to electrophysiological recordings.

The damped-oscillator pseudo-wavelet is presented as a method of time-frequency analysis along with a new spectral density measure, the data power. An instantaneous phase can be defined for this pseudo-wavelet, and it is easily inverted. The data power measure is tested on both computer generated data and in vivo intrahippocampal electrophysiological recordings from a rat.

Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons.

Homeostatic synaptic scaling alters the strength of synapses to compensate for prolonged changes in network activity and involves both excitatory and inhibitory neurons. The immediate-early gene Narp (neuronal activity-regulated pentraxin) encodes a secreted synaptic protein that can bind to and induce clustering of AMPA receptors (AMPARs). We found that Narp prominently accumulated at excitatory synapses on parvalbumin-expressing interneurons (PV-INs).

Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models.

Objective: Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Because carbohydrates are restricted in patients on the ketogenic diet, we evaluated the effects of limiting carbohydrate availability by reducing glycolysis using the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in experimental models of seizures and epilepsy.

Seizure suppression via glycolysis inhibition with 2-deoxy-D-glucose (2DG).

Metabolic regulation of neuronal excitability is increasingly recognized as a factor in seizure pathogenesis and control. Inhibiting or bypassing glycolysis may be one way through which the ketogenic diet provides an anticonvulsant effect. 2-deoxy-D-glucose (2DG), a nonmetabolizable glucose analog that partially inhibits glycolysis, was tested in several acute and chronic seizure models.

Epileptogenesis in the dentate gyrus: a critical perspective.

The dentate gyrus has long been a focal point for studies on the molecular, cellular, and network mechanisms responsible for epileptogenesis in temporal lobe epilepsy (TLE). Although several hypothetical mechanisms are considered in this chapter, two that have garnered particular interest and experimental support are: (1) the selective loss of vulnerable interneurons in the region of the hilus and (2) the formation of new recurrent excitatory circuits after mossy fiber sprouting. Histopathological data show that specific GABAergic interneurons in the hilus are lost in animal models of TLE, and several lines of electrophysiological evidence, including intracellular analyses of postsynaptic currents, support this hypothesis.

Unmasking recurrent excitation generated by mossy fiber sprouting in the epileptic dentate gyrus: an emergent property of a complex system.

Seizure-induced sprouting of the mossy fiber pathway in the dentate gyrus has been observed nearly universally in experimental models of limbic epilepsy and in the epileptic human hippocampus. The observation of progressive mossy fiber sprouting induced by kindling demonstrated that even a few repeated seizures are sufficient to alter synaptic connectivity and circuit organization. As it is now recognized that seizures induce synaptic reorganization in hippocampal and cortical pathways, the implications of seizure-induced synaptic reorganization for circuit properties and function have been subjects of intense interest.

2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure.

Temporal lobe epilepsy is a common form of drug-resistant epilepsy that sometimes responds to dietary manipulation such as the 'ketogenic diet'. Here we have investigated the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in the rat kindling model of temporal lobe epilepsy. We show that 2DG potently reduces the progression of kindling and blocks seizure-induced increases in the expression of brain-derived neurotrophic factor and its receptor, TrkB.

Models of epilepsy in the developing and adult brain: implications for neuroprotection.

Repeated seizures cause a sequence of molecular and cellular changes in both the developing and adult brain, which may lead to intractable epilepsy. This article reviews this sequence of neuronal alterations, with emphasis on the kindling model. At each step, the opportunity exists for strategic intervention to prevent or reduce the downstream consequences of epileptogenesis and seizure-induced adverse plasticity.

Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety.

Purpose: Seizures in the developing brain cause less macroscopic structural damage than do seizures in adulthood, but accumulating evidence shows that seizures early in life can be associated with persistent behavioral and cognitive impairments. We previously showed that long-term spatial memory in the eight-arm radial-arm maze was impaired in rats that experienced a single episode of kainic acid (KA)-induced status epilepticus during early development (postnatal days (P) 1-14). Here we extend those findings by using a set of behavioral paradigms that are sensitive to additional aspects of learning and behavior.