Lauren Murphree

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

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.

Antiseizure activity of novel γ-Aminobutyric acid (A) receptor subtype-selective benzodiazepine analogues in mice and rat models

The antiseizure activity of benzodiazepines (BDZs) 1-5 in mice and rats as animal models is described. These BDZs have selective efficacy for alpha2beta3gamma2 and alpha3beta3gamma2 GABA(A)-receptors. Significant anticonvulsant activity with little or no motor impairment and therapeutic indexes (TI) of 2.8-44 (mice, ip) were observed for compounds 2-4 in the subcutaneous metrazole seizure (scMET) test. In rats, orally (po) the TI was >5 to 105. These compounds represent novel leads in the search for anticonvulsants devoid of sedative, ataxic, and amnestic side effects.

GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy but cardiac ion channel effects limit its clinical utility.

Background/Aims: GBR12909 has been reported to possess anticonvulsant activity with focal brain perfusion to the hippocampus of pilocarpine, although an earlier publication suggested any anticonvulsant effects were only mild. Here we further explored the anticonvulsant potential of GBR12909 with a suite of anticonvulsant assays in both zebrafish and mammals and then explored whether it possessed any QT effects which might limit clinical utility. Methods: We assessed the anticonvulsant effects of GBR12909 in zebrafish pentylenetetrazole (PTZ), mammalian maximal electroshock and PTZ models of generalized epilepsy and a rodent hippocampal kindling model. Cardiac effects were assessed in zebrafish and man. Results: GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy. However, phase 1 human data indicated potential QT effects. Subsequent testing in a zebrafish QT assay confirmed marked arrhythmogenic potential. Conclusion: Further clinical development of GBR12909 in epilepsy was considered inappropriate because of insufficient window between the therapeutic effects and the cardiac arrhythmia problems identified in zebrafish assays. Any further development based on this mechanism of action should avoid the GBR12909 chemical scaffold, or involve structure-activity dissociation of its neurological and cardiac effects.

Animal models of geriatric epilepsy.

Geriatric epilepsy is a significant clinical problem that has not been studied adequately in animal models. This chapter will review the available literature with particular attention to models that have demonstrated how acute seizures and epilepsy in aged animals differ from those of younger animals. Studies include several strains of mice [e.g., El, DBA, senescence-accelerated mouse (SAM), Cacnb4 knockout] as well as acute seizure models in common strains of aged mice. Aged rats (including Fischer 344, Wistar, and Sprague-Dawley) have been used in acute seizure, lesion, and epilepsy models. This area of research remains largely unexplored and therefore provides numerous opportunities for new investigations.