An Overview of the Preclinical Aspects of Topiramate: Pharmacology, Pharmacokinetics, and Mechanism of Action

Abstract

In this overview, we discuss the discovery and development of topiramate (TPM) as an anticonvulsant, including notable aspects of its chemical, biologic, and pharmacokinetic properties. In particular, we highlight its anticonvulsant profile in traditional seizure tests and animal models of epilepsy and the results of recent electrophysiological and biochemical studies using cultured neurons that have revealed a unique combination of pharmacologic properties of TPM. Finally, we present a hypothesis for the mechanistic basis of the anticonvulsant activity of TPM, which proposes that TPM binds to certain membrane ion channel proteins at phosphorylation sites and thereby allosterically modulates channel conductance and secondarily inhibits protein phosphorylation.Topiramate (TPM; RWJ-17021-000, McN-4853) was originally synthesized as part of a research project to discover structural analogs of fructose-1,6-diphosphate capable of inhibiting the enzyme fructose 1,6-bisphosphatase, thereby blocking gluconeogenesis. Sulfamate derivatives of fructose were the initial focus of the synthetic effort because they contain unionized groups that might simulate phosphate binding to the enzyme and also facilitate access to the enzyme by enhancing membrane permeability.TPM was prepared as a synthetic intermediate in the project, and it is devoid of hypoglycemic activity. However, the structural resemblance of its 0-sulfamate moiety to the sulfonamide moiety in acetazolamide (and other arenesulfonamide anticonvulsants) prompted an evaluation of possible anticonvulsant effects. TPM was highly active in the traditional maximal electroshock seizure (MES) test in mice and rats and possessed a long duration of action (1-3). Furthermore, there was a wide separation between the effective anticonvulsant doses compared to those causing motor impairment. Development of TPM as an antiepileptic drug (AED) was subsequently pursued on the basis of its potency, duration of action, and high neuroprotective index.

Molecular Targets for Antiepileptic Drug Development

“…There is, however, evidence that topiramate may act indirectly on ion channels through regulation of their phosphorylation state. 29 Neurotrophins and their receptors are other potential targets. For example, brain-derived neurotrophic factor (BDNF) can modulate the functional properties of ion channels through TrkB-mediated activation of intracellular second messenger cascades and protein phosphorylation, and may also directly and rapidly gate ion channels.…”

“…[267][268][269] Topiramate may act indirectly by altering the phosphorylation state of its targets. 29,270 Like topiramate, felbamate has several different phar-macological actions that have been proposed as contributing to its clinical efficacy. Among these is a specific inhibitory effect on NMDA receptors.…”

“…As noted previously, however, topiramate may act indirectly on ion channels by effects on phosphorylation. 29 …”

“…Connexins (Cx) 26,29,30,32,36,37,40,43,45,46, and 47 are expressed in the brain, with marked variation according to developmental stage and cell type. 402 In astrocytes, where a key function for gap junctions is calcium wave signaling, Cx43 is the major connexin.…”

Topiramate Normalizes Hippocampal NPY-LI in Flinders Sensitive Line ‘Depressed’ Rats and Upregulates NPY, Galanin, and CRH-LI in the Hypothalamus: Implications for Mood-Stabilizing and Weight Loss-Inducing Effects

“…Multiple actions appear to account for its anticonvulsant effects, including inhibition of neuronal voltage-dependent sodium channels and L-type calcium-channel activation, enhancement of GABA A receptor transmission and reduction of glutamatergic AMPA (aamino-3-hydroxy-5-methyl-4-isoxazole-proprionate), and kainate receptor neurotransmission (Shank et al, 2000). In addition to anticonvulsant efficacy, other major clinical observations have been made.…”