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The central histaminergic actions are mediated by H1, H2, H3 and H4 receptors. The histamine H3 receptor regulates the release of histamine and a number of other neurotransmitters and thereby plays a role in cognitive and homeostatic processes. Elevated histamine levels suppress seizure activities and appear to confer neuroprotection. The H3 receptors have a number of enigmatic features like constitutive activity, interspecies variation, distinct ligand binding affinities and differential distribution of prototypic splice variants in the CNS. Furthermore, this Gi/Go‐protein‐coupled receptor modulates several intracellular signalling pathways whose involvement in epilepsy and neurotoxicity are yet to be ascertained and hence represent an attractive target in the search for new anti‐epileptogenic drugs. So far, H3 receptor antagonists/inverse agonists have garnered a great deal of interest in view of their promising therapeutic properties in various CNS disorders including epilepsy and related neurotoxicity. However, a number of experiments have yielded opposing effects. This article reviews recent works that have provided evidence for diverse mechanisms of antiepileptic and neuroprotective effects that were observed in various experimental models both in vitro and in vivo. The likely reasons for the apparent disparities arising from the literature are also discussed with the aim of establishing a more reliable basis for the future use of H3 receptor antagonists, thus improving their utility in epilepsy and associated neurotoxicity.

Histamine H3 receptor (H3R) antagonists/inverse agonists possess potential to treat diverse disease states of the central nervous system (CNS). Cognitive dysfunction and motor impairments are the hallmark of multifarious neurodegenerative and/or psychiatric disorders. This review presents the various neurobiological/neurochemical evidences available so far following H3R antagonists in the pathophysiology of Alzheimer's disease (AD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, and drug abuse each of which is accompanied by deficits of some aspects of cognitive and/or motor functions. Whether the H3R inverse agonism modulates the neurochemical basis underlying the disease condition or affects only the cognitive/motor component of the disease process is discussed with the aim to provide a rationale for their use in diverse disease states that are interlinked and are accompanied by some common motor, cognitive and attentional deficits.

Voltage-gated sodium channel blockers like phenytoin and carbamazepine have long been used in the treatment of epilepsy. Brain sodium channels continue to be an important target of many newer second-generation (fosphenytoin, oxcarbazepine, lamotrigine, felbamate, topiramate, zonisamide) and third-generation (eslicarbazepine, brivaracetam, carisbamate, fluorofelbamate, elpetrigine, lacosamide, rufinamide, safinamide, vinpocetine) antiepileptic drugs (AEDs). Some of the newer drugs show either state-dependent antiepileptic action or sodium channel subtype selectivity, although most agents do not differentiate between these channel subtypes. The present review highlights the preclinical and clinical efficacy, pharmacokinetics, drug interactions and adverse event profiles. It also addresses AED selection of sodium channel blockers that constitutes the third generation of AEDs.

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