Histamine H₃receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives

Abstract

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.

Anxiolytic and antidepressant-like activities of the novel and potent non-imidazole histamine H3 receptor antagonist ST-1283

“…The FST is sufficiently specific, given that it discriminates antidepressants from neuroleptics and anxiolytics 3,7. However, ligands enhancing locomotor activity may give rise to a false-positive effect in this test 34,35.…”

The histamine H3-receptor inverse agonist Pitolisant improves fear memory in mice

“…Since NMDA receptors play an important function in both consolidation and reconsolidation processes, it is possible that thioperamide and Pitolisant reversed dizocilpine-induced amnesia in our studies through direct activation of NMDA receptors by histamine released by these H 3 R inverse agonists. It is important to note that elevated levels of histamine in the brain and H 3 R inverse agonists can confer neuroprotection in various animal models of neurotoxicity (see Bhowmik et al [43] for a review). Thus, the ability of Pitolisant to attenuate dizocilpine-induced amnesia in our experiments could also result from a neuroprotective action.…”

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

“…One of the main strategies of pharmacotherapy for epilepsy is to correct the imbalance between excitatory, glutamate, and inhibitory, GABA, neurotransmission [133][134][135]. The central histaminergic system has been shown to reduce or protect from seizures [24,[136][137][138][139]. In preclinical studies, i.c.v.…”