Histamine H3 receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives

Abstract

The central histaminergic actions are mediated by H(1) , H(2) , H(3) and H(4) receptors. The histamine H(3) 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 H(3) 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, H(3) 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 H(3) receptor antagonists, thus improving their utility in epilepsy and associated neurotoxicity.

Figure 1

The schematic diagram is a hypothetical depiction of the H₃ receptor-mediated signalling pathways in the CNS and their probable implications. Activation of H₃ receptor, constitutively or in presence of an agonist, leads to the activation of many G_i/o-associated intracellular pathways. Active G_i/o-proteins negatively couple AC, thereby inhibiting the cAMP/PKA cascade and subsequent lowering of cAMP responsive element binding protein (CREB), a pro-survival transcription factor. Reduction in PKA activity may decrease release of neurotransmitters, for example histamine (HA), GABA, etc. Additionally, H₃ receptor activation also activates PI3K and MAPK pathways. Activated PI3K then activates Akt, a serine threonine kinase, which phosphorylates and hence inactivates pro-apoptotic GSK-3β. In the MAPK pathway, especially p44 and p42 MAPK (ERK1/2) are coupled to H₃ receptors; activated ERK has also been linked to epilepsy. The other three pathways known so far that are modulated upon H₃ receptor activation include increased activity of the enzyme PLA₂, whose inhibition confers neuroprotection in epileptic models; mobilization of intracellular Ca²⁺[Ca²⁺]_i; and finally the inhibition of Na⁺/H⁺ exchanger (NHE), a protein that buffers intra-neuronal pH and it's defective functioning is also implicated in epilepsy. Also, H₃ receptors possibly influence the function of other GPCRs and vice versa (e.g. dopamine D₁ receptor) by virtue of cross talk in heteromer containing cells.