5.1 What is the role of other histamine receptors in epilepsy?
H1R and H3R expression have been merely detected in one type of epilepsy animal model. The changes of histamine receptors need systemic animal researches and autopsy studies to elucidate further, especially H2R and H4R. In addition, H1R, H2R and H3R antagonists have been investigated in many epilepsy animal model, however, the report of H4R in epilepsy is still missing. Even the H4R shows the potential in regulating neuronal excitability (Desmadryl et al., 2012). Investigations should be implemented to detect the distribution and expression of H4R in epilepsy animal, and applying H4R agonists and antagonists to epilepsy intervention. What’ more, some studies found that action of H3R ligands relies on H1R or H2R, the specific histamine receptor KO mice are available to ensure the action of H3R antagonist through H1R or H2R.
Even the H3R antagonists receive a lot of attention upon its desirable anti-epileptic and anticonvulsant effects, the action manner of H3R antagonists is not fully understood. As H3R is identified as either autoreceptor or heteroreceptor, it may be very complex about how it regulates neural excitability and thus related in epilepsy. For example, it is still largely unknown whether histamine-independent signaling is involved in the anti-seizure effect of H3R antagonists/inverse agonists. In the cerebral ischemia/reperfusion injury, the H3R antagonists protect against the ischemia injury in a histamine independent manner by directly recruiting binding of CLIC4 with H3R (Yan et al., 2014). Whether the action of H3R antagonist is the same in epilepsy that is unclear. HDC inhibitors and HDC-KO animal are regarded as a good choice to answer this question.