4.3 The genetic and other therapeutics effects of targeting histamine and histamine receptors on epilepsy in animal model
Since histamine and its precursor L-histidine, as well as most H3R antagonists obtain positive outcomes. As pharmacological modulation is often associated with non-specific effect, genetically intervention can address the precise role of central histaminergic signaling epilepsy more specifically.
The H1R-KO mice showed more severe seizures with correlation of neuronal damage in the thalamus and RGC in P9 immature mice (Kukko-Lukjanov et al., 2010). Those authors then described the age-dependent susceptibility of H1R-KO mice to seizure-induced by KA administration: P14 H1R-KO mice showed no changes; P21 KO mice decreased survival rate with more severe seizures and enhanced neuronal damage in various brain regions; P60 KO mice increased the neuronal damage without changing the seizure severity (Kukko-Lukjanov et al., 2012). In the HDC-KO mice, the hyperthermia-induced febrile seizure was more severe that wide type (WT) mice (Dai et al., 2015). These findings indicate that deletion of H1R and HDC increases the susceptibility of epilepsy.
Based on the above researches results, it can be basically concluded that the central histaminergic signaling participates in epilepsy. Most importantly, the H3R antagonist shows powerful anti-epileptic and anticonvulsant effects in many epileptic animal models. The protective effect of H3R antagonist works mainly through H1R. However controversial opinion still exists (Alachkar et al., 2019; Sadek, Saad, Subramanian, Shafiullah, Łażewska & Kieć-Kononowiczc, 2016). What’s more, the action of H1R antagonists in seizure animal model also not consistent. The incomplete understanding of these issues needs further studies to investigate.