3. Histamine and its receptors in clinical research for epilepsy
As we mainly mentioned the histamine and its receptors in regulating the neuronal excitability, it is not surprise that histamine would play a role in epilepsy that mainly due to the imbalance of “excitation-inhibition”. Next, we address the action of histamine and its receptors in epilepsy in clinical studies and the effect of related ligands targeting the histamine receptor on epilepsy in preclinical trials that are summarized in Table 1.
In 1993, Yokoyama reported a 5-years-old boy increased the number of epileptic discharges after administration of d-chlorpheniramine (H1R antagonist) (Yokoyama, Iinuma, Yanai, Watanabe, Sakurai & Onodera, 1993). Since then, similar evidence has been observed in two 4 and 5 months old infancy, who developed tonic spasm after taking H1R antagonist ketotifen (Yasuhara, Ochi, Harada & Kobayashi, 1998). In children, case report indicated that uptake H1R antagonist desloratadine to treat atopic dermatitis, who develop absence seizure with typical electroencephalogram pathological pattern or idiopathic generalized epilepsy later (Cerminara, El-Malhany, Roberto, Lo Castro & Curatolo, 2013). More seriously, overdose taking the H1R antagonist diphenhydramine or ketotifen developed generalized tonic-clonic seizures and dysrhythmias in a teenager, or even toxic encephalopathy followed by localization-related epilepsy and mild mental retardation in infancy (Labarinas, Meulmester, Greene, Thomas, Virk & Erkonen, 2018; Yokoyama, Hirose, Uematsu, Haginoya, Iinuma & Kimura, 2012). The above findings demonstrated that the H1R antagonist has a pro-seizure effect, especially in case of overtaking.
Except for the action of H1R antagonist, the patient after uptake H2R antagonist also affects epilepsy. For example, a patient treated with famotidine (H2R antagonist) for gastric pain, then presented manic symptoms and developed two generalized seizures after the famotidine was discontinued (von Einsiedel, Roesch-Ely, Diebold, Sartor, Mundt & Bergemann, 2002). However, a larger observational cohort study showed that the use of H2R antagonist was not associated with an increased risk of seizures in the overall population or the cohorts stratified by epilepsy status, which including 8605 patients with seizure compared with 40000 controls (Sáez, González-Pérez, Gaist, Johansson, Nagy & García Rodríguez, 2016). It seems that H2R antagonist might not affect the risk of seizure. However, these findings are not direct evidence that could confirm that the effect of central H1R or H2R on epilepsy.
Autopsy reports could provide more direct evidence for the role of histamine and its receptor in epilepsy. However, related studies are limited. At present, there is only one literature reported that patients with MTLE showed a reduction in the H3R function in the hippocampus, and high efficacy of H3Rs Gai/o protein activation with low tissue contents of histamine in temporal cortex, which suggests the potential protective role of H3R and histamine in MTLE (Bañuelos-Cabrera et al., 2016). Most studies focus on identifying the role of H1R or H2R antagonist in epilepsy. More direct evidence from clinical studies is needed.
Based on the specific high constitutive activity of H3R, the H3R antagonists receive a lot of attention. Many H3R antagonist ligands show a good protective effect on epilepsy in preclinical studies, which we will discuss later. Antagonists of H3R are classified into imidazole-based and non-imidazole-based antagonists. The latter has high selectivity and affinity. The H3R antagonist, pitolisant shows good anti-epileptic effects in clinical. One third of patients received the positive response in phase II and pitolisant suppressed the generalized photoparoxysmal response of all epilepsy patients in the photosensitivity proof of concept model in early phase II clinical trials (Collart Dutilleul et al., 2016; Kasteleijn-Nolst Trenité, Parain, Genton, Masnou, Schwartz & Hirsch, 2013). Currently, pitolisant (WakixR) was approved by the European Commission for the treatment of narcolepsy in March 2016. There are several other H3R antagonists ligands under clinical development for other target indications but not epilepsy (Harwell & Fasinu, 2020). At present, most available clinical researches mainly focus on the effect of histamine receptor-related ligands, especially H1R, H2R, and H3R. Little is known about that the role of H4R in epilepsy from clinical studies. However, how the histamine content change in the subdivide brain, or the distribution change of histamine receptor subtypes, needs to validate further.