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.