1. Introduction
Epilepsy is one kind of common neurologic disease, affecting up to 70
million people worldwide (Trinka, Kwan, Lee & Dash, 2019).
Anti-epileptic drugs (AEDs) are the first choice for most patients. Even
so, the adverse effects of AEDs lead to improper seizure control of many
patients. What’s worse, there is approximately one-third of patients
become drug-resistant epilepsy (DRE) (Löscher, Klitgaard, Twyman &
Schmidt, 2013). For DRE, surgery is the ultimate therapy but less than
1% of patients preferred (Engel, 2018). Alternative treatments, such as
deep brain stimulation (DBS), laser interstitial thermal therapy, vagus
nerve stimulation and dietary modification, are also used for epilepsy
treatment (Kaeberle, 2018; Schaper et al., 2020), but anti-epileptic
effects are limited. Above therapeutic challenge in clinical may be due
to the fact that the mechanism of epilepsy is not fully understood.
Traditional theory supports that epilepsy results from the imbalance of
neural excitability. Classically, researches mainly focus on the
excitatory glutamatergic neurotransmission and inhibitory GABAergic
neurotransmission, both of which are the designed target of most of
AEDs.
Pieces of evidence have indicated that other neurontransmitters,
including histamine, 5-HT, and acetylcholine, also participating in the
modulation of neural excitability and the ictogenesis and
epileptogenesis (Meller, Brandt, Theilmann, Klein & Löscher, 2019;
Sugitate, Okubo, Nariai & Matsui, 2020; Zhao, Lin, Chen, Li & Huo,
2018). Among them, histamine has been the least understood. Histamine
was firstly isolated from the brain cortex by Kwiatkowski in 1943
(Kwiatkowski, 1943). Since then several studies have demonstrated that
histamine acts as a neurotransmitter in the brain (Haas, Sergeeva &
Selbach, 2008). A decline of histamine content has been found in
temporal neocortex of patients with pharmacoresistant mesial temporal
lobe epilepsy (MTLE) (Bañuelos-Cabrera et al., 2016). Indeed, several
H3R ligands have been discovered to target the epileptic treatment
(Sadek, Saad, Sadeq, Jalal & Stark, 2016). This review summarizes the
role of histamine and its receptors in neural excitability and epilepsy,
and further provides perspectives on future research directions.