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.