4. Histamine and its receptors in animal studies for epilepsy
There are many limitations to clinical researches. Animal models of epileptic seizures have an indispensable role in the advancement of investigating the causal role of histamine and its receptor in epilepsy, have been instrumental in the preclinical development of new antiepileptic agents. The models of epilepsy or seizures can be classified into genetic animal models and acquired animal models. For the former, it includes transgenic mice with spontaneous recurrent seizures, and animals with reflex seizure, such as DBA/2 mice, GEPR, and Krushinski-Molodkina (KM) animals. For the latter, there are usually two common ways to induce seizures in normal animals: electrical induction and chemical induction. Pentylenetetrazole (PTZ), pilocarpine (Ach M receptor agonist), strychnine (STR), kainic acid (KA, glutamate receptors agonists), and picrotoxin (GABAA receptor antagonist) are commonly used chemical substance to induce seizure. Maximal electroshock seizure (MES), amygdaloid kindling, 6-Hz stimulation and transauricular kindling are commonly used as electrical induction method of seizure. Besides, except for the electrical and chemical indication of seizures in normal animals, there are other seizure-induced models, such as audiogenic stimulation, vestibular stimulation and hyperthermia-induced febrile seizure (Löscher, 2011; Potschka, 2012). Actually, the electrical and chemical induction methods are combined use together in some cases. Next, we summarize findings of changes in histamine level or histamine receptor expression in across chemically and electrically-induced epilepsy animal models, as well as other animal models (Table 2). Moreover, we also pay attention to review the therapeutic effect of histamine or histamine receptors related ligands on epilepsy (Table 3), and genetic interventions, especially genetic-edited animal, as well as other interventions in epilepsy in animal researches. The change of histamine and histamine receptor and the therapeutics effect of histamine related ligands in epilepsy are showed in Fig.2.