4.2 The therapeutics effect of ligands targeting histamine and histamine receptors on epilepsy in animal model
There are several studies investigating the protective effects of histamine in epilepsy. The histamine precursor, carnosine and histidine showed a protective effect on PTZ kindling rat indicating by seizure onset delay, seizure stage decrease, as well as prolonging latency to myoclonic jerks (Chen, Li, Zhu, Shen & Wei, 2002; Zhang, Shen, Jin, Hu, Zhao & Chen, 2004). Similarly, histidine and histamine inhibit seizure in amygdala kindling rats (Ago, Ishikawa, Matsumoto, Ashequr Rahman & Kamei, 2006; Kamei, Ishizawa, Kakinoki & Fukunaga, 1998), audiogenic seizure (AGS) in GEPR-9s rats (Feng & Faingold, 2000; Feng, Naritoku, Randall & Faingold, 2001), and rhythmic vestibular stimulation epilepsy like mice (Yawata, Tanaka, Nakagawa, Watanabe, Murashima & Nakano, 2004), this effect is attenuated by H1R antagonist, pyrimidine, diphenhydramine and chlorpheiramine (Ago, Ishikawa, Matsumoto, Ashequr Rahman & Kamei, 2006; Kamei, Ishizawa, Kakinoki & Fukunaga, 1998), suggesting H1R medicates anti-seizure effect of histamine. However, Yoshida reported that L-histidine did not reduce seizure ranks and afterdischarge duration (ADD) in amygdaloid kindling rats (Yoshida, Noguchi & Tsuru, 2000). This may be due to the fact that the action of histidine will be affect by its administration dosage. For example, L-histidine prolonged the latency to the onset of bilateral forelimb clonus, without changing the seizure stages and ADD, however, daily treatment of L-histidine facilitated the seizure development (Wada, Shiraishi, Nakamura & Koshino, 1996). Ligands inhibiting the HNMT (thus increasing the brain histamine content), metoprine decreased the seizure stage in amygdala kindling rats and delayed the seizure onset in epileptic-like mice after the vestibular stimulation (Kamei, Ishizawa, Kakinoki & Fukunaga, 1998; Yawata, Tanaka, Nakagawa, Watanabe, Murashima & Nakano, 2004). In addition, metoprine decreased the duration and severity of clonic-tonic convulsions induced by AGS in KM rats and suppressed the spike wave discharge in WAG/Rij rats (Samotaeva, Birioukova, Midzyanovskaya, Kuznetsova, Bazyan & Tuomisto, 2012; Vinogradova, Shatskova & Tuomisto, 2007). These researches suggest preventing histamine degradation could effectively protect against epilepsy.
Next, we discuss the therapeutic effect of several H1R antagonists, including antazoline, cetirizine, chlorpheniramine, cyproheptadine, diphenhydramine, epinastine, ketotifen, loratadine, mepyramine, pyrilamine and triprolidine. In the MES-induced seizure model, antazoline, ketotifen, diphenhydramine, chlorpheniramine, and cyproheptadine show varying degrees of anti-seizure effects in adult mice or 3 weeks infant rats (Ishikawa et al., 2007; Swiader, Wielosz & Czuczwar, 2004), however, the ketotifen accelerates seizure in infant rats has been found in MES-induced seizure model (Yamada, Takizawa, Tamura & Kanda, 2012). The controversial outcome of ketotifen in MES infant rats, might due to the different dosage: orally administrated 5 or 10mg/kg leading positive effect, whereas large dose 30 mg/kg showing the opposite. Similarly, opposite outcomes of H1R antagonists manifesting in the rhythmic vestibular stimulation epilepsy like mice, diphenhydramine at a dosage of 15 mg/kg accelerated this process (Yawata, Tanaka, Nakagawa, Watanabe, Murashima & Nakano, 2004), whereas, diphenhydramine at 30 mg/kg delayed the convulsive seizure induction (Sturman, Freeman & Quinn, 2001). Besides, the H1R antagonist, pyrilamine, ketotifen and diphenhydramine, but not epinastine, loratadine and cetirizine, accelerates seizures in amygdala kindling model (Fujii, Tanaka, Harada, Hirai & Kamei, 2003; Yokoyama, Sato, Iinuma, Onodera & Watanabe, 1996). Additionally, another H1R antagonist, triprolidine increased seizures severity and neuronal damage in the septum, thalamus, CA3 region of the hippocampus, and retrosplenial granular cortex (RGC) in the KA-treated immature mice (Kukko-Lukjanov et al., 2010). Interestingly, the H1R antagonist ketotifen possessed a biphasic action, acutely it enhanced the anticonvulsant action of carbamazepine and phenobarbital while, following 7-day treatment, reduced the antiseizure activity of carbamazepine in MES (Swiader, Wielosz & Czuczwar, 2004). These findings demonstrate the controversial therapeutic effect of H1R antagonist in epilepsy, and the dosage of H1R antagonists might contribute that.
Reports about the ligands targeting H2R in epilepsy are limited. One study showed that an H2R agonist, amthamine decreased clonic-tonic seizure in picrotoxin-induced and PTZ-induced epilepsy mice model (Seeley & Sturman, 2001). Another reported that cimetidine, an H2R antagonist, given alone either acutely or chronically did not alter PTZ-induced seizure and also did not affect the anticonvulsant properties of AEDs, such as valproate, clonazepam or phenobarbital in PTZ model. (Swiader, Porebiak, Swiader, Wielosz & Czuczwar, 2006). Although potential positive therapeutics obtained from H2R agonist, systemic investigations are urge to reveal the role of H2R in epilepsy.
Up to date, many H3R ligands have been synthesis to target epilepsy. H3R antagonist, clobenpropit, thioperamide, and E177 delayed seizure onset, seizure stage, and prolonged the latency to myoclonic jerks and clonic generalized seizure in PTZ-induced seizure model (Alachkar et al., 2020; Zhang et al., 2003; Zhang, Chen, Chen, Hu & Ding, 2013; Zhang, Shen, Jin, Hu, Zhao & Chen, 2004). Similar to PTZ model, there are many H3R antagonist ligand, including thioperamide, iodophenpropit, AQ0145, clobenpropit, VUF5514, VUF5515 and VUF4929 decreased seizure stage in amygdala kindling model, except AQ0145, all ligands also showed protective effect in MES model (Harada, Fujii, Hirai, Shinomiya & Kamei, 2004; Harada, Hirai, Fujii, Harusawa, Kurihara & Kamei, 2004). The H3R antagonists DL77 showed anticonvulsant effect in MES-induced seizure, and the anticonvulsant effect of DL77 in MES model was reversed by H1R antagonist pyrilamine (Sadek, Saad, Subramanian, Shafiullah, Łażewska & Kieć-Kononowiczc, 2016), suggesting the action is H1R-dependent. Besides, in the rhythmic vestibular stimulation epilepsy like mice, H3R antagonist thioperamide decreased the induction of seizure (Yawata, Tanaka, Nakagawa, Watanabe, Murashima & Nakano, 2004). Furthermore, different degree of antiepileptic and anticonvulsant effects of novel non-imidazole H3R antagonist ligands have been found in PTZ, STR and MES-induced seizure model (Alachkar et al., 2018a; Alachkar et al., 2018b; Bastaki, Abdulrazzaq, Shafiullah, Więcek, Kieć-Kononowicz & Sadek, 2018; Sadek et al., 2014a; Sadek et al., 2016; Sadek, Saad, Schwed, Weizel, Walter & Stark, 2016; Song, Yan, Zhang, Guo, Zhou & Deng, 2020). H3R antagonist, ABT-239, delayed onset of seizure and reduced behavioral seizures and restored altered expression of Bax, cleaved caspase-3, phospho-Akt (Ser473) and CREB in KA mice (Bhowmik, Saini & Vohora, 2014). Another H3R antagonist E177, also shows protective effect in pilocarpine induced statue epilepticus rat indicating by increasing the survival rate and prolonging latency to the first seizure, and this effect was blocked by H3R agonist R-(α)-methylhistamine and H2R antagonist zolantidine, but not H1R antagonist pyrilamine (Alachkar et al., 2019). Moreover, the H3R naphthalene derivatives compound 13 also shows protective effect of seizure in PTZ and 6-Hz stimulation model (Łażewska et al., 2018). It needs to note that the H3R naphthalene derivatives compound 13 was accepted by the National Institute of Neurological Disorders and Stroke/National Institutes of Health (NINDS/NIH; Rockville, MD, USA) started an Anticonvulsant Screening Program (ASP) (Łażewska et al., 2018). This compound 13 shows the possibility to enter clinical trials and be marketed as pitolisant. Betahistine, an H1R agonist/H3R antagonist shows good protective effect indicating by preventing generalized tonic-clonic seizures induction and diminishing forelimb clonic seizures intensity in PTZ treated mice (Yazdi, Doostmohammadi, Pourhossein Majarshin & Beheshti, 2020). Betahistine reduced ADD without changing the seizure ranks in amygdaloid kindling rats (Yoshida, Noguchi & Tsuru, 2000).
The PTZ induced epileptic seizure model usually accompanied by learning and memory deficits, which can be rescued by L-histidine (Chen, Ren, Zhang & Hu, 2012; Zhang, Ma & Li, 2006), and H3R antagonist, thioperamide, JNJ-5207852, and E177 (Alachkar et al., 2020; Jia et al., 2006; Zhang, Chen, Chen, Hu & Ding, 2013), and this effect of L-histidine might through H2R but not H1R (Zhang, Chen, Chen, He & Hu, 2017). Histidine promotes the anticonvulsant efficacy of carbamazepine and ameliorates the memory deficits induced by chronic transuricular kindled seizure (Li et al., 2005; Li, Liu, Zhu, Zhou & Chen, 2006).
Although, in most cases, H3R antagonists/inverse agonists show good anti-seizure effects in different epilepsy models. The negative outcome also has been found in non-imidazole H3R antagonists/inverse agonists containing triazole moiety in PTZ mice (Song, Yan, Zhang, Guo, Zhou & Deng, 2020), and the non-imidazole H3R antagonists DL77 in STR rat (Sadek, Saad, Subramanian, Shafiullah, Łażewska & Kieć-Kononowiczc, 2016). The H3R antagonist, thioperamide shows no effect on seizure ranks and ADD in amygdaloid kindling rats (Yoshida, Noguchi & Tsuru, 2000). Whether histamine-independent signaling is involved in the anti-seizure effect of H3R antagonists/inverse agonists is still unknown.