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.