4.1 The change of central histaminergic signaling in epilepsy animal models
In the PTZ-induced generalized myoclonic seizures, most studies found that PTZ induced seizure accompanied by a decrease of histamine in the hippocampus, thalamus, and hypothalamus (Alachkar et al., 2020; Chen, Ren, Zhang & Hu, 2012; Singh, Pillai & Mehndiratta, 2014; Zhang, Chen, Chen, He & Hu, 2017; Zhang, Ma & Li, 2006), while no change of histamine in hippocampus and striatum also has been found (Szyndler et al., 2006). A similar phenomenon has been observed in MES-induced generalized tonic-clonic seizures: histamine decreased in the cortex, hippocampus, brainstem and hypothalamus, without changing glutamate and GABA levels in the TMN E2-region lesion rats (Jin et al., 2007). Moreover, it has been found that histamine content was decreased in amygdala of amygdala kindling-induced focal seizure with secondary generalized seizure (Kamei, Ishizawa, Kakinoki & Fukunaga, 1998). Besides, a reduction of brain histamine level has been found in transauricular kindling rats (Li, Liu, Zhu, Zhou & Chen, 2006), and 6-Hz stimulation mice (Jahan, Pillai & Vohora, 2017). In the audiogenic DBA/2 mice, a decrease of histamine level has been detected in the hypothalamus (Tuomisto, Sturman, Freeman & Tarhanen, 2003). And a decrease of blood histamine level has been found that hyperthermia-induced convulsion in infant rats (Gholipoor, Saboory, Roshan-Milani & Fereidoni, 2013). Histamine levels in the striatum, hippocampus, amygdala, midbrain, thalamus and hypothalamus of genetically epilepsy-prone KM rats were significantly lower than epilepsy resistant Wistar rats (Onodera, Tuomisto, Tacke & Airaksinen, 1992). However, in the KA-induced temporal lobe epilepsy, KA immediately increases brain histamine and histamine immunoreactive nerve fibers in the piriform cortex, amygdala, hippocampus and striatum after KA injection 6 hours later (Lintunen, Sallmen, Karlstedt & Panula, 2005). The reduction of histamine content observed in many brain regions across focal seizure and generalized seizures, suggesting that histamine involves in the pathological process of epilepsy. However, it is still unclear how histamine content change in the different stage of epilepsy.
In histamine receptor level, only H1R and H3R have been found change in epilepsy model. The mRNA expression of H1R transiently decreases in the midline areas and the ventral thalamus, and the mRNA expression of H3R isoforms with a full-length third intracellular loop firstly transiently decrease and increase after 1 week in the ventral posterior, posterior, and geniculate nuclei in the KA model (Jin, Lintunen & Panula, 2005). However, another research reported that KA transiently (after KA injection 6, 12 and 24 hours) increases brain mRNA of H3R isoforms with a full-length third intracellular loop in the hippocampal CA3, followed by piriform cortex and amygdala and then the hippocampal CA1 area (Lintunen, Sallmen, Karlstedt & Panula, 2005). Likewise, the H1R density increases in superior colliculus, central grey, nucleus interpositus and pontine nuclei in the genetic epilepsy-prone WAG/Rij rats (Midzyanovskaya & Tuomisto, 2003). The difference outcome between the former two studies may be caused by different sampling times and different brain regions. For the expression of histamine receptor under epilepsy, more researches are needed to elucidate the changes of histamine receptors, especially H2R and H4R.