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.