Central histaminergic signalling, neural excitability and epilepsy

Abstract

Epilepsy is a common neurological disorder characterized by repeated and spontaneous epileptic seizures and is not well controlled by current medication. Traditional theory suggests that epilepsy results from an imbalance of excitatory glutamate neurons and inhibitory GABAergic neurons. However, new evidence from clinical and preclinical research suggests that histamine in the CNS plays an important role in the modulation of neural excitability and in the pathogenesis of epilepsy. Many histamine receptor ligands have achieved curative effects in animal epilepsy models, among which the histamine H 3 receptor antagonist pitolisant has shown anti-epileptic effects in clinical trials. Recent studies, therefore, have focused on the potential action of histamine receptors to control and treat epilepsy. In this review, we summarize the findings from animal and clinical epilepsy research on the role of brain histamine and its receptors. We also identify current gaps in the research and suggest where further studies are most needed.

Histamine bidirectionally regulates the intrinsic excitability of parvalbumin‐positive neurons in the lateral globus pallidus and promotes motor behaviour

“…Accumulating studies have demonstrated that three types of histamine receptors (H 1 R, H 2 R and H 3 R) are found in the LGP of rodents, human and non‐human primate brains (Lozada et al, 2005; Nieto‐Alamilla et al, 2016). Perfusion of GP slices with the selective H 3 R agonist immepip inhibits glutamatergic transmission and reduces the spontaneous firing frequency of rat LGP neurons and ultimately promotes rotational behaviour after the systemic administration of apomorphine in experimental rats (Osorio‐Espinoza et al, 2011; Yang et al, 2022). Moreover, histamine has been reported to activate GP neurons through H 2 R and its associated intracellular G S protein–AC–PKA signalling pathway in brain slices in vitro (Chen et al, 2005; Haas & Panula, 2003).…”

“…Although the central histaminergic nervous system originates from the tuberomammillary nucleus (TMN) of the hypothalamus, its fibres extensively project to most regions in the brain, including the basal ganglia (Panula & Nuutinen, 2013; Yang et al, 2022; Zhuang, Li, et al, 2018). Past studies have reported that histamine plays an important role in sleep–wake regulation, learning and memory, food intake, body fluid balance and temperature regulation (Haas et al, 2008; Panula et al, 2015).…”

Inherent seizure susceptibility in patients with antihistamine-induced acute symptomatic seizure: a resting-state EEG analysis

“…However, the pathophysiological mechanisms by which antihistamines induce seizures are not fully understood. An experimental study found that H1-receptor knockout mice experienced longer and more seizures than wild-type mice 7 . In addition, the administration of H1-receptor antagonists increased seizure severity and neuronal damage in the septum, thalamus, hippocampus, and retrosplenial granular cortex of kainic acid-treated wild-type mice 7 .…”

“…An experimental study found that H1-receptor knockout mice experienced longer and more seizures than wild-type mice 7 . In addition, the administration of H1-receptor antagonists increased seizure severity and neuronal damage in the septum, thalamus, hippocampus, and retrosplenial granular cortex of kainic acid-treated wild-type mice 7 . These findings contribute to the knowledge that the central histaminergic neuronal system is a powerful modulator of brain activity, and that its functional disturbance is related to seizure disorders 31 .…”

“…Several lines of evidence suggest that antihistamines can induce neuronal excitability in the ventral tegmental area, substantia nigra, and ventromedial hypothalamus by acting on histamine receptors and enhance hippocampal CA1 synaptic excitation, leading to increase in seizure susceptibility and severity 7 – 9 . Considering that antihistamines tend to induce seizures by increasing electrical activity in specific brain regions and by enhancing the synaptic transmission of neuronal excitability 7 , 9 , quantitative electroencephalography (EEG) analyses of both neuronal activities in each brain region and large-scale network properties for the transmission of excitability may be optimal approaches for quantitatively evaluating seizure susceptibility after antihistamine use and for the diagnosis of AIS.…”