Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Abstract

Much has been learned over the past 20 years about the role of histamine as a neurotransmitter. This brief article attempts to evaluate the progress accomplished in this field, and discusses the therapeutic potential of the H3 receptor (H3R). All histaminergic neurons are localized in the tuberomammillary nucleus of the posterior hypothalamus and project to almost all regions of the CNS. Histamine exerts its effect via interaction with specific receptors (H1R, H2R, H3R and H4R). Antagonists of both H1R and H2R have been successful as blockbuster drugs for treating allergic conditions and gastric ulcers. H4R is still awaiting better functional characterization, but the H3R is an attractive target for potential therapies of CNS disorders. Indeed, considerable interest was raised by reports that pharmacological blockade of H3Rs exerted procognitive effects in a variety of animal tasks analyzing different types of memory. In addition, blockade of H3Rs increased wakefulness and reduced bodyweight in animal models. Such findings hint at the potential use of H3R antagonists/inverse agonists for the treatment of Alzheimer’s disease and other dementias, attention-deficit hyperactivity disorder, obesity and sleep disorders. As a result, an increasing number of H3R antagonists/inverse agonists progress through the clinic for the treatment of a variety of conditions, including attention-deficit hyperactivity disorder, cognitive disorders, narcolepsy and schizophrenia. Moreover, the use of H3R antagonists/inverse agonists that weaken traumatic memories may alleviate disorders such as post-traumatic stress syndrome, panic attacks, specific phobias and generalized anxiety. The use of H3R ligands for the treatment of neurodegenerative disorders is demonstrated in several studies, indicating a role of the histamine neurons and H3Rs in neuroprotection. Recently, direct evidence demonstrated that histaminergic neurons are organized into functionally distinct circuits, impinging on different brain regions, and displaying selective control mechanisms. This could imply independent functions of subsets of histaminergic neurons according to their respective origin and terminal projections. The possibility that H3Rs control only some of those functions implies that H3R-directed therapies may achieve selective effects, with minimal side effects, and this may increase the interest regarding this class of drugs.

Histamine neurons in the tuberomamillary nucleus: a whole center or distinct subpopulations?

“…Indeed, the histaminergic system can implement many functions, including the arousal state, brain energy metabolism, locomotor activity, neuroendocrine, autonomic, and vestibular functions, feeding, drinking, sexual behavior, and analgesia, presumably by engaging independent subpopulations of histaminergic neurons according to the brain regions required for a particular behavioral outcome. Consistent with this hypothesis, heterogeneity within the histaminergic neuronal population in response to stress (Miklos and Kovacs, 2003 ) and pharmacological stimulations was recently reported (Blandina et al, 2010 ; Passani and Blandina, 2011 ).…”

Betahistine Attenuates Seizures, Neurodegeneration, Apoptosis, and Gliosis in the Cerebral Cortex and Hippocampus in a Mouse Model of Epilepsy: A Histological, Immunohistochemical, and Biochemical Study

“…This was also confirmed by the marked decrease in the gene expression of caspase-3 and caspase-9. These findings matched that of Blandina et al (2010), who found that histamine protects cerebral cortex and hippocampus neurons from damage caused by kainic acid.…”

Histamine, histamine receptors, and neuropathic pain relief

“…H 3 receptors are mostly presynaptic, expressed as autoreceptors on histaminergic neurons involved in the negative feedback control of histamine levels (Arrang et al, 1983; Hough & Rice, 2011), while H 3 heteroreceptors on postsynaptic nonhistaminergic neurons also regulate negatively the release of neurotransmitters, such as ACh, dopamine, 5‐HT, and noradrenaline (Blandina, Munari, Giannoni, Mariottini, & Passani, 2010; Gemkow et al, 2009; Giannoni et al, 2010). Since the cloning of H 3 receptors (Lovenberg et al, 1999), there has been an increased interest within the pharmaceutical industry in developing ligands for this receptor to target several diseases, including neuropathic pain.…”

“…In line with this, electrophysiological studies performed in anaesthetized animals indicated that, after systemic administration, GSK189254 dose‐dependently decreased both evoked and spontaneous firing of wide dynamic range neurons in neuropathic, but not sham‐operated rats (McGaraughty et al, 2012). However, analgesia induced by the blockade of the H 3 receptor can also be mediated via H 3 heteroreceptors that regulate other neurotransmitters' release; the blockade of the H 3 receptor is known to increase the release of ACh, dopamine, 5‐HT, noradrenaline, and SP in the CNS (Blandina et al, 2010; Gemkow et al, 2009; Giannoni et al, 2010).…”