Inhibition of Astrocytic Histamine N-Methyltransferase as a Possible Target for the Treatment of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) represents the principal cause of dementia among the elderly. Great efforts have been established to understand the physiopathology of AD. Changes in neurotransmitter systems in patients with AD, including cholinergic, GABAergic, serotoninergic, noradrenergic, and histaminergic changes have been reported. Interestingly, changes in the histaminergic system have been related to cognitive impairment in AD patients. The principal pathological changes in the brains of AD patients, related to the histaminergic system, are neurofibrillary degeneration of the tuberomammillary nucleus, the main source of histamine in the brain, low histamine levels, and altered signaling of its receptors. The increase of histamine levels can be achieved by inhibiting its degrading enzyme, histamine N-methyltransferase (HNMT), a cytoplasmatic enzyme located in astrocytes. Thus, increasing histamine levels could be employed in AD patients as co-therapy due to their effects on cognitive functions, neuroplasticity, neuronal survival, neurogenesis, and the degradation of amyloid beta (Aβ) peptides. In this sense, the evaluation of the impact of HNMT inhibitors on animal models of AD would be interesting, consequently highlighting its relevance.

Drug Repurposing to Inhibit Histamine N-Methyl Transferase

“…From rigid docking studies, it is possible to observe that selected drugs and reference HNMT inhibitor (metoprine) showed interactions with amino acids located in the histamine-binding domain, and particularly with Tyr-146, Tyr-147, Val-173, Trp-179, Trp-183, Cys-196, and Tyr-198, which have been known to play important roles in HNMT inhibition [ 8 ]. The structures of selected compounds are showed in Figure 1 .…”

“…Initially, the re-docking of metoprine to the binding site of HNMT enzyme was carried out to validate that the reference ligand was docked to the HNMT receptor in the way in which it was experimentally observed. The resulting complex showed ten significant amino acids involved in the interactions: Tyr-15, Glu-28, Tyr-146, Tyr-147, Val-173, Trp-179, Trp-183, Cys-196, and Tyr-198, which are important for HNMT recognition [ 8 ] ( Figure S1C in Supplementary Materials ). The RMSD between the docked and the crystal structure of metoprine was only 0.98 Å (less than 1 Å), which is satisfactory.…”

“…Recently, enhancing histamine neurotransmission by inhibition of their catabolic enzyme HNMT has been proposed as a potential therapeutical strategy for AD patients [ 8 ], due to their effects on cognitive functions [ 20 ], neuroplasticity [ 21 ], neurogenesis [ 22 ], and the degradation of the amyloid beta (Aβ) peptide [ 23 ]. Consequently, a combination of computational approaches during drug repurposing offers benefits in AD drug development.…”

“…Alterations of the histaminergic system have been described in several neurological diseases [ 7 ]. Interestingly, decreased histamine levels have been shown in Alzheimer’s disease (AD), depression, and narcolepsy; as a result, the increase in histamine levels represents a new approach [ 8 ].…”

Review of microbiota gut brain axis and innate immunity in inflammatory and infective diseases

“…However, depending on the receptors it acts on, histamine can also have pro-inflammatory properties by promoting the production of various chemokines ( Kim et al., 2022 ). It was reported that histamine may be associated with neuroinflammatory diseases, which may exacerbate the severity of AD ( Flores-Clemente et al., 2021 ). The concentration and localization of histamine receptors in the central or systemic regions have a broad impact on the occurrence of neuroinflammation, and regulating the gut microbiota to cause changes in histamine has become a possible route for treating inflammation ( Carthy and Ellender, 2021 ).…”