Hordenine improves Parkinsonian‐like motor deficits in mice and nematodes by activating dopamine D2 receptor‐mediated signaling

Abstract

Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the striatum, leading to dopamine (DA) deficiency in the striatum and typical motor symptoms. A small molecule as a dietary supplement for PD would be ideal for practical reasons. Hordenine (HOR) is a phenolic phytochemical marketed as a dietary supplement found in cereals and germinated barley, as well as in beer, a widely consumed beverage. This study was aimed to identify HOR as a dopamine D2 receptor (DRD2) agonist in living cells, and investigate the alleviative effect and mechanism of HOR on PD-like motor deficits in mice and nematodes. Our results firstly showed that HOR is an agonist of DRD2, but not DRD1, in living cells. Moreover, HOR could improve the locomotor dysfunction, gait, and postural imbalance in MPTP-or 6-OHDA-induced mice or Caenorhabditis elegans, and prevent α-synuclein accumulation via the DRD2 pathway in C. elegans. Our results suggested that HOR could activate DRD2 to attenuate the PD-like motor deficits, and provide scientific evidence for the safety and reliability of HOR as a dietary supplement.

Exploring the broad-spectrum pharmacological activity of two less studied Australian native fruits: chemical characterisation using LCMS-driven metabolomics

“…79 Additionally, hordenine ( 33 ) and N -methyltyramine ( 36 ) were identified as functionally selective dopamine D2 receptor agonists which can be potential contributors to a mood-elevating effect. 80,81 N -Acetyltyramine ( 26 ) was found to be one of the key bioactive molecules that showed a strong antagonistic activity against several multidrug-resistant pathogenic bacteria. 82 In addition, one pyridine alkaloid ( N , N ′-bis(4-methoxybenzyl)pyridine-2,6-diamine 34 ), one quinoline alkaloid [1,5-dihydroxy-1,5-bis(quinolin-2-yl)pentan-3-one 54 ], one indole alkaloid (coconut ID: CNP0069107, 85 ) and one anthranilic acid alkaloid (glucopyranosyl anthranilate 51 ) were also reported in the native currant extracts.…”