Pharmacological Activities, Therapeutic Effects, and Mechanistic Actions of Trigonelline

Abstract

Trigonelline (TRG) is a natural polar hydrophilic alkaloid that is found in many plants such as green coffee beans and fenugreek seeds. TRG potentially acts on multiple molecular targets, including nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor γ, glycogen synthase kinase, tyrosinase, nerve growth factor, estrogen receptor, amyloid-β peptide, and several neurotransmitter receptors. In this review, we systematically summarize the pharmacological activities, medicinal properties, and mechanistic actions of TRG as a potential therapeutic agent. Mechanistically, TRG can facilitate the maintenance and restoration of the metabolic homeostasis of glucose and lipids. It can counteract inflammatory constituents at multiple levels by hampering pro-inflammatory factor release, alleviating inflammatory propagation, and attenuating tissue injury. It concurrently modulates oxidative stress by the blockage of the detrimental Nrf2 pathway when autophagy is impaired. Therefore, it exerts diverse therapeutic effects on a variety of pathological conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional effects, including neuroprotection from neurodegenerative disorders and diabetic peripheral neuropathy, neuromodulation, mitigation of cardiovascular disorders, skin diseases, diabetic mellitus, liver and kidney injuries, and anti-pathogen and anti-tumor activities. Further validations are required to define its specific targeting molecules, dissect the underlying mechanistic networks, and corroborate its efficacy in clinical trials.

Keywords: chronic metabolic diseases; inflammation; metabolic homeostasis; neuromodulation; oxidation; trigonelline.

Figure 1

A summary of therapeutic effects of TRG on multiple organs. TRG shows various beneficial roles in many pathological conditions. It can (1) modulate glucose and lipid homeostasis [4,5,6,7,8,9,10] (A); (2) suppress the inflammatory response and oxidative stress [11,12,13,14] (B,H,M); (2) facilitate recovery from neurological impairments such as neurodegenerative disorders [15,16,17,18], ischemia-induced brain damage [19,20], cognitive decline [21,22,23], diabetic peripheral neuropathy [24,25], depression, and epilepsy [26,27,28] (C); (3) mitigate DM and its complications [6,11,29,30,31,32] (A–F); (4) alleviate cellular injuries in the cardiovascular system [33,34], liver [35,36], kidney [37,38,39,40,41,42], gastric system [43,44], and skin [45,46,47] (D–F,I–L); and (5) inhibit proliferation and migration of tumor cells [48,49,50] (G). ↑, Increasing; ↓, decreasing. The graph was created with Biorender.com (accessed on 29 December 2023).

Figure 2

The proposed mechanistic actions of TRG on multiple targets. TRG can potentially bind to PPARγ, NGF, and several neurotransmitter receptors, restoring glucose and lipid homeostasis, promoting neuronal survival, and modulating neuronal activity [25,30,51] (A–C). TRG can act as a phytoestrogen to stimulate ER [52] (D). TRG can potentially bind to GSK (E), MPO, and Aβ (F), executing inhibitory effects [7,15,19]. TRG can prevent EMT (G), interfere with Nrf2 nuclear translocation (H), and suppress tyrosinase activity (I) [37,38,53,54,55]. The graph was created with Biorender.com (accessed on 29 December 2023).