Transcriptomics and biochemical evidence of trigonelline ameliorating learning and memory decline in the senescence-accelerated mouse prone 8 (SAMP8) model by suppressing proinflammatory cytokines and elevating neurotransmitter release

Abstract

In recent years, exploring natural compounds with functional properties to ameliorate aging-associated cognitive decline has become a research priority to ensure healthy aging. In the present study, we investigated the effects of Trigonelline (TG), a plant alkaloid, on memory and spatial learning in 16-week-old senescence-accelerated mouse model SAMP8 using an integrated approach for cognitive and molecular biology aspects. After 30 days of oral administration of TG at the dose of 5 mg/kg/day, the mice were trained in Morris Water Maze task. TG-treated SAMP8 mice exhibited significant improvement in the parameters of escape latency, distance moved, and annulus crossing index. Next, we performed a whole-genome transcriptome profiling of the mouse hippocampus using microarrays. Gene ontology analyses showed that a wide range of biological processes, including nervous system development, mitochondrial function, ATP synthesis, and several signaling pathways related to inflammation, autophagy, and neurotransmitter release, were significantly enriched in TG-treated SAMP8 compared to nontreated. Further, a nonlinear dimensionality reduction technique, Uniform Manifold Approximation and Projection (UMAP), was applied to identify clusters of functions that revealed TG primarily regulated pathways related to inflammation, followed by those involved in neurotransmitter release. In addition, a protein–protein interaction network analysis indicated that TG may exert its biological effects through negatively modulating Traf6-mediated NF-κB activation. Finally, ELISA test showed that TG treatment significantly decreased proinflammatory cytokines- TNFα and IL6 and increased neurotransmitters- dopamine, noradrenaline, and serotonin in mouse hippocampus. Altogether, our integrated bio-cognitive approach highlights the potential of TG in alleviating age-related memory and spatial impairment.

Pharmacological Activities, Therapeutic Effects, and Mechanistic Actions of Trigonelline

“…TRG (50 and 100 mg/kg) treatment improved cognitive performance by lowering the AGE and AChE levels and reversing oxidative damage in a D-galactose (D-gal)-induced amnesia model [ 22 ]. TRG ameliorated learning and memory decline in the senescence-accelerated mouse-prone 8 (SAMP8) model [ 23 ]. Particularly, TRG exerted effects in a wide range of biological processes including nervous system development, mitochondrial function, ATP synthesis, inflammation, autophagy, and neurotransmitter release through negatively modulating Traf6-mediated NF-kB activation in the SAMP8 model.…”

“…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 , ...…”

“…Particularly, TRG exerted effects in a wide range of biological processes including nervous system development, mitochondrial function, ATP synthesis, inflammation, autophagy, and neurotransmitter release through negatively modulating Traf6-mediated NF-kB activation in the SAMP8 model. TRG suppressed the expression of proinflammatory cytokines such as TNF-α and IL6 and enhanced the release of neurotransmitters including dopamine, noradrenaline, and serotonin in the mouse hippocampus [23]. 1C) Myeloperoxidase (MPO) plays an important role in stroke-related inflammation [72].…”

“…The hubs of the biological activities of TRG are glucose and lipid metabolic regulation and inflammatory and oxidative stress modulation, which result in homeostasis restoration and protective actions in many organs and tissues. 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..…”

A High-Throughput Screening of a Natural Products Library for Mitochondria Modulators

“…For example, trigonelline, an alkaloid previously isolated from plants such as fenugreek, Japanese radish, and coffee beans stands out for its potential to attenuate oxidative stress and show activity in mitochondrial dysfunction-linked conditions, such as diabetes, PD, AD, stroke, dementia, and depression [90]. Trigonelline improved memory function in AD and showed neuroprotective and antiapoptotic effects in a 6-OHDA-induced model of PD in rats [91][92][93]. Our work demonstrated that these beneficial effects may at least partially be attributed to its mitoprotective functions.…”