Pharmacological Basis for the Use of Evodiamine in Alzheimer’s Disease: Antioxidation and Antiapoptosis

Abstract

Evodiamine (Evo), a major alkaloid compound isolated from the dry unripened fruit of Evodia fructus, has a wide range of pharmacological activities. The present study sought to explore the neuroprotective effects of Evo in l-glutamate (l-Glu)-induced apoptosis of HT22 cells, and in a d-galactose and aluminum trichloride-developed Alzheimer’s disease (AD) mouse model. Evo significantly enhanced cell viability, inhibited the accumulation of reactive oxygen species, ameliorated mitochondrial function, increased the B-cell lymphoma-2 protein content, and inhibited the high expression levels of Bax, Bad, and cleaved-caspase-3 and -8 in l-Glu-induced HT22 cells. Evo also enhanced the phosphorylation activities of protein kinase B and the mammalian target of rapamycin in the l-Glu-induced HT22 cells. In the AD mouse model, Evo reduced the aimless and chaotic movements, reduced the time spent in the central area in the open field test, and decreased the escape latency time in the Morris water maze test. Evo reduced the deposition of amyloid beta 42 (Aβ42) in the brain, and increased the serum level of Aβ42, but showed no significant effects on Aβ40. In addition, six weeks of Evo administration significantly suppressed oxidative stress by modulating the related enzyme levels. In the central cholinergic system of AD mice, Evo significantly increased the serum levels of acetylcholine and choline acetyltransferase and decreased the level of acetylcholinesterase in the serum, hypothalamus, and brain. Our results provide experimental evidence that Evo can serve as a neuroprotective candidate for the prevention and/or treatment of neurodegenerative diseases.

Antiproliferative Effects of Alkaloid Evodiamine and Its Derivatives

“…Evodiamine has been traditionally used to cure headache, amenorrhea, postpartum hemorrhage and gastrointestinal disorders. The biological activities of evodiamine have been widely investigated, including anti-obesity [ 13 , 14 ], anti-inflammatory [ 15 , 16 ], anti-atherosclerotic [ 17 ], neuroprotective [ 18 , 19 ], anti-gastrointestinal motility [ 20 ], and antiproliferative effects [ 21 ]. Among them, the antiproliferative activity of the multitargeting molecule evodiamine is attractive.…”

Anti-Inflammatory and Tau Phosphorylation–Inhibitory Effects of Eupatin

“…Because GSK3β has inherently high activity, inhibiting and activating phosphorylation on Ser9 and Tyr216, respectively, are its primary means of regulation [19]. Furthermore, when overexpressed in mice, GSK3β causes tau hyperphosphorylation and leads to tau pathology similar to that in patients with AD [16,30]. Phosphorylation in regions bordering the microtubule-binding domain (the primary sites of GSK3β-mediated tau phosphorylation) has been noted to lead to tau detaching from microtubules, resulting in self-aggregation [31].…”

“…Patients with AD have reduced tau phosphatase activity, most of which is caused by PP2A [6]. OA has been identi ed as a potent PP2A activity inhibitor that can induce AD-like tau hyperphosphorylation in vitro and in vivo [32,33]. Our prior research revealed the occurrence of signi cant tau phosphorylation in Neuro-2a cells that were given OA or transfected with the pRK5-EGFP-Tau P301L plasmid, which encodes human mutant P301L-tau [33].…”

“…Okadaic acid (OA) potently inhibits protein phosphatase 2A (PP2A) and is capable of inducing in vitro and in vivo AD-like tau hyperphosphorylation [15,16]. We observed signi cant tau phosphorylation in Neuro-2a cells when using OA to identify the inhibition of tau phosphorylation by eupatin.…”

An Indole Alkaloid Extracted from Evodia rutaecarpa Inhibits Colonic Motility of Rats In Vitro

“…It has been used for several hundred years as traditional Chinese medicine and was first recorded in the Shennong Herbal Classic. Concerning the pharmacological action of Evo, more attention has been paid to its beneficial effects on cancer, obesity, nociception, inflammation, cardiovascular diseases, Alzheimer's disease, infectious diseases, and thermoregulation [1][2][3][4][5][6][7]. Recent studies have demonstrated that Evo may be involved in regulating gastrointestinal motility, but the evidence is insufficient, and the potential mechanisms remain unknown.…”