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.
Highlights
Alzheimer’s disease (AD), a chronic and progressive neurodegenerative disorder generally related to ageing, is characterized by cognitive dysfunction, impaired memory, and poor prognosis [1]
The addition of 25 mM L-Glu resulted in a 58.1% reduction in cell viability in HT22 cells (p < 0.001; FigurTeh2eAa)d, wdihtiiocnh wofa2s5simgnMifiLc-aGnltulyriemsuplrtoevdeidnbay538-.h1%prree-tdrueacttimonenitnocfeEllvvoiaabt idliotyseisnfrHomT252 tcoel4ls0 (μpM< (0p.0
In L-Glu-exposed HT22 cells, 23.3% of cells were apoptotic, compared with only 12.2% of cells that were pre-treated with 20 μM Evo (Figure 2B). 20 μM Evo alone had no significant effect on cell viability and apoptosis in HT22 cells (Figure S1A,B)
Summary
Alzheimer’s disease (AD), a chronic and progressive neurodegenerative disorder generally related to ageing, is characterized by cognitive dysfunction, impaired memory, and poor prognosis [1]. The pathological cause of AD is still mostly unknown, past findings have proven that patients with AD show an accumulation of abnormally folded beta-amyloid (Aβ) in senile plaques and neuronal apoptosis [2]. Oxidative stress has been reported as one of the key causes of neuronal apoptosis during the development of AD, which is associated with the remarkable accumulation of reactive oxygen species (ROS), mitochondrial dysfunction, and calcium accumulation [3]. ROS are catalyzed by a combination of redox active metal ions and Aβ in AD [4]. Jl.iMneorl.gSicci.s2y01s8te, 1m9,,xincluding decreased choline uptake and reduced choline acetyltransferase (C2hoAf T13) activity, have been noted in AD patients; the damaged cholinergic system may be further r(eCshpAonTs)iabcletivfoitryA, hβapvleaqbueeenfonromteadtioinn AanDdpinactireenatssi;nmg peahnowsphhiloer,ytlhaetiodnamofatgaeudpcrhooteliinne[r5g–ic7]s. KH)oiwn egvlieorb, ltahsetonmeuarmopurlottifeocrtimvee etofferecgtsuloafteEavpoo, petsopteicciparlolyteoinneAxpDressysmionpt[o1m5]s. ,Haonwdevtheer, uthnednereluyrionpgromteeccthivaeniesfmfescths aovfeEvnoo,teyspetecbieaellny soynstAemDastyicmapllytormeps,oarntedd.the underlying mechanisms have not yet been systematically reported
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