Evodiamine derivatives improve cognitive abilities in APPswe/PS1ΔE9 transgenic mouse models of Alzheimer's disease

Abstract

Background: Alzheimer's disease (AD) is a complex neurodegenerative disease. Due to the complexity of its molecular pathogenesis and the interaction of the numerous factors involved, the etiology and pathogenesis of AD have not been fully elucidated. Therefore, effective treatment for AD remains to be developed. Evodiamine, a quinolone alkaloid, has been found to improve learning and memory ability to in the APP^swe/PS1^△E9 mouse model of dementia. However, the cytotoxicity and physicochemical properties of evodiamine have limited its use in the treatment of AD.

Methods: Evodiamine and its derivatives were effectively synthesized by EDCI-mediated condensation at room temperature. These target compounds contained 1 thio- and 21 oxo-evodiamine derivatives with different substituted groups. The cytotoxicity of evodiamine and its derivatives and the neuroprotective effects of the evodiamine derivatives against H₂O₂-induced cell loss in SH-SY5Y cells were investigated using the WST-8 assay. The Morris water-maze test was used to detect the effect of evodiamine and its derivatives on improving learning and memory in APP^swe/PS1^△E9 mice.

Results: In this study, a series of oxo- and thio-evodiamine derivatives was synthesized. Several derivatives showed lower cytotoxicity and stronger neuroprotective effects than evodiamine and elicited enhanced cognitive improvement, especially in the test of spatial memory in APP^swe/PS1^△E9 mice.

Conclusion: Our study provides insights for developing novel evodiamine derivatives for chemical intervention and treatment of AD.

Keywords: evodiamine derivatives; mouse model; neuroprotective; spatial memory.

Figure 1

The structure and synthesis of evodiamine and its derivatives. Evodiamine and its derivatives were effectively synthesized by EDCI‐mediated condensation at room temperature

Figure 2

The SH‐SY5Y and HepG2 cells viability was assessed by the CCK‐8 assay. A, Effect of 5 μg/mL evodiamine and its derivatives on SH‐SY5Y cell viability (n = 6, ****P < .0001, ***P < .001, evodiamine derivatives treatment groups vs evodiamine treatment group). B, Effect of 5 μg/mL evodiamine and its derivatives on HepG2 cell viability (n = 6, ****P < .0001, ***P < .001, evodiamine derivatives treatment groups vs evodiamine treatment group)

Figure 3

Effects of evodiamine and its derivatives on H₂O₂‐induced cytotoxicity in SH‐SY5Y cells determined by CCK‐8 assay. The SH‐SY5Y cells were seeded in 96‐well plates (10 000 cells/well) and cultured for 24 h. Evodiamine and its derivatives (41, 47, 49, 51, 54, 58, 59, 60 and 61) were then added to the wells at doses of 0.5 µg/mL, 0.05 µg/mL and 0.005 µg/mL and the cells were cultured for 3 h. H₂O₂ was then added to the wells at a final concentration of 150 μmol/L and the cells were cultured for 24 h. Cell viability was then evaluated by CCK8 assay. The values shown are means ± SE (n = 3)

Figure 4

Behavioral performance of animals in the Morris water maze. A, Time spent in the quadrant that previously contained the platform (n = 7, *P < .05, evodiamine derivatives 49, 51, 58 and 60 vs APP^swe/PS1^ΔE9). B, Number of crossings to the previous location of the platform (n = 7, *P < .05, evodiamine derivatives 49, 51, 58 and 60 vs APP^swe/PS1^ΔE9)