Anti-apoptotic effects of trimethoxy-substituted monocarbonyl curcumin analogues in experimental Alzheimer’s disease

I n t r o d u c t i o n. Alzheimer’s disease (AD) is one of the most common dementia disorders with an alarming rate of spread. The significant medical, social and economic burden of this disease makes it necessary to develop new agents for its treatment. In this case, the action of these agents can be focused on specific pathophysiological mechanisms of the disease, for example, apoptosis.

A i m. To study the effect of new monocarbonyl curcumin analogues on the change in the apoptotic response in rat brain under experimental AD.

M a t e r i a l s a n d m e t h o d s. AD was simulated in female Wistar rats by injecting beta-amyloid aggregates (1-42) into the CA1 region of the hippocampus. The studied compounds (1E, 4E)-1,5-bis (3,4,5-trimethoxyphenyl) penta-1,4-dien-3-one (code named AZBAX4) and (1E, 4E)-1,5-bis (2,4,6-trimethoxyphenyl) penta-1,4-dien-3-one (code named AZBAX6) at doses of 20 mg/kg (orally) each compound and the reference drug, donepezil at a dose of 50 mg/kg (orally) were administered for 30 days from the start of pathology modeling. Thereafter, samples of the hippocampus and cerebral cortex were collected from the animals for assessment of the concentration of apoptosis-related biomarkers: cytochrome c, apoptosis-inducing factor, caspase-3 and PUMA protein.

R e s u l t s. The administration of AZBAX4 and AZBAX6 compounds, as well as of the reference drug, contributed to a significant decrease in the concentration of proapoptotic biomarkers both in the hippocampus and cerebral cortex. The concentration of biomarkers of the intrinsic pathway of apoptosis (apoptosis-inducing factor and cytochrome c) was significantly (p < 0.05) lower in animals treated with AZBAX4 compared to rats treated with AZBAX6 and donepezil.

C o n c l u s i o n. The present study showed the relevance of further investigation of (1E, 4E)-1,5-bis (3,4,5-trimethoxyphenyl) penta-1,4-dien-3-one as an anti-apoptotic agent for therapy of AD.

1. Dhapola R., Hota S.S., Sarma P. et al. Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer’s disease. Inflammopharmacology. 2021;29(6):1669-1681. DOI: 10.1007/s10787-021-00889-6.

2. Serrano-Pozo A., Growdon J.H. Is Alzheimer’s disease risk modifiable? J. Alzheimer’s Dis. 2019;67(3):795-819. DOI: 10.3233/JAD181028.

3. 2022 Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2022;18(4):700-789. DOI: 10.1002/alz.12638.

4. Barage S.H., Sonawane K.D. Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer’s disease. Neuropeptides. 2015;52:1-18. DOI: 10.1016/j.npep.2015.06.008.

5. Scheltens P., De Strooper B., Kivipelto M. et al. Alzheimer’s disease. Lancet. 2021;397(10284):1577-1590. DOI: 10.1016/S0140-6736(20)32205-4.

6. Song L., Yao L., Zhang L. et al. Schizandrol A protects against Aβ1-42-INDUCED autophagy via activation of PI3K/AKT/mTOR pathway in SH-SY5Y cells and primary hippocampal neurons. Naunyn Schmiedebergs Arch. Pharmacol. 2020;393(9):1739-1752. DOI: 10.1007/s00210-019-01792-2.

7. Thakur S., Dhapola R., Sarma P. et al. Neuroinflammation in Alzheimer’s disease: current progress in molecular signaling and therapeutics. Inflammation. 2023;46(1):1-17. DOI: 10.1007/s10753-022-01721-1.

8. Wang H., Sun M., Li W. et al. Biomarkers associated with the pathogenesis of Alzheimer’s disease. Front. Cell. Neurosci. 2023;17:1279046. DOI: 10.3389/fncel.2023.1279046.

9. Paquet C., Nicoll J.A., Love S. et al. Downregulated apoptosis and autophagy after anti-Aβ immunotherapy in Alzheimer’s disease. Brain Pathol. 2018;28(5):603-610. DOI: 10.1111/bpa.12567.

10. Morley J.E., Farr S.A., Nguyen A.D. Alzheimer disease. Clin. Geriatr. Med. 2018;34(4):591-601. DOI: 10.1016/j.cger.2018.06.006.

11. Sugiura R., Satoh R., Takasaki T. ERK: A double-edged sword in cancer. ERK-dependent apoptosis as a potential therapeutic strategy for cancer. Cells. 2021;10(10):2509. DOI: 10.3390/cells10102509.

12. Erekat N.S. Apoptosis and its therapeutic implications in neurodegenerative diseases. Clin. Anat. 2022;35(1):65-78. DOI: 10.1002/ca.23792.

13. Kumari S., Dhapola R., Reddy D.H. Apoptosis in Alzheimer’s disease: insight into the signaling pathways and therapeutic avenues. Apoptosis. 2023;28(7-8):943-957. DOI: 10.1007/s10495-023-01848-y.

14. Pozdnyakov D.I., Vikhor A.A., Rukovitsina V.M., Oganesyan E.T. Correction of mitochondrial dysfunction with trimethoxy-substituted monocarbonyl curcumin analogues in experimental Alzheimer’s disease. Pharmacy and Pharmacology. 2023;11(6):471-481. DOI: 10.19163/2307-9266-2023-11-6-471-481. (In Russ.)

15. Mead R., Gilmour S.G., Mead A. Statistical Principles for the Design of Experiments: Applications to Real Experiments. Cambridge, UK: Cambridge University Press, 2012.

16. Paxinos G., Watson C. The Rat Brain in Stereotaxic Coordinates. Amsterdam, The Netherlands: Elsevier, 2007.

17. Rosales-Corral S.A., Lopez-Armas G., Cruz-Ramos J. et al. Alterations in lipid levels of mitochondrial membranes induced by amyloid-β: a protective role of melatonin. Int. J. Alzheimer’s Dis. 2012;2012:459806. DOI:10.1155/2012/459806.

18. Hussain H., Ahmad S., Shah S.W.A. et al. Neuroprotective potential of synthetic mono-carbonyl curcumin analogs assessed by molecular docking studies. Molecules. 2021;26(23):7168. DOI: 10.3390/molecules26237168.

19. Zong L., Liang Z. Apoptosis-inducing factor: a mitochondrial protein associated with metabolic diseases – a narrative review. Cardiovasc. Diagn. Ther. 2023;13(3):609-622. DOI: 10.21037/cdt-23-123.

20. Novo N., Romero-Tamayo S., Marcuello C. et al. Beyond a platform protein for the degradosome assembly: The Apoptosis-Inducing Factor as an efficient nuclease involved in chromatinolysis. PNAS Nexus. 2022;2(2):pgac312. DOI: 10.1093/pnasnexus/pgac312.

21. Vikhor A.A., Pozdnyakov D.I. (2024). Correction of the neuroinflammation reaction with monocarbonyl analogues of curcumin in cells of the hippocampus and cerebral cortex in rats with experimental Alzheimer’s disease. In Volga Shores: Modern Technologies in Medicine, Biology and Veterinary Medicine: collection of writings of the I International Scientific and Practical Forum; Saratov State Medical University named after V.I. Razumovsky. Saratov. P. 17–18. (In Russ.)

22. Li S., Stern A.M. Bioactive human Alzheimer brain soluble Aβ: pathophysiology and therapeutic opportunities. Mol. Psychiatry. 2022;27(8):3182-3191. DOI: 10.1038/s41380-022-01589-5.