Nootropic herbal formulations for the treatment of Alzheimer’s disease: In vivo pharmacological assay and molecular docking studies

Year 2020, Volume: 50 Issue: 2, 116 - 124, 27.08.2020

Naveen Kumar Kotla Shibnath Kamila Shivani Patel Joel Kothapally Aparna Kongara Satheesh Madhav

Abstract

Background and Aims: The main aim of the study was to enhance the cognitive function of the brain by nootropic herbal formulations in animal models. Polyphyto herbal formulations were known to enhance the cognition and memory function by several pathways such as anti-oxidative, anti-inflammatory, and cell signaling pathways. In this study, six formulations were prepared by mixing specified plant parts and were coded as NHF1, NHF2, NHF3, NHF4, NHF5, and NHF6. Methods: The potency of the formulations was assessed by In vivo (photo actometer, rod walking test, pole climbing test, and Ellman’s acetylcholinesterase test) studies. Results: NHF1 and NHF5 exhibited greater activity than the standard drug donepezil in vivo (Ellman’s acetylcholinesterase test) analysis. NHF1 and NHF5 formulations containing plant parts were further investigated against several published literatures for the identification of chemical constituents and those chemical constituents were subjected to molecular docking and in silico ADME prediction studies to figure out the possible compounds responsible for the cholinesterase inhibition activity. Conclusion: In conclusion, the computational studies also reveal that presence of chemical constituents such as sarsasapogenin (13.13 nM), racemosol (16.26 nM), and beta-sitosterol (30.47 nM) having binding energy (-10.75 kcal/mol), (-10.63 kcal/mol), (-10.25 kcal/mol), might be directly responsible for the nootropic activity.

Keywords

Herbal, nootropic, acetylcholinesterase, Alzheimer, autodock 4.2.6, sarsasapogenin, SwissADME

References

• Aggleton, J. P., Pralus, A., Nelson, A. J., & Hornberger, M. (2016). Thalamic pathology and memory loss in early Alzheimer’s disease: moving the focus from the medial temporal lobe to Papez circuit. Brain, 139(Pt 7), 1877–1890.
• Ayaz, M., Junaid, M., Ullah, F., Subhan, F., Sadiq, A., Ali, G., Ahmad, S. (2017). Anti-Alzheimer’s Studies on β-Sitosterol Isolated from Polygonum hydropiper L. Frontiers in Pharmacology, 8(697).
• Chinedu, E., Arome, D., & Ameh, F. S. (2013). A new method for determining acute toxicity in animal models. Toxicology International, 20(3), 224–226.
• Cook, L., & Weidley, E. (1957). Behavioral effects of some psychopharmacological agents. Annals of the New York Academy of Sciences, 66(3), 740–752.
• Da Silva Goncalves, A., Franca, T. C., & Vital de Oliveira, O. (2016). Computational studies of acetylcholinesterase complexed with fullerene derivatives: a new insight for Alzheimer disease treatment. Journal of Biomolecular Structure and Dynamics, 34(6), 1307–1316.
• Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7, 42717.
• De la Monte, S. M. (2012). Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res, 9(1), 35–66.
• Dos Santos Pisoni, D., Sobieski da Costa, J., Gamba, D., Petzhold, C. L., de Amorim Borges, A. C., Ceschi, M. A., Saraiva Gonçalves, C. A. (2010). Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine analogues from terpenic cyclanones. European journal of medicinal chemistry, 45(2), 526–535.
• Dunham, N. W., & Miya, T. S. (1957). A note on a simple apparatus for detecting neurological deficit in rats and mice. Journal of the American Pharmaceutical Association, 46(3), 208-209.
• Ellman, G. L., Courtney, K. D., Andres, V., & Featherstone, R. M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology, 7(2), 88–95.
• Ghribia, L., Ghouilaa, H., Omrib, A., Besbesb, M., & Janneta, H. B. (2014). Antioxidant and anti-acetylcholinesterase activities of extracts and secondary metabolites from Acacia cyanophylla. Asian Pac J Trop Biomed, 4(Suppl 1), 417–423.
• Kashyap, P., Muthusamy, K., Niranjan, M., Trikha, S., & Kumar, S. (2020). Sarsasapogenin: A steroidal saponin from Asparagus racemosus as multi target directed ligand in Alzheimer’s disease. Steroids, 153, 108529.
• Katsila, T., Spyroulias, G. A., Patrinos, G. P., & Matsoukas, M. T. (2016). Computational approaches in target identification and drug discovery. Computational and Structural Biotechnology Journal, 14, 177–184.
• Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., & Bolton, E. E. (2019). PubChem 2019 update: improved access to chemical data. Nucleic Acids Res, 47(D1), d1102-d1109.
• Kulkarni, R., Girish, K. J., & Kumar, A. (2012). Nootropic herbs (Medhya Rasayana) in Ayurveda: An update. Pharmacognosy reviews, 6(12), 147–153.
• McKhann, G. M., Albert, M. S., Grossman, M., Miller, B., Dickson, D., & Trojanowski, J. Q. (2001). Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch Neurol, 58(11), 1803–1809.
• Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDock- Tools4: Automated docking with selective receptor flexibility. J Comput Chem, 30(16), 2785–2791.
• Murray, A. P., Faraoni, M. B., Castro, M. J., Alza, N. P., & Cavallaro, V. (2013). Natural AChE Inhibitors from Plants and their Contribution to Alzheimer’s Disease Therapy. Curr Neuropharmacol, 11(4), 388–413.
• Musthaba, M., Baboota, S., Athar, T. M., Thajudeen, K. Y., Ahmed, S., & Ali, J. (2010). Patented herbal formulations and their therapeutic applications. Recent Pat Drug Deliv Formul, 4(3), 231–244.
• O’Boyle, N. M., Banck, M., James, C. A., Morley, C., Vandermeersch, T., & Hutchison, G. R. (2011). Open Babel: An open chemical toolbox. Journal of Cheminformatics, 3(1), 33.
• Odebiyi, O. O., & Sofowora, E. A. (1978). Phytochemical screening of Nigerian medicinal plants II. Lloydia, 41(3), 234–246.
• Rashed, K. N., Cardoso Sucupira, A. C., Moita Neto, J. M., & Feitosa, C. (2013). Evaluation of Acetylcholinesterase inhibition by Alnus rugosa L. stems methanol extract and phytochemical content. International Journal of Biomedical and Advance Research, 4(9), 606–609.
• Reddy, D. S., & Kulkarni, S. K. (1998). Possible role of nitric oxide in the nootropic and antiamnesic effects of neurosteroids on agingand dizocilpine-induced learning impairment. Brain Research, 799(2), 215–229.
• Shibnath, K., Madhav, N. V. S., & Sarkar, C. N. (2016). Safety and efficacy study of herbal polyphyto formulations: For its learning and memory enhancing properties. International Journal of Pharmacy and Pharmaceutical Sciences, 8(7).
• Velavan, S., Nagulendran, K. R., Mahesh R., Hazeena Begum V. (2007). The Chemistry, Pharmacological and Therapeutic Applications of Asparagus racemosus- A Review. Pharmacognosy Reviews, 1, 350-360.
• Soman, I., Mengi, S. A., & Kasture, S. B. (2004). Effect of leaves of Butea frondosa on stress, anxiety, and cognition in rats. Pharmacology, Biochemistry, and Behavior, 79(1), 11–16.
• Sy, L. K., Lok, C. N., Wang, J. Y., Liu, Y., Cheng, L., Wan, P. K., Che, C. M. (2016). Identification of “sarsasapogenin-aglyconed” timosaponins as novel Abeta-lowering modulators of amyloid precursor protein processing. Chemical Science, 7(5), 3206–3214.
• Thomsen, T., Kewitz, H., & Pleul, O. (1988). Estimation of cholinesterase activity (EC 3.1.1.7; 3.1.1.8) in undiluted plasma and erythrocytes as a tool for measuring in vivo effects of reversible inhibitors. Journal of Clinical Chemistry and Clinical Biochemistry, 26(7), 469–475.
• Trease, G. E., & Evans, W. C. (1996). Phenols and phenolic glycosides. Pharmacognosy Journal, 14, 218–254.
• Waldemar, G., Dubois, B., Emre, M., Georges, J., McKeith, I. G., Rossor, M., Winblad, B. (2007). Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. European Journal of Neurology, 14(1), e1–26.
• Wang, W., Wang, W., Yao, G., Ren, Q., Wang, D., Wang, Z., Song, S. (2018). Novel sarsasapogenin-triazolyl hybrids as potential anti- Alzheimer’s agents: Design, synthesis and biological evaluation. European Journal of Medicinal Chemistry, 151, 351–362.
• Yang, G. X., Ge, S. L., Wu, Y., Huang, J., Li, S. L., Wang, R., & Ma, L. (2018). Design, synthesis and biological evaluation of 3-piperazinecarboxylate sarsasapogenin derivatives as potential multifunctional anti-Alzheimer agents. European Journal of Medicinal Chemistry, 156, 206–215.
• Zeng, Q., Li, L., Jin, Y., Chen, Z., Duan, L., Cao, M., & Wu, Z. (2019). A Network Pharmacology Approach to Reveal the Underlying Mechanisms of Paeonia lactiflora Pall. On the Treatment of Alzheimer’s Disease. Evidence-Based Complementary and Alternative Medicine, Volume 2019, Article ID 8706589.