Author(s):
Ashwija Kolakemar, Shivaprakash Gangachannaiah, Sadhana N Holla, Mohandas Rao KG, Smita Shenoy, Rajashekar Chinta, Chetan Hasmukh Mehta, Usha Yogendra Nayak
Email(s):
shiva.g@manipal.edu
DOI:
10.52711/0974-360X.2024.00029 
Address:
Ashwija Kolakemar1, Shivaprakash Gangachannaiah*1, Sadhana N Holla1, Mohandas Rao KG2, Smita Shenoy1, Rajashekar Chinta3, Chetan Hasmukh Mehta4, Usha Yogendra Nayak4
1Department of Pharmacology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal - 576104, Karnataka, India.
2Department of Basic Medical Sciences, Manipal Academy of Higher Education, Manipal - 576104, Karnataka, India.
3Department of Pharmacology, Manipal University College, Malaysia, Melaka, Malaysia.
4Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576104, Karnataka, India.
*Corresponding Author
Published In:
Volume - 17,
Issue - 1,
Year - 2024
ABSTRACT:
Introduction: Alzheimer's disease (AD) is a neurodegenerative condition characterised by the gradual loss of hippocampal and cortical neurons, resulting in diminished memory and cognitive function. Siponimod (SPM) a selective modulator of sphingosine 1-phosphate receptor subtype 1 and 5(S1P1,S1P5 receptors), was found to have neuroprotective effect in neurological disorders. The present study was conducted to evaluate its beneficial effects in AD. Materials and Methods: In-silico molecular docking and molecular dynamic simulation studies were carried to know its potential interactions with selected target proteins. In-vivo study was conducted inthirty rats divided randomly into five groups with six rats per group: Control group received Carboxy methyl cellulose; disease group were administered aluminium chloride (AlCl3);standard group received rivastigmine (RVST) with AlCl3; and the test groups received SPM (0.05mg/kg and 0.2mg/kg) with AlCl3. Morris water maze test and elevated plus maze was used to evaluate learning and memory. Behavioural changes and biochemical parameters estimation were performed at the end of experiment. Results: The molecular docking study using selected protein and ligands showed higher docking score and stable interactions at acetylcholinesterase (AChE) protein with SPM.Behavioural studies showed: decrease in transfer latency time in elevated plus maze; decrease in time to reach target platform and increase in time spent in target quadrant in Morris water maze test in SPM treated rats. Biochemical evaluation showed marked decrease in malondialdehyde (MDA), nitrite, myeloperoxidase (MPO)levels and increased antioxidant levels in SPM treated groups. SPM exhibited significant inhibitory activity onAChE. Conclusion: SPM was found to be effective in ameliorating AlCl3 induced AD. The observed benefits in restoring learning and memory were attributed to its inhibitory activity on AChE and its ability to suppress free radical mediated oxidative damage.
Cite this article:
Ashwija Kolakemar, Shivaprakash Gangachannaiah, Sadhana N Holla, Mohandas Rao KG, Smita Shenoy, Rajashekar Chinta, Chetan Hasmukh Mehta, Usha Yogendra Nayak. Sphingosine-1-Phosphate Receptor Modulator – Siponimod: An Evaluation to Ameliorate Aluminium Chloride Induced Behavioural Change and Biochemical effects. Research Journal of Pharmacy and Technology. 2024; 17(1):179-7. doi: 10.52711/0974-360X.2024.00029
Cite(Electronic):
Ashwija Kolakemar, Shivaprakash Gangachannaiah, Sadhana N Holla, Mohandas Rao KG, Smita Shenoy, Rajashekar Chinta, Chetan Hasmukh Mehta, Usha Yogendra Nayak. Sphingosine-1-Phosphate Receptor Modulator – Siponimod: An Evaluation to Ameliorate Aluminium Chloride Induced Behavioural Change and Biochemical effects. Research Journal of Pharmacy and Technology. 2024; 17(1):179-7. doi: 10.52711/0974-360X.2024.00029 Available on: https://rjptonline.org/AbstractView.aspx?PID=2024-17-1-29
REFERENCES:
1. WHO.Dementia,[Internet].2023[ cited 2023 April 16]. Available from:https://www.who.int/news-room/fact-sheets/detail/dementia.
2. Alzheimer’s disease facts and figures. Alzheimers Dement. 2022; 18(4): 700–89. doi:10.1002/alz.12638
3. Khan S, Barve KH, Kumar MS. Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease. Curr Neuropharmacol. 2020; 18(11): 1106–25. doi:10.2174/1570159X18666200528142429.
4. Sudha. R, Sathesh Kumar Sukumaran. Anti-Oxidants used for the Treatment of Alzheimer Disease. Research J. Pharm. and Tech. 2020; 13(1): 475-480.
5. Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957; 20(1): 11–21. doi:10.1136/jnnp.20.1.11.
6. VV Buchake, AP Muthal, RB Saudagar , RS Bachhav. A Neurodegenerative disorder-Alzheimer disease: A Treatise. Research J. Pharmacology and Pharmacodynamics. 2010; 2(4): 268-273
7. Tahami Monfared AA, Byrnes MJ, White LA, Zhang Q. Alzheimer’s Disease: Epidemiology and Clinical Progression. Neurol Ther. 2022; 11(2): 553-569. doi:10.1007/s40120-022-00338-8.
8. Casey DA, Antimisiaris D, O’Brien J. Drugs for Alzheimer’s Disease: Are They Effective? Pharm Ther. 2010; 35(4): 208.
9. Gergely P, Nuesslein-Hildesheim B, Guerini D, Brinkmann V, Traebert M, Bruns C, et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol. 2012; 167(5): 1035–47. doi:10.1111/j.1476-5381.2012.02061.x.
10. Chaudhry BZ, Cohen JA, Conway DS. Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis. Neurotherapeutics. 2017; 14(4): 859–73. doi:10.1007/s13311-017-0565-4.
11. Tavares A, Barret O, Alagille D, Morley T, Papin C, Maguire RP et al. Brain distribution of MS565, an imaging analogue of siponimod (BAF312), in non-human primates. European Journal of Neurology. 2014; 21: 504-504.
12. Benedict RHB, Tomic D, Cree BA, Fox R, Giovannoni G, Bar-Or A, et al. Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses. Neurology. 2021; 96(3): e376–86. doi:10.1212/WNL.0000000000011275.
13. Gentile A, Musella A, Bullitta S, Fresegna D, De Vito F, Fantozzi R, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation. 2016; 13(1): 207 doi:10.1186/s12974-016-0686-4.
14. Roos K, Wu C, Damm W, Reboul M, Stevenson JM, Lu C, et al. OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules. J Chem Theory Comput. 2019; 15(3): 1863–74. doi:10.1021/acs.jctc.8b01026. Epub 2019 Mar 4.
15. Chen IJ, Foloppe N. Drug-like bioactive structures and conformational coverage with the LigPrep/ConfGen suite: comparison to programs MOE and catalyst. J Chem Inf Model. 2010; 50(5): 822–39. doi:10.1021/ci100026x.
16. K. J. Bowers et al., "Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters," SC '06: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing, Tampa, FL, USA, 2006, pp. 43-43. doi: 10.1109/SC.2006.54.
17. Paget GE, Barnes JM. Toxicity tests. Evaluation of drug activities: Pharmacometrics. 1964; 1: 135-65
18. Vorhees C V., Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 2006; 1(2): 848–58. doi:10.1038/nprot.2006.116.
19. Itoh J, Nabeshima T, Kameyama T. Utility of an elevated plus-maze for the evaluation of memory in mice: effects of nootropics, scopolamine and electroconvulsive shock. Psychopharmacology (Berl). 1990; 101(1): 27–33. doi:10.1007/BF02253713
20. Claiborne A. Catalase activity. In: Greenwald AR., editor. Handbook of Methods for Oxygen Radical Research. Boca Raton, FL: CRC Press; 1984: 283–284.
21. Rahman I, Kode A, Biswas SK. Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc. 2006; 1(6): 3159–65. doi:10.1038/nprot.2006.378.
22. Karthick C, Periyasamy S, Jayachandran KS, Anusuyadevi M. Intrahippocampal Administration of Ibotenic Acid Induced Cholinergic Dysfunction via NR2A/NR2B Expression: Implications of Resveratrol against Alzheimer Disease Pathophysiology. Front Mol Neurosci. 2016; 9: 28. doi:10.3389/fnmol.2016.00028.
23. Ellman GL, Courtney KD, Andres V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961; 7(2): 88-95. doi:10.1016/0006-2952(61)90145-9.
24. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979; 95(2): 351–8. doi:10.1016/0003-2697(79)90738-3.
25. Mullane KM, Kraemer R, Smith B. Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium. J Pharmacol Methods. 1985; 14(3): 157–67. doi:10.1016/0160-5402(85)90029-4.
26. Nampoothiri M, John J, Kumar N, Mudgal J, Nampurath GK, Chamallamudi MR. Modulatory role of simvastatin against aluminium chloride-induced behavioural and biochemical changes in rats. Behav Neurol. 2015; 2015: 210169. doi:10.1155/2015/210169.
27. Sabsabi S, Mikhael E, Jalkh G, Macaron G, Rensel M. Clinical Evaluation of Siponimod for the Treatment of Secondary Progressive Multiple Sclerosis: Pathophysiology, Efficacy, Safety, Patient Acceptability and Adherence. Patient Prefer Adherence. 2022; 16: 1307–19. doi:10.2147/PPA.S221882.
28. Fischer R, Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev. 2015 ; 2015: 610813. doi:10.1155/2015/610813.
29. Dringen R, Gutterer JM, Hirrlinger J. Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem. 2000; 267(16): 4912–6. doi:10.1046/j.1432-1327.2000.01597.x.
30. Bhattacharya SK, Bhattacharya A, Kumar A GS. Antioxidant activity of Bacopa monniera in rat frontal cortex, striatum and hippocampus. Phytother Res. 2000; 14(3): 174–9. doi:10.1002/(sici)1099-1573(200005)14:3<174::aid-ptr624>3.0.co;2-o.
31. Green PS, Mendez AJ, Jacob JS, Crowley JR, Growdon W, Hyman BT, et al. Neuronal expression of myeloperoxidase is increased in Alzheimer’s disease. J Neurochem. 2004; 90(3): 724–33. doi:10.1111/j.1471-4159.2004.02527.x.
32. Alghamdi BSA. Possible prophylactic anti-excitotoxic and anti-oxidant effects of virgin coconut oil on aluminium chloride-induced Alzheimer’s in rat models. J Integr Neurosci. 2018; 17(3–4): 593–607. doi:10.3233/JIN-180089.
33. Justin Thenmozhi A, William Raja TR, Manivasagam T, Janakiraman U, Essa MM. Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminium chloride induced rat model of Alzheimer’s disease. Nutr Neurosci. 2017; 20(6): 360–8. doi:10.1080/1028415X.2016.1144846.
34. Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, Imhof C, et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation. 2012 Jul 2;9(1):151. doi:10.1186/1742-2094-9-151.
35. Zhang L, Zhao B, Yew DT, Kusiak JW, Roth GS. Processing of Alzheimer’s amyloid precursor protein during H2O2-induced apoptosis in human neuronal cells. Biochem Biophys Res Commun. 1997; 235(3): 845–8. doi:10.1006/bbrc.1997.6698.
36. Mouton-Liger F, Paquet C, Dumurgier J, Bouras C, Pradier L, Gray F, et al. Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway. Biochim Biophys Acta. 2012 ; 1822(6): 885–96. doi:10.1016/j.bbadis.2012.01.009.
37. García-Ayllón MS, Small DH, Avila J, Sáez-Valero J. Revisiting the Role of Acetylcholinesterase in Alzheimer’s Disease: Cross-Talk with P-tau and β-Amyloid. Front Mol Neurosci. 2011; 4: 22. doi:10.3389/fnmol.2011.00022.
38. Herholz K, Weisenbach S, Kalbe E. Deficits of the cholinergic system in early AD. Neuropsychologia. 2008; 46(6): 1642–7. doi:10.1016/j.neuropsychologia.2007.11.024