Neuroprotective Role of Ranolazine in Parkinson Disease: Drosophila Melanogaster Model

  • Parvesh Department of Pharmacology, Sarvhind College of Pharmacy, Rewari, Haryana, India
  • Sandeep Kumar MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University) Mullana, Ambala, Haryana, India
  • Govind Singh Department of Pharmaceutical Sciences, Maharishi Dayanand University, Rohtak, India;
  • Ramchander Khatri Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, Delhi 110017, India;
  • Sunil Shukla Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar, India;
  • Kamal Kaushik Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar, India;
  • Amit Lather Geeta Institute of Pharmacy, Geeta University, Panipat
  • Tanuj Hooda MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University) Mullana, Ambala, Haryana, India
Keywords: Ranolazine, Drosophila melanogaster, Leucine-rich repeat kinase 2;, LRRK2, Neuroprotection, Parkinson disease

Abstract


Background/Aim: Among the neurological ailments, Parkinson disease (PD) might be one of the most mysterious and intricate ones. The brain produces less dopamine as PD worsens, making it harder for a person to control their movements. In literature the effect of ranolazine (Rn) in the CNS has been proposed for the management of pain and epilepsy. So, it was hypothesised that ranolazine could act in neuroprotection. Aim of this study was to explore ranolazine effect in Parkinson and neuronal cells. 

Methods: Drosophila melanogaster has been employed. Five groups, each with 100 flies were: Group 1: control; Group 2: vehicle treated; Group 3: PD + ranolazine treated (1 mg/mL); Group 4: PD + ranolazine treated (2 mg/mL); Group-5: PD + ranolazine treated (4 mg/mL). PD was induced by paraquat. Part A involved the estimation of mortality index at 2-6 h. Estimation of climbing assay at 2 h, 4 h and 6 h and biochemical parameters such as oxidative stress were performed at 6 h.

Results: At different concentration of ranolazine percentage climbing of flies was found improved. Ranolazine at dose of 4 mg/mL showed significant reduction in percentage mortality at 24 h. Ranolazine at dose of 4 mg/mL showed a significant effect on total protein content level. Ranolazine 1 mg/mL showed significant effect and 2 mg/mL showed significant reduction in superoxide dismutase (SOD) level as compared to vehicle group. Ranolazine 1 mg/mL, 2 mg/mL and 4 mg/mL showed significant reduction in malondialdehyde (MDA) level as compared to vehicle group. 

Conclusion: The present findings suggest that ranolazine has a good neuroprotective potential in the treatment of PD in flies. Further studies still required to be performed so as to explore its potential in clinical trials.

References

Zafar S, Yaddanapudi SS. Parkinson Disease. Stat Pearls [Internet]. Treasure Island (FL): Statz Pearls Publishing; 2024 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470193/. [Cited: 4-Sept- 2024].

Gourie-Devi M, Gururaj G, Satishchandra P, Subbakrishna DK. Prevalence of neurological disorders in Bangalore, India: A community-based study with a comparison between urban and rural areas. Neuroepidemiology. 2004;23:261-8. doi: 10.1159/000080090.

de Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, et al. Prevalence of Parkinson's disease in Europe: A collaborative study of population-based cohorts. Neurologic diseases in the elderly research group. Neurology. 2000;54(11 Suppl 5):S21-3. PMID: 10854357.

Fung, T, Fung VS, Thompson PD. Rigidity & spasticity. In: Jankovic JJ, Tolosa E, eds. Parkinson’s disease and movement disorders. 4th ed. Hagerstown, MD: Lippincott Williams & Wilkins 2007; p. 504-13.

Caballol N, Martí MJ, Tolosa E. Cognitive dysfunction and dementia in Parkinson disease. Movement Disorders. 2007;22(Suppl 17):S358–66. doi: 10.1002/mds.21677.

Kuopio AM, Marttila RJ, Helenius H, Toivonen M, Rinne UK. The quality of life in Parkinson's disease. Mov Disord. 2000;15:216-23. doi: 10.1002/1531-8257(200003)15:2<216::aid-mds1003>3.0.co;2-#.

Karlsen KH, Tandberg E, Arsland D, Larsen JP. Health related quality of life in Parkinson's disease: A prospective longitudinal study. J Neurol Neurosurg Psychiatry. 2000;69:584-9. doi: 10.1136/jnnp.69.5.584

Abraham S, Soundararajan CC, Vivekanandhan S, Behari M. Erythrocyte antioxidant enzymes in Parkinson's disease. Indian J Med Res. 2005;121:111-5. PMID: 15756044

Sanyal J, Bandyopadhyay SK, Banerjee TK, Mukherjee SC, Chakraborty DP, Ray BC, et al. Plasma levels of lipid peroxides in patients with Parkinson's disease. Eur Rev Med Pharmacol Sci. 2009;13:129-32. PMID: 19499848.

Samii A, Nutt JG, Ransom BR. Parkinson's disease. Lancet. 2004;363(9423):1783–93. doi: 10.1016/S0140-6736(04)16305-8.

Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiat. 2008;79(4):368-76. doi: 10.1136/jnnp.2007.131045.

Yao SC, Hart AD, Terzella MJ. An evidencebased osteopathic approach to Parkinson disease. Osteopathic Family Physician. 2013;5(3);96–101. doi: 10.1016/j.osfp.2013.01.003.

Blandini F, Nappi G, Tassorelli C, Martignoni E. Functional changes of the basal ganglia circuitry in Parkinson's disease. Prog Neurobiol. 2000;62:63-88. doi: 10.1016/s0301-0082(99)00067-2.

Remy P, Doder M, Lees A, Turjanski N, Brooks D. Depression in Parkinson's disease: Loss of dopamine and noradrenaline innervation in the limbic system. Brain. 2005;128(Pt 6):1314-22. doi: 10.1093/brain/awh445.

Aldasoro M, Guerra-Ojeda S, Aguirre-Rueda D, Mauricio MD, Vila JM, Marchio P, et al. Effects of ranolazine on astrocytes and neurons in primary culture. PLoS One. 2016;11(3):e0150619. doi: 10.1371/journal.pone.0150619.

Aryal B, Lee Y. Disease model organism for Parkinson disease: Drosophila melanogaster. BMB Rep. 2019;52(4):250-8. doi: 10.5483/BMBRep.2019.52.4.204.

Hooda T, Sharma S, Goyal N. In-silico designing, synthesis, SAR and microbiological evaluation of novel amide derivatives of 2-(3-methylbenzo[b]thiophen-6-yl)-1-(4-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylic Acid. IJPER. 2019;3(2):53. doi: 10.5530/ijper.53.3s.117.

Hooda T, Sharma S, Goyal N. Synthesis, in-silico designing, SAR and microbiological evaluation of novel amide derivatives of 1-(4-Nitrophenyl)-2-(3-methylbenzo[b] thiophen-6-yl)-1H-benzo[d]imidazole-5-carboxylic Acid. IJPER. 2020;54(2):471-83. doi: 10.5530/ijper.54.2.54.

Lather A, Sharma S, Khatkar A. Naringenin derivatives as glucosamine-6-phosphate synthase inhibitors: Synthesis, antioxidants, antimicrobial, preservative efficacy, molecular docking and in silico ADMET analysis. BMC Chemistry. 2020b;14-41:1-15. doi: 10.1186/s13065-020-00693-3.

Lather A, Sharma S, Khatkar S, Khatkar A. Docking related survey on heterocyclic compounds based on glucosamine-6-phosphate synthase inhibitors and their antimicrobial potential. Curr Pharmaceut Design. 2020a;26(15):1650-65. doi: 10.2174/1381612826666200217115211.

Nagoshi E. Drosophila models of sporadic Parkinson’s disease. Int J of Molecular Sci. 2018;19(11):3343. doi: 10.3390/ijms19113343.

Madabattula ST, Strautman JC, Bysice AM, O'Sullivan JA, Androschuk A, Rosenfelt C, et al. Quantitative analysis of climbing defects in a Drosophila model of neurodegenerative disorders. J Vis Exp. 2015;(100):e52741. doi: 10.3791/52741.

Manjila SB, Hasan G. Flight and Climbing assay for assessing motor functions in Drosophila. Bio Protoc. 2018;8(5):e2742. doi: 10.21769/BioProtoc.2742.

Sharma P, Mittal P. Paraquat (herbicide) as a cause of Parkinson's Disease. Parkinsonism Relat Disord. 2024;119:105932. doi: 10.1016/j.parkreldis.2023.105932.

Lowary OH, Roserbrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem. 1951;193:265-75. PMID: 14907713

Mæhre HK, Dalheim L, Edvinsen GK, Elvevoll EO, Jensen IJ. Protein determination-method matters. Foods. 2018;7(1):5. doi: 10.3390/foods7010005.

Kono Y. Generation of superoxide radical during auto oxidation of hydroxylamine and an assay of superoxide dismutase. Arch Biochem Biophy. 1978;186:189-95. doi: 10.1016/0003-9861(78)90479-4.

Chandramohan G, Al-Numair KS, Paugalendi KV. Restoration of altered plasma erythrocyte and liver antioxidant levels by 3-hydroxymethyl xylitol in streptozotocin diabetic rats. IJIB. 2009;5:176-81.

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.

Kumar S, Singh G. Effect of zonisamide and Nigella sativa on blood-brain barrier permeability and neurological severity in traumatic brain injury-induced mice. Pharm Sci Asia. 2023;50(1):34-40. doi:10.29090/psa.2023.01.22.160.

Kumar S, Singh G. Neuroprotective potential of Zonisamide and Nigella sativa on traumatic brain injury-induced oxidative stress in mice. Int J of Health Sci. 202;6(S5):8629–41. doi: 10.53730/ijhs.v6nS5.10641.

Published
2025/02/28
Section
Original article