Design, characterization and evaluation of a novel dosage form of rebamipide as transdermal patches in rodent model of Parkinson’s disease

Akanksha Mishra; Sairam Krishnamurthy

doi:10.56782/pps.650

Published : 2026-02-23

Design, characterization and evaluation of a novel dosage form of rebamipide as transdermal patches in rodent model of Parkinson’s disease

Dr. Akanksha Mishra

Dr. Sairam krishnamurthy

DOI: https://doi.org/10.56782/pps.650

Abstract

Rebamipide at 80 mg/kg oral twice daily was previously found effective against a hemiparkinson’s model in rats. However, the high dose and frequency limit its advantages. Therefore, for the first time, a novel dosage form of rebamipide as transdermal patches was formulated, characterized and evaluated againt a rodent model of Parkinson’s disease. Four different transdermal formulations containing rebamipide were prepared using the solvent casting method (4 mg rebamipide/patch). Transdermal patches were observed to be uniform in terms of physicochemical characteristics. Rebamipide was administered through both the oral (80 mg/kg twice daily) and transdermal route (one patch daily) from Day-4 to Day-27 after unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA) in male rats. Patches increased levels of dopamine, dopamine transporters, tyrosine hydroxylase, and glucocerebrosidase enzymatic activity and decreased α-synuclein pathology and motor deficits in 6-OHDA-infused rats. All the animal-related parameters include 6 rats per group, and behavioral studies include 12 rats per group. Repeated measures of two-way ANOVA was used for the analysis of behavioral parameters and ex vivo permeability. Remaining in vivo parameters, physicochemical characteristics (weight, thickness, folding endurance, surface pH, swelling, moisture loss and drug content uniformity) and skin irritation studies were analyzed by one-way ANOVA. Rebamipide concentration using HPLC was analyzed by an unpaired t test. The effects of rebamipide patches and oral groups against 6-OHDA toxicity were similar and the concentration of rebamipide in plasma and cerebrospinal fluid of both groups was also observed to be the same. These preclinical findings suggest that a low rebamipide dose administered once daily through a newly-prepared transdermal patch (4 mg drug/patch) showed similar potential as a high oral rebamipide dose (80 mg/kg) administered twice daily in rats against 6-OHDA toxicity. Further studies including detailed pharmacokinetic and mechanistic data are required in order to translate the information successfully from animal to clinical studies.

Keywords:

Rebamipide, ransdermal patches, 6-Hydroxydopamine, Parkinson’s disease, Glucocerebrosidase

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Mishra, A., & Krishnamurthy, S. (2026). Design, characterization and evaluation of a novel dosage form of rebamipide as transdermal patches in rodent model of Parkinson’s disease. Prospects in Pharmaceutical Sciences. https://doi.org/10.56782/pps.650

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References

1. Kim, G.H., et al., Efficacy and Safety of Rebamipide versus Its New Formulation, AD-203, in Patients with Erosive Gastritis: A Randomized, Double-Blind, Active Control, Noninferiority, Multicenter, Phase 3 Study. Gut Liver, 2021. 15(6): p. 841-850. DOI: 10.5009/gnl20338

2. Kak, M., Rebamipide in gastric mucosal protection and healing: An Asian perspective. World Journal of Gastrointestinal Pharmacology and Therapeutics, 2025. 16(1): p. 101753. 10.4292/wjgpt.v16.i1.101753

3. Mishra, A. and S. Krishnamurthy, Rebamipide Mitigates Impairments in Mitochondrial Function and Bioenergetics with α-Synuclein Pathology in 6-OHDA-Induced Hemiparkinson’s Model in Rats. Neurotoxicity research, 2019. 35(3): p. 542-562. DOI: 10.1007/s12640-018-9983-2

4. Stocchi, F. and C.W. Olanow, Obstacles to the Development of a Neuroprotective Therapy for Parkinson's Disease. Movement Disorders, 2013. 28(1): p. 3-7. DOI: 10.1002/mds.25337

5. Naito, Y. and T. Yoshikawa, Rebamipide: a gastrointestinal protective drug with pleiotropic activities. Expert review of gastroenterology & hepatology, 2010. 4(3): p. 261-270. DOI: 10.1586/egh.10.25

6. Shioya, Y., et al., Metabolic fate of the anti-ulcer agent,(±)-2-(4-chlorobenzoylamino)-3-[2 (1H)-quinolinon-4-yl] propionic acid (OPC-12759): Absorption, distribution, and excretion in rats and dogs. Iyakuhin Kenkyu, 1989. 20: p. 522-533.

7. Stojančević, M., et al., Application of bile acids in drug formulation and delivery. Frontiers in Life Science, 2013. 7(3-4): p. 112-122. DOI: 10.1080/21553769.2013.879925

8. Pradhan, R., et al., Development of a rebamipide solid dispersion system with improved dissolution and oral bioavailability. Archives of Pharmacal Research, 2015. 38(4): p. 522-533. DOI: 10.1007/s12272-014-0399-0

9. Savjani, K.T., A.K. Gajjar, and J.K. Savjani, Drug solubility: importance and enhancement techniques. ISRN Pharm. 2012. 2012. Art. No: 195727. DOI: 10.5402/2012/195727

10. Alavijeh, M.S., et al., Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery. NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics, 2005. 2(4): p. 554-571. DOI: 10.1602/neurorx.2.4.554

11. Ashford, M., Gastrointestinal tract–physiology and drug absorption. Aulton’s pharmaceutics e-book: the design and manufacture of medicines, 2017: p. 300.

12. Ngo, L., et al., Population pharmacokinetic analysis of rebamipide in healthy Korean subjects with the characterization of atypical complex absorption kinetics. Journal of pharmacokinetics and pharmacodynamics, 2017. 44(4): p. 291-303. DOI: 10.1007/s10928-017-9519-z

13. Huang, B.-B., et al., Permeabilities of rebamipide via rat intestinal membranes and its colon specific delivery using chitosan capsule as a carrier. World journal of gastroenterology, 2008. 14(31): p. 4928-4937. DOI: 10.3748/wjg.14.4928

14. Fukui, K., et al., Rebamipide reduces amyloid-β 1–42 (Aβ42) production and ameliorates Aβ43-lowered cell viability in cultured SH-SY5Y human neuroblastoma cells. Neuroscience Research, 2017. 124: p. 40-50, http://dx.doi.org/10.1016/j.neures.2017.05.005.

15. Shin, B.S., et al., Oral absorption and pharmacokinetics of rebamipide and rebamipide lysinate in rats. Drug development and industrial pharmacy, 2004. 30(8): p. 869-876. DOI: 10.1081/ddc-200034577

16. Isaac, M. and C. Holvey, Transdermal patches: the emerging mode of drug delivery system in psychiatry. Therapeutic advances in psychopharmacology, 2012. 2(6): p. 255-263.DOI: 10.1177/2045125312458311

17. Dhaval R. Kalaria, M.S., Vandana Patravale, Virginia Merino, Yogeshvar N. Kalia,, Simultaneous controlled iontophoretic delivery of pramipexole and rasagiline in vitro and in vivo: Transdermal polypharmacy to treat Parkinson’s disease,. European Journal of Pharmaceutics and Biopharmaceutics,, 2018. 127: p. 204-212. DOI: 10.1016/j.ejpb.2018.02.031

18. Sheth, N.S. and R.B. Mistry, Formulation and evaluation of transdermal patches and to study permeation enhancement effect of eugenol. Journal of Applied Pharmaceutical Science, 2011. 1(3): p. 96.

19. de Szalay, S. and P. Wertz, Protective Barriers Provided by the Epidermis. International Journal of Molecular Sciences, 2023. 24: p. 3145. DOI: 10.3390/ijms24043145

20. Nikki, L., P. Khanh, and M. Yousuf, Role of skin enzymes in metabolism of topical drugs. Metabolism and Target Organ Damage, 2024. 4(4): p. 32. DOI: 10.20517/mtod.2024.17

21. Farlow, M.R. and M. Somogyi, Transdermal patches for the treatment of neurologic conditions in elderly patients: a review. The Primary Care Companion to CNS Disorders, 2011. 13(6). PCC.11r01149, DOI: 10.4088/PCC.11r01149

22. Waters, C., The development of the rotigotine transdermal patch: a historical perspective. Neurologic clinics, 2013. 31(3): p. S37-S50. DOI: 10.1016/j.ncl.2013.04.012

23. Löschmann, P.-A., et al., Stereoselective reversal of MPTP-induced parkinsonism in the marmoset after dermal application of N-0437. European journal of pharmacology, 1989. 166(3): p. 373-380. DOI: 10.1016/0014-2999(89)90348-8

24. Obae, K., N. Yoshida, and K. Kajihara, Transdermal absorption enhancer and transdermal absorption enhancement aid. 2017, Google Patents. Application U.S. Patent Application No. 15/519,246.

25. Chandrashekar, N. and R.S. Rani, Physicochemical and pharmacokinetic parameters in drug selection and loading for transdermal drug delivery. Indian journal of pharmaceutical sciences, 2008. 70(1): p. 94. DOI: 10.4103/0250-474X.40340

26. Shabbir, M., et al., Formulation Considerations And Factors Affecting Transdermal Drug Delivery System-A Review. Vol. 2. 2014. 20-35.

27. Prausnitz, M.R. and R. Langer, Transdermal drug delivery. Nature biotechnology, 2008. 26(11): p. 1261. DOI: 10.1038/nbt.1504

28. Cooper, D.L., et al., Pharmacokinetic interactions between rebamipide and selected nonsteroidal anti-inflammatory drugs in rats. European Journal of Pharmaceutical Sciences, 2014. 53: p. 28-34. DOI: 10.1016/j.mex.2014.06.002

29. Naik, A., Y.N. Kalia, and R.H. Guy, Transdermal drug delivery: overcoming the skin’s barrier function. Pharmaceutical science & technology today, 2000. 3(9): p. 318-326. DOI: 10.1016/s1461-5347(00)00295-9

30. Jang, D.J., et al., The Development of Super-Saturated Rebamipide Eye Drops for Enhanced Solubility, Stability, Patient Compliance, and Bioavailability. Pharmaceutics, 2023. 15(3). Art. No: 950, DOI: 10.3390/pharmaceutics15030950

31. Muzib, Y.I., R. Mannam, and R. Yellamelli, DRUG IN ADHESIVE TRANSDERMAL SYSTEM OF FUROSEMIDE: IN VITRO IN VIVO EVALUATION. International Journal of Applied Pharmaceutics, 2023: 15(4), p. 106-113. DOI: 10.22159/ijap.2023v15i4.47681

32. Ha, E.-S.; Lee, S.-K.; Jeong, J.-S.; Sim, W.-Y.; Yang, J.-I.; Kim, J-S.; Kim, M.-S.Solvent effect and solubility modeling of rebamipide in twelve solvents at different temperatures. Journal of Molecular Liquids, 2019. 288: p. 111041. DOI: 10.1016/j.molliq.2019.111041

33. Guo, Y., Y. Wang, and L. Xu, Enhanced bioavailability of rebamipide nanocrystal tablets: Formulation and in vitro/in vivo evaluation. Asian Journal of Pharmaceutical Sciences, 2015. 10(3): p. 223-229. DOI: 10.1016/j.ajps.2014.09.006

34. Narala, A., S. Guda, and K. Veerabrahma, Lipid Nanoemulsions of Rebamipide: Formulation, Characterization, and In Vivo Evaluation of Pharmacokinetic and Pharmacodynamic Effects. AAPS PharmSciTech, 2019. 20(1): Art. No: 26. DOI: http://dx.doi.org/10.1208/s12249-018-1225-7

35. Jin, G., et al., Design and evaluation of in vivo bioavailability in beagle dogs of bilayer tablet consisting of immediate release nanosuspension and sustained release layers of rebamipide. International Journal of Pharmaceutics, 2022. 619: Art. No: 121718. DOI: 10.1016/j.ijpharm.2022.121718

36. Kawano, Y., et al., Preparation and Evaluation of Rebamipide Colloidal Nanoparticles Obtained by Cogrinding in Ternary Ground Mixtures. Colloids and Interfaces, 2020. 4(4): Art. No: 43. DOI: 10.3390/colloids4040043

37. Malaiya, M.K., et al., Controlled delivery of rivastigmine using transdermal patch for effective management of alzheimer's disease. Journal of Drug Delivery Science and Technology, 2018. 45: p. 408-414. DOI: 10.1016/j.jddst.2018.03.030

38. Nair, R.S., et al., Matrix type transdermal patches of captopril: Ex vivo permeation studies through excised rat skin. Journal of Pharmacy Research, 2013. 6(7): p. 774-779. DOI: 10.1016/j.jopr.2013.07.003

39. Phadtare, D.G., Phadtare, G.N., Nilesh, B.S., & Asawat, M., Hypromellose - A Choice Of Polymer In Extended Release Tablet Formulation. World Journal Of Pharmacy And Pharmaceutical Sciences, 2014. 3(9): p. 551-566.

40. Mustafa, M.A., et al., Design, Fabrication and Characterization of Transdermal Patches Using Different Natural Polymers Containing Caffeine and Ibuprofen for Long-Term Management of Migraine. International Journal of Pharmaceutical Investigation, 2024. 14(4). 1192-1200 DOI: 10.5530/ijpi.14.4.130

41. Williams, A.C. and B.W. Barry, Penetration enhancers. Adv. Drug Deliv. Rev. 2004. 56(5): p. 603-18, DOI: 10.1016/j.addr.2003.10.025

42. Parhi, R. and S. Padilam, In vitro permeation and stability studies on developed drug-in-adhesive transdermal patch of simvastatin. Bulletin of Faculty of Pharmacy, Cairo University, 2018. 56(1): p. 26-33. DOI: 10.1016/j.bfopcu.2018.04.001

43. Chessa, M., et al., Effect of penetration enhancer containing vesicles on the percutaneous delivery of quercetin through new born pig skin. Pharmaceutics, 2011. 3(3): p. 497-509. DOI: 10.3390/pharmaceutics3030497

44. Singh, A. and A. Bali, Formulation and characterization of transdermal patches for controlled delivery of duloxetine hydrochloride. Journal of Analytical Science and Technology, 2016. 7(1): Art. No: 25. 10.1186/s40543-016-0105-6

45. Som, I., K. Bhatia, and M. Yasir, Status of surfactants as penetration enhancers in transdermal drug delivery. Journal of pharmacy & bioallied sciences, 2012. 4(1): p. 2-9. DOI: 10.4103/0975-7406.92724

46. Prabhakara, P., et al., Preparation and evaluation of Transdermal patches of Papaverine hydrochloride. International Journal of Research in Pharmaceutical Sciences, 2010. 1(3): p. 259-266. DOI: 10.1016/j.ijpharm.2009.12.050

47. Gannu, R., et al., Enhanced bioavailability of lacidipine via microemulsion based transdermal gels: formulation optimization, ex vivo and in vivo characterization. International journal of pharmaceutics, 2010. 388(1-2): p. 231-241. DOI: 10.3109/03639045.2011.641564

48. Censi, R., et al., Permeation and skin retention of quercetin from microemulsions containing Transcutol® P. Drug development and industrial pharmacy, 2012. 38(9): p. 1128-1133.

49. Kusum Devi, V., et al., Design and evaluation of matrix diffusion controlled transdermal patches of verapamil hydrochloride. Drug development and industrial pharmacy, 2003. 29(5): p. 495-503. DOI: 10.1081/ddc-120018638

50. Raghuraman, S., et al., Design and evaluation of propranolol hydrochloride buccal films. Indian journal of pharmaceutical sciences, 2002. 64(1): p. 32-36.

51. Parhi, R. and P. Suresh, Transdermal delivery of Diltiazem HCl from matrix film: Effect of penetration enhancers and study of antihypertensive activity in rabbit model. Journal of advanced research, 2016. 7(3): p. 539-550. DOI: 10.1208/s12249-008-9167-0

52. Ammar, H., et al., Polymeric matrix system for prolonged delivery of tramadol hydrochloride, part I: physicochemical evaluation. AAPS PharmSciTech, 2009. 10, 7-20. DOI: 10.1208/s12249-008-9167-0.

53. Ubaidulla, U., et al., Transdermal therapeutic system of carvedilol: effect of hydrophilic and hydrophobic matrix on in vitro and in vivo characteristics. AAPS PharmSciTech, 2007. 8(1): Art. No: 2. DOI: 10.1208/pt0801002

54. Draize, J.H., G. Woodard, and H.O. Calvery, Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. Journal of pharmacology and Experimental Therapeutics, 1944. 82(3): p. 377-390.

55. Sarkar, G., et al., Taro corms mucilage/HPMC based transdermal patch: an efficient device for delivery of diltiazem hydrochloride. International journal of biological macromolecules, 2014. 66: p. 158-165. DOI: 10.1016/j.ijbiomac.2014.02.024

56. Ramadan, E., et al., Design and in vivo pharmacokinetic study of a newly developed lamivudine transdermal patch. Future Journal of Pharmaceutical Sciences, 2018. 4(2): p. 166-174. DOI: 10.1016/j.fjps.2018.03.002

57. Muddana, N.R., et al. Neuro-pharmacokinetics based prediction of p-glycoprotein liability in early drug discovery. in Drug Metabolism Reviews. 2014. Informa Healthcare Telephone House, 69-77 Paul Street, London EC2A 4LQ, England.

58. Paxinos, G. and C. Watson, The Rat Brain Stereotaxic Co-Ordinates. 2007: Academic Press. p. 456

59. Rozas, G., M. Guerra, and J. Labandeira-Garcıa, An automated rotarod method for quantitative drug-free evaluation of overall motor deficits in rat models of parkinsonism. Brain Research Protocols, 1997. 2(1): p. 75-84. DOI: 10.1016/s1385-299x(97)00034-2

60. Fernandez, A., A.G. De La Vega, and I. Torres-Aleman, Insulin-like growth factor I restores motor coordination in a rat model of cerebellar ataxia. Proceedings of the National Academy of Sciences, 1998. 95(3): p. 1253-1258. 10.1073/pnas.95.3.1253

61. Ungerstedt, U., Postsynaptic supersensitivity after 6‐hydroxy‐dopamine induced degeneration of the nigro‐striatal dopamine system. Acta Physiologica, 1971. 82(S367): p. 69-93. DOI: 10.1111/j.1365-201x.1971.tb11000.x

62. Sanberg, P.R., et al., The catalepsy test: its ups and downs. Behavioral neuroscience, 1988. 102(5): p. 748-759. DOI: 10.1037//0735-7044.102.5.748

63. Geed, M., et al., Silibinin pretreatment attenuates biochemical and behavioral changes induced by intrastriatal MPP+ injection in rats. Pharmacology Biochemistry and Behavior, 2014. 117: p. 92-103. DOI: 10.1016/j.pbb.2013.12.008

64. Takeshita, H., et al., Modified forelimb grip strength test detects aging-associated physiological decline in skeletal muscle function in male mice. Scientific Reports, 2017. 7: Art. No: 42323. DOI: 10.1038/srep42323

65. Meyer, O.A., et al., A method for the routine assessment of fore-and hindlimb grip strength of rats and mice. Neurobehavioral toxicology, 1979. 1(3): p. 233-236.

66. Rocha, E.M., et al., Sustained systemic glucocerebrosidase inhibition induces brain α-synuclein aggregation, microglia and complement C1q activation in mice. Antioxidants & redox signaling, 2015. 23(6): p. 550-564. DOI: 10.1089/ars.2015.6307

67. Shi, Y., et al., A potent preparation method combining neutralization with microfluidization for rebamipide nanosuspensions and its in vivo evaluation. Drug development and industrial pharmacy, 2013. 39(7): p. 996-1004. DOI: 10.3109/03639045.2012.689765

68. Manglani, U. R.; Khan, I. J.; Soni, K.; P. Loya, P.; Saraf, M. N. Development and validation of HPLC-UV method for the estimation of rebamipide in human plasma. Indian J. Pharm. Sci. 2006. 68(4), 475-478. DOI: 10.4103/0250-474X.27821

69. Cooper, D.L. and S. Harirforoosh, A simple high performance liquid chromatography method for determination of rebamipide in rat urine. MethodsX, 2014. 1: p. 49-55. DOI: 10.1016/j.mex.2014.06.002

70. Jeter, C.B.; Rozas, N.S.; Sadowsky, J.M.; Jones, D.J. Parkinson's Disease Oral Health Module: Interprofessional Coordination of Care. MedEdPORTAL 2018. 14: Art. No: 10699. DOI: 10.15766/mep_2374-8265.10699

71. Haavik, J. and K. Toska, Tyrosine hydroxylase and Parkinson's disease. Molecular neurobiology, 1998. 16(3): p. 285-309. DOI: 10.1007/bf02741387

72. Nutt, J.G., J.H. Carter, and G.J. Sexton, The dopamine transporter: importance in Parkinson's disease. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 2004. 55(6): p. 766-773. DOI: 10.1002/ana.20089

73. Gainetdinov, R.R.; Jones, S.R.; Fumagalli, F.; Wightman, R.M.; Caron, M.G. Re-evaluation of the role of the dopamine transporter in dopamine system homeostasis1. Brain Res Brain Res Rev. 1998. 26(2-3): p. 148-153. DOI: 10.1016/S0165-0173(97)00063-5

74. Sieb, J.P.; Themann, P.; Warnecke, T.; Lauterbach, T.; Berkels, R.; Grieger, F.; Lorenzl, S. Caregivers’ and physicians’ attitudes to rotigotine transdermal patch versus oral Parkinson’s disease medication: an observational study. Curr Med Res Opin. 2015. 31(5): p. 967-974. DOI: 10.1185/03007995.2015.1030376

75. Carrozzino, D.; Morberg, B.M.; Siri, C.; Pezzoli, G.; Bech, P. Evaluating psychiatric symptoms in Parkinson's Disease by a clinimetric analysis of the Hopkins Symptom Checklist (SCL-90-R). Prog Neuropsychopharmacol Biol Psychiatry., 2018. 81: p. 131-137. DOI: 10.1016/j.pnpbp.2017.10.024

76. Vervoort, G.; Bengevoord, A.; Strouwen, C.; Bekkers, E.M.; Heremans, E.; Vandenberghe, W.; Nieuwboer, A. Progression of postural control and gait deficits in Parkinson's disease and freezing of gait: a longitudinal study. Parkinsonism & related disorders, 2016. 28: p. 73-79. DOI: 10.1016/j.parkreldis.2016.04.029

77. Rodriguez-Oroz, M.C., Jahanshahi, M.; Krack, P.; Litvan, I.; Macias, R.; Bezard, E.; Obeso, J.A. Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms. The Lancet Neurology, 2009. 8(12): p. 1128-1139. DOI: 10.1016/s1474-4422(09)70293-5

78. Zhu, Y., J. Zhang, and Y. Zeng Overview of tyrosine hydroxylase in Parkinson's disease. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 2012. 11(4): p. 350-358. DOI: 10.2174/187152712800792901

79. Voutilainen, M.H., De Lorenzo F, Stepanova P, Bäck S, Yu LY, Lindholm P, Pörsti E, Saarma M, Männistö PT, Tuominen RK. Evidence for an additive neurorestorative effect of simultaneously administered CDNF and GDNF in hemiparkinsonian rats: implications for different mechanism of action. eNeuro, 2017, 4(1): Art. No: e0117-16.2017. DOI: 10.1523/eneuro.0117-16.2017

80. Di Maio, R., Barrett PJ, Hoffman EK, Barrett CW, Zharikov A, Borah A, Hu X, McCoy J, Chu CT, Burton EA, Hastings TG, Greenamyre JT. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci Transl Med. , 2016. 8(342): Art. No: 342ra78. DOI: 10.1126/scitranslmed.aaf3634

81. Migdalska‐Richards, A. and A.H. Schapira, The relationship between glucocerebrosidase mutations and Parkinson disease. Journal of neurochemistry, 2016. 139(S1): p. 77-90. DOI: 10.1111/jnc.13385

82. Gegg, M.E., Burke D, Heales SJ, Cooper JM, Hardy J, Wood NW, Schapira AH. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol. 2012. 72(3): p. 455-463. DOI: 10.1002/ana.23614.

83. Cleeter, M.W., Chau KY, Gluck C, Mehta A, Hughes DA, Duchen M, Wood NW, Hardy J, Mark Cooper J, Schapira AH. Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage. Neurochemistry international, 2013. 62(1): p. 1-7. 10.1016/j.neuint.2012.10.010

84. Mazzulli, J.R., Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011. 146(1): p. 37-52. DOI: 10.1016/j.cell.2011.06.001

85. Arief Budi Yulianti, Sony Heru Sumarsono, Ahmad Ridwan, Ayda T. Yusuf. Increase of Oxidative Stress and Accumulation of α-Synuclein in Wistar Rat's Midbrain Treated with Rotenone. ITB Journal, 2012. 44 A(4): p. 317-332. DOI: 10.5614/itbj.sci.2012.44.4.3

86. Gu, X.-S., Wang F, Zhang CY, Mao CJ, Yang J, Yang YP, Liu S, Hu LF, Liu CF. Neuroprotective Effects of Paeoniflorin on 6-OHDA-Lesioned Rat Model of Parkinson’s Disease. Neurochem Res. 2016. 41(11): p. 2923-2936. DOI: 10.1007/s11064-016-2011-0

Dr. Akanksha Mishra

akanksha.pharma1@gmail.com

Affiliation:

Institute of Pharmaceutical Sciences, University of Lucknow, Lucknow India

Bio Statement (e.g., department and rank)

Dr. Akanksha Mishra

Assistant Professor

Institute of Pharmaceutical Sciences,

University of Lucknow, Lucknow-226021

email: akanksha.pharma1@gmail.com

Dr. Sairam krishnamurthy

ksairam.phe@iitbhu.ac.in

Affiliation:

Indian Institute of Technology (Banaras Hindu University) Varanasi India

Bio Statement (e.g., department and rank)

Corresponding author:

*Dr. Sairam Krishnamurthy

Professor

Neurotherapeutics Lab, Department of Pharmaceutical Engineering & Technology

Indian Institute of Technology (Banaras Hindu University)

Varanasi-221005, India

Email: ksairam.phe@iitbhu.ac.in; saibliss@hotmail.com

Ph: +91-9935509199; Fax: +91-542-2368428