Ameliorative Effects Of Vortioxetine In 3-Npa Induced Huntington's Disease
DOI:
https://doi.org/10.53555/jaz.v46i1.5097Keywords:
Vortioxetine, Huntington's Disease, Antioxidant, 3-NPA, Oxidative stressAbstract
Huntington's Disease (HD) is an autosomal dominant neurodegenerative disease caused by a mutation in the Huntingtin (HTT) gene. Clinically progressive motor dysfunction with cognitive decline, neuropsychiatric disorders like mood and behavioural abnormalities, and choreiform movements are its hallmarks. To lessen 3-nitropropionic acid (3-NPA)-induced HD-like pathology in a rodent model, this study sought to assess the neuroprotective pharmacological effects of vortioxetine, a primarily antidepressant drug that exhibits agonistic activity on the 5-HT1A receptor and antagonizes the serotonin transporter (SERT). The mitochondrial complex II inhibitor 3-NPA disrupts aerobic metabolism of cellular energy, induces oxidative stress, and causes neuronal damage like the pathophysiology of HD. To induce HD-like symptoms, 3-NPA (10 mg/kg intraperitoneally) was administered to male Wistar rats every other day for 28 days. Vortioxetine was subsequently administered orally at 5 and 10 mg/kg every day. Cognitive function was measured using the Morris Water Maze and Elevated Plus Maze, while the Rota rod test was used to measure motor coordination, and the Actophotometer was used to measure locomotor activity. Biochemical analyses measured striatal neurotransmitters, mitochondrial enzyme activity, and oxidative/nitrosative stress-related markers. Histopathological analysis of the cortex and hippocampal regions was performed to determine its impact on neuronal integrity. Vortioxetine treatment reduced oxidative stress, preserved the expression of mitochondrial electron transport complexes I, II, and IV, restored neurotransmitter equilibrium, and significantly ameliorated motor and cognitive deficits. Histopathology results showed a dose-dependent reduction in the evidence of neuronal degeneration, suggesting a neuroprotective effect. Thus, our findings suggest that Vortioxetine may exert its therapeutic effects in Huntington's disease by improving mitochondrial function, reducing oxidative stress, and acting on the serotonin pathways. Thereby, vortioxetine, in addition to its known antidepressant properties, may emerge as possible treatment options in HD management. One might note limitations such as the need for validation in genetic HD models and long-term studies. Future studies should explore its therapeutic potential and molecular targets. The study emphasizes how Vortioxetine, including its role as a pharmacological agent, can be used for the treatment of neurodegenerative diseases, particularly in Huntington's disease (HD), alleviating neuropsychiatric disorders. Additional clinical trials should determine the long-term safety and efficacy of vortioxetine for humans.
Downloads
References
1. Aebi, H.; Wyss, S.R.; Scherz, B.; Skvaril, F. Heterogeneity of erythrocyte catalase II. Isolation and characterization of normal and variant erythrocyte catalase and their subunits. Eur. J. Biochem. 1974, 48, 137–145. DOI
2. Aliaghaei, A.; Boroujeni, M.E.; Ahmadi, H.; Bayat, A.-H.; Tavirani, M.R.; Abdollahifar, M.A.; Pooyafar, M.H.; Mansouri, V. Dental pulp stem cell transplantation ameliorates motor function and prevents cerebellar atrophy in rat model of cerebellar ataxia. Cell Tissue Res. 2019, 376, 179–187. DOI
3. Alshehri, S.; Al-Abbasi, F.A.; Ghoneim, M.M.; Imam, S.S.; Afzal, M.; Alharbi, K.S.; Nadeem, M.S.; Sayyed, N.; Kazmi, I. Anti-Huntington's Effect of Butin in 3-Nitropropionic Acid-Treated Rats: Possible Mechanism of Action. Neurotox. Res. 2022, 40, 66–77. DOI
4. Alshehri, S.; Imam, S.S. Rosinidin Attenuates Lipopolysaccharide-Induced Memory Impairment in Rats: Possible Mechanisms of Action Include Antioxidant and Anti-Inflammatory Effects. Biomolecules 2021, 11, 1747. DOI
5. Bol'shakova, I.V.; Lozovskaia, E.L.; Sapezhinskiĭ, I. Antioxidant properties of a series of extracts from medicinal plants. Biofizika 1997, 42, 480–483.
6. Brouillet, E.; Jacquard, C.; Bizat, N.; Blum, D. 3-Nitropropionic acid: A mitochondrial toxin to uncover physiopathological mechanisms underlying striatal degeneration in Huntington's disease. J. Neurochem. 2005, 95, 1521–1540. DOI
7. Bucci, L.R. Selected herbals and human exercise performance. Am. J. Clin. Nutr. 2000, 72, 624S–636S. DOI
8. Carmo, C.; Naia, L.; Lopes, C.; Rego, A.C. Mitochondrial Dysfunction in Huntington's Disease BT---Polyglutamine Disorders; Nóbrega, C., Pereira de Almeida, L., Eds.; Springer International Publishing: Cham, Switzerland, 2018; pp. 59–83. DOI
9. Caterino, M.; Squillaro, T.; Montesarchio, D.; Giordano, A.; Giancola, C.; Melone, M.A.B. Huntingtin protein: A new option for fixing the Huntington's disease countdown clock. Neuropharmacology 2018, 135, 126–138. DOI
10. Chao, T.-K.; Hu, J.; Pringsheim, T. Risk factors for the onset and progression of Huntington disease. Neurotoxicology 2017, 61, 79–99. DOI
11. Dhadde, S.B.; Nagakannan, P.; Roopesh, M.; Anand Kumar, S.R.; Thippeswamy, B.S.; Veerapur, V.P.; Badami, S. Effect of embelin against 3-nitropropionic acid-induced Huntington's disease in rats. Biomed. Pharmacother. 2016, 77, 52–58. DOI
12. Dhir, A.; Akula, K.K.; Kulkarni, S.K. Tiagabine, a GABA uptake inhibitor, attenuates 3-nitropropionic acid-induced alterations in various behavioral and biochemical parameters in rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 2008, 32, 835–843. DOI
13. Etemad, A.; Sheikhzadeh, F.; Ahmadiasl, N. Evaluation of brain-derived neurotrophic factor in diabetic rats. Neurol. Res. 2015, 37, 217–222. DOI
14. Farias, J.G.; Puebla, M.; Acevedo, A.; Tapia, P.J.; Gutierrez, E.; Zepeda, A.; Calaf, G.; Juantok, C.; Reyes, J.G. Oxidative stress in rat testis and epididymis under intermittent hypobaric hypoxia: Protective role of ascorbate supplementation. J. Androl. 2010, 31, 314–321. DOI
15. Feleus, S.; van Schaijk, M.; Roos, R.A.; de Bot, S.T. The Many Faces of Huntington's Chorea Treatment: The Impact of Sudden Withdrawal of Tiapride after 40 Years of Use and a Systematic Review. J. Pers. Med. 2022, 12, 589. DOI
16. Finkbeiner, S. Huntington's disease. Cold Spring Harb. Perspect. Biol. 2011, 3, a007476. DOI
17. George, E. Tissue sulfhydryl groups. Arch. Biochem. Biophys. 1959, 82, 70–77.
18. Gil-Mohapel, J.S.; Brocardo, P.R.; Christie, B. The role of oxidative stress in Huntington's disease: Are antioxidants good therapeutic candidates? Curr. Drug Targets 2014, 15, 454–468. DOI
19. Gipson, T.A.; Neueder, A.; Wexler, N.S.; Bates, G.P.; Housman, D. Aberrantly spliced HTT, a new player in Huntington's disease pathogenesis. RNA Biol. 2013, 10, 1647–1652. DOI
20. Heinrikson, R.L.; Meredith, S.C. Amino acid analysis by reverse-phase high-performance liquid chromatography: Precolumn derivatization with phenylisothiocyanate. Anal. Biochem. 1984, 136, 65–74. DOI
21. Jamwal, S.; Kumar, P. Spermidine ameliorates 3-nitropropionic acid (3-NP)-induced striatal toxicity: Possible role of oxidative stress, neuroinflammation, and neurotransmitters. Physiol. Behav. 2016, 155, 180–187. DOI
22. Johri, A.; Beal, M.F. Antioxidants in Huntington's disease. Biochim. Biophys. Acta 2012, 1822, 664–674. DOI
23. Kaur, N.; Jamwal, S.; Deshmukh, R.; Gauttam, V.; Kumar, P. Beneficial effect of rice bran extract against 3-nitropropionic acid induced experimental Huntington's disease in rats. Toxicol. Rep. 2015, 2, 1222–1232. DOI
24. Khan, A.; Jamwal, S.; Bijjem, K.R.V.; Prakash, A.; Kumar, P. Neuroprotective effect of hemeoxygenase-1/glycogen synthase kinase-3β modulators in 3-nitropropionic acid-induced neurotoxicity in rats. Neuroscience 2015, 287, 66–77. DOI
25. King, T.E.; Ohnishi, T.; Winter, D.B.; Wu, J.T. Biochemical and EPR probes for structure-function studies of iron sulfur centers of succinate dehydrogenase. Adv. Exp. Med. Biol. 1976, 74, 182–227. DOI
26. Kumar, A.; Ratan, R.R. Oxidative Stress and Huntington's Disease: The Good, The Bad, and The Ugly. J. Huntingt. Dis. 2016, 5, 217–237. DOI
27. Kumar, P.; Kalonia, H.; Kumar, A. Possible GABAergic mechanism in the neuroprotective effect of gabapentin and lamotrigine against 3-nitropropionic acid induced neurotoxicity. Eur. J. Pharmacol. 2012, 674, 265–274. DOI
28. Lazarova, M.B.; Petkov, V.D.; Markovska, V.L.; Petkov, V.V.; Mosharrof, A. Effects of meclofenoxate and Extr. Rhodiolae roseae L. on electroconvulsive shock-impaired learning and memory in rats. Methods Find. Exp. Clin. Pharmacol. 1986, 8, 547–552.
29. Lee, M.-W.; Lee, Y.-A.; Park, H.-M.; Toh, S.-H.; Lee, E.-J.; Jang, H.-D.; Kim, Y.-H. Antioxidative phenolic compounds from the roots of Rhodiola sachalinensis A. Bor. Arch. Pharm. Res. 2000, 23, 455–458. DOI
30. Linh, P.T.; Kim, Y.H.; Hong, S.P.; Jian, J.J.; Kang, J.S. Quantitative determination of salidroside and tyrosol from the underground part ofRhodiola rosea by high performance liquid chromatography. Arch. Pharm. Res. 2000, 23, 349–352. DOI
31. Lum, P.T.; Sekar, M.; Gan, S.H.; Bonam, S.R.; Shaikh, M.F. Protective effect of natural products against Huntington's disease: An overview of scientific evidence and understanding their mechanism of action. ACS Chem. Neurosci. 2021, 12, 391–418. DOI
32. MacDonald, M.E.; Ambrose, C.M.; Duyao, M.P.; Myers, R.H.; Lin, C.; Srinidhi, L.; Barnes, G.; Taylor, S.A.; James, M.; Groot, N.; et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell 1993, 72, 971–983. DOI
33. Mehan, S.; Monga, V.; Rani, M.; Dudi, R.; Ghimire, K. Neuroprotective effect of solanesol against 3-nitropropionic acid-induced Huntington's disease-like behavioral, biochemical, and cellular alterations: Restoration of coenzyme-Q10-mediated mitochondrial dysfunction. Indian J. Pharmacol. 2018, 50, 309–319. DOI
34. Okaichi, Y.; Ishikura, Y.; Akimoto, K.; Kawashima, H.; Toyoda-Ono, Y.; Kiso, Y.; Okaichi, H. Arachidonic acid improves aged rats' spatial cognition. Physiology & behavior 2005, 84, 617–623.
35. Pagel, P.; Blome, J.; Wolf, H.U. High-performance liquid chromatographic separation and measurement of various biogenic compounds possibly involved in the pathomechanism of Parkinson's disease. J. Chromatogr. B Biomed. Sci. Appl. 2000, 746, 297–304. DOI
36. Pan, L.; Feigin, A. Huntington's disease: New frontiers in therapeutics. Curr. Neurol. Neurosci. Rep. 2021, 21, 10. DOI
37. Panossian, A.; Wikman, G. Effect of adaptogens on the central nervous system. Arq. Bras. Fitomed. Cient. 2005, 3, 29–51.
38. Panossian, A.; Wikman, G. Effects of adaptogens on the central nervous system and the molecular mechanisms associated with their stress---protective activity. Pharmaceuticals 2010, 3, 188–224. DOI
39. Panossian, A.; Wikman, G. Pharmacology of Schisandra chinensis Bail.: An overview of Russian research and uses in medicine. J. Ethnopharmacol. 2008, 118, 183–212. DOI
40. Panossian, A.; Wikman, G.; Wagner, H. Plant adaptogens III. Earlier and more recent aspects and concepts on their mode of action. Phytomedicine 1999, 6, 287–300. DOI
41. Rawlins, M.D.; Wexler, N.S.; Wexler, A.R.; Tabrizi, S.J.; Douglas, I.; Evans, S.J.W.; Smeeth, L. The Prevalence of Huntington's Disease. Neuroepidemiology 2016, 46, 144–153. DOI
42. Roos, R.A.C. Huntington's disease: A clinical review. Orphanet J. Rare Dis. 2010, 5, 40. DOI
43. Ross, C.A.; Reilmann, R. E1 Diagnostic criteria for huntington's disease based on natural history. J. Neurol. Neurosurg. Psychiatry 2016, 87, A45. DOI
44. Ross, C.A.; Tabrizi, S.J. Huntington's disease: From molecular pathogenesis to clinical treatment. Lancet Neurol. 2011, 10, 83–98. DOI
45. Sandhir, R.; Mehrotra, A.; Kamboj, S.S. Lycopene prevents 3-nitropropionic acid-induced mitochondrial oxidative stress and dysfunctions in nervous system. Neurochem. Int. 2010, 57, 579–587. DOI
46. Sastry, K.V.H.; Moudgal, R.P.; Mohan, J.; Tyagi, J.S.; Rao, G.S. Spectrophotometric determination of serum nitrite and nitrate by copper-cadmium alloy. Anal. Biochem. 2002, 306, 79–82. DOI
47. Schriner, S.E.; Avanesian, A.; Liu, Y.; Luesch, H.; Jafari, M. Protection of human cultured cells against oxidative stress by Rhodiola rosea without activation of antioxidant defenses. Free Radic. Biol. Med. 2009, 47, 577–584. DOI
48. Shalaby, H.N.; El-Tanbouly, D.M.; Zaki, H.F. Topiramate mitigates 3-nitropropionic acid-induced striatal neurotoxicity via modulation of AMPA receptors. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2018, 118, 227–234. DOI
49. Shin, B.; Jung, R.; Oh, H.; Owens, G.E.; Lee, H.; Kwak, S.; Lee, R.; Cotman, S.L.; Lee, J.-M.; MacDonald, M.E.; et al. Novel DNA Aptamers that Bind to Mutant Huntingtin and Modify Its Activity. Molecular therapy. Nucleic Acids. 2018, 11, 416–428. DOI
50. Stack, E.C.; Matson, W.R.; Ferrante, R.J. Evidence of oxidant damage in Huntington's disease: Translational strategies using antioxidants. Ann. N. Y. Acad. Sci. 2008, 1147, 79–92. DOI
51. Stoker, T.B.; Mason, S.L.; Greenland, J.C.; Holden, S.T.; Santini, H.; Barker, R.A. Huntington's disease: Diagnosis and management. Pract. Neurol. 2022, 22, 32–41. DOI
52. Tabrizi, S.J.; Flower, M.D.; Ross, C.A.; Wild, E.J. Huntington disease: New insights into molecular pathogenesis and therapeutic opportunities. Nat. Rev. Neurol. 2020, 16, 529–546. DOI
53. Tabrizi, S.J.; Ghosh, R.; Leavitt, B.R. Huntingtin lowering strategies for disease modification in Huntington's disease. Neuron 2019, 101, 801–819. DOI
54. Túnez, I.; Tasset, I.; Pérez-De La Cruz, V.; Santamaría, A. 3-Nitropropionic acid as a tool to study the mechanisms involved in Huntington's disease: Past, present and future. Molecules 2010, 15, 878–916. DOI
55. Wang, L.; Wang, J.; Yang, L.; Zhou, S.-M.; Guan, S.-Y.; Yang, L.-K.; Shi, Q.-X.; Zhao, M.-G.; Yang, Q. Effect of Praeruptorin C on 3-nitropropionic acid induced Huntington's disease-like symptoms in mice. Biomed. Pharmacother. 2017, 86, 81–87. DOI
56. Weir, D.W.; Sturrock, A.; Leavitt, B.R. Development of biomarkers for Huntington's disease. Lancet Neurol. 2011, 10, 573–590. DOI
57. Wollenman, L.C.; Ploeg, M.R.V.; Miller, M.L.; Zhang, Y.; Bazil, J.N. The effect of respiration buffer composition on mitochondrial metabolism and function. PLoS ONE. 2017, 12, e0187523. DOI
58. Yoshikawa, M.; Nakamura, S.; Li, X.; Matsuda, H. Reinvestigation of absolute stereostructure of (−)-rosiridol: Structures of monoterpene glycosides, rosiridin, rosiridosides A, B, and C, from Rhodiola sachalinensis. Chem. Pharm. Bull. 2008, 56, 695–700. DOI
59. Zuccato, C.; Cattaneo, E. Role of brain-derived neurotrophic factor in Huntington's disease. Prog. Neurobiol. 2007, 81, 294–330. DOI
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Zakir Hidayatallah
This work is licensed under a Creative Commons Attribution 4.0 International License.
