30DEC

Libyan International Conference for Health Sciences

The First Libyan International Conference for Health Sciences (2024): Open University, Tripoli, Libya
Mediterranean Journal of Pharmacy and Pharmaceutical Sciences
https://ppj.org.ly/article/doi/10.5281/zenodo.13751022

Mediterranean Journal of Pharmacy and Pharmaceutical Sciences

Original article

Ascorbic acid has an anxiolytic-like effect in the presence of flumazenil in rats

Suhera M. Aburawi, Jamal M. Saad, Reda A. Al-Tubuly, Ahmed F. Eldrogi

http://dx.doi.org/10.5281/zenodo.13751022 Mediterr J Pharm Pharm Sci, vol.4, n3, p.57-64, 2024
PDF
PDF
Downloads: 0
Views: 215

Abstract

Ascorbic acid (vitamin C) is a water-soluble vitamin; it is present in the highest concentration in the brain. Ascorbic acid in high doses acts as a potential treatment for various neuropathological and psychiatric conditions. Flumazenil is a benzodiazepine antagonist; it competitively inhibits the activity of benzodiazepine and non-benzodiazepine substances that interact with benzodiazepine receptors site on the GABA/benzodiazepine receptor complex. This study aims to investigate the effect of flumazenil on the anxiolytic action of ascorbic acid using an elevated plus maze model of anxiety in rats. Male Albino Wistar rats weighing between 250 and 320 grams were used. Rats were divided into four equal groups of seven rats each and treated as follows: Group I, the control group received a single dose of 1.0% tween 80; Group II treated with a single dose of 125 mg/kg ascorbic acid; Group III was injected by a single dose of 1.0 mg/kg flumazenil; Group IV received a combination treatment of 125 mg/kg ascorbic acid and 1.0 mg/kg flumazenil. Behavioural measurements using a plus maze were scored 30 min after the administration. The parameters scored are the time spent on the open and closed arms, the lines and number of entries into open and closed arms, and the anxiety measure. Ascorbic acid decreased anxiety measure and increased the total lines and total number of entries; this effect was abolished by the administration of flumazenil with ascorbic acid. Thus, ascorbic acid produces an anxiolytic-like effect in rats; this effect was abolished by flumazenil administration with ascorbic acid. This may indicate that the GABA/benzodiazepine receptor complex has to be stimulated to produce the anxiolytic effect.

Keywords

Anxiety, benzodiazepine, drug interaction, GABA, vitamin C

References

  1. Ballaz SJ, Rebec GV (2019) Neurobiology of vitamin C: Expanding the focus from antioxidant to endogenous neuromodulator. Pharmacological Research. 146. 104321. doi: 10.1016/j.phrs.2019.104321
  2. Barnes M, Kodicek E (1972) Biological hydroxylations and ascorbic acid with special regard to collagen metabolism. Vitamins and Hormones. 30: 1-43. doi: 10.1016/S0083-6729(08)60793-1
  3. Ferrada L, Barahona MJ, Salazar K, Vandenabeele P, Nualart F (2019) Vitamin C controls neuronal necroptosis under oxidative stress. Redox Biology. 29: 101408. doi: 10.1016/j.redox.2019.101408
  4. Han Q, Wu F, Li H, Cao Y, Chen G, Wang F (2022) SVCT2-mediated ascorbic acid uptake buffers stress responses via DNA hydroxymethylation reprogramming of the S100 calcium-binding protein A4 gene. Redox Biology. 58: 102543. doi: 10.1016/j.redox.2022.102543
  5. Ben Saad JM, Eldrogi AF, Al-Tubuly RA, Aburawi SM (2016) Neurobehavioral effect of alprazolam in presence of ascorbic acid using albino rats. Lebda Medical Journal. 2 (1): 68-82. doi: Nil.
  6. Sivilotti LA (2016) Flumazenil, naloxone and the ‘coma cocktail’. British Journal of Clinical Pharmacology. 81 (3): 428-436. doi: 10.1111/bcp.12731
  7. An H, Godwin J (2016) Flumazenil in benzodiazepine overdose. Canadian Medical Association Journal. 188 (17-18): E537. doi: 10.1503/cmaj. 160357
  8. Kucken AM, Teissére JA, Seffinga-Clark J, Wagner DA, Czajkowski C (2003) Structural requirements for imidazobenzodiazepine binding to GABAA receptors. Molecular Pharmacology. 63 (2): 289-296. doi: 10.1124/ mol.63.2.289
  9. Shoar NS, Bistas KG, Patel P, Saadabadi A (2024) Flumazenil. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Bookshelf ID: NBK470180. PMID: 29262246.
  10. Collinge J, Pycock CJ, Taberner PV (1983) Studies on the interaction between cerebral 5-hydroxytryptamine and gamma-aminobutyric acid in the mode of action of diazepam in the rat. British Journal of Pharmacology. 79 (3): 637-643. doi: 10.1111/j.1476-5381.1983.tb10000.x
  11. Aburawi S, Ahmed S, Elhwuegi A, Saad SF, Attia AS (2001) Brain glycine levels in triazolam-treated albino rats. Journal of Neural Transmission. 108: 527-539. doi: 10.1007/s007020170054
  12. Sherif FM, Harro J, El-Hwuegi A, Oreland L. Anxiolytic-like effect of the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA) on rat exploratory activity. Pharmacology, Biochemistry, and Behaviour. 1994 Dec;49(4):801-5. doi: 10.1016/0091-3057(94)90226-7
  13. Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology. 92 (2): 180-185. doi: 10.1007/BF00177912
  14. File SE (1990) One-trial tolerance to the anxiolytic effects of chlordiazepoxide in the plus-maze. Psycho-pharmacology. 100 (2): 281-282. doi: 10.1007/BF02244419
  15. Schneider P, Ho Y-J, Spanagel R, Pawlak CR (2011) A novel elevated plus-maze procedure to avoid the one-trial tolerance problem. Frontiers in Behavioral Neuroscience. 5 (43): 1-8. doi: 10.3389/fnbeh.2011.00043
  16. File SE, Zangrossi H Jr (1993) "One-trial tolerance" to the anxiolytic actions of benzodiazepines in the elevated plus-maze, or the development of a phobic state? Psychopharmacology. 110 (1-2): 240-244. doi: 10.1007/ BF02246980
  17. Bertoglio LJ, Carobrez AP (2002) Anxiolytic effects of ethanol and phenobarbital are abolished in test-experienced rats submitted to the elevated plus maze. Pharmacology, Biochemistry, and Behaviour. 73 (4): 963-969. doi: 10.1016/s0091-3057(02)00958-9
  18. Garcia AMB, Cardenas FP, Morato S (2005) Effect of different illumination levels on rat behavior in the elevated plus-maze. Physiology and Behaviour. 85 (3): 265-270. doi: 10.1016/j.physbeh.2005.04.007
  19. Pawlak CR, Karrenbauer BD, Schneider P, Ho Y-J (2012) The elevated plus-maze test: Differential psycho-pharmacology of anxiety-related behavior. Emotion Review. 4 (1): 1-19. doi: 10.1177/1754073911421374
  20. Aburawi SM, Elhwuegi AS, Ahmed SS, Saad SF, Attia AS (2003) Behavioral effects of acute and chronic triazolam treatments in albino rats. Life Sciences. 73 (24): 3095-107. doi: 10.1016/s0024-3205(03)00612-x
  21. Aburawi SM, Sadaa KA, Elshalakani MH, Altubuly RA (2013) Effect of sildenafil citrate on behaviour and excitatory and inhibitory amino acids levels in Albino rat's brain. Jordan Journal of Pharmaceutical Sciences. 6 (2): 242-257. doi: 10.12816/0000370
  22. Pitsikas N, Tarantilis PA (2020) The GABAA-benzodiazepine receptor antagonist flumazenil abolishes the anxiolytic effects of the active constituents of Crocus sativus L. Crocins in rats. Molecules. 25 (23): 5647. doi: 10.3390/molecules25235647
  23. Gallo AT, Addis S, Martyn V, Ramanathan H, Wilkerson GK, Bennett KS, Hood SD, Stampfer H, Hulse GK (2023) The role of flumazenil in generalised anxiety disorder: a pilot naturalistic open-label study with a focus on treatment resistance. Therapeutic Advances in Psychopharmacology. 13. doi: 10.1177/20451253231156400
  24. Sherif FM, Ahmed SS (1995) Basic aspects of GABA-transaminase in neuropsychiatric disorders. Clinical Biochemistry. 28 (2):145-54. doi: 10.1016/0009-9120(94)00074-6
  25. Szuhany KL, Simon NM (2022) Anxiety disorders: A review. Journal of the American Medical Association. 328 (24): 2431-2445. doi: 10.1001/jama.2022.22744
  26. Sorice A, Guerriero E, Capone F, Colonna G, Castello G, Costantini S (2014) Ascorbic acid: its role in immune system and chronic inflammation diseases. Mini Reviews in Medicinal Chemistry. 14 (5): 444-452. doi: 10.2174 /1389557514666140428112602
  27. Moretti M, Fraga DB, Rodrigues ALS (2017) Ascorbic acid to manage psychiatric disorders. CNS Drugs. 31 (7): 571-583. doi: 10.1007/s40263-017-0446-8
  28. Liu T, Zhong S, Liao X, Chen J, He T, Lai S, Jia Y (2015) A meta-analysis of oxidative stress markers in depression. PLoS ONE. 10 (10): e0138904. doi: 10.1371/journal.pone.0138904
  29. Shivavedi N, Kumar M, Tej GNVC, Nayak PK (2017) Metformin and ascorbic acid combination therapy ameliorates type 2 diabetes mellitus and comorbid depression in rats. Brain Research. 1674: 1-9. doi: 10.1016/ j.brainres.2017.08.019
  30. Aburawi SM (2021) Vitamin C and human diseases: An overview. Mediterranean Journal of Pharmacy and Pharmaceutical Sciences. 1 (4): 25-36. doi: 10.5281/zenodo.5805947
  31. Cort WM (1982) Antioxidant properties of ascorbic acid in foods; American Chemical Society: Washington, DC, USA. 533-550. ISBN: 9780841206328.
  32. Yen GC, Duh PD, Tsai HL (2002) Antioxidant and pro-oxidant properties of ascorbic acid and gallic acid. Food and Chemistry. 79 (3): 307-313. doi: 10.1016/S0308-8146(02)00145-0
  33. Delrobaei F, Fatemi I, Shamsizadeh A, Allahtavakoli M (2019) Ascorbic acid attenuates cognitive impairment and brain oxidative stress in ovariectomized mice. Pharmacological Reports. 71 (1): 133-138. doi. 10.1016/ j.pharep.2018.10.001
  34. Cryan JF, Sweeney FF (2011) The age of anxiety: role of animal models of anxiolytic action in drug discovery. British Journal of Pharmacology. 164 (4): 1129-1161. doi: 10.1111/j.1476-5381.2011.01362.x
  35. Harrison FE, May JM (2009) Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2. Free Radical Biology and Medicine. 46 (6): 719-730. doi: 10.1016/j.freeradbiomed.2008.12.018
  36. Naseer MI, Lee HY, Kim MO (2010) Neuroprotective effect of vitamin C against the ethanol and nicotine modulation of GABAB receptor and PKA-alpha expression in prenatal rat brain. Synapse. 64 (6): 467-477. doi: 10.1002/syn.20752
  37. Rosa PB, Neis VB, Ribeiro CM, Moretti M, Rodrigues ALS (2016) Antidepressant-like effects of ascorbic acid and ketamine involve modulation of GABAA and GABAB receptors. Pharmacological Reports. 68 (5): 996-1001. doi: 10.1016/j.pharep.2016.05.010
  38. Calero CI, Vickers E, Moraga Cid G, Aguayo LG, von Gersdorff H, Calvo DJ (2011) Allosteric modulation of retinal GABA receptors by ascorbic acid. Journal of Neuroscience. 31 (26): 9672-9682. doi: 10.1523/ JNEUROSCI.5157-10.2011
  39. Hossain R, Khan RA, Sarkar C, Islam MS, Dey D, Jain D, Faria F, Akbor R, Atolani O, Oliveira SM, Siyadatpanah A, Pereira MD, Islam MT (2021) Quercetin and/or ascorbic acid modulatory effect on phenobarbital-induced sleeping mice possibly through GABAA and GABAB receptor interaction pathway. Pharmaceuticals. 14 (8): 721. doi: 10.3390/ph14080721
  40. Grigor'ev IP, Neokesariĭskiĭ AA (1986) Effect of ascorbic acid on the binding of 3H-GABA and 3H-glutamic acid to synaptosomes of the rat cerebral cortex. Biulleten Ekspweimental noi Biologii i Meditsiny. 102 (9): 288-289. PMID: 2875748.
  41. Tan KR, Rudolph U, Lüscher C (2011) Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends in Neurosciences. 34 (4): 188-197. doi: 10.1016/j.tins.2011.01.004
  42. Rudolph U, Möhler H (2004) Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annual Review of Pharmacology and Toxicology. 44: 475-98. doi: 10.1146/annurev.pharmtox.44.101802.121429
  43. Rowlett JK, Platt DM, Lelas S, Atack JR, Dawson GR (2004) Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates. Proceedings of the National Academy of Sciences of the United States of America. 102 (3): 915-920. doi: 10.1073/pnas. 0405621102
  44. Vinkers CH, Klanker M, Groenink L, Korte SM, Cook JM, Van Linn ML, Hopkins SC, Olivier B (2009) Dissociating anxiolytic and sedative effects of GABAA-ergic drugs using temperature and locomotor responses to acute stress. Psychopharmacology. 204 (2): 299. doi: 10.1007/s00213-009-1460-4
  45. Atack JR, Hutson PH, Collinson N, Marshall G, Bentley G, Moyes C, Cook SM, Collins I, Wafford K, McKernan RM, Dawson GR (2005) Anxiogenic properties of an inverse agonist selective for alpha3 subunit-containing GABAA receptors. British Journal of Pharmacology. 144 (3): 357-366. doi: 10.1038/sj.bjp.0706056
  46. Dias R, Sheppard WF, Fradley RL, Garrett EM, Stanley JL, Tye SJ, Goodacre S, Lincoln RJ, Cook SM, Conley R, Hallett D, Humphries AC, Thompson SA, Atack JR, McKernan RM, Dawson GR, Reynolds DS (2005) Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines. Journal of Neurosciences. 25 (46): 10682-10688. doi: 10.1523/JNEUROSCI.1166-05.2005
  47. Islam MT, Molla S, Zihad NK, Umer M, Rahman S, Zaman F, Das AK, Afzal MI, Salehi B, Akter MS, Mubarak MS, Martins N, Imran M, Chaudhary N, Iqbal Z, Sharifi-Rad J (2020) Ascorbic acid antagonizes the sedative effect of diazepam possibly through inhibition of GABA(Aρ₁) and GABA(B1) receptors. Cellular and Molecular Biology. 66 (4): 15-19. doi: 10.14715/cmb/2020.66.4.3
  48. Ishola IO, Chatterjee M, Tota S, Tadigopulla N, Adeyemi OO, Palit G, Shukla R (2012) Antidepressant and anxiolytic effects of amentoflavone isolated from Cnestis ferruginea in mice. Pharmacology, Biochemistry, and Behavior. 103 (2): 322-331. doi: 10.1016/j.pbb.2012.08.017
  49. Safavynia SA, Keating G, Speigel I, Fidler JA, Kreuzer M, Rye DB, Jenkins A, García PS (2016) Effects of γ-aminobutyric acid type a receptor modulation by flumazenil on emergence from general anaesthesia. Anaesthesiology. 125 (1): 147-58. doi: 10.1097/ALN.0000000000001134
  50. Nelson LS, Howland MA, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS (2019) Goldfrank's toxicologic emergencies, 11e. McGraw-Hill. Kepler Std by Cenveo® Publisher Services. ISBN: 978-1-259-85961-8.
  51. Doble A, Martin IL (1992) Multiple benzodiazepine receptors: no reason for anxiety. Trends in Pharmacological Sciences. 13 (2): 76-81. doi: 10.1016/0165-6147(92)90027-4
  52. Polc P, Bonetti EP, Schaffner R, Haefely W (1982) A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro15-1788, benzodiazepine tranquilizers, beta-carbolines, and phenobarbitone. Naunyn-Schmiedeberg's Archives of Pharmacology. 321 (4): 260-264. doi: 10.1007/BF00498510
  53. Nutt DJ, Glue P, Lawson C, Wilson S (1990) Flumazenil provocation of panic attacks: evidence for altered benzodiazepine receptor sensitivity in panic disorder. Archives of General Psychiatry. 47 (10): 917-925. doi: 10.1001/archpsyc.1990.01810220033004
  54. Votey SR, Bosse GM, Bayer MJ, Hoffman JR (1991) Flumazenil: a new benzodiazepine antagonist. Annals of Emergency Medicine. 20 (2): 181-188. doi: 10.1016/s0196-0644(05)81219-3
  55. Brogden RN, Goa KL (1991) Flumazenil. A reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs. 42 (6): 1061-1089. doi: 10.2165/00003495-199142060-00010
  56. Dhaliwal JS, Rosani A, Saadabadi A (2024) Diazepam. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Bookshelf ID: NBK537022. PMID: 30725707.
  57. Baraldi M, Avallone R, Corsi L, Venturini I, Baraldi C, Zeneroli ML (2009) Natural endogenous ligands for benzodiazepine receptors in hepatic encephalopathy. Metabolic Brain Disease. 24 (1): 81-93. doi: 10.1007/ s11011-008-9111-8
  58. Izquierdo I, Medina JH (1991) GABAA receptor modulation of memory: the role of endogenous benzodia-zepines. Trends in Pharmacological Sciences. 12 (7): 260-265. doi: 10.1016/0165-6147(91)90567-c

Submitted date:
08/22/2024

Reviewed date:
09/08/2024

Accepted date:
09/12/2024

Publication date:
09/11/2024

66e22a6ea9539566fb232724 medjpps Articles
Links & Downloads
2789-1895 (Electronic) 2958-3101 (Printed)
Mediterr J Pharm Pharm Sci ©2024 All rights reserved.

Mediterr J Pharm Pharm Sci

Share this page
Page Sections