Iranian
Biomedical Journal
Volume 30, Issue 3 And 2 (4-2026)
IBJ 2026, 30(3 And 2): 141-152 |
Back to browse issues page
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Mantashashvili T, Nakaidze L, Shengelia M, Koshoridze N. Antidepressant Effects of L-Arginine and Its Role in Brain Energy Metabolism. IBJ 2026; 30 (3 and 2) :141-152
URL: http://ibj.pasteur.ac.ir/article-1-5314-en.html
URL: http://ibj.pasteur.ac.ir/article-1-5314-en.html
Abstract:
Background: Mitochondrial dysfunction and impaired cellular energy metabolism are increasingly recognized as key contributing factors in depression. This study evaluated the amino acid L-arginine as a potential agent for behavioral rescue and bioenergetic restoration using a corticosterone-induced rat model of depression.
Methods: Male rats were randomly assigned to four groups (n = 10): control (DMSO intraperitoneally [i.p.] + water oral gavage), corticosterone-induced depression (20 mg/kg, i.p. for 14 days), L-arginine treatment (150 mg/kg, oral gavage for 14 days), and fluoxetine (10 mg/kg, oral gavage for 14 days). To ensure handling equivalence, all oral administrations were performed via gavage (1.0 mL/100 g). Behavioral rescue was assessed via open field, forced swim (FST), and tail suspension (TST) tests. Hippocampal energy metabolism and PI3K/Akt/mTOR pathway activation were analyzed.
Results: L-arginine significantly improved the hippocampal bioenergetic profile, demonstrating efficacy comparable to the positive control fluoxetine. It led to a significant reduction in immobility time during FST and TST, alongside restoring glycolysis, the tricarboxylic acid cycle, and mitochondrial respiratory chain activities. Concurrently, L-arginine enhanced the activation state of the PI3K/Akt/mTOR signaling pathway (phosphorylated Akt/Akt and p-mTOR/mTOR ratios) and improved the functional state of the mitochondrial permeability transition pore. These metabolic and signaling improvements strongly correlated with the rescue of depressive-like behaviors.
Conclusion: Our findings demonstrate that L-arginine possesses potent antidepressant-like potential, mediated through bioenergetic restoration and signaling pathway modulation. By activating key metabolic processes in the hippocampus, L-arginine effectively restores impaired cellular energy homeostasis, suggesting its promise as a metabolic modulator for alleviating neurobiological disturbances associated with depressive conditions.
Methods: Male rats were randomly assigned to four groups (n = 10): control (DMSO intraperitoneally [i.p.] + water oral gavage), corticosterone-induced depression (20 mg/kg, i.p. for 14 days), L-arginine treatment (150 mg/kg, oral gavage for 14 days), and fluoxetine (10 mg/kg, oral gavage for 14 days). To ensure handling equivalence, all oral administrations were performed via gavage (1.0 mL/100 g). Behavioral rescue was assessed via open field, forced swim (FST), and tail suspension (TST) tests. Hippocampal energy metabolism and PI3K/Akt/mTOR pathway activation were analyzed.
Results: L-arginine significantly improved the hippocampal bioenergetic profile, demonstrating efficacy comparable to the positive control fluoxetine. It led to a significant reduction in immobility time during FST and TST, alongside restoring glycolysis, the tricarboxylic acid cycle, and mitochondrial respiratory chain activities. Concurrently, L-arginine enhanced the activation state of the PI3K/Akt/mTOR signaling pathway (phosphorylated Akt/Akt and p-mTOR/mTOR ratios) and improved the functional state of the mitochondrial permeability transition pore. These metabolic and signaling improvements strongly correlated with the rescue of depressive-like behaviors.
Conclusion: Our findings demonstrate that L-arginine possesses potent antidepressant-like potential, mediated through bioenergetic restoration and signaling pathway modulation. By activating key metabolic processes in the hippocampus, L-arginine effectively restores impaired cellular energy homeostasis, suggesting its promise as a metabolic modulator for alleviating neurobiological disturbances associated with depressive conditions.
Type of Study: Full Length/Original Article |
Subject:
Tissue Engineering and Cell Biology
References
1. Kovich H, Kim W, Quaste AM. Pharmacologic treatment of depression. Am Fam Physician. 2023;107(2):173-81.
2. Jiang M, Wang L, Sheng H. Mitochondria in depression: The dysfunction of mitochondrial energy metabolism and quality control systems. CNS Neurosci Ther. 2024;30(2):14576. [DOI:10.1111/cns.14576]
3. ZhaoT, Liu T, Wang L, Xie K, Tang H, Tang M. Dysfunction of neurotransmitter metabolism is associated with the severity of depression in first-diagnosed, drug-naïve depressed patients. J Affect Disord. 2024:349:332-41. [DOI:10.1016/j.jad.2024.01.023]
4. Ghafori SS, Yousefi Z, Bakhtiari E, Mohammadi MH, Hassanzadeh G. Neutrophil-to-lymphocyte ratio as a predictive biomarker for early diagnosis of depression: A narrative review. Brain Behav Immun Health. 2024:36:100734. [DOI:10.1016/j.bbih.2024.100734]
5. Castellano-Gonzalez G, Jacobs KR, Don E, Cole NJ, Adams S, Lim CK, et al. Kynurenine 3-monooxygenase activity in human primary neurons and effect on cellular bioenergetics identifies new neurotoxic mechanisms. Neurotox Res. 2019:35(3):530-41. [DOI:10.1007/s12640-019-9997-4]
6. Gebara E, Zanoletti O, Ghosal S, Grosse J, Schneider BL, Knott G, et al. Mitofusin-2 in the nucleus accumbens regulates anxiety and depression-like behaviors through mitochondrial and neuronal actions. Biol Psychiatry. 2021;89(11):1033-44. [DOI:10.1016/j.biopsych.2020.12.003]
7. Ruegsegger GN, Vanderboom PM, Dasari S, Klaus KA, Kabiraj P, McCarthy CB, et al. Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain. JCI Insight. 2019;4(18):130681. [DOI:10.1172/jci.insight.130681]
8. Li D, Liao Q, Tao Y, Ni S, Wang C, Xu D, et al. Downregulation of CRTC1 is involved in CUMS-induced depression-like behavior in the hippocampus and its RNA sequencing analysis. Mol Neurobiol. 2022;59(7):4405-18. [DOI:10.1007/s12035-022-02787-6]
9. Głombik K, Kukla-Bartoszek M, Curzytek K, Detka J, Basta-Kaim A, Budziszewska B. The effects of prenatal dexamethasone exposure on brain metabolic homeostasis in adulthood: Implications for depression. Int J Mol Sci. 2023;2492:1156. [DOI:10.3390/ijms24021156]
10. Perić I, Costina V, Djordjević S, Gass P, Findeisen P, Inta D, et al. Tianeptine modulates synaptic vesicle dynamics and favors synaptic mitochondria processes in socially isolated rats. Sci Re. 2021;11(1):17747. [DOI:10.1038/s41598-021-97186-7]
11. Scaini G, Maggi DD, De-Nês BT, Gonçalves CL, Ferreir GL, Teodorak BP, et al. Activity of mitochondrial respiratory chain is increased by chronic administration of antidepressants. Acta Neuropsychiatr. 2011;23(3):112-8. [DOI:10.1111/j.1601-5215.2011.00548.x]
12. Lu S, Li C, Jin X, Zhu L, Shen J, Bai M, et al. Baicalin improves the energy levels in the prefrontal cortex of mice exposed to chronic unpredictable mild stress. Heliyon. 2022;8(12):12083. [DOI:10.1016/j.heliyon.2022.e12083]
13. Mishra SK, Hidau MK, Rai S. Memantine treatment exerts an antidepressant-like effect by preventing hippocampal mitochondrial dysfunction and memory impairment via upregulation of CREB/BDNF signaling in the rat model of chronic unpredictable stress-induced depression. Neurochem Int. 2021:142:104932. [DOI:10.1016/j.neuint.2020.104932]
14. Ľupták M, Fišar Z, Hroudová J. Effect of novel antipsychotics on energy metabolism -in vitro study in pig brain mitochondria. Mol Neurobiol. 2021;58(11):5548-63. [DOI:10.1007/s12035-021-02498-4]
15. Fizíková I, Dragašek J, Račay P. Mitochondrial dysfunction, altered mitochondrial oxygen, and energy metabolism associated with the pathogenesis of schizophrenia. Int J Mol Sci. 2023;24(9):7991. [DOI:10.3390/ijms24097991]
16. Głombik K, Stachowicz A, Trojan E, Ślusarczyk J, Suski M, Chmera K, et al. Mitochondrial proteomics investigation of frontal cortex in an animal model of depression: Focus on chronic antidepressant drug treatment. Pharmacol Rep. 2017;70(2):322-30. [DOI:10.1016/j.pharep.2017.11.016]
17. Wu WZ, Ling-Hu T, Zhao YH, Zhao W, Cui J, Tian JS, et al. A unique insight for Xiaoyao San exerts antidepressant effects by modulating hippocampal glucose catabolism using stable isotope-resolved metabolomics. J Ethnopharmacol. 2023:300:115702. [DOI:10.1016/j.jep.2022.115702]
18. Wang B, Shi H, Yang B, Miao Z, Sun M, Yang H, et al. The mitochondrial Ahi1/GR participates the regulation on mtDNA copy numbers and brain ATP levels and modulates depressive behaviors in mice. Cell Commun Signal. 2023;21(1):21. [DOI:10.1186/s12964-022-01034-8]
19. Cynober L. Citrulline: Just a biomarker or a conditionally essential amino acid and a pharmaconutrient in critically ill patients? Crit Care. 2013;17(2):122. [DOI:10.1186/cc12534]
20. Głombik K, Detka J, Kurek, Budziszewska B. Impaired brain energy metabolism: Involvement in depression and hypothyroidism. Front Neurosci. 2020:14:586939. [DOI:10.3389/fnins.2020.586939]
21. Paddon-Jones D, Børsheim E, Wolfe RR. Potential ergogenic effects of arginine and creatine supplementation. J Nutr. 2004;134(10):2888-94. [DOI:10.1093/jn/134.10.2888S]
22. Zhgenti N, Bibilashvili O, Shengelia M, Burjanadze G, Koshoridze M, Davitashvili E, et al. Effect of nicotine on the energy metabolism of substantia nigra cells in MPTP-induced Parkinson's disease. Iran J Basic Med Sci. 2025;28(10):1417-28. [DOI:10.1080/1028415X.2025.2516619]
23. Pan SM, Zhou YF, Zuo N, Jiao RQ, Kong LD, Pan Y. Fluoxetine increases astrocytic glucose uptake and glycolysis in corticosterone-induced depression through restricting GR-TXNIP-GLUT1 Pathway. Front Pharmacol. 2022:13:872375. [DOI:10.3389/fphar.2022.872375]
24. Strope TA, Birky CJ, Wilkins HM. The role of bioenergetics in neurodegeneration. Int J Mol Sci. 2022;23(16):9212. [DOI:10.3390/ijms23169212]
25. Cryan JF, Mombereau C, Vassout A. The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev. 2005;29(4-5):571-625. [DOI:10.1016/j.neubiorev.2005.03.009]
26. Cryan JF, Valentino RJ, Lucki I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev. 2005;29(4-5):547-69. [DOI:10.1016/j.neubiorev.2005.03.008]
27. Tassone A, Meringolo M, Ponterio G, Bonsi P, Schirinzi T, Martella G. Mitochondrial bioenergy in neurodegenerative disease: Huntington and parkinson. Int J Mol Sci. 2023;24(8):7221. [DOI:10.3390/ijms24087221]
28. Forman HJ, Zhang H. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy. Nat Rev Drug Discov. 2021;20(9):689-709. [DOI:10.1038/s41573-021-00233-1]
29. Mantashashvili T, Nakaidze L, Ananiashvili G Burjanadze G, Koshoridze N. L-arginine as a potential antidepressant: Effects on cognitive function and antioxidant enzyme activity in depressed rats. Highlights in BioScience. 2025;8(7):36462. [DOI:10.36462/H.BioSci.202503]
30. Juneja K, Bhuchakra HP, Sadhukhan S, Mehta I, Niharika A, Thareja S, et al. Creatine supplementation in depression: A review of mechanisms, efficacy, clinical outcomes, and future directions. Cureus. 2024;16(10):71638. [DOI:10.7759/cureus.71638]
31. Zhuravliova E, Barbakadze T, Zaalishvili E, Chilashvili M, Koshoridze N, Mikeladze D. Social isolation in rats inhibits oxidative metabolism, decreases the content of mitochondrial K-Ras and activates mitochondrial hexokinase. Behav Brain Res. 2009;205(2):377-83. [DOI:10.1016/j.bbr.2009.07.009]
32. Rezin GT, Amboni G, Zugno AI, Quevedo J, Streck EL. Mitochondrial dysfunction and psychiatric disorders. Neurochem Res. 2009;34(6):1021-9. [DOI:10.1007/s11064-008-9865-8]
33. Goetzl EJ, Wolkowitz OM, Srihari VH, Reus VI, Goetzl L, Kapogiannis D, et al. Abnormal levels of mitochondrial proteins in plasma neuronal extracellular vesicles in major depressive disorder. Mol Psychiatry. 2021;26(12):7355-62. [DOI:10.1038/s41380-021-01268-x]
34. Scialò F, Fernández-Ayala DJ, Sanz A. Role of mitochondrial reverse electron transport in ROS signaling: Potential roles in health and disease. Front Physiol. 2017:8:428. [DOI:10.3389/fphys.2017.00428]
35. Chavda V, Lu B. Reverse electron transport at mitochondrial complex I in ischemic stroke, aging, and age-related diseases. Antioxidants (Basel). 2023;12(4):895. [DOI:10.3390/antiox12040895]
36. Xu X, Pang Y, Fan X. Mitochondria in oxidative stress, inflammation and aging: From mechanisms to therapeutic advances. Signal Transduct Target Ther. 2025;10(1):190-99. [DOI:10.1038/s41392-025-02253-4]
37. Wang CH, Wu SB, Wu YT, Wei YH. Oxidative stress response elicited by mitochondrial dysfunction: Implication in the pathophysiology of aging. Exp Biol Med (Maywood). 2013;238(5):450-60. [DOI:10.1177/1535370213493069]
38. Pols T, Singh Sh, Deelman‐Driessen C, Gaastra BF, Poolman B. Enzymology of the pathway for ATP production by arginine breakdown. FEBS J. 2021;288(1):293-309. [DOI:10.1111/febs.15337]
39. Guo L, Carraro M, Sartori G, Minervini G, Eriksson O, Petronilli V, et al. Arginine 107 of yeast ATP synthase subunit g mediates sensitivity of the mitochondrial permeability transition to phenylglyoxal. J Biol Chem. 2018;293(38):14632-45. [DOI:10.1074/jbc.RA118.004495]
40. Forester BP, Zuo CS, Ravichandran C, Harper DG, Du F, Kim S, et al. Coenzyme Q10 effects on creatine kinase activity and mood in geriatric bipolar depression. J Geriatr Psychiatry Neurol. 2012; 25(1):43-50. [DOI:10.1177/0891988712436688]
41. Al-Hakeim HK, Razzaq Al-Issa AA, Maes M. Serum agrin and talin are increased in major depression while agrin and creatine phosphokinase are associated with chronic fatigue and fibromyalgia symptoms in depression. Metab Brain Dis. 2020;35(1):225-35. [DOI:10.1007/s11011-019-00506-0]
42. Chen Y, Guan W, Wang ML, Lin XY. PI3K-AKT/mTOR signaling in psychiatric disorders: A valuable target to stimulate or suppress? Int J Neuropsychopharmacol. 2024;27(2):10. [DOI:10.1093/ijnp/pyae010]
43. Guo N, Wang X, Xu M, Bai J, Yu H, Zhang L. PI3K/AKT signaling pathway: Molecular mechanisms and therapeutic potential in depression. Pharmacol Res. 2024:206:107300. [DOI:10.1016/j.phrs.2024.107300]
44. Bonelli M, Terenziani R, Zoppi S, Fumarola C, La Monica S, Cretella D, et al. Dual inhibition of CDK4/6 and PI3K/AKT/mTOR signaling impairs energy metabolism in MPM cancer cells. Int J Mol Sci. 2020;21(14):5165. [DOI:10.3390/ijms21145165]
45. Su WY, Tian LY, Guo LP, Huang LQ, Gao WY. PI3K signaling-regulated metabolic reprogramming: From mechanism to application. Biochim Biophys Acta Rev Cancer. 2023;1878(5):188952. [DOI:10.1016/j.bbcan.2023.188952]
46. Buel GR, Dang HQ, Asara JM, Blenis J, Mutvei AP. Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1. J Biol Chem. 2022;298(6):102030. [DOI:10.1016/j.jbc.2022.102030]
47. Fontana F, Giannitti G, Marchesi S, Limonta P. The PI3K/Akt pathway and glucose metabolism: A dangerous liaison in cancer. Int J Biol Sci. 2024;20(8):3113-25. [DOI:10.7150/ijbs.89942]
| Rights and permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
IBJ is a member of Committee on Publication Ethics (COPE)
and follows its guidelines |
The articles of this journal are licensed under
a Creative Commons Attribution-NonDerivatives 4.0 International License. .png) |
 IBJ is owned and published by Pasteur Institute of Iran |