Effects of Coenzyme Q10, Ramipril, and Vinpocetine on the Regulation of Oxidative Stress and Cognition in Rats with Chronic Insomnia and REM Sleep Deprivation.

Year 2026, Volume: 18 Issue: 1 , 1302 - 1314 , 02.04.2026

Tanya Sharma , Amberkar Mohanbabu Vittalrao , Meena Kumari K , Divya Thomas , Mohandas Rao K G , Ravindra Maradi

https://doi.org/10.37212/jcnos.1822847

https://izlik.org/JA57DU76CB

Abstract

This study evaluated the impact of various drugs on cognitive function and oxidative stress in a chronic insomnia rat model induced by rapid eye movement (REM) sleep deprivation using modified multiple-platform method. Forty-eight albino rats were divided into eight groups (n=6 per group): the control group; REM sleep-deprived groups, which were treated with water, corn oil, donepezil, vinpocetine, Coenzyme Q10 + corn oil, ramipril, and Coenzyme Q10 + corn oil + ramipril. Spatial learning and memory were assessed using the Morris water maze. On the 3rd and 4th days of the acquisition trials, the latency of Coenzyme Q10, ramipril and their combination was lower than that of REM sleep-deprived rats. In the probe trial, sleep-deprived rats spent significantly less time in the target quadrant than REM controls . In contrast, vinpocetine, Coenzyme Q10 and the combination of ramipril + Coenzyme Q10 resulted in a significantly greater percentage of time spent in the target quadrant than REM sleep-deprived rats . Biochemical analysis of hippocampal tissue revealed that, compared with REM sleep-deprived rats, those treated with donepezil, vinpocetine, ramipril, Coenzyme Q10, or their combination presented reduced malondialdehyde and acetylcholinesterase levels but increased reduced glutathione levels. In conclusion, these findings suggest that donepezil, vinpocetine, ramipril, Coenzyme Q10, and their combination effectively ameliorate the cognitive deficits and oxidative stress induced by REM sleep deprivation.

Keywords

Acetylcholinesterase , cognition , reduced glutathione , morris water maze , sleep deprivation , oxidative stress

Ethical Statement

The experiment was conducted after obtaining approval from the Institutional animal ethical committee (Reg. No 94/1999/CPCSEA (IAEC/KMC/130/2019).

Supporting Institution

nil

Thanks

I thank along with the coauthors for allowing us to resubmit the file.

References

• Alkadhi K, Zagaar M, Alhaider I, Salim S, Aleisa A. (2013). Neurobiological consequences of sleep deprivation. Curr Neuropharmacol.11(3):231-249. https://doi.org/10.2174/1570159X11311030001
• Amberkar MV, Linthoinganbi L, Kumari MK, Rao MKG. (2023). Cognitive enhancing activities of coenzyme Q10, ramipril, and vinpocetine through modulating neuroinflammatory response and oxidative damage inflicted by acute REM sleep deprivation in rats. Biomedical and Pharmacology Journal, 16(4):2021–2030. https://dx.doi.org/10.13005/bpj/2778
• Anderson C, Teo K, Gao P et al. (2011). Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies. Lancet Neurol. 10: 43–53.
• Baydas G, Nedzvetskii VS, Nerush PA, Kirichenko S V, Yoldas T. (2003). Altered expression of NCAM in hippocampus and cortex may underlie memory and learning deficits in rats with streptozotocin-induced diabetes mellitus. Life Sci. 73(15):1907-1916. https://doi.org/10.1016/S0024-3205(03)00561-7
• Beal MF. (2004). Mitochondrial dysfunction and oxidative damage in Alzheimer’s and Parkinson’s diseases and coenzyme Q 10 as a potential treatment. J Bioenerg Biomembr. 36(4):381-386. https://doi.org/10.1023/B:JOBB.0000041772.74810.92
• Beckman KB, Ames BN. (1998). The free radical theory of aging matures. Physiol Rev.78(2): 547-581. https://doi.org/10.1152/physrev.1998.78.2.547
• Bhanot JL, Chhina GS, Singh B, Sachdeva U, Kumar VM. (1989). REM sleep deprivation and food intake. Indian J Physiol Pharmacol. 33(3):139-145.
• Bukareva OP, Pavlova ON, Gromova DS. et al. (2025). Sleep Deprivation and the Development of Oxidative Stress in Animal Models. Neurosci Behav Physi 55, 1065–1069. https://doi.org/10.1007/s11055-025-01864-2
• Chen P, Ban W, Wang W, You Y, Yang Z. (2023). The Devastating Effects of Sleep Deprivation on Memory: Lessons from Rodent Models. Clocks & Sleep, 5(2), 276-294. https://doi.org/10.3390/clockssleep5020022
• Davinelli S, Scapagnini G , Corbi G. (2024). Sleep and oxidative stress: A bidirectional relationship and the role of NRF2. Antioxidants. 13(2): 123. https://doi.org/10.3390/antiox13020123
• Dhanasekaran M, Ren J. (2005). The emerging role of coenzyme Q-10 in aging, neurodegeneration, cardiovascular disease, cancer and diabetes mellitus. Curr Neurovasc Res. 2(5):447-459. https://doi.org/10.2174/156720205774962656.
• Draper HH, Hadley M. (1990). Malondialdehyde determination as index of lipid Peroxidation. Methods Enzymol. 186(C):421-431. https://doi.org/10.1016/0076-6879(90)86135-I
• Dumont M, Kipiani K, Yu F, et al. (2011). Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis.27(1):211-223. https://doi.org/10.3233/JAD-2011-110209
• D’souza D, Subhas BG, Shetty SR, Balan P. (2012). Estimation of serum malondialdehyde in potentially malignant disorders and postantioxidant treated patients: A biochemical study. Contemp Clin Dent. 3(4):448-451. https://doi.org/10.4103/0976-237X.107438
• Ellman GL, Courtney KD, Andres V, Featherstone RM. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 7(2):88-95. https://doi.org/10.1016/0006-2952(61)90145-9
• Everson CA, Bergmann BM, Rechtschaffen A. (1989). Sleep deprivation in the rat: III. Total sleep deprivation. Sleep. 12(1):13-21. https://doi.org/10.1093/sleep/12.1.13
• Guo HB, Cheng YF, Wu JG, et al, (2015). Donepezil improves learning and memory deficits in APP/PS1 mice by inhibition of microglial activation. Neuroscience 290: 530-542. https://doi.org/10.1016/j.neuroscience.2015.01.058.
• Gupta S, Singh P, Sharma BM, Sharma B. (2015). Neuroprotective Effects of Agomelatine and Vinpocetine Against Chronic Cerebral Hypoperfusion-Induced Vascular Dementia. Curr Neurovasc Res.12(3):240-252. https://doi.org/10.2174/1567202612666150603130235
• Hameed AK, Jabbar SS, Barrak MH, et al. (2024). Pathophysiology and the Biochemical and Clinical Significance of Malondialdehyde.International. J. Health and Med Res. 3(10):735- 740. https://doi.org/10.58806/ijhmr.2024.v3i10n05
• Karimfar MH, Noorafshan A, Rashidiani-Rashidabadi A, et al. (2014). Curcumin prevents the structural changes induced in the rats’ deep cerebellar nuclei by sodium metabisulfite, a preservative agent. Asian Pac J Trop Med. 7S1:S301-S305. https://doi.org/10.1016/S1995-7645(14)60250-9
• Kim HG, Moon M, Choi JG, et al. (2014). Donepezil inhibits the amyloidbeta oligomer-induced microglial activation in vitro and in vivo. Neurotoxicology 40: 23-32. https://doi.org/10.1016/j.neuro.2013.10.004
• Kumar MS, Vittalrao AM, Kumari MK, Vinay M. (2023). Evaluation of Cognition Enhancing Activities of Telmisartan, Nimodipine and their Combinations in REM Sleep-deprived Wistar Rats. Ind. J. Pharm. Edu. Res. 57(3s): s610-s619. https://doi.org/10.5530/ijper.57.3s.6
• Le Bon O. (2021). An asymmetrical hypothesis for the NREM-REM sleep alternation—What is the NREM-REM cycle? Front. Neurosci, 15: 627193. https://doi.org/10.3389/fnins.2021.627193
• Machado RB, Hipólide DC, Benedito-Silva AA, Tufik S. (2004). Sleep deprivation induced by the modified multiple platform technique: quantification of sleep loss and recovery Brain Res.1004(1-2):45- 51. https://doi.org/10.1016/j.brainres.2004.01.019
• Mir FA, Lark ARS, Nehs CJ. (2025). Unraveling the interplay between sleep, redox metabolism, and aging: implications for brain health and longevity. Front Aging 6:1605070. https://doi.org/10.3389/fragi.2025.1605070
• Nade VS, Kawale LA, Valte KD, Shendye NV. (2015). Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory. Indian J Pharmacol.47(3):263-269. https://doi.org/10.4103/0253-7613.157114
• Nath Mallick B, Thakkar M, Gangabhagirathi R. (1995). Rapid eye movement sleep deprivation decreases membrane fluidity in the rat brain. Neurosci Res.22(1):117-122. https://doi.org/10.1016/0168-0102(95)93696-Y
• NeuroLaunch Editorial Team. (2024). Donepezil side effects on sleep: Navigating nighttime challenges. NeuroLaunch. https://neurolaunch.com/donepezil-side-effects-sleep/
• Pala R, Beyaz F, Tuzcu M, et al. (2018). The effects of coenzyme Q10 on oxidative stress and heat shock proteins in rats subjected to acute and chronic exercise. J Exerc Nutr Biochem.22(3):14-20. https://doi.org/10.20463/jenb.2018.0019
• Park HW, Park CG, Park M, et al. (2020). Intrastriatal administration of coenzyme Q10 enhances neuroprotection in a Parkinson’s disease rat model. Sci Rep. 10(1):9572. https://doi.org/10.1038/s41598- 020-66493-w
• Peever J, Fuller PM. (2016). Neuroscience: A Distributed Neural Network Controls REM Sleep. Curr Biol. 11;26(1):R34-R35. https://doi.org/10.1016/j.cub.2015.11.011
• Pradhan N, Singh C & Singh A. (2021) Coenzyme Q10 a mitochondrial restorer for various brain disorders. Naunyn-Schmiedeberg's Arch Pharmacol 394: 2197–2222 https://doi.org/10.1007/s00210-021- 02161-8.
• Rahman I, Kode A, Biswas SK. (2006). Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc. 1(6):3159-3165. https://doi.org/10.1038/nprot.2006.378
• Rasch B, Born J. (2013). About sleep’s role in memory. Physiol Rev. 93(2),681-766. https://doi.org/10.1152/physrev.00032.2012
• Reimund E. (1994). The free radical flux theory of sleep. Med Hypotheses .43(4):231-233. https://doi.org/10.1016/0306-9877(94)90071-X
• Ruskin DN, Liu C, Dunn KE, Bazan NG, LaHoste GJ. (2004). Sleep deprivation impairs hippocampus-mediated contextual learning but not amygdala-mediated cued learning in rats. Eur J Neurosci. 19(11):3121-3124. https://doi.org/10.1111/j.0953-816X.2004.03426.x
• Saavedra JM. (2012). Angiotensin II AT (1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci (Lond). 123(10):567-590. https://doi.org/10.1042/CS20120078
• Sateia MJ. (2014). International classification of sleep disorders-third edition highlights and modifications. Chest. 146(5):1387-1394. https://doi.org/10.1378/chest.14-0970
• Shang Y, Wang L, Li Y, Gu P. (2016). Vinpocetine Improves Scopolamine Induced Learning and Memory Dysfunction in C57 BL/6J Mice. Biol Pharm Bull. 39(9):1412-1418. https://doi.org/10.1248/bpb.b15-00881
• Shekarian M, Komaki A, Shahidi S, Sarihi A, Salehi I, Raoufi S. (2020). The protective and therapeutic effects of vinpocetine, a PDE1 inhibitor, on oxidative stress and learning and memory impairment induced by an intracerebroventricular (ICV) injection of amyloid beta (aβ) peptide. Behav Brain Res. 383:112512. https://doi.org/10.1016/j.bbr.2020.112512
• Shekarian M, Salehi I, Raoufi S, et al. (2023). Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer’s disease. BMC Neurosci 24: 20. https://doi.org/10.1186/s12868-023-00790-8
• Shin CY, Kim H-S, Cha K-H, et al. (2018). Effects of Donepezil, an Acetylcholinesterase Inhibitor, on Impaired Learning and Memory in Rodents. Biomol Ther (Seoul). 26(3):274-281. https://doi.org/10.4062/biomolther.2017.189
• Sies H. (2021). Oxidative eustress: On constant alert for redox homeostasis. Redox Biol. 41:101867. https://doi.org/10.1016/j.redox.2021.101867
• Silva RH, Abílio VC, Takatsu AL, et al. (2004). Role of hippocampal oxidative stress in memory deficits induced by sleep deprivation in mice. Neuropharmacol.46(6):895-903. https://doi.org/10.1016/j.neuropharm.2003.11.032
• Thamaraiselvi K, Mathangi DC, Subhashini AS. (2012). REM sleep deprivation – A Stressor. Int J Biol Med Res. 3(4): 2390-94.
• Toth LA. (1996). Strain differences in the somnogenic effects of interferon inducers in mice. J Interferon Cytokine Res. 16(12):1065-1072. https://doi.org/10.1089/jir.1996.16.1065
• van Hulzen ZJ, Coenen AM. (1981) Paradoxical sleep deprivation and locomotor activity in rats. Physiol Behav. 27(4):741-4. doi: 10.1016/0031-9384(81)90250-x
• Vorhees C V, Williams MT. (2006). Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 1(2):848-58. https://doi.org/10.1038/nprot.2006.116
• Vorhees CV, Williams MT. (2014). Assessing spatial learning and memory in rodents. ILAR J.55(2):310-332. https://doi.org/10.1093/ilar/ilu013
• Yıldızhan K, Nazıroğlu M. (2019). Microglia and its role in neurodegenerative diseases. Journal of Cellular Neuroscience and Oxidative Stress, 11(2), 861-873.
• Youngblood BD, Zhou J, Smagin GN, Ryan DH, Harris RBS. (1997). Sleep Deprivation by the “Flower Pot” Technique and Spatial Reference Memory. Physiol Behav. 61(2):249-256. https://doi.org/10.1016/S0031-9384(96)00363-0
• Zang J, Wu Y, Su X, et al. (2021). Inhibition of PDE1-B by Vinpocetine Regulates Microglial Exosomes and Polarization Through Enhancing Autophagic Flux for Neuroprotection Against Ischemic Stroke. Front. Cell Dev. Biol. 8:616590. doi:10.3389/fcell.2020.616590
• Zhao Z, Li Y, Chen H, et al. (2014). Xylaria nigripes mitigates spatial memory impairment induced by rapid eye movement sleep deprivation. Int J Clin Exp Med.7(2):356-362.
• Zhou Z, Orchard SG, Nelson MR. et al. (2024). Angiotensin Receptor Blockers and Cognition: a Scoping Review. Curr Hypertens Rep 26, 1–19. https://doi.org/10.1007/s11906-023-01266-0