Skip to main content

Advertisement

Log in

Nigella sativa and thymoquinone attenuate oxidative stress and cognitive impairment following cerebral hypoperfusion in rats

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Nigella sativa, a plant widely used in traditional medicine, possesses anti-inflammatory, antioxidant and neuroprotective properties. In the present study, we investigated the effect of hydroalcoholic extract of N. sativa seeds (NSE) and its active constituent, thymoquinone (TQ), on learning and memory deficits, hippocampal acetylcholine esterase (AChE) activity, and markers of redox status, mainly lipid peroxidation and superoxide dismutase (SOD) activity following cerebral hypoperfusion in rats. Cerebral hypoperfusion was induced by permanent occlusion of bilateral common carotid arteries (2VO). Male Wistar rats were administered either a vehicle (sham group: 10 ml/kg/day, ip), NSE (100, 200, and 400 mg/kg/day, ip), TQ (10, 20, and 40 mg/kg/day, ip), or donepezil (5 mg/kg/day, ip) for 10 days (three days before and seven days after ligation). Spatial learning and memory deficits were investigated using the Morris water maze (MWM) task. 2VO produced significant learning and memory deficits as evidenced by increased latency time to reach the hidden platform, increased swimming time, and decreased time spent in the target quadrant in the probe trial in the MWM task. There was also a significant increase in the lipid peroxidation level and AChE activity, and a significant decrease in SOD activity in the hippocampal portion of hypoperfused rats, as compared with the sham group. Treatment with NSE (400 mg/kg/day; p < 0.001) and TQ (40 mg/kg/day; p < 0.001), as well as donepezil significantly prevented learning and memory impairments and alleviated changes in the hippocampal lipid peroxide level and SOD and AChE activities in this model. In conclusion, our data suggest that N. sativa and thymoquinone have a beneficial role in cerebrovascular insufficiency states and dementia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Ali B, Blunden G (2003) Pharmacological and toxicological properties of Nigella sativa. Phytother Res 17:299–305

    Article  CAS  PubMed  Google Scholar 

  • Alkharfy KM, Ahmad A, Khan RM, Al-Shagha WM (2015) Pharmacokinetic plasma behaviors of intravenous and oral bioavailability of thymoquinone in a rabbit model. Eur J Drug Metab Pharmacokinet 40:319–323

    Article  CAS  PubMed  Google Scholar 

  • Asai M, Iwata N, Yoshikawa A, Aizaki Y, Ishiura S, Saido TC, Maruyama K (2007) Berberine alters the processing of Alzheimer’s amyloid precursor protein to decrease Aβ secretion. Biochem Biophys Res Commun 352:498–502

    Article  CAS  PubMed  Google Scholar 

  • Azzubaidi MS, Saxena AK, Talib NA, Ahmed QU, Dogarai BB (2012) Protective effect of treatment with black cumin oil on spatial cognitive functions of rats that suffered global cerebrovascular hypoperfusion. Acta Neurobiol Exp (Wars) 72:154

    Google Scholar 

  • Badary OA, Taha RA, Gamal El-Din AM, Abdel-Wahab MH (2003) Thymoquinone is a potent superoxide anion scavenger. Drug Chem Toxicol 26:87–98

    Article  CAS  PubMed  Google Scholar 

  • Bin Sayeed MS, Asaduzzaman M, Morshed H, Hossain MM, Kadir MF, Rahman MR (2013) The effect of Nigella sativa Linn. Seed on memory, attention and cognition in healthy human volunteers. J Ethnopharmacol 148:780–786

    Article  PubMed  Google Scholar 

  • Blake M, Boccia M (2018) Basal forebrain cholinergic system and memory. Curr Top Behav Neurosci 37:253–273

    Article  CAS  PubMed  Google Scholar 

  • Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310

    Article  CAS  PubMed  Google Scholar 

  • Clausen A, Xu X, Bi X, Baudry M (2012) Effects of the superoxide dismutase/catalase mimetic EUK-207 in a mouse model of Alzheimer's disease: protection against and interruption of progression of amyloid and tau pathology and cognitive decline. J Alzheimers Dis 30:183–208

    Article  CAS  PubMed  Google Scholar 

  • Dehkordi FR, Kamkhah AF (2008) Antihypertensive effect of Nigella sativa seed extract in patients with mild hypertension. Fundam Clin Pharmacol 22:447–452

    Article  CAS  PubMed  Google Scholar 

  • Dhanasekaran M, Tharakan B, Holcomb LA, Hitt AR, Young KA, Manyam BV (2007) Neuroprotective mechanisms of ayurvedic antidementia botanical Bacopa monniera. Phytother Res 21:965–969

    Article  CAS  PubMed  Google Scholar 

  • el Tahir KE, Ashour MM, al-Harbi MM (1993) The respiratory effects of the volatile oil of the black seed (Nigella sativa) in Guinea-pigs: elucidation of the mechanism(s) of action. Gen Pharmacol 24:1115–1122

    Article  PubMed  Google Scholar 

  • El-Far AH, Korshom MA, Mandour AA, El-Bessoumy AA, El-Sayed YS (2017) Hepatoprotective efficacy of Nigella sativa seeds dietary supplementation against lead acetate-induced oxidative damage in rabbit - purification and characterization of glutathione peroxidase. Biomed Pharmacother 89:711–718

    Article  CAS  PubMed  Google Scholar 

  • Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  Google Scholar 

  • El-Naggar T, Gómez-Serranillos MP, Palomino OM, Arce C, Carretero ME (2010) Nigella sativa L. seed extract modulates the neurotransmitter amino acids release in cultured neurons in vitro. Biomed Res Int 2010:1–8

    Google Scholar 

  • Farkas E, Institóris Á, Domoki F, Mihály A, Luiten PG, Bari F (2004) Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion. Brain Res 1008:252–260

    Article  CAS  PubMed  Google Scholar 

  • Farkas E, Timmer NM, Domoki F, Mihály A, Luiten PG, Bari F (2005) Post-ischemic administration of diazoxide attenuates long-term microglial activation in the rat brain after permanent carotid artery occlusion. Neurosci Lett 387:168–172

    Article  CAS  PubMed  Google Scholar 

  • Farkas E, Luiten PG, Bari F (2007) Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev 54:162–180

    Article  CAS  PubMed  Google Scholar 

  • Farkhondeh T, Samarghandian S, Shahri AMP, Samini F (2018) The neuroprotective effects of Thymoquinone: a review. Dose-Response 16:1559325818761455

    Article  PubMed  PubMed Central  Google Scholar 

  • Farooqui Z, Ahmed F, Rizwan S, Shahid F, Khan AA, Khan F (2017) Protective effect of Nigella sativa oil on cisplatin induced nephrotoxicity and oxidative damage in rat kidney. Biomed Pharmacother 85:7–15

    Article  CAS  PubMed  Google Scholar 

  • Gunstad J et al (2005) Progressive morphometric and cognitive changes in vascular dementia. Arch Clin Neuropsychol 20:229–241

    Article  PubMed  Google Scholar 

  • Gupta S, Singh P, Sharma BJJS, Diseases C (2016) Neuroprotective effects of nicorandil in chronic cerebral hypoperfusion-induced vascular dementia. Prog Brain Res 25:2717–2728

    Google Scholar 

  • Hamel E (2004) Cholinergic modulation of the cortical microvascular bed. Prog Brain Res 145:171–178

    Article  CAS  PubMed  Google Scholar 

  • He Z, Liao Y, Zheng M, Zeng F-D, Guo L-J (2008) Piracetam improves cognitive deficits caused by chronic cerebral hypoperfusion in rats. Cell Mol Neurobiol 28:613–627

    Article  CAS  PubMed  Google Scholar 

  • Hosseini M, Mohammadpour T, Karami R, Rajaei Z, Reza Sadeghnia H, Soukhtanloo M (2015) Effects of the hydro-alcoholic extract of Nigella sativa on scopolamine-induced spatial memory impairment in rats and its possible mechanism. Chin J Integr Med 21:438–444

    Article  PubMed  Google Scholar 

  • Hosseinzadeh H, Parvardeh S, Asl MN, Sadeghnia HR, Ziaee T (2007) Effect of thymoquinone and Nigella sativa seeds oil on lipid peroxidation level during global cerebral ischemia-reperfusion injury in rat hippocampus. Phytomedicine 14:621–627

    Article  CAS  PubMed  Google Scholar 

  • Hosseinzadeh H, Sadeghnia HR, Ghaeni FA, Motamedshariaty VS, Mohajeri SA (2012) Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats. Phytother Res 26:381–386

    Article  CAS  PubMed  Google Scholar 

  • Jalali nodoushan M, Roghani M (2009) The effect of Nigella sativa on learning and memory in male diabetic rats. Basic Clin Neurosci 1:32–34

  • Jing Z, Shi C, Zhu L, Xiang Y, Chen P, Xiong Z, Li W, Ruan Y, Huang L' (2015) Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment. J Cereb Blood Flow Metab 35:1249–1259

    Article  PubMed  PubMed Central  Google Scholar 

  • Jrah Harzallah H, Grayaa R, Kharoubi W, Maaloul A, Hammami M, Mahjoub T (2012) Thymoquinone, the Nigella sativa bioactive compound, prevents circulatory oxidative stress caused by 1, 2-dimethylhydrazine in erythrocyte during colon postinitiation carcinogenesis. Oxidative Med Cell Longev 2012:1–6

    Article  CAS  Google Scholar 

  • Jukic M, Politeo O, Maksimovic M, Milos M, Milos M (2007) In vitro acetylcholinesterase inhibitory properties of thymol, carvacrol and their derivatives thymoquinone and thymohydroquinone. Phytother Res 21:259–261

    Article  CAS  PubMed  Google Scholar 

  • Kanter M (2008) Nigella sativa and derived thymoquinone prevents hippocampal neurodegeneration after chronic toluene exposure in rats. Neurochem Res 33:579–588

    Article  CAS  PubMed  Google Scholar 

  • Kanter M (2011) Protective effects of thymoquinone on the neuronal injury in frontal cortex after chronic toluene exposure. J Mol Histol 42:39–46

    Article  CAS  PubMed  Google Scholar 

  • Khan A, Vaibhav K, Javed H, Moshahid Khan M, Tabassum R, Ahmed ME, Srivastava P, Khuwaja G, Islam F, Saeed Siddiqui M, Shafi MM, Islam F (2012) Attenuation of Aβ-induced neurotoxicity by thymoquinone via inhibition of mitochondrial dysfunction and oxidative stress. Mol Cell Biochem 369:55–65

    Article  CAS  PubMed  Google Scholar 

  • Khan RA, Najmi AK, Khuroo AH, Goswami D, Akhtar M (2014) Ameliorating effects of thymoquinone in rodent models of schizophrenia. Afr J Pharm Pharmacol 8:413–421

    Article  CAS  Google Scholar 

  • Kim DS, Kim J-Y, Han YS (2007) Alzheimer's disease drug discovery from herbs: neuroprotectivity from β-amyloid (1-42) insult. J Altern Complement Med 13:333–340

    Article  PubMed  Google Scholar 

  • Liao Y, Wang R, Tang X-C (2004) Centrophenoxine improves chronic cerebral ischemia induced cognitive deficit and neuronal degeneration in rats. Acta Pharmacol Sin 25:1590–1596

    CAS  PubMed  Google Scholar 

  • Liu H, Zhang J (2012) Cerebral hypoperfusion and cognitive impairment: the pathogenic role of vascular oxidative stress. Int J Neurosci 122:494–499

    Article  CAS  PubMed  Google Scholar 

  • Liu H-x, Zhang J-j, Zheng P, Zhang Y (2005) Altered expression of MAP-2, GAP-43, and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment. Mol Brain Res 139:169–177

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Wu J, Gu J, Xiong Z, Wang F, Wang J, Wang W, Chen J (2007) Baicalein improves cognitive deficits induced by chronic cerebral hypoperfusion in rats. Pharmacol Biochem Behav 86:423–430

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Wu J, Xu K, Cai F, Gu J, Ma L, Chen J (2010) Neuroprotection by baicalein in ischemic brain injury involves PTEN/AKT pathway. J Neurochem 112:1500–1512

    Article  CAS  PubMed  Google Scholar 

  • Ma S et al (2017) Erythropoietin rescues memory impairment in a rat model of chronic cerebral hypoperfusion via the EPO-R/JAK2/STAT5/PI3K/Akt/GSK-3β pathway. Mol Neurobiol:1–10

  • Madesh M, Balasubramanian KA (1998) Microtiter plate assay for superoxide dismutase using MTT reduction by superoxide. Indian J Biochem Biophys 35:184–188

    CAS  PubMed  Google Scholar 

  • Mahmoud M, El-Abhar H, Saleh S (2002) The effect of Nigella sativa oil against the liver damage induced by Schistosoma mansoni infection in mice. J Ethnopharmacol 79:1–11

    Article  CAS  PubMed  Google Scholar 

  • Mansour MA, Nagi MN, El-Khatib AS, Al-Bekairi AM (2002) Effects of thymoquinone on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase in different tissues of mice: a possible mechanism of action. Cell Biochem Funct 20:143–151

    Article  CAS  PubMed  Google Scholar 

  • Moghaddasi M, Taati M, Asadian P, Khalatbary AR, Asaei R, Pajouhi NJTJPS (2017) The effects of two-stage carotid occlusion on spatial memory and pro-inflammatory markers in the hippocampus of rats. J Physiol Sci 67:415–423

    Article  CAS  PubMed  Google Scholar 

  • Mousavi S, Tayarani-Najaran Z, Asghari M, Sadeghnia H (2010) Protective effect of Nigella sativa extract and thymoquinone on serum/glucose deprivation-induced PC12 cells death. Cell Mol Neurobiol 30:591–598

    Article  CAS  PubMed  Google Scholar 

  • Norouzi F et al (2016) The effects of Nigella sativa on sickness behavior induced by lipopolysaccharide in male Wistar rats. Avicenna J Phytomed 6:104

    PubMed  PubMed Central  Google Scholar 

  • Norwood A, Tan M, May M, Tucci M, Benghuzzi H (2005) Comparison of potential chemotherapeutic agents, 5-fluoruracil, green tea, and thymoquinone on colon cancer cells. Biomed Sci Instrum 42:350–356

    Google Scholar 

  • Radad K, Moldzio R, Taha M, Rausch WD (2009) Thymoquinone protects dopaminergic neurons against MPP+ and rotenone. Phytother Res 23:696–700

    Article  CAS  PubMed  Google Scholar 

  • Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, Booker L, Oremus M (2008) Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 148:379–397

    Article  PubMed  Google Scholar 

  • Ramadan MF (2007) Nutritional value, functional properties and nutraceutical applications of black cumin (Nigella sativa L.): an overview. Int J Food Sci Technol 42:1208–1218

    Article  CAS  Google Scholar 

  • Rchid H, Chevassus H, Nmila R, Guiral C, Petit P, Chokaïri M, Sauvaire Y (2004) Nigella sativa seed extracts enhance glucose-induced insulin release from rat-isolated Langerhans islets. Fundam Clin Pharmacol 18:525–529

    Article  CAS  PubMed  Google Scholar 

  • Roman GC (2004) Brain hypoperfusion: a critical factor in vascular dementia. Neurol Res 26:454–458

    Article  PubMed  Google Scholar 

  • Roman GC, Kalaria RN (2006) Vascular determinants of cholinergic deficits in Alzheimer' disease and vascular dementia. Neurobiol Aging 27:1769–1785

    Article  CAS  PubMed  Google Scholar 

  • Royall DR (2002) Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33:2147–2148

    Article  PubMed  Google Scholar 

  • Sadeghnia HR, Kamkar M, Assadpour E, Boroushaki MT, Ghorbani A (2013) Protective effect of safranal, a constituent of Crocus sativus, on quinolinic acid-induced oxidative damage in rat hippocampus. Iran J Basic Med Sci 16:73–82

    PubMed  PubMed Central  Google Scholar 

  • Sadoshima S, Ibayashi S, Fujii K, Nagao T, Sugimori H, Fujishima M (1995) Inhibition of acetylcholinesterase modulates the autoregulation of cerebral blood flow and attenuates ischemic brain metabolism in hypertensive rats. J Cereb Blood Flow Metab 15:845–851

    Article  CAS  PubMed  Google Scholar 

  • Sahak MKA, Mohamed AM, Hashim NH, Hasan Adli DS (2013) Nigella sativa Oil Enhances the Spatial Working Memory Performance of Rats on a Radial Arm Maze. Evid Based Complement Alternat Med 2013

  • Sato A, Sato Y, Uchida S (2001) Regulation of regional cerebral blood flow by cholinergic fibers originating in the basal forebrain. Int J Dev Neurosci 19:327–337

    Article  CAS  PubMed  Google Scholar 

  • Sato A, Sato Y, Uchida S (2004) Activation of the intracerebral cholinergic nerve fibers originating in the basal forebrain increases regional cerebral blood flow in the rat's cortex and hippocampus. Neurosci Lett 361:90–93

    Article  CAS  PubMed  Google Scholar 

  • Saxena AK, Abdul-Majeed SS, Gurtu S, Mohamed WMJA, genomics t (2015) Investigation of redox status in chronic cerebral hypoperfusion-induced neurodegeneration in rats. Appl Transl Genom 5:30–32

  • Sedaghat R, Roghani M, Khalili M (2014) Neuroprotective effect of thymoquinone, the Nigella Sativa bioactive compound, in 6-hydroxydopamine-induced hemi-parkinsonian rat model. Iran J Pharm Res 13:227

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sharieatzadeh M, MalkyRad A, Hovaida R, Rahzani K, AghaJohary M, Fazli D (2011) The effect of Nigella sativa on oxidative stress. J Shahrekord Univ Med Sci 12:21–26

    Google Scholar 

  • Shimizu S, Kanetaka H, Hirose D, Sakurai H, Hanyu HJD, extra gcd (2015) Differential effects of acetylcholinesterase inhibitors on clinical responses and cerebral blood flow changes in patients with Alzheimer's disease: a 12-month, randomized, and open-label trial. Dement Geriatr Cogn Dis Extra 5:135–146

  • Tanaka K, Ogawa N, Mizukawa K, Asanuma M, Kondo Y, Nishibayashi S, Mori A (1994) Acetylcholinesterase inhibitor ENA-713 protects against ischemia-induced decrease in pre- and postsynaptic cholinergic indices in the gerbil brain following transient ischemia. Neurochem Res 19:117–122

    Article  CAS  PubMed  Google Scholar 

  • Ullah I, Ullah N, Naseer MI, Lee HY, Kim MO (2012) Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons. BMC Neurosci 13:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vattananupon S, Chadvongvan P, Akarasereenont P, Tapechum S, Tilokskulchai K, Pakaprot N (2017) Brahmi extract attenuated spatial learning and memory impairment and cell death of rat hippocampal CA1 neurons after the 2-VO induced chronic cerebral hypoperfusion. Siriraj Med J 65:105–111

  • Wang J, Zhang HY, Tang XC (2009) Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment. Acta Pharmacol Sin 30:879–888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wienkotter N, Hopner D, Schutte U, Bauer K, Begrow F, El-Dakhakhny M, Verspohl EJ (2008) The effect of nigellone and thymoquinone on inhibiting trachea contraction and mucociliary clearance. Planta Med 74:105–108

    Article  CAS  PubMed  Google Scholar 

  • Xie T, Wang WP, Mao ZF, Qu ZZ, Luan SQ, Jia LJ, Kan MC (2012) Effects of epigallocatechin-3-gallate on pentylenetetrazole-induced kindling, cognitive impairment and oxidative stress in rats. Neurosci Lett 516:237–241

    Article  CAS  PubMed  Google Scholar 

  • Xu Y, Zhang J-j, Xiong L, Zhang L, Sun D, Liu H (2010) Green tea polyphenols inhibit cognitive impairment induced by chronic cerebral hypoperfusion via modulating oxidative stress. J Nutr Biochem 21:741–748

    Article  CAS  PubMed  Google Scholar 

  • Yan M-L, Ai J (2017) A rodent model for chronic brain hypoperfusion related diseases: permanent bilateral occlusion of the common carotid arteries (2VO) in rats. Mol Neurobiol

  • Yassin MM (2005) Prophylactic efficacy of crushed garlic lobes, black seed or olive oils on cholinesterase activity in central nervous system parts and serum of lead intoxicated rabbits. Turk J Biol 29:173–180

    Google Scholar 

  • Zhang D, Xiao Y, Lv P, Teng Z, Dong Y, Qi Q, Liu Z (2018) Edaravone attenuates oxidative stress induced by chronic cerebral hypoperfusion injury: role of ERK/Nrf2/HO-1 signaling pathway. Neurol Res 40:1–10

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hamid R. Sadeghnia.

Ethics declarations

Declaration of conflicting interests

The authors declare no conflict of interest with respect to the research, authorship, and/or publication of this article.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fanoudi, S., Alavi, M.S., Hosseini, M. et al. Nigella sativa and thymoquinone attenuate oxidative stress and cognitive impairment following cerebral hypoperfusion in rats. Metab Brain Dis 34, 1001–1010 (2019). https://doi.org/10.1007/s11011-019-00394-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-019-00394-4

Keywords

Navigation