Vol 54, No 6 (2020)
Research Paper
Published online: 2020-11-30

open access

Page views 1592
Article views/downloads 799
Get Citation

Connect on Social Media

Connect on Social Media

Thymoquinone ameliorates delayed cerebral injury and cerebral vasospasm secondary to experimental subarachnoid haemorrhage

Enes Akkaya1, Şevket Evran2, Fatih Çalış3, Serdar Çevik4, Salim Katar5, Ersin Karataş6, Abdurrahim Koçyiğit6, Mustafa Yasin Sağlam7, Mustafa Aziz Hatiboğlu6, Hakan Hanımoğlu8, Mehmet Yaşar Kaynar9
Pubmed: 33252137
Neurol Neurochir Pol 2020;54(6):576-584.


Aim of the study. Among subarachnoid haemorrhage (SAH) patients, delayed cerebral injury (DCI) and infarction are the most important causes of death and major disability. Cerebral vasospasm (cVS) and DCI remain the major cause of death and disability. Thymoquinone (TQ) is the substance most responsible for the biological activity of nigella sativa (NS) and is useful in the treatment of ischaemic and neurodegenerative diseases, oxidative stress, inflammatory events, cardiovascular and neurological diseases. We conducted an experimental study aimed to investigate the preventive and corrective effects of TQ.

Materials and methods. 24 Sprague-Dawley rats were randomly divided into three groups. The first was the control group which was a sham surgery group. The second group was the SAH group where the double haemorrage SAH protocol was used to induce vasospasm. The third group was the SAH+TQ group, where cVS was induced by the SAH protocol and the animals received oral 2 cc thymoquinone solution for seven days at a dose of 10 mg/kg, after the induction of SAH. The rats were euthanised seven days after the first procedure. The degree of cerebral vasospasm was evaluated by measuring the basilar artery luminal area and arterial wall thickness. Apoptosis was measured by the western blot method at brainstem neural tissue. Oxidative stress was measured by the Erel Method. Endothelin-1 was measured with ELISA analysis at blood. Statistical analysis was performed.

Results. Endothelin-1 values were found to be statistically significantly lower in the control and SAH+TQ groups compared to the SAH group (P < 0.001). Mean lumen area values were significantly higher in the control and SAH+TQ groups than in the SAH group (P < 0.001). In the control and SAH+TQ groups, wall thickness values decreased significantly compared to the SAH group (P < 0.001). OSI values were significantly lower in the control and SAH+TQ groups than in the SAH group (P < 0.001). Apoptosis was significantly lower in the control and SAH+TQ groups than in the SAH group (P < 0.001).

Conclusion. Our results show that post-SAH TQ inhibits/improves DCI and cVS with positive effects on oxidative stress, apoptosis, ET-1, lumen area, and vessel wall thickness, probably due to its anti-ischaemic, antispasmodic, antioxidant, anti-inflammatory, anti-apoptotic and neuroprotective effects.

Article available in PDF format

View PDF Download PDF file


  1. Borel CO, McKee A, Parra A, et al. Possible role for vascular cell proliferation in cerebral vasospasm after subarachnoid hemorrhage. Stroke. 2003; 34(2): 427–433.
  2. Abla AA, Wilson DA, Williamson RW, et al. The relationship between ruptured aneurysm location, subarachnoid hemorrhage clot thickness, and incidence of radiographic or symptomatic vasospasm in patients enrolled in a prospective randomized controlled trial. J Neurosurg. 2014; 120(2): 391–397.
  3. Baggott CD, Aagaard-Kienitz B. Cerebral vasospasm. Neurosurg Clin N Am. 2014; 25(3): 497–528.
  4. Bele S, Proescholdt MA, Hochreiter A, et al. Continuous intra-arterial nimodipine infusion in patients with severe refractory cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a feasibility study and outcome results. Acta Neurochir (Wien). 2015; 157(12): 2041–2050.
  5. Woo CC, Kumar AP, Sethi G, et al. Thymoquinone: potential cure for inflammatory disorders and cancer. Biochem Pharmacol. 2012; 83(4): 443–451.
  6. Beheshti F, Khazaei M, Hosseini M. Neuropharmacological effects of Nigella sativa. Avicenna J Phytomed. 2016; 6(1): 104–116.
  7. Detremmerie CMS, Leung SWS, Vanhoutte PM. Activation of NQO-1 mediates the augmented contractions of isolated arteries due to biased activity of soluble guanylyl cyclase in their smooth muscle. Naunyn Schmiedebergs Arch Pharmacol. 2018; 391(11): 1221–1235.
  8. Elmaci I, Altinoz MA. Thymoquinone: An edible redox-active quinone for the pharmacotherapy of neurodegenerative conditions and glial brain tumors. A short review. Biomed Pharmacother. 2016; 83: 635–640.
  9. Gholamnezhad Z, Havakhah S, Boskabady MH. Preclinical and clinical effects of Nigella sativa and its constituent, thymoquinone: A review. J Ethnopharmacol. 2016; 190: 372–386.
  10. Javidi S, Razavi BM, Hosseinzadeh H. A review of Neuropharmacology Effects of Nigella sativa and Its Main Component, Thymoquinone. Phytother Res. 2016; 30(8): 1219–1229.
  11. Tavakkoli A, Mahdian V, Razavi BM, et al. Review on Clinical Trials of Black Seed (Nigella sativa ) and Its Active Constituent, Thymoquinone. J Pharmacopuncture. 2017; 20(3): 179–193.
  12. Akhondian J, Parsa A, Rakhshande H. The effect of Nigella sativa L. (black cumin seed) on intractable pediatric seizures. Med Sci Monit. 2007; 13(12): CR555–CR559.
  13. Akhondian J, Kianifar H, Raoofziaee M, et al. The effect of thymoquinone on intractable pediatric seizures (pilot study). Epilepsy Res. 2011; 93(1): 39–43.
  14. Raza M, Alghasham AA, Alorainy MS, et al. Potentiation of Valproate-induced Anticonvulsant Response by Nigella sativa Seed Constituents: The Role of GABA Receptors. Int J Health Sci (Qassim). 2008; 2(1): 15–25.
  15. Shao YY, Li B, Huang YM, et al. Thymoquinone Attenuates Brain Injury via an Anti-oxidative Pathway in a Status Epilepticus Rat Model. Transl Neurosci. 2017; 8: 9–14.
  16. Meguro T, Clower BR, Carpenter R, et al. Improved rat model for cerebral vasospasm studies. Neurol Res. 2001; 23(7): 761–766.
  17. Hildebrandt S, Steinhart H, Paschke A, et al. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72(3): 248–254.
  18. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem. 2004; 37(4): 277–285.
  19. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005; 38(12): 1103–1111.
  20. Weyer GW, Nolan CP, Macdonald RL. Evidence-based cerebral vasospasm management. Neurosurg Focus. 2006; 21(3): E8.
  21. Ehlert A, Schmidt C, Wölfer J, et al. Molsidomine for the prevention of vasospasm-related delayed ischemic neurological deficits and delayed brain infarction and the improvement of clinical outcome after subarachnoid hemorrhage: a single-center clinical observational study. J Neurosurg. 2016; 124(1): 51–58.
  22. Dabus G, Nogueira RG. Current options for the management of aneurysmal subarachnoid hemorrhage-induced cerebral vasospasm: a comprehensive review of the literature. Interv Neurol. 2013; 2(1): 30–51.
  23. Cossu G, Messerer M, Oddo M, et al. To look beyond vasospasm in aneurysmal subarachnoid haemorrhage. Biomed Res Int. 2014; 2014: 628597.
  24. Findlay JM, Nisar J, Darsaut T. Cerebral Vasospasm: A Review. Can J Neurol Sci. 2016; 43(1): 15–32.
  25. Dorsch NW. A review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage Part II: Management. J Clin Neurosci. 1994; 1(2): 78–92.
  26. Hijdra A, van Gijn J, Nagelkerke NJ, et al. Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage. Stroke. 1988; 19(10): 1250–1256.
  27. Hendrix P, Foreman PM, Harrigan MR, et al. Endothelial Nitric Oxide Synthase Polymorphism Is Associated with Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage. World Neurosurg. 2017; 101: 514–519.
  28. Idris-Khodja N, Schini-Kerth V. Thymoquinone improves aging-related endothelial dysfunction in the rat mesenteric artery. Naunyn Schmiedebergs Arch Pharmacol. 2012; 385(7): 749–758.
  29. Mohamed A, Afridi DM, Garani O, et al. Thymoquinone inhibits the activation of NF-kappaB in the brain and spinal cord of experimental autoimmune encephalomyelitis. Biomed Sci Instrum. 2005; 41: 388–393.
  30. Salem ML. Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. Int Immunopharmacol. 2005; 5(13-14): 1749–1770.
  31. Al-Ghamdi MS. The anti-inflammatory, analgesic and antipyretic activity of Nigella sativa. J Ethnopharmacol. 2001; 76(1): 45–48.
  32. Hosseinzadeh H, Parvardeh S, Asl MN, et al. Effect of thymoquinone and Nigella sativa seeds oil on lipid peroxidation level during global cerebral ischemia-reperfusion injury in rat hippocampus. Phytomedicine. 2007; 14(9): 621–627.
  33. Dariani S, Baluchnejadmojarad T, Roghani M. Thymoquinone attenuates astrogliosis, neurodegeneration, mossy fiber sprouting, and oxidative stress in a model of temporal lobe epilepsy. J Mol Neurosci. 2013; 51(3): 679–686.
  34. Alhebshi AH, Gotoh M, Suzuki I. Thymoquinone protects cultured rat primary neurons against amyloid β-induced neurotoxicity. Biochem Biophys Res Commun. 2013; 433(4): 362–367.
  35. Sedaghat R, Roghani M, Khalili M. Neuroprotective effect of thymoquinone, the nigella sativa bioactive compound, in 6-hydroxydopamine-induced hemi-parkinsonian rat model. Iran J Pharm Res. 2014; 13(1): 227–234.
  36. Hobbenaghi R, Javanbakht J, Sadeghzadeh Sh, et al. Neuroprotective effects of Nigella sativa extract on cell death in hippocampal neurons following experimental global cerebral ischemia-reperfusion injury in rats. J Neurol Sci. 2014; 337(1-2): 74–79.
  37. Kanter M. Nigella sativa and derived thymoquinone prevents hippocampal neurodegeneration after chronic toluene exposure in rats. Neurochem Res. 2008; 33(3): 579–588.
  38. Ahmad A, Khan RMA, Alkharfy KM. Effects of selected bioactive natural products on the vascular endothelium. J Cardiovasc Pharmacol. 2013; 62(2): 111–121.
  39. Suddek GM. Thymoquinone-induced relaxation of isolated rat pulmonary artery. J Ethnopharmacol. 2010; 127(2): 210–214.
  40. Ghayur MN, Gilani AH, Janssen LJ. Intestinal, airway, and cardiovascular relaxant activities of thymoquinone. Evid Based Complement Alternat Med. 2012; 2012: 305319.
  41. Przybycien-Szymanska MM, Ashley WW. Biomarker Discovery in Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage. J Stroke Cerebrovasc Dis. 2015; 24(7): 1453–1464.
  42. Matsuda N, Ohkuma H, Naraoka M, et al. Role of oxidized LDL and lectin-like oxidized LDL receptor-1 in cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg. 2014; 121(3): 621–630.
  43. Cahill J, Calvert JW, Solaroglu I, et al. Vasospasm and p53-induced apoptosis in an experimental model of subarachnoid hemorrhage. Stroke. 2006; 37(7): 1868–1874.
  44. Ullah I, Ullah N, Naseer MI, et al. Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons. BMC Neurosci. 2012; 13: 11.
  45. Cheng MF, Song JN, Li DD, et al. The role of rosiglitazone in the proliferation of vascular smooth muscle cells after experimental subarachnoid hemorrhage. Acta Neurochir (Wien). 2014; 156(11): 2103–2109.