Timokinon Nanoformülasyonlarının Nörolojik Bozukluklardaki Terapötik Potansiyeli

Öz

Nigella sativa L.’nin başlıca biyoaktif bileşiği olan timokinon (2-izopropil-5-metil-1,4-benzokinon), oksidatif stres ve nöroinflamasyonu hedefleyen çok yönlü farmakodinamik özellikleri nedeniyle nöroprotektif bir aday olarak öne çıkmaktadır. Nörodejeneratif hastalıkların patogenezinde reaktif oksijen türlerinin artışı, mitokondriyal disfonksiyon, nöroinflamatuvar yolak aktivasyonu ve nörotransmitter dengesizlikleri merkezi rol oynamaktadır. Deneysel çalışmalar, timokinonun Alzheimer ve Parkinson hastalığı, depresyon, epilepsi, serebral iskemi ve travmatik beyin hasarı modellerinde nöronal hücre canlılığını artırdığını, davranışsal ve motor işlev bozukluklarını iyileştirdiğini göstermektedir. Ayrıca antioksidan savunma sistemlerini güçlendirdiği, proinflamatuvar sitokinleri baskıladığı, apoptotik sinyal yolaklarını modüle ettiği ve oksidatif hasarı azalttığı belirtilmektedir. Timokinonun Toll-benzeri reseptörler, nükleer faktör kappa hafif zincirli aktive edici B hücreleri, interlökin-6, interlökin-1β ve tümör nekroz faktör-α gibi inflamatuvar bileşenleri modüle ederek belirgin antiinflamatuvar etkiler ortaya koyduğu da gösterilmiştir. Bununla birlikte, düşük suda çözünürlük, fotodegradasyon eğilimi, hızlı sistemik eliminasyon ve sınırlı oral biyoyararlanım timokinonun klinik uygulamaya aktarımını önemli ölçüde sınırlamaktadır. Ayrıca kan-beyin bariyeri, merkezi sinir sistemine etkin ilaç iletimi açısından kritik bir biyolojik engel oluşturmaktadır. Nanoteknoloji temelli taşıyıcı sistemler, bu farmasötik sınırlılıkları aşmada etkili bir strateji sunmaktadır. Polimerik ve lipidik nanopartiküller ile yüzey modifikasyonlu nanotaşıyıcılar; çözünürlüğü ve stabiliteyi artırmakta, kontrollü ve sürdürülebilir salım sağlamakta ve beyin dokusunda biyoyararlanımı anlamlı biçimde iyileştirmektedir. Bu derleme, timokinonun nöroprotektif etkilerini deneysel veriler ve klinik translasyon potansiyeli çerçevesinde değerlendirmekte ve nanoformülasyon stratejilerinin sağladığı farmakokinetik ve terapötik avantajları analiz etmektedir. Bu kapsamda analiz edilen 15 çalışmadan elde edilen bulgular, timokinon nanoformülasyonlarının nörodejeneratif hastalıkların tedavisinde umut vadeden güçlü adaylar olduğunu göstermekte; ancak klinik uygulamaya geçiş için daha yüksek kalitede ve standardize çalışmalara ihtiyaç olduğunu ortaya koymaktadır.

Anahtar Kelimeler

• Timokinon
• Nigella sativa
• Nanopartiküller
• Nöroproteksiyon
• Nörodejeneratif hastalıklar

Therapeutic Potential of Thymoquinone Nanoformulations in Neurological Disorders

Öz

Thymoquinone (2-isopropyl-5-methyl-1,4-benzoquinone), the principal bioactive constituent of Nigella sativa L., has gained considerable attention as a neuroprotective agent owing to its multifaceted pharmacodynamic actions targeting oxidative stress and neuroinflammation. Excessive reactive oxygen species generation, mitochondrial dysfunction, activation of neuroinflammatory cascades, and neurotransmitter imbalance play central roles in the pathogenesis of neurodegenerative disorders. Experimental studies demonstrate that thymoquinone enhances neuronal viability and alleviates behavioral and motor impairments in models of Alzheimer’s disease, Parkinson’s disease, depression, epilepsy, cerebral ischemia, and traumatic brain injury. Mechanistically, it strengthens endogenous antioxidant defense systems, suppresses pro-inflammatory cytokine production, modulates apoptotic signaling pathways, and attenuates oxidative damage. Its anti-inflammatory effects are mediated through regulation of Toll-like receptors, nuclear factor kappa B, interleukin-6, interleukin-1β, and tumor necrosis factor-α. Despite these promising effects, clinical translation remains limited due to poor aqueous solubility, susceptibility to photodegradation, rapid systemic elimination, low oral bioavailability, and restricted permeability across the blood–brain barrier. Nanotechnology-based delivery systems offer a rational strategy to overcome these pharmaceutical and biological barriers. Polymeric and lipid-based nanoparticles, along with surface-modified nanocarriers, enhance solubility and stability, provide controlled and sustained release, and significantly improve brain bioavailability. This review evaluates the neuroprotective effects of thymoquinone within the framework of experimental evidence and clinical translational potential, and analyzes the pharmacokinetic and therapeutic advantages provided by nanoformulation strategies. Findings from 15 studies analyzed within this scope demonstrate that thymoquinone nanoformulations are promising candidates for the treatment of neurodegenerative diseases; however, higher-quality and standardized studies are needed for successful translation into clinical applications.

Anahtar Kelimeler

• Thymoquinone
• Nigella sativa
• Nanoparticles
• Neuroprotection
• Neurodegenerative diseases

Kaynakça

1. Abulfadl, Y. S., El-Maraghy, N. N., Ahmed, A. E., Nofal, S., Abdel-Mottaleb, Y., & Badary, O. A. (2018). Thymoquinone alleviates the experimentally induced Alzheimer’s disease inflammation by modulation of TLRs signaling. Human & experimental toxicology, 37(10), 1092-1104.
2. Ahmad, A., Husain, A., Mujeeb, M., Khan, S. A., Najmi, A. K., Siddique, N. A., & Anwar, F. (2013). A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pacific journal of tropical biomedicine, 3(5), 337-352.
3. Ahmad, N., Ahmad, R., Al Qatifi, S., Alessa, M., Al Hajji, H., & Sarafroz, M. (2020). A bioanalytical UHPLC based method used for the quantification of Thymoquinone-loaded-PLGA-nanoparticles in the treatment of epilepsy. BMC chemistry, 14(1), 10.
4. Ahmad, N., Ahmad, R., Alam, M. A., Samim, M., Iqbal, Z., & Ahmad, F. J. (2016). Quantification and evaluation of thymoquinone loaded mucoadhesive nanoemulsion for treatment of cerebral ischemia. International Journal of Biological Macromolecules, 88, 320-332.
5. Akhondian, J., Kianifar, H., Raoofziaee, M., Moayedpour, A., Toosi, M. B., & Khajedaluee, M. (2011). The effect of thymoquinone on intractable pediatric seizures (pilot study). Epilepsy research, 93(1), 39-43.
6. Alam, M., Najmi, A. K., Ahmad, I., Ahmad, F. J., Akhtar, M. J., Imam, S. S., & Akhtar, M. (2018). Formulation and evaluation of nano lipid formulation containing CNS acting drug: molecular docking, in-vitro assessment and bioactivity detail in rats. Artificial cells, nanomedicine, and biotechnology, 46(sup2), 46-57.
7. Alam, M., Zameer, S., Najmi, A. K., Ahmad, F. J., Imam, S. S., & Akhtar, M. (2020). Thymoquinone loaded solid lipid nanoparticles demonstrated antidepressant-like activity in rats via indoleamine 2, 3-dioxygenase pathway. Drug Research, 70(05), 206-213.
8. Alam, S., Khan, Z. I., Mustafa, G., Kumar, M., Islam, F., Bhatnagar, A., & Ahmad, F. J. (2012). Development and evaluation of thymoquinone-encapsulated chitosan nanoparticles for nose-to-brain targeting: a pharmacoscintigraphic study. International journal of nanomedicine, 5705-5718.

9. Alkefai, N. H. (2025). Optimization and evaluation of thymoquinone-loaded transniosome in situ gel for intranasal treatment of Parkinson's disease. Journal of Drug Delivery Science and Technology, 104, 106565.
10. Al-Majed, A. A., Al-Omar, F. A., & Nagi, M. N. (2006). Neuroprotective effects of thymoquinone against transient forebrain ischemia in the rat hippocampus. European journal of pharmacology, 543(1-3), 40-47.
11. Arslan, S. O., Uysal, F., Koç, A., & Özünlü, S. A. Ç. (2025). Nigella sativa oil attenuates neuroinflammation and cognitive deficits in a rat model of Alzheimer's disease. Cukurova Medical Journal, 50(2), 317-327.
12. Bates, G. P., Dorsey, R., Gusella, J. F., Hayden, M. R., Kay, C., Leavitt, B. R., ... & Tabrizi, S. J. (2015). Huntington disease. Nature reviews Disease primers, 1(1), 15005.
13. Cobourne-Duval, M. K., Taka, E., Mendonca, P., & Soliman, K. F. (2018). Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NFκB pathway signaling targets in LPS/IFNγ-activated BV-2 microglia cells. Journal of neuroimmunology, 320, 87-97.
14. Cobourne-Duval, M. K., Taka, E., Mendonca, P., Bauer, D., & Soliman, K. F. (2016). The antioxidant effects of thymoquinone in activated BV-2 murine microglial cells. Neurochemical research, 41(12), 3227-3238.
15. Dariani, S., Baluchnejadmojarad, T., & Roghani, M. (2013). Thymoquinone attenuates astrogliosis, neurodegeneration, mossy fiber sprouting, and oxidative stress in a model of temporal lobe epilepsy. Journal of Molecular Neuroscience, 51(3), 679-686.
16. Dong, J., Zhang, X., Wang, S., Xu, C., Gao, M., Liu, S., ... & Han, Y. (2021). Thymoquinone prevents dopaminergic neurodegeneration by attenuating oxidative stress via the Nrf2/ARE pathway. Frontiers in pharmacology, 11, 615598.
17. Doolaanea, A. A., Mansor, N. I., Mohd Nor, N. H., & Mohamed, F. (2016). Co-encapsulation of Nigella sativa oil and plasmid DNA for enhanced gene therapy of Alzheimer’s disease. Journal of microencapsulation, 33(2), 114-126.
18. Ebrahimi, S. S., Oryan, S., Izadpanah, E., & Hassanzadeh, K. (2017). Thymoquinone exerts neuroprotective effect in animal model of Parkinson’s disease. Toxicology letters, 276, 108-114.
19. El Caid, M. B., Ait Haddou, M., El Asri, O., Aboudlou, L., Atyane, L. H., Ramteke, V., & Ait Hammou, R. (2025). Neuroprotective potential of saffron metabolites in Parkinson's disease. PharmaNutrition, 100448.
20. Fahmy, H. M., Ahmed, M. M., Mohamed, A. S., Shams-Eldin, E., Abd El-Daim, T. M., El-Feky, A. S., ... & Fathy, M. M. (2022). Novel lipid-coated mesoporous silica nanoparticles loaded with thymoquinone formulation to increase its bioavailability in the brain and organs of Wistar rats. BMC Pharmacology and Toxicology, 23(1), 71.
21. Fahmy, H. M., Noor, N. A., Mohammed, F. F., Elsayed, A. A., & Radwan, N. M. (2014). Nigella sativa as an anti-inflammatory and promising remyelinating agent in the cortex and hippocampus of experimental autoimmune encephalomyelitis-induced rats. The Journal of Basic & Applied Zoology, 67(5), 182-195.
22. Farkhondeh, T., Samarghandian, S., Shahri, A. M. P., & Samini, F. (2018). The neuroprotective effects of thymoquinone: a review. Dose-response, 16(2), 1559325818761455.
23. Gomes, T. M., Sousa, P., Campos, C., Perestrelo, R., & Câmara, J. S. (2024). Secondary bioactive metabolites from foods of plant origin as theravention agents against neurodegenerative disorders. Foods, 13(14), 2289.
24. Hannan, M. A., Rahman, M. A., Sohag, A. A. M., Uddin, M. J., Dash, R., Sikder, M. H., ... & Kim, B. (2021). Black cumin (Nigella sativa L.): A comprehensive review on phytochemistry, health benefits, molecular pharmacology, and safety. Nutrients, 13(6), 1784.
25. Hassan, S. H., Sharaf, I. A., Mohamed, A. S., Salama, M., Kamel, M. A., & Hafez, H. A. (2025). Green-Synthesized Silver Nanoparticles with Nigella sativa: A Multifaceted Approach against Parkinson’s Disease in Rats via MicroRNA Modulation. ACS Chemical Neuroscience, 16(19), 3801-3815.
26. Hatipoglu, D., Burak Ates, M., Senturk, G., Koca, O., Bulut, A., & Donmez, N. (2025). Neuroprotective role of Nigella Sativa seed oil in mitigating bisphenol a-induced neurodegeneration. Scientific Reports, 15(1), 22477.
27. He, F., Ru, X., & Wen, T. (2020). NRF2, a transcription factor for stress response and beyond. International journal of molecular sciences, 21(13), 4777.
28. Ibrahim, K. G., Hudu, S. A., Jega, A. Y., Taha, A., Yusuf, A. P., Usman, D., ... & Erlwanger, K. H. (2024). Thymoquinone: A comprehensive review of its potential role as a monotherapy for metabolic syndrome. Iranian Journal of Basic Medical Sciences, 27(10), 1214.
29. Isaev, N. K., Chetverikov, N. S., Stelmashook, E. V., Genrikhs, E. E., Khaspekov, L. G., & Illarioshkin, S. N. (2020). Thymoquinone as a potential neuroprotector in acute and chronic forms of cerebral pathology. Biochemistry (Moscow), 85(2), 167-176.
30. Ismail, N., Ismail, M., Azmi, N. H., Bakar, M. F. A., Yida, Z., Abdullah, M. A., & Basri, H. (2017a). Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats. Biomedicine & Pharmacotherapy, 95, 780-788.
31. Ismail, N., Ismail, M., Azmi, N. H., Bakar, M. F. A., Yida, Z., Stanslas, J., ... & Abdullah, M. A. (2017b). Beneficial effects of TQRF and TQ nano-and conventional emulsions on memory deficit, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble Aβ levels in high fat-cholesterol diet-induced rats. Chemico-Biological Interactions, 275, 61-73.
32. Javidi, S., Razavi, B. M., & Hosseinzadeh, H. (2016). A review of neuropharmacology effects of Nigella sativa and its main component, thymoquinone. Phytotherapy research, 30(8), 1219-1229.
33. Joyner, P. M., & Cichewicz, R. H. (2011). Bringing natural products into the fold–exploring the therapeutic lead potential of secondary metabolites for the treatment of protein-misfolding-related neurodegenerative diseases. Natural product reports, 28(1), 26-47.
34. Juurlink, B. H., & Paterson, P. G. (1998). Review of oxidative stress in brain and spinal cord injury: suggestions for pharmacological and nutritional management strategies. The journal of spinal cord medicine, 21(4), 309-334.
35. Kannan, R., George, S., PS, B. C., Maliakel, B., Ittiyavirah, S., & Krishnakumar, I. M. (2022). Thymoquinone-rich black cumin oil improves sleep quality, alleviates anxiety/stress on healthy subjects with sleep disturbances–a pilot polysomnography study. Journal of Herbal Medicine, 32, 100507.
36. Kantar, D., Acun, A. D., & Danışman, B. (2022). Effects of thymoquinone on scopolamine-induced spatial and echoic memory changes through regulation of lipid peroxidation and cholinergic impairment. Behavioural brain research, 431, 113972.
37. Kazemi, R., Yazdanpanah, E., Esmaeili, S. A., Yousefi, B., Baharlou, R., & Haghmorad, D. (2024). Thymoquinone improves experimental autoimmune encephalomyelitis by regulating both pro-inflammatory and anti-inflammatory cytokines. Molecular biology reports, 51(1), 256.
38. Khan, F. Z., Mostaid, M. S., & Apu, M. N. H. (2022). Molecular signaling pathway targeted therapeutic potential of thymoquinone in Alzheimer’s disease. Heliyon, 8(7).
39. Khola, N., Dabla, S., & Maurya, P. K. (2026). Role of secondary metabolites in neurodegenerative disorders. In Secondary Metabolites in Stress and Disease Management (pp. 421-441). Academic Press.
40. Kumar, V., Sharma, S., & Singh, A. (2025). Nanoparticles: a new frontier in neurodegenerative disease therapy. Frontiers in Medical Technology, 7, 1654003.
41. Lee, R. H. C., Lee, M. H. H., Wu, C. Y. C., Couto E Silva, A., Possoit, H. E., Hsieh, T. H., Minagar, A., & Lin, H. W. (2018). Cerebral ischemia and neuroregeneration. Neural regeneration research, 13(3), 373–385.
42. Mielcarek, M. (2015). Huntington's disease is a multi-system disorder. Rare diseases, 3(1), e1058464.
43. Mohamed, A. B., Mohamed, A. Z., & Saly, M. D. (2020). Effect of thymoquinone against aluminum chloride-induced Alzheimer-like model in rats: a neurophysiological and behavioral study. The medical journal of Cairo university, 88(March), 355-365.
44. Müslümanoğlu, A. Y., & Tayfun. K. (2020). Türkiye'de geleneksel ve tamamlayıcı tıp'da fitoterapi hangi aşamada. Canat HL, Kadıoğlu A (Ed.), Genito-Üriner Hastalıklarda Fitoterapinin Yeri (s. 9-10). Nobel Tıp Kitabevleri
45. Nazir, S., Farooq, R. K., Khan, H., Alam, T., & Javed, A. (2021). Thymoquinone harbors protection against Concanavalin A‐induced behavior deficit in BALB/c mice model. Journal of Food Biochemistry, 45(3), e13348.
46. Nazir, S., Farooq, R. K., Nasir, S., Hanif, R., & Javed, A. (2022). Therapeutic effect of Thymoquinone on behavioural response to UCMS and neuroinflammation in hippocampus and amygdala in BALB/c mice model. Psychopharmacology, 239(1), 47-58.
47. Nehal, N., Nabi, B., Rehman, S., Pathak, A., Iqubal, A., Khan, S. A., ... & Ali, J. (2021). Chitosan coated synergistically engineered nanoemulsion of Ropinirole and nigella oil in the management of Parkinson's disease: Formulation perspective and In vitro and In vivo assessment. International journal of biological macromolecules, 167, 605-619.
48. Nemati, S. H., Bigdeli, M. R., Moghadam, F. M., & Sharifi, K. (2023). Neuroprotective effects of niosomes loaded with thymoquinone in the cerebral ischemia model of male Wistar rats. Nanomedicine: Nanotechnology, Biology and Medicine, 48, 102637.
49. Nguyen, T. T., Nguyen, T. T. D., Vo, T. K., Tran, N. M. A., Nguyen, M. K., Van Vo, T., & Van Vo, G. (2021). Nanotechnology-based drug delivery for central nervous system disorders. Biomedicine & Pharmacotherapy, 143, 112117.
50. Ozceylan, O., & Sezgin-Bayindir, Z. (2024). Current overview on the use of nanosized drug delivery systems in the treatment of neurodegenerative diseases. ACS omega, 9(33), 35223-35242.
51. Pala, M., Meral, I., Acikgoz, N. P., Mengi, M., Gokce, M. B. E., Unsal, R., ... & Yilmaz, S. G. (2024). Thymoquinone ameliorates symptoms of Parkinson’s disease in a 6-OHDA rat model by downregulation of miR-204-3p. Behavioural Pharmacology, 35(4), 201-210.
52. Pazhamalai, V., Vignesh, S., Sreeram, E., SS, M., & Rajakumari, K. (2026). Integration of Nanotechnology and Secondary Metabolites for Neurodegenerative Disease. In Nanoparticles Agents and Secondary Metabolites in Neurodegenerative Diseases (pp. 287-316). IGI Global Scientific Publishing.
53. Pisoschi, A. M., & Pop, A. (2015). The role of antioxidants in the chemistry of oxidative stress: A review. European journal of medicinal chemistry, 97, 55-74.
54. Pottoo, F. H., Ibrahim, A. M., Alammar, A., Alsinan, R., Aleid, M., Alshehhi, A., ... & Alhajri, N. (2022). Thymoquinone: review of its potential in the treatment of neurological diseases. Pharmaceuticals, 15(4), 408.
55. Rahat, I., Imam, S. S., Rizwanullah, M., Alshehri, S., Asif, M., Kala, C., & Taleuzzaman, M. (2021). Thymoquinone-entrapped chitosan-modified nanoparticles: formulation optimization to preclinical bioavailability assessments. Drug Delivery, 28(1), 973-984.
56. Ramachandran, S., & Thangarajan, S. (2016). A novel therapeutic application of solid lipid nanoparticles encapsulated thymoquinone (TQ-SLNs) on 3-nitroproponic acid induced Huntington’s disease-like symptoms in wistar rats. Chemico-Biological Interactions, 256, 25-36.
57. Ramachandran, S., & Thangarajan, S. (2018). Thymoquinone loaded solid lipid nanoparticles counteracts 3-Nitropropionic acid induced motor impairments and neuroinflammation in rat model of Huntington’s disease. Metabolic Brain Disease, 33(5), 1459-1470.
58. Rathore, C., Rathbone, M. J., Chellappan, D. K., Tambuwala, M. M., Pinto, T. D. J. A., Dureja, H., ... & Negi, P. (2020). Nanocarriers: more than tour de force for thymoquinone. Expert opinion on drug delivery, 17(4), 479-494.
59. Saadat, M., Dahmardeh, N., Sheikhbahaei, F., & Mokhtari, T. (2024). Therapeutic potential of thymoquinone and its nanoformulations in neuropsychological disorders: a comprehensive review on molecular mechanisms in preclinical studies. Naunyn-Schmiedeberg's Archives of Pharmacology, 397(6), 3541-3564.
60. Sadeghi, E., Imenshahidi, M., & Hosseinzadeh, H. (2023). Molecular mechanisms and signaling pathways of black cumin (Nigella sativa) and its active constituent, thymoquinone: a review. Molecular biology reports, 50(6), 5439-5454.
61. Salehi, B., Albayrak, S., Antolak, H., Kręgiel, D., Pawlikowska, E., Sharifi-Rad, M., ... & Sharifi-Rad, J. (2018). Aloe genus plants: from farm to food applications and phytopharmacotherapy. International journal of molecular sciences, 19(9), 2843.
62. Salim, S. (2017). Oxidative stress and the central nervous system. The Journal of pharmacology and experimental therapeutics, 360(1), 201-205.
63. Sayeed, M. S. B., Asaduzzaman, M., Morshed, H., Hossain, M. M., Kadir, M. F., & Rahman, M. R. (2013). The effect of Nigella sativa Linn. seed on memory, attention and cognition in healthy human volunteers. Journal of ethnopharmacology, 148(3), 780-786.
64. Sayeed, M. S. B., Shams, T., Hossain, S. F., Rahman, M. R., Mostofa, A. G. M., Kadir, M. F., ... & Asaduzzaman, M. (2014). Nigella sativa L. seeds modulate mood, anxiety and cognition in healthy adolescent males. Journal of ethnopharmacology, 152(1), 156-162.
65. Sharifi-Rad, M., Lankatillake, C., Dias, D. A., Docea, A. O., Mahomoodally, M. F., Lobine, D., ... & Sharifi-Rad, J. (2020). Impact of natural compounds on neurodegenerative disorders: from preclinical to pharmacotherapeutics. Journal of Clinical Medicine, 9(4), 1061.
66. Shu-li, G. E., Jian-jian, D. O. N. G., Chen-chen, X. U., & Nan, C. H. E. N. G. (2023). Inhibitory effect of thymoquinone on neuroinflammation in Parkinson's disease model by regulating NLRP3 inflammatory bodies. Journal of Hainan Medical University, 29(17).
67. Singh, A. K., Rai, S. N., Maurya, A., Mishra, G., Awasthi, R., Shakya, A., ... & Singh, M. P. (2021). Therapeutic potential of phytoconstituents in management of Alzheimer’s disease. Evidence‐Based Complementary and Alternative Medicine, 2021(1), 5578574.
68. Stefanescu, R., Stanciu, G. D., Luca, A., Paduraru, L., & Tamba, B. I. (2020). Secondary metabolites from plants possessing inhibitory properties against beta-amyloid aggregation as revealed by thioflavin-T assay and correlations with investigations on transgenic mouse models of Alzheimer’s disease. Biomolecules, 10(6), 870.
69. Velagapudi, R., Kumar, A., Bhatia, H. S., El-Bakoush, A., Lepiarz, I., Fiebich, B. L., & Olajide, O. A. (2017). Inhibition of neuroinflammation by thymoquinone requires activation of Nrf2/ARE signalling. International Immunopharmacology, 48, 17-29.
70. Wang, Y., Gao, H., Zhang, W., Zhang, W., & Fang, L. (2015). Thymoquinone inhibits lipopolysaccharide-induced inflammatory mediators in BV2 microglial cells. International Immunopharmacology, 26(1), 169-173.
71. Xiao, X. Y., Zhu, Y. X., Bu, J. Y., Li, G. W., Zhou, J. H., & Zhou, S. P. (2016). Evaluation of neuroprotective effect of thymoquinone nanoformulation in the rodent cerebral ischemia‐reperfusion model. BioMed Research International, 2016(1), 2571060.
72. Yan, W., Liu, Y., Mansooridara, S., Kalantari, A. S., Sadeghian, N., Taslimi, P., ... & Zangeneh, M. M. (2020). Chemical characterization and neuroprotective properties of copper nanoparticles green-synthesized by nigella sativa L. seed aqueous extract against methadone-induced cell death in adrenal phaeochromocytoma (PC12) cell line. Journal of Experimental Nanoscience, 15(1), 280-296.
73. Yusuf, M., Khan, M., Alrobaian, M. M., Alghamdi, S. A., Warsi, M. H., Sultana, S., & Khan, R. A. (2021). Brain targeted Polysorbate-80 coated PLGA thymoquinone nanoparticles for the treatment of Alzheimer's disease, with biomechanistic insights. Journal of Drug Delivery Science and Technology, 61, 102214.
74. Zhang, F., & Jiang, L. (2015). Neuroinflammation in Alzheimer’s disease. Neuropsychiatric disease and treatment, 243-256.
75. Zhao, B., Zhang, S., Amin, N., Pan, J., Wu, F., Shen, G., ... & Geng, Y. (2024). Thymoquinone regulates microglial M1/M2 polarization after cerebral ischemia-reperfusion injury via the TLR4 signaling pathway. Neurotoxicology, 101, 54-67.