An Overview of the Neuropharmacological Potential of Thymoquinone and its
Targeted Delivery Prospects for CNS Disorder

Rishabh      Verma; Ali      Sartaj; Farheen   Fatima   Qizilbash; Mohammed   M.   Ghoneim; Sultan      Alshehri; Syed   Sarim   Imam; Chandra      Kala; Md.   Shamsher   Alam; Sadaf   Jamal   Gilani; Mohamad      Taleuzzaman
Abstract

At present, people and patients worldwide are relying on the medicinal plant as a therapeutic agent over pharmaceuticals because the medicinal plant is considered safer, especially for chronic disorders. Several medicinal plants and their components are being researched and explored for their possible therapeutic contribution to CNS disorders. Thymoquinone (TQ) is one such molecule. Thymoquinone, one of the constituents of Plant Nigella Sativa, is effective against several neurodegenerative diseases like, Alzheimer's, Depression, Encephalomyelitis, Epilepsy, Ischemia, Parkinson's, and Traumatic. This review article presents the neuropharmacological potential of TQ's, their challenges, and delivery prospects, explicitly focusing on neurological disorders along with their chemistry, pharmacokinetics, and toxicity. Since TQ has some pharmacokinetic challenges, scientists have focused on novel formulations and delivery systems to enhance bioavailability and ultimately increase its therapeutic value. In the present work, the role of nanotechnology in neurodegenerative disease and how it improves the bioavailability and delivery of a drug to the site of action has been discussed. There are a few limitations to developing novel drug formulations, including solubility, pH, and compatibility of nanomaterials. Since here we are targeting CNS disorders, the bloodbrain barrier (BBB) becomes an additional challenge.
Hence, the review summarized the novel aspects of delivery and biocompatible nanoparticles-based approaches for targeted drug delivery into CNS, enhancing TQ bioavailability and its neurotherapeutic effects.
Keywords: CNS disorder, thymoquinone, neuropharmacological, bioavailability, BBB, encephalomyelitis.
Graphical Abstract

[1] 
Traditional medicine report by the secretariat  Available from:
                    http://www.who.int/ [cited 2021 Aug 16]
[2] 
Jamshidi-Kia, F.; Lorigooini, Z.; Amini-Khoei, H. Medicinal plants: History and future perspective. J. Herbmed. Pharmacol.,  2018, 7(1), 1-7.
[http://dx.doi.org/10.15171/jhp.2018.01] 
[3] 
Adib-Hajbaghery, M.; Rafiee, S. Medicinal plants use by elderly people in Kashan, Iran. Nurs. Midwifery Stud.,  2018, 7(2), 67.
[http://dx.doi.org/10.4103/nms.nms_109_17] 
[4] 
De Luca, V.; Salim, V.; Atsumi, S.M.; Yu, F. Mining the biodiversity of plants: A revolution in the making. Science,  2012, 336(6089), 1658-1661.
[http://dx.doi.org/10.1126/science.1217410] [PMID:  22745417] 
[5] 
Ramadan, M.F. Nutritional value, functional properties and nutraceutical applications of black cumin (Nigella sativa L.): an overview. Int. J. Food Sci. Technol.,  2007, 42(10), 1208-1218.
[http://dx.doi.org/10.1111/j.1365-2621.2006.01417.x] 
[6] 
Ahmad, A.; Husain, A.; Mujeeb, M.; Khan, S.A.; Najmi, A.K.; Siddique, N.A.; Damanhouri, Z.A.; Anwar, F. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pac. J. Trop. Biomed.,  2013, 3(5), 337-352.
[http://dx.doi.org/10.1016/S2221-1691(13)60075-1] [PMID:  23646296] 
[7] 
Myers, A.L.; Zhang, Y.P.; Kramer, M.A.; Bornmann, W.G.; Kaseb, A.; Yang, P.; Tran, H.T. A practical synthesis and X-ray crystallographic analysis of dithymoquinone, a photodimer of thymoquinone. Lett. Org. Chem.,  2012, 9(10), 762-766.
[http://dx.doi.org/10.2174/157017812803901890] [PMID:  24883052] 
[8] 
Ahmad, N.; Ahmad, R.; Alam, M.A.; Samim, M.; Iqbal, Z.; Ahmad, F.J. Quantification and evaluation of thymoquinone loaded mucoadhesive nanoemulsion for treatment of cerebral ischemia. Int. J. Biol. Macromol.,  2016, 88(Jul), 320-332.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.03.019] [PMID:  26976069] 
[9] 
Salem, M.L. Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. Int. Immunopharmacol.,  2005, 5(13-14), 1749-1770.
[http://dx.doi.org/10.1016/j.intimp.2005.06.008] [PMID:  16275613] 
[10] 
Salmani, J.M.; Asghar, S.; Lv, H.; Zhou, J. Aqueous solubility and degradation kinetics of the phytochemical anticancer thymoquinone; probing the effects of solvents, pH and light. Molecules,  2014, 19(5), 5925-5939.
[http://dx.doi.org/10.3390/molecules19055925] [PMID:  24815311] 
[11] 
Ismail, N.; Ismail, M.; Shahid, I.; Latiffah, A.L. Anti-aggregation effects of thymoquinone against Alzheimers -amyloid in vitro. J. Med. Plants Res.,  2013, 7(31), 2280-2288.
[http://dx.doi.org/10.5897/JMPR10.852] 
[12] 
Bin Sayeed, M.S.; Asaduzzaman, M.; Morshed, H.; Hossain, M.M.; Kadir, M.F.; Rahman, M.R. The effect of Nigella sativa Linn. seed on memory, attention and cognition in healthy human volunteers. J. Ethnopharmacol.,  2013, 148(3), 780-786.
[http://dx.doi.org/10.1016/j.jep.2013.05.004] [PMID:  23707331] 
[13] 
Abdel-Fattah, A.M.; Matsumoto, K.; Watanabe, H. Antinociceptive effects of Nigella sativa oil and its major component, thymoquinone, in mice. Eur. J. Pharmacol.,  2000, 400(1), 89-97.
[http://dx.doi.org/10.1016/S0014-2999(00)00340-X] [PMID:  10913589] 
[14] 
Hemmati, S.; Sadeghi, M.A.; Yousefi-Manesh, H.; Eslamiyeh, M.; Vafaei, A.; Foroutani, L.; Donyadideh, G.; Dehpour, A.; Rezaei, N. Protective effects of Leukadherin1 in a rat model of targeted experimental autoimmune encephalomyelitis (EAE): Possible role of P47phox and MDA downregulation. J. Inflamm. Res.,  2020, 13, 411-420.
[http://dx.doi.org/10.2147/JIR.S258991] [PMID:  32821147] 
[15] 
Perveen, T.; Haider, S.; Zuberi, N.A.; Saleem, S.; Sadaf, S.; Batool, Z. Increased 5-HT levels following repeated administration of Nigella sativa L. (Black seed) oil produce antidepressant effects in rats. Sci. Pharm.,  2013, 82(1), 161-170.
[http://dx.doi.org/10.3797/scipharm.1304-19] [PMID:  24634848] 
[16] 
Sedaghat, A.; Ram, M.K.; Zayed, A.; Kamal, R.; Shanahan, N. Investigation
of physical properties of graphene-cement composite for
structural applications. Open J. Compos. Mater.,  2014, 04(01)
[http://dx.doi.org/10.4236/ojcm.2014.41002] 
[17] 
Rashid, A.K.; Abul, K.N.; Arshad, H.K.; Darpan, G.; Mohd, A. Ameliorating effects of thymoquinone in rodent models of schizophrenia. Afr. J. Pharm. Pharmacol.,  2014, 8(15), 413-421.
[http://dx.doi.org/10.5897/AJPP2013.3968] 
[18] 
Javidi, S.; Razavi, B.M.; Hosseinzadeh, H. A review of neuropharmacology effects of Nigella sativa and its main component, thymoquinone. Phytother. Res.,  2016, 30(8), 1219-1229.
[http://dx.doi.org/10.1002/ptr.5634] [PMID:  27169925] 
[19] 
Soni, S.; Ruhela, R.K.; Medhi, B. Nanomedicine in Central Nervous System (CNS) disorders: A present and future prospective. Adv. Pharm. Bull.,  2016, 6(3), 319-335.
[http://dx.doi.org/10.15171/apb.2016.044] [PMID:  27766216] 
[20] 
Lombardo, D.; Kiselev, M.A.; Caccamo, M.T. Smart nanoparticles
for drug delivery application: Development of versatile nanocarrier
platforms in biotechnology and nanomedicine. J. Nanomater.,  2019, 2019, 2019.
[http://dx.doi.org/10.1155/2019/3702518] 
[21] 
Domínguez Monedero, A.; Álvarez Díaz, A.; Suárez Merino, B.; Goñi de Cerio, F. Neurological conditions and the blood-brain barrier. Limitations and strategies for drug delivery to the brain. Rev. Neurol.,  2014, 58(5), 213.
[http://dx.doi.org/10.33588/rn.5805.2013314] 
[22] 
Tajes, M.; Ramos-Fernández, E.; Weng-Jiang, X.; Bosch-Morató, M.; Guivernau, B.; Eraso-Pichot, A.; Salvador, B.; Fernàndez-Busquets, X.; Roquer, J.; Muñoz, F.J. The blood-brain barrier: Structure, function and therapeutic approaches to cross it. Mol. Membr. Biol.,  2014, 31(5), 152-167.
[http://dx.doi.org/10.3109/09687688.2014.937468] [PMID:  25046533] 
[23] 
Wong, H.L.; Wu, X.Y.; Bendayan, R. Nanotechnological advances for the delivery of CNS therapeutics. Adv. Drug Deliv. Rev.,  2012, 64(7), 686-700.
[http://dx.doi.org/10.1016/j.addr.2011.10.007] [PMID:  22100125] 
[24] 
Khanbabaie, R.; Jahanshahi, M. Revolutionary impact of nanodrug delivery on neuroscience. Curr. Neuropharmacol.,  2012, 10(4), 370-392.
[http://dx.doi.org/10.2174/157015912804499456] [PMID:  23730260] 
[25] 
Fortuna, A.; Alves, G.; Soares-da-Silva, P.; Falcão, A. Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: New set of data for predictive in silico ADME models. Epilepsy Res.,  2013, 107(1-2), 37-50.
[http://dx.doi.org/10.1016/j.eplepsyres.2013.08.013] [PMID:  24050973] 
[26] 
Masserini, M. Nanoparticles for brain drug delivery. ISRN Biochem.,  2013, 2013, 238428.
[http://dx.doi.org/10.1155/2013/238428] [PMID:  25937958] 
[27] 
Alhebshi, A.H.; Gotoh, M.; Suzuki, I. Thymoquinone protects cultured rat primary neurons against amyloid β-induced neurotoxicity. Biochem. Biophys. Res. Commun.,  2013, 433(4), 362-367.
[http://dx.doi.org/10.1016/j.bbrc.2012.11.139] [PMID:  23537659] 
[28] 
Di Matteo, V.; Esposito, E. Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Curr. Drug Targets CNS Neurol. Disord.,  2003, 2(2), 95-107.
[http://dx.doi.org/10.2174/1568007033482959] [PMID:  12769802] 
[29] 
Ferrari, C.K.B. Diet, herbs, and nutritional protection against oxidative stress in neurological diseases. In: Qureshi, G.A.; Parvez, S.H.;
Eds. Oxidative Stress and Neurodegenerative Disorders; Elsevier Science: Amsterdam, 2007, pp. 525-541.
[http://dx.doi.org/10.1016/B978-044452809-4/50164-2] 
[30] 
Ismail, N.; Ismail, M.; Mazlan, M.; Latiff, L.A.; Imam, M.U.; Iqbal, S.; Azmi, N.H.; Ghafar, S.A.; Chan, K.W. Thymoquinone prevents β-amyloid neurotoxicity in primary cultured cerebellar granule neurons. Cell. Mol. Neurobiol.,  2013, 33(8), 1159-1169.
[http://dx.doi.org/10.1007/s10571-013-9982-z] [PMID:  24101432] 
[31] 
Callahan, P.M.; Hutchings, E.J.; Kille, N.J.; Chapman, J.M.; Terry, A.V. Jr Positive allosteric modulator of α7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates. Neuropharmacology,  2013, 67, 201-212.
[http://dx.doi.org/10.1016/j.neuropharm.2012.10.019] [PMID:  23168113] 
[32] 
Vicens, P.; Ribes, D.; Heredia, L.; Torrente, M.; Domingo, J.L. Effects of an alpha7 nicotinic receptor agonist and stress on spatial memory in an animal model of Alzheimer’s disease. BioMed Res. Int.,  2013, 2013, 952719.
[http://dx.doi.org/10.1155/2013/952719] [PMID:  24058919] 
[33] 
Ibrahim AbdEl Fattah. L.; Zickri, M.B.; Aal, L.A.; Heikal, O.; Osama, E. The effect of thymoquinone, α7 receptor agonist and α7 receptor allosteric modulator on the cerebral cortex in experimentally induced Alzheimer’s disease in relation to MSCs activation. Int. J. Stem Cells,  2016, 9(2), 230-238.
[http://dx.doi.org/10.15283/ijsc16021] [PMID:  27572711] 
[34] 
Alhibshi, A.H.; Odawara, A.; Suzuki, I. Neuroprotective efficacy of thymoquinone against amyloid beta-induced neurotoxicity in human induced pluripotent stem cell-derived cholinergic neurons. Biochem. Biophys. Rep.,  2019, 17, 122-126.
[http://dx.doi.org/10.1016/j.bbrep.2018.12.005] [PMID:  30623116] 
[35] 
Elibol, B.; Beker, M.; Terzioglu-Usak, S.; Dalli, T.; Kilic, U. Thymoquinone administration ameliorates Alzheimer’s disease-like phenotype by promoting cell survival in the hippocampus of amyloid beta1-42 infused rat model. Phytomedicine,  2020, 79, 153324.
[http://dx.doi.org/10.1016/j.phymed.2020.153324] [PMID:  32920292] 
[36] 
Gilhotra, N.; Dhingra, D. Thymoquinone produced antianxiety-like effects in mice through modulation of GABA and NO levels. Pharmacol. Rep.,  2011, 63(3), 660-669.
[http://dx.doi.org/10.1016/S1734-1140(11)70577-1] [PMID:  21857076] 
[37] 
Samad, N.; Manzoor, N.; Muneer, Z.; Bhatti, S.A.; Imran, I. Reserpine-induced altered neuro-behavioral, biochemical and histopathological assessments prevent by enhanced antioxidant defence system of thymoquinone in mice. Metab. Brain Dis.,  2021, 36(8), 2535-2552. Epub ahead of print
[http://dx.doi.org/10.1007/s11011-021-00789-2] [PMID:  34309746] 
[38] 
Spitzer, R.L.; Kroenke, K.; Linzer, M.; Hahn, S.R.; Williams, J.B.; deGruy, F.V., III; Brody, D.; Davies, M. Health-related quality of life in primary care patients with mental disorders. Results from the PRIME-MD 1000 Study. JAMA,  1995, 274(19), 1511-1517.
[http://dx.doi.org/10.1001/jama.1995.03530190025030] [PMID:  7474219] 
[39] 
Sharp, L.K.; Lipsky, M.S. Screening for depression across the lifespan: A review of measures for use in primary care settings. Am. Fam. Physician,  2002, 66(6), 1001-1008.
[PMID:  12358212] 
[40] 
Howren, M.B.; Lamkin, D.M.; Suls, J. Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis. Psychosom. Med.,  2009, 71(2), 171-186.
[http://dx.doi.org/10.1097/PSY.0b013e3181907c1b] [PMID:  19188531] 
[41] 
Dowlati, Y.; Herrmann, N.; Swardfager, W.; Liu, H.; Sham, L.; Reim, E.K. A meta-analysis of cytokines in major depression. Biol. Psychiatry,  2010, 67(5), 446-457.
[http://dx.doi.org/10.1016/j.biopsych.2009.09.033] 
[42] 
Hashioka, S. Antidepressants and neuroinflammation: Can antidepressants calm glial rage down? Mini Rev. Med. Chem.,  2011, 11(7), 555-564.
[http://dx.doi.org/10.2174/138955711795906888] [PMID:  21699486] 
[43] 
Hosseini, M.; Zakeri, S.; Khoshdast, S.; Yousefian, F.T.; Rastegar, M.; Vafaee, F.; Kahdouee, S.; Ghorbani, F.; Rakhshandeh, H.; Kazemi, S.A. The effects of Nigella sativa hydro-alcoholic extract and thymoquinone on lipopolysaccharide - induced depression like behavior in rats. J. Pharm. Bioallied Sci.,  2012, 4(3), 219-225.
[http://dx.doi.org/10.4103/0975-7406.99052] [PMID:  22923964] 
[44] 
Nazir, S.; Farooq, R.K.; Khan, H.; Alam, T.; Javed, A. Thymoquinone harbors protection against Concanavalin A-induced behavior deficit in BALB/c mice model. J. Food Biochem.,  2021, 45(3), e13348.
[http://dx.doi.org/10.1111/jfbc.13348] [PMID:  32618005] 
[45] 
Liu, J.; Wang, A.; Li, L.; Huang, Y.; Xue, P.; Hao, A. Oxidative stress mediates hippocampal neuron death in rats after lithium-pilocarpine-induced status epilepticus. Seizure,  2010, 19(3), 165-172.
[http://dx.doi.org/10.1016/j.seizure.2010.01.010] [PMID:  20149694] 
[46] 
Waldbaum, S.; Liang, L.P.; Patel, M. Persistent impairment of mitochondrial and tissue redox status during lithium-pilocarpine-induced epileptogenesis. J. Neurochem.,  2010, 115(5), 1172-1182.
[http://dx.doi.org/10.1111/j.1471-4159.2010.07013.x] [PMID:  21219330] 
[47] 
Shao, Y.Y.; Li, B.; Huang, Y.M.; Luo, Q.; Xie, Y.M.; Chen, Y.H. Thymoquinone attenuates brain injury via an anti-oxidative pathway in a status epilepticus rat model. Transl. Neurosci.,  2017, 8(1), 9-14.
[http://dx.doi.org/10.1515/tnsci-2017-0003] [PMID:  28400978] 
[48] 
Farkhondeh, T.; Samarghandian, S.; Azimin-Nezhad, M.; Samini, F. Effect of chrysin on nociception in formalin test and serum levels of noradrenalin and corticosterone in rats. Int. J. Clin. Exp. Med.,  2015, 8(2), 2465-2470.
[PMID:  25932190] 
[49] 
Baluchnejadmojarad, T.; Roghani, M. Coenzyme q10 ameliorates neurodegeneration, mossy fiber sprouting, and oxidative stress in intrahippocampal kainate model of temporal lobe epilepsy in rat. J. Mol. Neurosci.,  2013, 49(1), 194-201.
[http://dx.doi.org/10.1007/s12031-012-9886-2] [PMID:  23008120] 
[50] 
Xie, C.; Sun, J.; Qiao, W.; Lu, D.; Wei, L.; Na, M.; Song, Y.; Hou, X.; Lin, Z. Administration of simvastatin after kainic acid-induced status epilepticus restrains chronic temporal lobe epilepsy. PLoS One,  2011, 6(9), e24966.
[http://dx.doi.org/10.1371/journal.pone.0024966] [PMID:  21949812] 
[51] 
Jokeit, H.; Schacher, M. Neuropsychological aspects of type of epilepsy and etiological factors in adults. Epilepsy Behav.,  2004, 5(Suppl. 1), S14-S20.
[http://dx.doi.org/10.1016/j.yebeh.2003.11.003] [PMID:  14725842] 
[52] 
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.
[http://dx.doi.org/10.1007/s12031-013-0043-3] [PMID:  23794216] 
[53] 
Petito, C.K.; Feldmann, E.; Pulsinelli, W.A.; Plum, F. Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology,  1987, 37(8), 1281-1286.
[http://dx.doi.org/10.1212/WNL.37.8.1281] [PMID:  3614648] 
[54] 
Chan, P.H. Reactive oxygen radicals in signaling and damage in the ischemic brain. J. Cereb. Blood Flow Metab.,  2001, 21(1), 2-14.
[http://dx.doi.org/10.1097/00004647-200101000-00002] [PMID:  11149664] 
[55] 
Samarghandian, S.; Farkhondeh, T.; Samini, F. A review on possible therapeutic effect of Nigella sativa and thymoquinone in neurodegenerative diseases. CNS Neurol. Disord. Drug Targets,  2018, 17(6), 412-420.
[http://dx.doi.org/10.2174/1871527317666180702101455] [PMID:  29962349] 
[56] 
Ashraf, H.; Heidari, R.; Nejati, V. Antihyperglycemic and antihyperlipidemic effects of fruit aqueous extract of Berberis integerrima Bge. in streptozotocin-induced diabetic rats. Iran. J. Pharm. Res.,  2014, 13(4), 1313-1318.
[PMID:  25587320] 
[57] 
Parlar, A.; Arslan, S.O. Thymoquinone reduces ischemia and reperfusion-induced intestinal injury in rats, through anti-oxidative and anti-inflammatory effects. Turk. J. Surg.,  2020, 36(1), 96-104.
[http://dx.doi.org/10.5578/turkjsurg.4583] [PMID:  32637881] 
[58] 
Venda, L.L.; Cragg, S.J.; Buchman, V.L.; Wade-Martins, R. α-Synuclein and dopamine at the crossroads of Parkinson’s disease. Trends Neurosci.,  2010, 33(12), 559-568.
[http://dx.doi.org/10.1016/j.tins.2010.09.004] [PMID:  20961626] 
[59] 
Mosley, R.L.; Benner, E.J.; Kadiu, I.; Thomas, M.; Boska, M.D.; Hasan, K.; Laurie, C.; Gendelman, H.E. Neuroinflammation, oxidative stress and the pathogenesis of Parkinson’s disease. Clin. Neurosci. Res.,  2006, 6(5), 261-281.
[http://dx.doi.org/10.1016/j.cnr.2006.09.006] [PMID:  18060039] 
[60] 
Radad, K.S.; Al-Shraim, M.M.; Moustafa, M.F.; Rausch, W.D. Neuroprotective role of thymoquinone against 1-methyl-4-phenylpyridinium-induced dopaminergic cell death in primary mesencephalic cell culture. Neurosciences (Riyadh),  2015, 20(1), 10-16.
[PMID:  25630775] 
[61] 
Ardah, M.T.; Merghani, M.M.; Haque, M.E. Thymoquinone prevents neurodegeneration against MPTP in vivo and modulates α-synuclein aggregation in vitro. Neurochem. Int.,  2019, 128, 115-126.
[http://dx.doi.org/10.1016/j.neuint.2019.04.014] [PMID:  31028778] 
[62] 
Dong, J.; Zhang, X.; Wang, S.; Xu, C.; Gao, M.; Liu, S.; Li, X.; Cheng, N.; Han, Y.; Wang, X.; Han, Y. Thymoquinone prevents dopaminergic neurodegeneration by attenuating oxidative stress via the Nrf2/ARE pathway. Front. Pharmacol.,  2021, 11, 615598.
[http://dx.doi.org/10.3389/fphar.2020.615598] [PMID:  33519481] 
[63] 
Velagapudi, R.; Kumar, A.; Bhatia, H.S.; El-Bakoush, A.; Lepiarz, I.; Fiebich, B.L.; Olajide, O.A. Inhibition of neuroinflammation by thymoquinone requires activation of Nrf2/ARE signalling. Int. Immunopharmacol.,  2017, 48, 17-29.
[http://dx.doi.org/10.1016/j.intimp.2017.04.018] [PMID:  28458100] 
[64] 
Bourne, K.Z.; Ferrari, D.C.; Lange-Dohna, C.; Rossner, S.; Wood, T.G.; Perez-Polo, J.R. Differential regulation of BACE1 promoter activity by nuclear factor-kappaB in neurons and glia upon exposure to beta-amyloid peptides. J. Neurosci. Res.,  2007, 85(6), 1194-1204.
[http://dx.doi.org/10.1002/jnr.21252] [PMID:  17385716] 
[65] 
Nakajima, K.; Matsushita, Y.; Tohyama, Y.; Kohsaka, S.; Kurihara, T. Differential suppression of endotoxin-inducible inflammatory cytokines by nuclear factor kappa B (NFkappaB) inhibitor in rat microglia. Neurosci. Lett.,  2006, 401(3), 199-202.
[66] 
Heneka, M.T.; Carson, M.J.; El Khoury, J.; Landreth, G.E.; Brosseron, F.; Feinstein, D.L.; Jacobs, A.H.; Wyss-Coray, T.; Vitorica, J.; Ransohoff, R.M.; Herrup, K.; Frautschy, S.A.; Finsen, B.; Brown, G.C.; Verkhratsky, A.; Yamanaka, K.; Koistinaho, J.; Latz, E.; Halle, A.; Petzold, G.C.; Town, T.; Morgan, D.; Shinohara, M.L.; Perry, V.H.; Holmes, C.; Bazan, N.G.; Brooks, D.J.; Hunot, S.; Joseph, B.; Deigendesch, N.; Garaschuk, O.; Boddeke, E.; Dinarello, C.A.; Breitner, J.C.; Cole, G.M.; Golenbock, D.T.; Kummer, M.P. Neuroinflammation in Alzheimer’s disease. Lancet Neurol.,  2015, 14(4), 388-405.
[http://dx.doi.org/10.1016/S1474-4422(15)70016-5] [PMID:  25792098] 
[67] 
Dai, Y.Q.; Jin, D.Z.; Zhu, X.Z.; Lei, D.L. Triptolide inhibits COX-2 expression via NF-kappa B pathway in astrocytes. Neurosci. Res.,  2006, 55(2), 154-160.
[http://dx.doi.org/10.1016/j.neures.2006.02.013] [PMID:  16600409] 
[68] 
Oskouei, Z.; Mehri, S.; Kalalinia, F.; Hosseinzadeh, H. Evaluation of the effect of thymoquinone in d-galactose-induced memory impairments in rats: Role of MAPK, oxidative stress, and neuroinflammation pathways and telomere length. Phytother. Res.,  2021, 35(4), 2252-2266.
[http://dx.doi.org/10.1002/ptr.6982] [PMID:  33325602] 
[69] 
Abulfadl, Y.S.; El-Maraghy, N.N.; Ahmed, A.E.; Nofal, S.; Abdel-Mottaleb, Y.; Badary, O.A. Thymoquinone alleviates the experimentally induced Alzheimer’s disease inflammation by modulation of TLRs signaling. Hum. Exp. Toxicol.,  2018, 37(10), 1092-1104.
[http://dx.doi.org/10.1177/0960327118755256] [PMID:  29405769] 
[70] 
Ebrahimi, S.S.; Oryan, S.; Izadpanah, E.; Hassanzadeh, K. Thymoquinone exerts neuroprotective effect in animal model of Parkinson’s disease. Toxicol. Lett.,  2017, 276(276), 108-114.
[http://dx.doi.org/10.1016/j.toxlet.2017.05.018] [PMID:  28526446] 
[71] 
Ballout, F.; Habli, Z.; Rahal, O.N.; Fatfat, M.; Gali-Muhtasib, H. Thymoquinone-based nanotechnology for cancer therapy: Promises and challenges. Drug Discov. Today,  2018, 23(5), 1089-1098.
[http://dx.doi.org/10.1016/j.drudis.2018.01.043] [PMID:  29374534] 
[72] 
Pathan, S.A.; Jain, G.K.; Zaidi, S.M.; Akhter, S.; Vohora, D.; Chander, P.; Kole, P.L.; Ahmad, F.J.; Khar, R.K. Stability-indicating ultra-performance liquid chromatography method for the estimation of thymoquinone and its application in biopharmaceutical studies. Biomed. Chromatogr.,  2011, 25(5), 613-620.
[http://dx.doi.org/10.1002/bmc.1492] [PMID:  20734352] 
[73] 
Khan, M.A.; Aldebasi, Y.H.; Alsuhaibani, S.A.; AlSahli, M.A.; Alzohairy, M.A.; Khan, A.; Younus, H. Therapeutic potential of thymoquinone liposomes against the systemic infection of Candida albicans in diabetic mice. PLoS One,  2018, 13(12)
[74] 
Goyal, S.N.; Prajapati, C.P.; Gore, P.R.; Patil, C.R.; Mahajan, U.B.; Sharma, C.; Talla, S.P.; Ojha, S.K. Therapeutic potential and pharmaceutical development of thymoquinone: A multitargeted molecule of natural origin. Front. Pharmacol.,  2017, 8, 656.
[http://dx.doi.org/10.3389/fphar.2017.00656] [PMID:  28983249] 
[75] 
El-Far, A.H.; Al Jaouni, S.K.; Li, W.; Mousa, S.A. Protective roles of thymoquinone nanoformulations: Potential nanonutraceuticals in human diseases. Nutrients,  2018, 10(10), 1369.
[http://dx.doi.org/10.3390/nu10101369] [PMID:  30257423] 
[76] 
Jakaria, M.; Cho, D.Y.; Ezazul Haque, M.; Karthivashan, G.; Kim, I.S.; Ganesan, P.; Choi, D.K. Neuropharmacological potential and delivery prospects of thymoquinone for neurological disorders. Oxid. Med. Cell. Longev.,  2018, 2018, 1209801.
[http://dx.doi.org/10.1155/2018/1209801] [PMID:  29743967] 
[77] 
Gilani, S.J.; Imam, S.S.; Ahmed, A.; Chauhan, S.; Mirza, M.A.; Taleuzzaman, M. Formulation and evaluation of thymoquinone niosomes: Application of developed and validated RP-HPLC method in delivery system. Drug Dev. Ind. Pharm.,  2019, 45(11), 1799-1806.
[http://dx.doi.org/10.1080/03639045.2019.1660366] [PMID:  31448962] 
[78] 
Nihei, T.; Suzuki, H.; Aoki, A.; Yuminoki, K.; Hashimoto, N.; Sato, H.; Seto, Y.; Onoue, S. Development of a novel nanoparticle formulation of thymoquinone with a cold wet-milling system and its pharmacokinetic analysis. Int. J. Pharm.,  2016, 511(1), 455-461.
[http://dx.doi.org/10.1016/j.ijpharm.2016.07.038] [PMID:  27451272] 
[79] 
Alam, M.; Najmi, A.K.; Ahmad, I.; Ahmad, F.J.; Akhtar, M.J.; Imam, S.S.; Akhtar, M. Formulation and evaluation of nano lipid formulation containing CNS acting drug: Molecular docking, in-vitro assessment and bioactivity detail in rats. Artif. Cells Nanomed. Biotechnol.,  2018, 46(Suppl. 2), 46-57.
[http://dx.doi.org/10.1080/21691401.2018.1451873] 
[80] 
Ismail, N.; Ismail, M.; Azmi, N.H.; Bakar, M.F.A.; Yida, Z.; Stanslas, J.; Sani, D.; Basri, H.; Abdullah, M.A. 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. Chem. Biol. Interact.,  2017, 275, 61-73.
[http://dx.doi.org/10.1016/j.cbi.2017.07.014] [PMID:  28734741] 
[81] 
Xiao, X.Y.; Zhu, Y.X.; Bu, J.Y.; Li, G.W.; Zhou, J.H.; Zhou, S.P. Evaluation of Neuroprotective Effect of Thymoquinone Nanoformulation in the Rodent Cerebral Ischemia-Reperfusion Model. BioMed Res. Int.,  2016, 2016, 2571060.
[http://dx.doi.org/10.1155/2016/2571060] [PMID:  27725936] 
[82] 
Kalam, M.A.; Raish, M.; Ahmed, A.; Alkharfy, K.M.; Mohsin, K.; Alshamsan, A.; Al-Jenoobi, F.I.; Al-Mohizea, A.M.; Shakeel, F. Oral bioavailability enhancement and hepatoprotective effects of thymoquinone by self-nanoemulsifying drug delivery system. Mater. Sci. Eng. C,  2017, 76, 319-329.
[http://dx.doi.org/10.1016/j.msec.2017.03.088] [PMID:  28482534] 
[83] 
Odeh, F.; Ismail, S.I.; Abu-Dahab, R.; Mahmoud, I.S.; Al Bawab, A. Thymoquinone in liposomes: A study of loading efficiency and biological activity towards breast cancer. Drug Deliv.,  2012, 19(8), 371-377.
[http://dx.doi.org/10.3109/10717544.2012.727500] [PMID:  23043626] 
[84] 
Ravindran, J.; Nair, H.B.; Sung, B.; Prasad, S.; Tekmal, R.R.; Aggarwal, B.B. Thymoquinone poly (lactide-co-glycolide) nanoparticles exhibit enhanced anti-proliferative, anti-inflammatory, and chemosensitization potential. Biochem. Pharmacol.,  2010, 79(11), 1640-1647.
[http://dx.doi.org/10.1016/j.bcp.2010.01.023] [PMID:  20105430] 
[85] 
Abdelwahab, S.I.; Sheikh, B.Y.; Taha, M.M.; How, C.W.; Abdullah, R.; Yagoub, U.; El-Sunousi, R.; Eid, E.E. Thymoquinone-loaded nanostructured lipid carriers: Preparation, gastroprotection, in vitro toxicity, and pharmacokinetic properties after extravascular administration. Int. J. Nanomedicine,  2013, 8, 2163-2172.
[http://dx.doi.org/10.2147/IJN.S44108] [PMID:  23818776] 
[86] 
Doolaanea, A.A.; Mansor, N.; Mohd Nor, N.H.; Mohamed, F. Co-encapsulation of Nigella sativa oil and plasmid DNA for enhanced gene therapy of Alzheimer’s disease. J. Microencapsul.,  2016, 33(2), 114-126.
[http://dx.doi.org/10.3109/02652048.2015.1134689] [PMID:  26982435] 
[87] 
Yusuf, M.; Khan, M.; Alrobaian, M.M.; Alghamdi, S.A.; Warsi, M.H.; Sultana, S.; Khan, R.A. Brain targeted Polysorbate-80 coated PLGA thymoquinone Nanoparticles for the treatment of Alzheimer’s disease, with biomechanistic insights. J. Drug Deliv. Sci. Technol.,  2020, 102214.
[88] 
Ahmad, N.; Ahmad, R.; Al Qatifi, S.; Alessa, M.; Al Hajji, H.; Sarafroz, M. A bioanalytical UHPLC based method used for the quantification of Thymoquinone-loaded-PLGA-nanoparticles in the treatment of epilepsy. BMC Chem.,  2020, 14(1), 10.
[http://dx.doi.org/10.1186/s13065-020-0664-x] [PMID:  32083254] 
[89] 
Tubesha, Z.; Bakar, Z.A.; Ismail, M. Characterization and stability evaluation of thymoquinone nanoemulsions prepared by high-pressure homogenization. J. Nanomater.,  2013, 2013, 453290.
[90] 
Alam, S.; Khan, Z.I.; Mustafa, G.; Kumar, M.; Islam, F.; Bhatnagar, A.; Ahmad, F.J. Development and evaluation of thymoquinone-encapsulated chitosan nanoparticles for nose-to-brain targeting: A pharmacoscintigraphic study. Int. J. Nanomedicine,  2012, 7, 5705-5718.
[http://dx.doi.org/10.2147/IJN.S35329] [PMID:  23180965] 
[91] 
Shah, M.; Naseer, M.I.; Choi, M.H.; Kim, M.O.; Yoon, S.C. Amphiphilic PHA-mPEG copolymeric nanocontainers for drug delivery: Preparation, characterization and in vitro evaluation. Int. J. Pharm.,  2010, 400(1-2), 165-175.
[http://dx.doi.org/10.1016/j.ijpharm.2010.08.008] [PMID:  20713137] 
[92] 
Rathore, C.; Rathbone, M.J.; Chellappan, D.K.; Tambuwala, M.M.; Pinto, T.J.A.; Dureja, H.; Hemrajani, C.; Gupta, G.; Dua, K.; Negi, P. Nanocarriers: More than tour de force for thymoquinone. Expert Opin. Drug Deliv.,  2020, 17(4), 479-494.
[http://dx.doi.org/10.1080/17425247.2020.1730808] [PMID:  32077770] 
[93] 
Upadhyay, R.K. Drug delivery systems, CNS protection, and the blood brain barrier. BioMed Res. Int.,  2014, 2014, 869269.
[http://dx.doi.org/10.1155/2014/869269] [PMID:  25136634] 
[94] 
Patra, J.K.; Das, G.; Fraceto, L.F. Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnology,  2018, 16(1), 71.
[http://dx.doi.org/10.1186/s12951-018-0392-8] 
[95] 
Menon, P.K.; Muresanu, D.F.; Sharma, A.; Mössler, H.; Sharma, H.S. Cerebrolysin, a mixture of neurotrophic factors induces marked neuroprotection in spinal cord injury following intoxication of engineered nanoparticles from metals. CNS Neurol. Disord. Drug Targets,  2012, 11(1), 40-49.
[http://dx.doi.org/10.2174/187152712799960781] [PMID:  22229324] 
[96] 
Roney, C.; Kulkarni, P.; Arora, V.; Antich, P.; Bonte, F.; Wu, A.; Mallikarjuana, N.N.; Manohar, S.; Liang, H.F.; Kulkarni, A.R.; Sung, H.W.; Sairam, M.; Aminabhavi, T.M. Targeted nanoparticles for drug delivery through the blood-brain barrier for Alzheimer’s disease. J. Control. Release,  2005, 108(2-3), 193-214.
[http://dx.doi.org/10.1016/j.jconrel.2005.07.024] [PMID:  16246446] 
[97] 
Krol, S. Challenges in drug delivery to the brain: Nature is against us. J. Control. Release,  2012, 164(2), 145-155.
[http://dx.doi.org/10.1016/j.jconrel.2012.04.044] [PMID:  22609350] 
[98] 
Desai, N. Challenges in development of nanoparticle-based therapeutics. AAPS J.,  2012, 14(2), 282-295.
[http://dx.doi.org/10.1208/s12248-012-9339-4] [PMID:  22407288] 
[99] 
Jain, S.; Cherukupalli, S.K.; Mahmood, A.; Gorantla, S.; Rapalli, V.K.; Dubey, S.K.; Singhvi, G. Emerging nanoparticulate systems: Preparation techniques and stimuli responsive release characteristics. J. Appl. Pharm. Sci.,  2019, 9(08), 130-143.
[http://dx.doi.org/10.7324/JAPS.2019.90817] 
[100] 
Jin, G.Z.; Chakraborty, A.; Lee, J.H.; Knowles, J.C.; Kim, H.W. Targeting with nanoparticles for the therapeutic treatment of brain diseases. J. Tissue Eng.,  2020, 11, 2041731419897460.
[http://dx.doi.org/10.1177/2041731419897460] [PMID:  32180936] 
[101] 
Patel, T.; Zhou, J.; Piepmeier, J.M.; Saltzman, W.M. Polymeric nanoparticles for drug delivery to the central nervous system. Adv. Drug Deliv. Rev.,  2012, 64(7), 701-705.
[http://dx.doi.org/10.1016/j.addr.2011.12.006] [PMID:  22210134] 
[102] 
Teleanu, D.M.; Chircov, C.; Grumezescu, A.M.; Volceanov, A.; Teleanu, R.I. Impact of nanoparticles on brain health: An up to date overview. J. Clin. Med.,  2018, 7(12), 490.
[http://dx.doi.org/10.3390/jcm7120490] 
[103] 
Machtoub, L.; Kasugai, Y. Amyotrophic Lateral Sclerosis: Advances and Perspectives of Neuronanomedicine; CRC Press: Boca Raton, FL, 2016. 
[http://dx.doi.org/10.1201/b15632] 
[104] 
Saraiva, C.; Praça, C.; Ferreira, R.; Santos, T.; Ferreira, L.; Bernardino, L. Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases. J. Control. Release,  2016, 235, 34-47.
[http://dx.doi.org/10.1016/j.jconrel.2016.05.044] [PMID:  27208862] 
[105] 
Tosi, G.; Vandelli, M.A.; Forni, F.; Ruozi, B. Nanomedicine and neurodegenerative disorders: So close yet so far. Expert Opin. Drug Deliv.,  2015, 12(7), 1041-1044.
[http://dx.doi.org/10.1517/17425247.2015.1041374] [PMID:  25912814] 
[106] 
Elmowafy, M.; Samy, A.; Raslan, M.A.; Salama, A.; Said, R.A.; Abdelaziz, A.E.; El-Eraky, W.; El Awdan, S.; Viitala, T. Enhancement of bioavailability and pharmacodynamic effects of thymoquinone via Nanostructured Lipid Carrier (NLC) formulation. AAPS PharmSciTech,  2016, 17(3), 663-672.
[http://dx.doi.org/10.1208/s12249-015-0391-0] [PMID:  26304932] 
[107] 
Ahmad, A.; Khan, R.M.; Alkharfy, K.M.; Raish, M.; Al-Jenoobi, F.I.; Al-Mohizea, A.M. Effects of thymoquinone on the pharmacokinetics and pharmacodynamics of glibenclamide in a rat model. Nat. Prod. Commun.,  2015, 10(8), 1395-1398.
[http://dx.doi.org/10.1177/1934578X1501000821] [PMID:  26434126] 
[108] 
Lupidi, G.; Camaioni, E.; Khalifé, H.; Avenali, L.; Damiani, E.; Tanfani, F.; Scirè, A. Characterization of thymoquinone binding to human α1-acid glycoprotein. J. Pharm. Sci.,  2012, 101(7), 2564-2573.
[http://dx.doi.org/10.1002/jps.23138] [PMID:  22467430] 
[109] 
Lupidi, G.; Scire, A.; Camaioni, E.; Khalife, K.H.; De Sanctis, G.; Tanfani, F.; Damiani, E. Thymoquinone, a potential therapeutic agent of Nigella sativa, binds to site I of human serum albumin. Phytomedicine,  2010, 17(10), 714-720.
[http://dx.doi.org/10.1016/j.phymed.2010.01.011] [PMID:  20171066] 
[110] 
El-Najjar, N.; Ketola, R.A.; Nissilä, T.; Mauriala, T.; Antopolsky, M.; Jänis, J.; Gali-Muhtasib, H.; Urtti, A.; Vuorela, H. Impact of protein binding on the analytical detectability and anticancer activity of thymoquinone. J. Chem. Biol.,  2011, 4(3), 97-107.
[http://dx.doi.org/10.1007/s12154-010-0052-4] [PMID:  22229047] 
[111] 
El-Najjar, N.; Ketola, R.; Urtti, A.; Gali-Muhtaseb, H.; Vuorela, H. Impact of protein binding on thymoquinone’s analytical detection. Planta Med.,  2010, 76(12), 76-p351.
[http://dx.doi.org/10.1055/s-0030-1264649] 
[112] 
Nagi, M.N.; Almakki, H.A. Thymoquinone supplementation induces quinone reductase and glutathione transferase in mice liver: Possible role in protection against chemical carcinogenesis and toxicity. Phytother. Res.,  2009, 23(9), 1295-1298.
[http://dx.doi.org/10.1002/ptr.2766] [PMID:  19277968] 
[113] 
Khalife, K.H.; Lupidi, G. Nonenzymatic reduction of thymoquinone in physiological conditions. Free Radic. Res.,  2007, 41(2), 153-161.
[http://dx.doi.org/10.1080/10715760600978815] [PMID:  17364941] 
[114] 
Al-Ali, A.; Alkhawajah, A.A.; Randhawa, M.A.; Shaikh, N.A. Oral and intraperitoneal LD50 of thymoquinone, an active principle of Nigella sativa, in mice and rats. J. Ayub Med. Coll. Abbottabad,  2008, 20(2), 25-27.
[PMID:  19385451] 
[115] 
Mansour, M.A.; Ginawi, O.T.; El-Hadiyah, T.; El-Khatib, A.S.; Al-Shabanah, O.A.; Al-Sawaf, H.A. Effects of volatile oil constituents of Nigella sativa on carbon tetrachloride-induced hepatotoxicity in mice: Evidence for antioxidant effects of thymoquinone. Res. Commun. Mol. Pathol. Pharmacol.,  2001, 110(3-4), 239-251.
[PMID:  12760491] 
[116] 
Alam, M.; Vikas, G. Subacute 28 days repeated toxicity assessment of thymoquinone (volatile oil of black seed) in wistar rats. Indian J. Sci. Res.,  2020, 75.
[117] 
Ong, Y.S.; Saiful Yazan, L.; Ng, W.K.; Noordin, M.M.; Sapuan, S.; Foo, J.B.; Tor, Y.S. Acute and subacute toxicity profiles of thymoquinone-loaded nanostructured lipid carrier in BALB/c mice. Int. J. Nanomedicine,  2016, 11(11), 5905-5915.
[http://dx.doi.org/10.2147/IJN.S114205] [PMID:  27877037] 
Cite As
Current Drug Metabolism

An Overview of the Neuropharmacological Potential of Thymoquinone and its Targeted Delivery Prospects for CNS Disorder

Abstract

Graphical Abstract
