Abstract
Recently, studies conducted with astrocyte cells have drawn attention to neurodegeneration pathologies caused by aluminum exposure. In particular, investigating the potential of herbal therapeutic agents to prevent this effect of aluminum has gained importance. The purpose of this study was to investigate the therapeutic and preventive effects of piperine, curcumin, and the combination of these compounds on reactive primary astrocyte cells. In order to examine the preventive effect, certain concentrations of compounds were applied to the cells before the aluminum application, and to be able to determine the therapeutic effect, the compounds were examined after the aluminum application. The efficacy of the compounds was analyzed in terms of cell viability, apoptosis, necrosis, and cytokine release. In conclusion, the results of the study showed that the use of different concentrations of piperine, curcumin, and their combination had significantly higher % cell viability on aluminum-induced damage in astrocyte cells compared to the damaged control group. In addition, a decrease in the number of apoptotic and necrotic cells was observed in the same groups, which indicated that piperine increased curcumin activity. The decrease in the amount of IL-6 and TGF-β cytokines also supported that piperine increased the effectiveness of curcumin. Considering all these results, it can be said that in terms of aluminum damage in astrocyte cells, the bioavailability-enhancing property of piperine on curcumin was shown for the first time in the literature. In line with these results, it is inevitable to carry out further studies.
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The data sets created or analyzed during the present study are available from the corresponding author on reasonable request.
References
Abdel Wahab SI, Abdul AB, Alzubairi AS, Mohamed Elhassan M, Mohan S (2009) In vitro ultramorphological assessment of apoptosis induced by Zerumbone on (HeLa). J Biomed Biotechnol. https://doi.org/10.1155/2009/769568
Arcaro CA, Gutierres VO, Assis RP, Moreira TF, Costa PI, Baviera AM, Brunetti IL (2014) Piperine, a natural bioenhancer, nullifies the antidiabetic and antioxidant activities of curcumin in streptozotocin-diabetic rats. PLoS ONE 9:e113993. https://doi.org/10.1371/journal.pone.0113993
Ban C, Jo M, Park YH, Kim JH, Han JY, Lee KW, Kweon DH, Choi YJ (2020) Enhancing the oral bioavailability of curcumin using solid lipid nanoparticles. Food Chem. https://doi.org/10.1016/j.foodchem.2019.125328
Bishnoi M, Chopra K, Rongzhu L, Kulkarni SK (2011) Protective effect of curcumin and its combination with piperine (bioavailability enhancer) against haloperidol-associated neurotoxicity: cellular and neurochemical evidence. Neurotox Res 20:215–225. https://doi.org/10.1007/s12640-010-9229-4
Blass JP (2011) Neurochemical mechanisms in disease. Springer Science & Business Media. https://doi.org/10.1007/978-1-4419-7104-3
Caito S, Aschner M (2015) Neurotoxicity of metals. Handb Clin Neurol 131:169–189. https://doi.org/10.1016/B978-0-444-62627-1.00011-1
Ciapetti G, Granchi D, Savarino L, Cenni E, Magrini E, Baldini N, Giunti A (2002) In vitro testing of the potential for orthopedic bone cements to cause apoptosis of osteoblast-like cells. Biomaterials 23:617–627. https://doi.org/10.1016/S0142-9612(01)00149-1
Cohen BI, Pagnillo BS, Musikant BL, Deutsch AS (2000) An in vitro study of the cytotoxicity of two root canal sealers. J Endod 26:228–229. https://doi.org/10.1097/00004770-200004000-00008
Dey M, Singh RK (2022) Exposure of aluminium to C6 glioma cells modulates molecular and functional neurotoxic markers. J Biochem Mol Toxicol. https://doi.org/10.1002/jbt.23210
Diniz LP, Tortelli V, Matias I, Morgado J, Araujo APB, Melo HM, Seixas da Silva GS, Alves-Leon SV, de Souza JM, Ferreira ST, de Felice FG, Gomes FCA (2017) Astrocyte transforming growth factor beta 1 protects synapses against Aβ oligomers in Alzheimer’s disease model. J Neurosci 37:6797–6809. https://doi.org/10.1523/JNeurosci.3351-16.2017
Gorinova C, Aluani D, Yordanov Y, Kondeva-Burdina M, Tzankova V, Popova C, Yoncheva K (2016) In vitro evaluation of antioxidant and neuroprotective effects of curcumin loaded in Pluronic micelles. Biotechnol Biotechnol Equip 30:991–997. https://doi.org/10.1080/13102818.2016.1186500
Haftcheshmeh MS, Karimzadeh MR, Azhdari S, Vahedi P, Abdollahi E, Momtazi-Borojeni AA (2020) Modulatory effects of curcumin on the atherogenic activities of inflammatory monocytes: evidence from in vitro and animal models of human atherosclerosis. BioFactors 46:341–355. https://doi.org/10.1002/biof.1603
Haq IU, Imran M, Nadeem M, Tufail T, Gondal TA, Mubarak MS (2021) Piperine: a review of its biological effects. Phytother Res 35:680–700. https://doi.org/10.1002/ptr.6855
Hewlings SJ, Kalman DS (2017) Curcumin: a review of its effects on human health. Foods. https://doi.org/10.3390/foods6100092
Hu Y, Fang X, Wang J, Ren TT, Zhao YY, Dai JF, Qin XY, Lan R (2022) Astragalin attenuates AlCl3/D-galactose-induced aging-like disorders by inhibiting oxidative stress and neuroinflammation. Neurotoxicology 91:60–68. https://doi.org/10.1016/j.neuro.2022.05.003
Jangra A, Kwatra M, Singh T, Pant R, Kushwah P, Sharma Y, Saroha B, Datusalia AK, Bezbaruah BK (2016) Piperine augments the preventive effect of curcumin against lipopolysaccharide-induced neurobehavioral and neurochemical deficits in mice. Inflammation 39:1025–1038. https://doi.org/10.1007/s10753-016-0332-4
Kar F, Hacioglu C, Uslu S, Kanbak G (2019) Curcumin acts as post-preventive effects on rat hippocampal synaptosomes in a neuronal model of aluminum-induced toxicity. Neurochem Res 44:2020–2029. https://doi.org/10.1007/s11064-019-02839-9
Laabbar W, Abbaoui A, Elgot A, Mokni M, Amri M, Masmoudi-Kouki O, Gamrani H (2021) Aluminum induced oxidative stress, astrogliosis and cell death in rat astrocytes, is prevented by curcumin. J Chem Neuroanat. https://doi.org/10.1016/j.jchemneu.2020.101915
Lemire J, Appanna VD (2011) Aluminum toxicity and astrocyte dysfunction: a metabolic link to neurological disorders. J Inorg Biochem 105:1513–1517. https://doi.org/10.1016/j.jinorgbio.2011.07.001
Lemire J, Mailloux R, Puiseux-Dao S, Appanna VD (2009) Aluminum-induced defective mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells. J Neurosci Res 87:1474–1483. https://doi.org/10.1002/jnr.21965
Liaquat L, Sadir S, Batool Z, Tabassum S, Shahzad S, Afzal A, Haider S (2019) Acute aluminum chloride toxicity revisited: study on DNA damage and histopathological, biochemical and neurochemical alterations in rat brain. Life Sci 217:202–211. https://doi.org/10.1016/j.lfs.2018.12.009
Mahran RI, Shu P, Colacino J, Hagras MM, Sun D, Brenner DE (2021) Cellular pharmacology of curcumin with and without piperine. bioRxiv. https://doi.org/10.1101/2021.07.14.452424
Manap ASA, Tan ACW, Leong WH, Chia AYY, Vijayabalan S, Arya A, Wong EH, Rizwan F, Bindal U, Koshy S, Madhavan P (2019) Synergistic effects of curcumin and piperine as potent acetylcholine and amyloidogenic inhibitors with significant neuroprotective activity in sh-sy5y cells via computational molecular modeling and in vitro assay. Front Aging Neurosci. https://doi.org/10.3389/fnagi.2019.00206
Matias I, Buosi AS, Gomes FCA (2016) Functions of flavonoids in the central nervous system: astrocytes as targets for natural compounds. Neurochem Int 95:85–91. https://doi.org/10.1016/j.neuint.2016.01.009
Mhaske DB, Sreedhaaran S, Mahadik KR (2018) Role of piperine as an affective bioenhancer in drug absorption. Pharm Anal Acta 9:7. https://doi.org/10.4172/2153-2435.1000591
Mohajeri M, Sadeghizadeh M, Najafi F, Javan M (2015) Polymerized nano-curcumin attenuates neurological symptoms in EAE model of multiple sclerosis through down regulation of inflammatory and oxidative processes and enhancing neuroprotection and myelin repair. Neuropharmacology 99:156–167. https://doi.org/10.1016/j.neuropharm.2015.07.013
Mohammadi A, Khanbabaei H, Zandi F, Ahmadi A, Haftcheshmeh SM, Johnston TP, Sahebkar A (2022) Curcumin: a therapeutic strategy for targeting the Helicobacter pylori-related diseases. Microb Pathog 166:105552. https://doi.org/10.1016/j.micpath.2022.105552
Nampoothiri M, John J, Kumar N, Mudgal J, Nampurath GK, Chamallamudi MR (2015) Modulatory role of simvastatin against aluminum chloride-induced behavioral and biochemical changes in rats. Behav Neurol. https://doi.org/10.1155/2015/210169
Niu Q (2018) Overview of the relationship between aluminum exposure and health of human being. Neurotoxicity of Aluminum 1–31
Noor NA, Hosny EN, Khadrawy YA, Mourad IM, Othman AI, Aboul Ezz HS, Mohammed HS (2022) Effect of curcumin nanoparticles on streptozotocin-induced male Wistar rat model of Alzheimer’s disease. Metab Brain Dis 37:343–357. https://doi.org/10.1007/s11011-021-00897-z
Nordin A, Saim AB, Idrus RBH (2021) Honey ameliorate negative effects in neurodegenerative diseases: an evidence-based review. Sains Malays 50:791–801. https://doi.org/10.17576/jsm-2021-5003-20
Obulesu M, Jhansilakshmi M (2014) Neuroinflammation in Alzheimer’s disease: an understanding of physiology and pathology. Int J Neurosci 124:227–235. https://doi.org/10.3109/00207454.2013.831852
Oshiro S, Kawahara M, Kuroda Y, Zhang C, Cai Y, Kitajima S, Shirao M (2000) Glial cells contribute more to iron and aluminum accumulation but are more resistant to oxidative stress than neuronal cells. Biochim Biophys Acta 1502:405–414. https://doi.org/10.1016/S0925-4439(00)00065-X
Prema A, Thenmozhi AJ, Manivasagam T, Mohamed Essa M, Guillemin GJ (2017) Fenugreek seed powder attenuated aluminum chloride-induced tau pathology, oxidative stress, and inflammation in a rat model of alzheimer’s disease. J Alzheimers Dis 60:S209–S220. https://doi.org/10.3233/JAD-161103
Puglia C, Frasca G, Musumeci T, Rizza L, Puglisi G, Bonina F, Chiechio S (2012) Curcumin loaded NLC induces histone hypoacetylation in the CNS after intraperitoneal administration in mice. Eur J Pharm Biopharm 81:288–293. https://doi.org/10.1016/j.ejpb.2012.03.015
Qianqian Y, Zhu K, Ding Y, Han R, Cheng D (2022) Comparative study of aluminum (Al) speciation on apoptosis-promoting process in PC12 cells: correlations between morphological characteristics and mitochondrial kinetic disorder. J Inorg Biochem 232:111835. https://doi.org/10.1016/j.jinorgbio.2022.111835
Rahimi K, Hassanzadeh K, Khanbabaei H, Haftcheshmeh SM, Ahmadi A, Izadpanah E, Mohammadi A, Sahebkar A (2021) Curcumin: a dietary phytochemical for targeting the phenotype and function of dendritic cells. Curr Med Chem 28:1549–1564. https://doi.org/10.2174/0929867327666200515101228
Reichert KP, Pillat MM, Schetinger MRC, Bottari NB, Palma TV, Assmann CE, Gutierres JM, Ulrich H, Andrade CM, Exley C, Morsch VMM (2020) Aluminum-induced alterations of purinergic signaling in embryonic neural progenitor cells. Chemosphere 251:126642. https://doi.org/10.1016/j.chemosphere.2020.126642
Santaguida S, Janigro D, Hossain M, Oby E, Rapp E, Cucullo L (2006) Side by side comparison between dynamic versus static models of blood–brain barrier in vitro: a permeability study. Brain Res 1109:1–13. https://doi.org/10.1016/j.brainres.2006.06.027
Schildge S, Bohrer C, Beck K, Schachtrup C (2013) Isolation and culture of mouse cortical astrocytes. J Vis Exp. https://doi.org/10.3791/50079
Singh PK, Kotia V, Ghosh D, Mohite GM, Kumar A, Maji SK (2013) Curcumin modulates α-synuclein aggregation and toxicity. ACS Chem Neurosci 4:393–407. https://doi.org/10.1021/cn3001203
Singh S, Jamwal S, Kumar P (2015) Piperine enhances the preventive effect of curcumin against 3-NP induced neurotoxicity: possible neurotransmitters modulation mechanism. Neurochem Res 40:1758–1766. https://doi.org/10.1007/s11064-015-1658-2
Singh S, Kumar P (2016) Neuroprotective activity of curcumin in combination with piperine against quinolinic acid induced neurodegeneration in rats. Pharmacology 97:151–160. https://doi.org/10.1159/000443896
Singh S, Kumar P (2017) Neuroprotective potential of curcumin in combination with piperine against 6-hydroxy dopamine induced motor deficit and neurochemical alterations in rats. Inflammopharmacology 25:69–79. https://doi.org/10.1007/s10787-016-0297-9
Tiwari A, Mahadik KR, Gabhe SY (2020) Piperine: a comprehensive review of methods of isolation, purification, and biological properties. Med Drug Discov 7:100027. https://doi.org/10.1016/j.medidd.2020.100027
Tsatsakis AM (2021) Toxicological risk assessment and multi-system health impacts from exposure. Elsevier 247–258. https://doi.org/10.1016/B978-0-323-85215-9.00048-9
Weng MH, Chen SY, Li ZY, Yen GC (2020) Camellia oil alleviates the progression of Alzheimer’s disease in aluminum chloride-treated rats. Free Radic Biol Med 152:411–421. https://doi.org/10.1016/j.freeradbiomed.2020.04.004
Yadav V, Krishnan A, Vohora D (2020) A systematic review on Piper longum L.: bridging traditional knowledge and pharmacological evidence for future translational research. J Ethnopharmacol 247:112255. https://doi.org/10.1016/j.jep.2019.112255
Yilmaz EN, Bay S, Ozturk G, Ucisik MH (2020) Neuroprotective effects of curcumin-loaded emulsomes in a laser axotomy-induced CNS injury model. Int J Nanomedicine 15:9211–9229. https://doi.org/10.2147/IJN.S272931
Zhang H, Wang P, Yu H, Yu K, Cao Z, Xu F, Yang X, Song M, Li Y (2018) Aluminum trichloride-induced hippocampal inflammatory lesions are associated with IL-1Β-activated IL-1 signaling pathway in developing rats. Chemosphere 203:170–178. https://doi.org/10.1016/j.chemosphere.2018.03.162
Acknowledgements
This study was summarized from Şebnem Erfen’s master’s thesis. We would like to thank Ilgın Özdemir for helping in the design of the article figures.
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Both EAÇ and ŞE were responsible for the concept and design of the study and performed the data acquisition and analysis. Also, both of them are the sole responsible author who wrote the original draft. This study was summarized from Şebnem Erfen’s master’s thesis.
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Erfen, Ş., Akbay Çetin, E. Therapeutic and Preventive Effects of Piperine and its Combination with Curcumin as a Bioenhancer Against Aluminum-Induced Damage in the Astrocyte Cells. Neurotox Res 40, 2027–2045 (2022). https://doi.org/10.1007/s12640-022-00600-9
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DOI: https://doi.org/10.1007/s12640-022-00600-9