Email this article Oral administration of crocin-loaded solid lipid nanoparticles inhibits neuroinflammation in a rat model of epileptic seizures by activating SIRT1 expression
, Mohammadreza Gholami, Touraj Zamir Nasta, Elham Arkan, Fariborz Bahrehmand, Sajad Fakhri, Cyrus Jalili Abstract
Background and purpose: Epilepsy is a group of chronic neurological diseases caused by a complex set of neuronal hyper electrical activities and oxidative stress of neurons. Crocin is a natural bioactive agent of saffron with different pharmacological properties and low bioavailability. This study aimed to evaluate crocin-loaded solid lipid nanoparticles (SLNC) for neuroprotection activity and efficacy against pentylenetetrazol (PTZ)-induced epilepsy.
Experimental approach: The rats were pretreated with SLNC and pure-crocin (PC; 25 and 50 mg/kg/day; P.O.) for 28 days before PTZ induction. Behavioral functions were evaluated by passive avoidance learning (PAL) tasks. Then, total antioxidant capacity (TAC), malondialdehyde (MDA), and pro-inflammatory factors were measured in the brain tissue using ELISA kits. Gene expression levels were analyzed with real-time polymerase chain reaction and immunohistochemical assay was used to assess the protein expression of sirtuin1 SIRT 1).
Findings/Results: SLNC was prepared with an average particle size of 98.25 nm and 98.33% encapsulation efficiency. Memory deficit improved in rats treated with SLNC. Administering SLNC at 25 and 50 mg/kg significantly reduced MDA and proinflammatory cytokines while increasing TAC. Additionally, administering SLNC before treatment increased the levels of SIRT1, peroxisome proliferator-activated receptor coactivator 1α, cAMP-regulated enhancer binding protein, and brain-derived neurotrophic factor. Furthermore, SLNC administration resulted in the downregulation of caspase-3 and inflammation factor expression.
Conclusion and implications: Overall, the obtained results showed that SLNC has better protective effects on oxidative stress in neurons, neurocognitive function, and anti-apoptotic and neuromodulatory activity than PC, suggesting that it is a promising therapeutic strategy for inhibiting seizures.
Keywords
Full Text:
PDFReferences
Wang SJ, Zhao XH, Chen W, Bo N, Wang XJ, Chi ZF, et al. Sirtuin 1 activation enhances the PGC-1α/mitochondrial antioxidant system pathway in status epilepticus. Mol Med Rep. 2015;11(1):521-526.DOI: 10.3892/mmr.2014.2724.
Geronzi U, Lotti F, Grosso S. Oxidative stress in epilepsy. Expert Rev Neurother. 2018;18(5): 427-434.DOI: 10.1080/14737175.2018.1465410.
Anitha A, Thanseem I, Iype M, Thomas SV. Mitochondrial dysfunction in cognitive neurodevelopmental disorders: Cause or effect? Mitochondrion. 2023;69:18-32.DOI: 10.1016/j.mito.2023.01.002.
Jia X, Wang Q, Ji J, Lu W, Liu Z, Tian H, et al. Mitochondrial transplantation ameliorates hippocampal damage following status epilepticus. Animal Model Exp Med. 2023;6(1):41-50.DOI: 10.1002/ame2.12310.
Li D, Zhang L, Tuo J, Zhang F, Tai Z, Liu X, et al. PGC-1α affects epileptic seizures by regulating mitochondrial fusion in epileptic rats. Neurochem Res. 2023;48(5):1361-1369.DOI: 10.1007/s11064-022-03834-3.
Kupis W, Pałyga J, Tomal E, Niewiadomska E. The role of sirtuins in cellular homeostasis. J Physiol. Biochem. 2016;72(3):371-380. DOI: 10.1007/s13105-016-0492-6.
Méndez-Armenta M, Nava-Ruíz C, Juárez-Rebollar D, Rodríguez-Martínez E, Gómez PY. Oxidative stress associated with neuronal apoptosis in experimental models of epilepsy. Oxid. Med. Cell. Longev. 2014;2014:293689,1-12.DOI: 10.1155/2014/293689.
Kamali AN, Zian Z, Bautista JM, Hamedifar H, Hossein-Khannazer N, Hosseinzadeh R, et al. The potential role of pro-inflammatory and anti-inflammatory cytokines in epilepsy pathogenesis. Endocr. Metab. Immune. Disord. Drug Targets. 2021;21(10):1760-1774.DOI: 10.2174/1871530320999201116200940.
Soltani Khaboushan A, Yazdanpanah N, Rezaei N. Neuroinflammation and proinflammatory cytokines in epileptogenesis. Mol. Neurobiol. 2022;59(3): 1724-1743. DOI: 10.1007/s12035-022-02725-6.
Rashid M, Brim H, Ashktorab H. Saffron, its active components, and their association with DNA and histone modification: a narrative review of current knowledge. Nutrients. 2022;14(16):3317,1-12.DOI: 10.3390/nu14163317.
Zeinali M, Zirak MR, Rezaee SA, Karimi G, Hosseinzadeh H. Immunoregulatory and anti-inflammatory properties of Crocus sativus (Saffron) and its main active constituents: a review. Iran J Basic Med Sci. 2019;22(4):334-344.DOI: 10.22038/ijbms.2019.34365.8158.
Naderi R, Pardakhty A, Faraji Abbasi M, Ranjbar M, Iranpour M. Preparation and evaluation of crocin loaded in nanoniosomes and their effects on ischemia-reperfusion injuries in rat kidney. Sci Rep. 2021;11(1):23525,1-12.DOI: 10.1038/s41598-021-02073-w.
Zhong K, Qian C, Lyu R, Wang X, Hu Z, Yu J, et al. Anti-epileptic effect of crocin on experimental temporal lobe epilepsy in mice. Front. Pharmacol. 2022;13:757729,1-13.DOI: 10.3389/fphar.2022.757729.
Hosseinzadeh H, Talebzadeh F. Anticonvulsant evaluation of safranal and crocin from Crocus sativus in mice. Fitoterapia. 2005;76(7-8):722-724.DOI: 10.1016/j.fitote.2005.07.008.
Gupta J, Fatima MT, Islam Z, Khan RH, Uversky VN, Salahuddin P. Nanoparticle formulations in the diagnosis and therapy of Alzheimer's disease. Int J Biol Macromol. 2019;130:515-526.DOI: 10.1016/j.ijbiomac.2019.02.156.
Mu H, Holm R. Solid lipid nanocarriers in drug delivery: characterization and design. Expert Opin Drug Deliv. 2018;15(8):771-785.DOI: 10.1080/17425247.2018.1504018.
Scioli Montoto S, Muraca G, Ruiz ME. Solid lipid nanoparticles for drug delivery: pharmacological and biopharmaceutical aspects. Front Mol Biosci. 2020;7:587997,1-24.DOI: 10.3389/fmolb.2020.587997.
Mukherjee S, Ray S, Thakur RS. Solid lipid nanoparticles: a modern formulation approach in drug delivery system. Indian J Pharm Sci. 2009;71(4):349-358.DOI: 10.4103/0250-474X.57282.
Yoshino F, Yoshida A, Umigai N, Kubo K, Lee MCI. Crocetin reduces the oxidative stress induced reactive oxygen species in the stroke-prone spontaneously hypertensive rats (SHRSPs) brain. J Clin Biochem Nutr. 2011;49(3):182-187.DOI: 10.3164/jcbn.11-01.
Yadav A, Sunkaria A, Singhal N, Sandhir R. Resveratrol loaded solid lipid nanoparticles attenuate mitochondrial oxidative stress in vascular dementia by activating Nrf2/HO-1 pathway. Neurochem Int. 2018;112:239-254.DOI: 10.1016/j.neuint.2017.08.001.
Huang R, Zhu Y, Lin L, Song S, Cheng L, Zhu R. Solid lipid nanoparticles enhanced the neuroprotective role of curcumin against epilepsy through activation of Bcl-2 family and P38 MAPK pathways. ACS Chem. Neurosci. 2020;11(13): 1985-1995.DOI: 10.1021/acschemneuro.0c00242.
Aghaz F, Vaisi-Raygani A, Khazaei M, Arkan E, Sajadimajd S, Mozafari H, et al. Co-encapsulation of tretinoin and resveratrol by solid lipid nanocarrier (SLN) improves mice in vitro matured oocyte/ morula-compact stage embryo development. Theriogenology. 2021;171:1-13.DOI: 10.1016/j.theriogenology.2021.05.007.
Reed LJ. A simple method of estimating fifty percent endpoint. Am J Hyg. 1938;27:493-497. DOI: 10.1093/oxfordjournals.aje.a118408.
Jalili C, Salahshoor M, Pourmotabbed A, Moradi S, Roshankhah S, Shabanizadeh Darehdori A, et al. The effects of aqueous extract of Boswellia serrata on hippocampal region CA1 and learning deficit in kindled rats. Res Pharm Sci. 2014;9(5):351-358.PMID: 25657807.
Zamir-Nasta T, Pazhouhi M, Ghanbari A, Abdolmaleki A, Jalili C. Expression of cyclin D1, p21, and estrogen receptor alpha in aflatoxin G1-induced disturbance in testicular tissue of albino mice. Res Pharm Sci. 2021;16(2):182-192.DOI: 10.4103/1735-5362.310525.
Cordeiro S, Silva B, Martins AM, Ribeiro HM, Gonçalves L, Marto J. Antioxidant-loaded mucoadhesive nanoparticles for eye drug delivery: a new strategy to reduce oxidative stress. Processes. 2021;9(2):379,1-18.DOI: 10.3390/pr9020379.
Espinós C, Galindo MI, García-Gimeno MA, Ibáñez-Cabellos JS, Martínez-Rubio D, Millán JM, et al. Oxidative stress, a crossroad between rare diseases and neurodegeneration. Antioxidants (Basel). 2020;9(4):313,1-26.DOI: 10.3390/antiox9040313.
Li RJ, Liu Y, Liu HQ, Li J. Ketogenic diets and protective mechanisms in epilepsy, metabolic disorders, cancer, neuronal loss, and muscle and nerve degeneration. J Food Biochem. 2020;44(3):e13140,1-14.DOI: 10.1111/jfbc.13140.
Merelli A, Repetto M, Lazarowski A, Auzmendi J. Hypoxia, oxidative stress, and inflammation: three faces of neurodegenerative diseases. J Alzheimers Dis. 2021;82(s1):S109-S126.DOI: 10.3233/JAD-201074.
Yuan X, Fu Z, Ji P, Guo L, Al-Ghamdy AO, Alkandiri A, et al. Selenium nanoparticles pre-treatment reverse behavioral, oxidative damage, neuronal loss and neurochemical alterations in pentylenetetrazole-induced epileptic seizures in mice. Int J Nanomedicine. 2020;15:6339-6353.DOI: 10.2147/IJN.S259134.
Goldberg EM, Coulter DA. Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nat Rev Neurosci. 2013;14(5):337-349.DOI: 10.1038/nrn3482.
Maes M, Supasitthumrong T, Limotai C, Michelin AP, Matsumoto AK, de Oliveira Semão L, et al. Increased oxidative stress toxicity and lowered antioxidant defenses in temporal lobe epilepsy and mesial temporal sclerosis: associations with psychiatric comorbidities. Mol Neurobiol. 2020;57(8):3334-3348.DOI: 10.1007/s12035-020-01949-8.
Ishola IO, Akinleye MO, Afolayan OO, Okonkwo HE, Animashaun OT, Agbaje EO. Anticonvulsant activity of Nymphaea lotus Linn. extract in mice: the role of GABAergic-glutamatergic neurotransmission and antioxidant defense mechanisms. Epilepsy Res. 2022;181:106871. DOI: 10.1016/j.eplepsyres.2022.106871.
Mohammed El Tabaa M, Mohammed El Tabaa M, Anis A, Mohamed Elgharabawy R, Borai El-Borai N. GLP-1 mediates the neuroprotective action of crocin against cigarette smoking-induced cognitive disorders via suppressing HMGB1-RAGE/TLR4-NF-κB pathway. Int Immunopharmacol. 2022;110:108995,1-13.DOI: 10.1016/j.intimp.2022.108995.
Lin L, Liu G, Yang L. Crocin improves cognitive behavior in rats with Alzheimer's disease by regulating endoplasmic reticulum stress and apoptosis. Biomed Res Int. 2019;2019:9454913,1-9. DOI: 10.1155/2019/9454913.
Gokce EH, Korkmaz E, Dellera E, Sandri G, Bonferoni MC, Ozer O. Resveratrol-loaded solid lipid nanoparticles versus nanostructured lipid carriers: evaluation of antioxidant potential for dermal applications. Int J Nanomedicine. 2012;7:1841-1850.DOI: 10.2147/IJN.S29710.
Terrone G, Balosso S, Pauletti A, Ravizza T, Vezzani A. Inflammation and reactive oxygen species as disease modifiers in epilepsy. Neuropharmacology. 2020;167:107742,1-45.DOI: 10.1016/j.neuropharm.2019.107742.
McElroy PB, Liang LP, Day BJ, Patel M. Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation. Exp Neurol. 2017;298(Pt A):13-22.DOI: 10.1016/j.expneurol.2017.08.009.
Cheng Y, Wang D, Wang B, Li H, Xiong J, Xu S, et al. HMGB1 translocation and release mediate cigarette smoke-induced pulmonary inflammation in mice through a TLR4/MyD88-dependent signaling pathway. Mol Biol Cell. 2017;28(1):201-209.DOI: 10.1091/mbc.E16-02-0126.
Zhang S, Hu L, Jiang J, Li H, Wu Q, Ooi K, et al. HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia. J Neuroinflammation. 2020;17(1):15,1-20.DOI: 10.1186/s12974-019-1673-3.
Jin W, Zhang Y, Xue Y, Han X, Zhang X, Ma Z, et al. Crocin attenuates isoprenaline-induced myocardial fibrosis by targeting TLR4/NF-κB signaling: connecting oxidative stress, inflammation, and apoptosis. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(1):13-23.DOI: 10.1007/s00210-019-01704-4.
Zhang Y, Fei F, Zhen L, Zhu X, Wang J, Li S, et al. Sensitive analysis and simultaneous assessment of pharmacokinetic properties of crocin and crocetin after oral administration in rats. J Chromatogr B Analyt Technol Biomed Life Sci. 2017;1044-1045:1-7. DOI: 10.1016/j.jchromb.2016.12.003.
Lautenschläger M, Sendker J, Hüwel S, Galla HJ, Brandt S, Düfer M, et al. Intestinal formation of trans-crocetin from saffron extract (Crocus sativus L.) and in vitro permeation through intestinal and blood brain barrier. Phytomedicine. 2015;22(1):36-44.DOI: 10.1016/j.phymed.2014.10.009.
Salatin S, Barar J, Barzegar-Jalali M, Adibkia K, Kiafar F, Jelvehgari M. Development of a nanoprecipitation method for the entrapment of a very water soluble drug into Eudragit RL nanoparticles. Res Pharm Sci. 2017;12(1):1-14.DOI: 10.4103/1735-5362.199041.
Kakehbaraei S, Arab-Zozani M, Kakebaraei S. De novo hyaluronic acid-based biomaterial: a promising perspective to manage neurodegenerative diseases. Int J Polym Mater Polym Biomater. 2024:1-15.DOI:10.1080/00914037.2024.2360956.
Gastaldi L, Battaglia L, Peira E, Chirio D, Muntoni E, Solazzi I, et al. Solid lipid nanoparticles as vehicles of drugs to the brain: current state of the art. Eur J Pharm Biopharm. 2014;87(3):433-444. DOI: 10.1016/j.ejpb.2014.05.004.
Lippacher A, Müller RH, Mäder K. Preparation of semisolid drug carriers for topical application based on solid lipid nanoparticles. Int J Pharm. 2001;214(1-2):9-12.DOI: 10.1016/s0378-5173(00)00623-2.
Azmand MJ, Rajaei Z. Effects of crocin on spatial or aversive learning and memory impairments induced by lipopolysaccharide in rats. Avicenna J Phytomed. 2021;11(1):79-90.PMID: 33628722.
Farhadi L, Hojati V, Khaksari M, Vaezi G. Neuroprotective effects of crocin against ethanol neurotoxicity in the animal model of fetal alcohol spectrum disorders. Neurochem Res. 2022;47(4):1001-1011.DOI: 10.1007/s11064-021-03501-z.
Lushchekina SV, Kots ED, Novichkova DA, Petrov KA, Masson P. Role of acetylcholinesterase in β-amyloid aggregation studied by accelerated molecular dynamics. BioNanoScience. 2017;7(2):396-402.DOI: 10.1007/s12668-016-0375-x.
Zhang JY, Jiang H, Gao W, Wu J, Peng K, Shi YF, et al. The JNK/AP1/ATF2 pathway is involved in H2O2-induced acetylcholinesterase expression during apoptosis. Cell Mol Life Sci. 2008;65(9):1435-1445.DOI: 10.1007/s00018-008-8047-9.
Wang C, Cai X, Hu W, Li Z, Kong F, Chen X, et al. Investigation of the neuroprotective effects of crocin via antioxidant activities in HT22 cells and in mice with Alzheimer's disease. Int J Mol Med. 2019;43(2):956-966.DOI: 10.3892/ijmm.2018.4032.
Geromichalos GD, Lamari FN, Papandreou MA, Trafalis DT, Margarity M, Papageorgiou A, et al. Saffron as a source of novel acetylcholinesterase inhibitors: molecular docking and in vitro enzymatic studies. J Agric Food Chem. 2012;60(24):6131-6138.DOI: 10.1021/jf300589c.
Avgerinos KI, Vrysis C, Chaitidis N, Kolotsiou K, Myserlis PG, Kapogiannis D. Effects of saffron (Crocus sativus L.) on cognitive function. a systematic review of RCTs. Neurol Sci. 2020;41(10):2747-2754.DOI: 10.1007/s10072-020-04427-0.
Moazen-Zadeh E, Abbasi SH, Safi-Aghdam H, Shahmansouri N, Arjmandi-Beglar A, Hajhosseinn Talasaz A, et al. Effects of saffron on cognition, anxiety, and depression in patients undergoing coronary artery bypass grafting: a randomized double-blind placebo-controlled trial. J Altern Complement Med. 2018;24(4):361-368.DOI: 10.1089/acm.2017.0173.
Hosseini Dastgerdi H, Radahmadi M, Reisi P. Comparative study of the protective effects of crocin and exercise on long-term potentiation of CA1 in rats under chronic unpredictable stress. Life Sci. 2020;256:118018,1-10.DOI: 10.1016/j.lfs.2020.118018.
Soeda S, Aritake K, Urade Y, Sato H, Shoyama Y. Neuroprotective activities of saffron and crocin. Adv Neurobiol. 2016;12:275-292.DOI: 10.1007/978-3-319-28383-8_14.
Jalili C, Kiani A, Gholami M, Bahrehmand F, Fakhri S, Kakehbaraei S, et al. Brain targeting based nanocarriers loaded with resveratrol in Alzheimer's disease: a review. IET Nanobiotechnol. 2023;17(3):154-170.DOI: 10.1049/nbt2.12127.
Gonzalez-Carter D, Liu X, Tockary TA, Dirisala A, Toh K, Anraku Y, et al. Targeting nanoparticles to the brain by exploiting the blood-brain barrier impermeability to selectively label the brain endothelium. Proc Natl Acad Sci U S A. 2020;117(32):19141-19150.DOI: 10.1073/pnas.2002016117.
Zamir-Nasta T, Abbasi A, Kakebaraie S, Ahmadi A, Pazhouhi M, Jalili C. Aflatoxin G1 exposure altered the expression of BDNF and GFAP, histopathological of brain tissue, and oxidative stress factors in male rats. Res Pharm Sci. 2022;17(6):677-685.DOI: 10.4103/1735-5362.359434.
Sharma P, Kumar A, Singh D. Dietary flavonoids interaction with CREB-BDNF pathway: an unconventional approach for comprehensive management of epilepsy. Curr Neuropharmacol. 2019;17(12):1158-1175.DOI: 10.2174/1570159X17666190809165549.
Yu X, Guan Q, Wang Y, Shen H, Zhai L, Lu X, et al. Anticonvulsant and anti-apoptosis effects of salvianolic acid B on pentylenetetrazole-kindled rats via AKT/CREB/BDNF signaling. Epilepsy Res. 2019;154:90-96.DOI: 10.1016/j.eplepsyres.2019.05.007.
Vahdati Hassani F, Naseri V, Razavi BM, Mehri S, Abnous K, Hosseinzadeh H. Antidepressant effects of crocin and its effects on transcript and protein levels of CREB, BDNF, and VGF in rat hippocampus. Daru. 2014;22(1):16,1-9.DOI: 10.1186/2008-2231-22-16.
Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol. Cell Biol. 2012;13(4):225-238.DOI: 10.1038/nrm3293.
Chuang YC, Chen SD, Jou SB, Lin TK, Chen SF, Chen NC, et al. Sirtuin 1 regulates mitochondrial biogenesis and provides an endogenous neuroprotective mechanism against seizure-induced neuronal cell death in the hippocampus following status epilepticus. Int J Mol Sci. 2019; 20(14):3588.DOI: 10.3390/ijms20143588.
El Nashar EM, Obydah W, Alghamdi MA, Saad S, Yehia A, Maryoud A, et al. Effects of Stevia rebaudiana Bertoni extracts in the rat model of epilepsy induced by pentylenetetrazol: Sirt-1, at the crossroads between inflammation and apoptosis. J Integr Neurosci. 2022; 21(1):21,1-14.DOI: 10.31083/j.jin2101021.
Chen Y, Xie Y, Wang H, Chen Y. SIRT1 expression and activity are up-regulated in the brain tissue of epileptic patients and rat models. Nan Fang Yi Ke Da Xue Xue Bao. 2013;33(4):528-532.PMID: 23644113.
Sun XJ, Zhao X, Xie JN, Wan H. Crocin alleviates schizophrenia-like symptoms in rats by upregulating silent information regulator-1 and brain derived neurotrophic factor. Compr Psychiatry. 2020;103:152209,1-7.DOI: 10.1016/j.comppsych.2020.152209.
Wei QY, Xu YM, Lau ATY. Recent progress of nanocarrier-based therapy for solid malignancies. Cancers (Basel). 2020;12(10):2783. DOI: 10.3390/cancers12102783.
Khan AR, Yang X, Fu M, Zhai G. Recent progress of drug nanoformulations targeting to brain. J Control Release. 2018;291:37-64.DOI: 10.1016/j.jconrel.2018.10.004.
Graverini G, Piazzini V, Landucci E, Pantano D, Nardiello P, Casamenti F, et al. Solid lipid nanoparticles for delivery of andrographolide across the blood-brain barrier: in vitro and in vivo evaluation. Colloids Surf. Biointerface. 2018;161:302-313.DOI: 10.1016/j.colsurfb.2017.10.062.
Refbacks
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.