Skip to main content
SpringerLink
Log in

Neuroprotective Effects of Crocin Against Ethanol Neurotoxicity in the Animal Model of Fetal Alcohol Spectrum Disorders

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Several experimental and clinical findings suggest that ethanol consumption during pregnancy activates an oxidative-inflammatory cascade followed by wide apoptotic neurodegeneration within several brain areas, including the hippocampus. Crocin can protect neurons because of its antioxidant, anti-inflammatory, and antiapoptotic effects. This study evaluated the crocin protective impact on ethanol-related neuroinflammation and neuronal apoptosis in the hippocampus of rat pups exposed to alcohol over postnatal days. Ethanol (5.25 g/kg) was administrated in milk solution (27.8 ml/kg) by intragastric intubation 2–10 days after birth. The animals received crocin (15, 30, and 45 mg/kg) 2–10 days after birth. The hippocampus-dependent memory and spatial learning were evaluated 36 days after birth using the Morris water maze task. Further, the concentrations of TNF-α and antioxidant enzymes were determined using ELISA assay to examine the antioxidant and anti-inflammatory activities. Also, immunohistochemical staining was performed to evaluate the glial fibrillary acidic protein (GFAP), Ionized calcium binding adaptor molecule 1(Iba-1), and caspase-3 expression. The administration of crocin significantly attenuated spatial memory impairment (P < 0.01) after ethanol neurotoxicity. Also, crocin led to a significant enhancement in SOD (P < 0.05) and GSH-PX (P < 0.01), whereas it caused a reduction in the TNF-α and MDA concentrations compared to the ethanol group (P < 0.01). Moreover, the hippocampal level of caspase-3 (P < 0.01) and the number of GFAP and Iba-1-positive cells decreased in the crocin group (P < 0.001). Crocin suppresses apoptotic signaling mediated by the oxidative-inflammatory cascade in rat pups exposed to ethanol after birth.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Raghunathan R, Wu C, Singh M, Liu CH, Miranda RC, Larin KV (2018) Evaluating the effects of maternal alcohol consumption on murine fetal brain vasculature using optical coherence tomography. J Biophotonics 11(5):e201700238

    Article  PubMed  PubMed Central  Google Scholar 

  2. Abbott CW, Rohac DJ, Bottom RT, Patadia S, Huffman KJ (2018) Prenatal ethanol exposure and neocortical development: a transgenerational model of FASD. Cereb Cortex 28(8):2908–2921

    Article  PubMed  Google Scholar 

  3. Amin FU, Shah SA, Kim MO (2016) Glycine inhibits ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in postnatal rat brain. Neurochem Int 96:1–12

    Article  CAS  PubMed  Google Scholar 

  4. Carloni S, Mazzoni E, Balduini W (2004) Caspase-3 and calpain activities after acute and repeated ethanol administration during the rat brain growth spurt. J Neurochem 89(1):197–203

    Article  CAS  PubMed  Google Scholar 

  5. Kelly SJ, Goodlett CR, Hannigan JH (2009) Animal models of fetal alcohol spectrum disorders: impact of the social environment. Dev Disabil Res Rev 15(3):200–208

    Article  PubMed  PubMed Central  Google Scholar 

  6. Brocardo PS, Gil-Mohapel J, Christie BR (2011) The role of oxidative stress in fetal alcohol spectrum disorders. Brain Res Rev 67(1–2):209–225

    Article  CAS  PubMed  Google Scholar 

  7. Wang X, Michaelis EK (2010) Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2:12

    PubMed  PubMed Central  Google Scholar 

  8. Vallés SL, Blanco AM, Pascual M, Guerri C (2004) Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol 14(4):365–371

    Article  PubMed  Google Scholar 

  9. Verkhratsky A, Zorec R, Parpura V (2017) Stratification of astrocytes in healthy and diseased brain. Brain Pathol 27(5):629–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hovens IB, Nyakas C, Schoemaker RG (2014) A novel method for evaluating microglial activation using ionized calcium-binding adaptor protein-1 staining: cell body to cell size ratio. Neuroimmunol Neuroinflamm 1:82–88

    Article  Google Scholar 

  11. Boitard C, Cavaroc A, Sauvant J, Aubert A, Castanon N, Layé S et al (2014) Impairment of hippocampal-dependent memory induced by juvenile high-fat diet intake is associated with enhanced hippocampal inflammation in rats. Brain Behav Immun 40:9–17

    Article  CAS  PubMed  Google Scholar 

  12. Wright JW, Masino AJ, Reichert JR, Turner GD, Meighan SE, Meighan PC et al (2003) Ethanol-induced impairment of spatial memory and brain matrix metalloproteinases. Brain Res 963(1–2):252–261

    Article  CAS  PubMed  Google Scholar 

  13. Gil-Mohapel J, Boehme F, Kainer L, Christie BR (2010) Hippocampal cell loss and neurogenesis after fetal alcohol exposure: insights from different rodent models. Brain Res Rev 64(2):283–303

    Article  CAS  PubMed  Google Scholar 

  14. Miki T, Harris SJ, Wilce PA, Takeuchi Y, Bedi KS (2004) Effects of age and alcohol exposure during early life on pyramidal cell numbers in the CA1–CA3 region of the rat hippocampus. Hippocampus 14(1):124–134

    Article  CAS  PubMed  Google Scholar 

  15. Safakhah HA, Taghavi T, Rashidy-Pour A, Vafaei AA, Sokhanvar M, Mohebbi N et al (2016) Effects of saffron (Crocus sativus L.) stigma extract and its active constituent crocin on neuropathic pain responses in a rat model of chronic constriction injury. Iran J Pharm Res IJPR 15(1):253

    CAS  PubMed  Google Scholar 

  16. Mehri S, Abnous K, Mousavi SH, Shariaty VM, Hosseinzadeh H (2012) Neuroprotective effect of crocin on acrylamide-induced cytotoxicity in PC12 cells. Cell Mol Neurobiol 32(2):227–235

    Article  CAS  PubMed  Google Scholar 

  17. Ochiai T, Ohno S, Soeda S, Tanaka H, Shoyama Y, Shimeno H (2004) Crocin prevents the death of rat pheochromyctoma (PC-12) cells by its antioxidant effects stronger than those of α-tocopherol. Neurosci Lett 362(1):61–64

    Article  CAS  PubMed  Google Scholar 

  18. Ochiai T, Shimeno H, Mishima K-I, Iwasaki K, Fujiwara M, Tanaka H et al (2007) Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochimica et Biophysica Acta (BBA) 1770(4):578–584

    Article  CAS  Google Scholar 

  19. Papandreou MA, Kanakis CD, Polissiou MG, Efthimiopoulos S, Cordopatis P, Margarity M et al (2006) Inhibitory activity on amyloid-β aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents. J Agric Food Chem 54(23):8762–8768

    Article  CAS  PubMed  Google Scholar 

  20. Naghizadeh B, Mansouri SMT, Mashhadian NV (2010) Crocin attenuates cisplatin-induced renal oxidative stress in rats. Food Chem Toxicol 48(10):2650–2655

    Article  CAS  PubMed  Google Scholar 

  21. Soeda S, Ochiai T, Paopong L, Tanaka H, Shoyama Y, Shimeno H (2001) Crocin suppresses tumor necrosis factor-α-induced cell death of neuronally differentiated PC-12 cells. Life Sci 69(24):2887–2898

    Article  CAS  PubMed  Google Scholar 

  22. Shafahi M, Vaezi G, Shajiee H, Sharafi S, Khaksari M (2018) Crocin inhibits apoptosis and astrogliosis of hippocampus neurons against methamphetamine neurotoxicity via antioxidant and anti-inflammatory mechanisms. Neurochem Res 43(12):2252–2259

    Article  CAS  PubMed  Google Scholar 

  23. West JR, Hamre KM, Pierce DR (1984) Delay in brain growth induced by alcohol in artificially reared rat pups. Alcohol (Fayetteville, NY) 1(3):213–222

    Article  CAS  Google Scholar 

  24. Toosi A, Shajiee H, Khaksari M, Vaezi G, Hojati V (2019) Obestatin improve spatial memory impairment in a rat model of fetal alcohol spectrum disorders via inhibiting apoptosis and neuroinflammation. Neuropeptides 74:88–94

    Article  CAS  PubMed  Google Scholar 

  25. Zare Mehrjerdi F, Shoshtari A, Mohseni F, Khastar H, Norozi P, Asadi Y et al (2018) Sulfur dioxide reduces hippocampal cells death and improves learning and memory deficits in rat model of transient global ischemia/reperfusion. Iran J Basic Med Sci 21(10):998–1003

    PubMed  PubMed Central  Google Scholar 

  26. Erfani S, Moghimi A, Aboutaleb N, Khaksari M (2019) Protective effects of Nesfatin-1 peptide on cerebral ischemia reperfusion injury via inhibition of neuronal cell death and enhancement of antioxidant defenses. Metab Brain Dis 34(1):79–85

    Article  CAS  PubMed  Google Scholar 

  27. Ghanbari F, Khaksari M, Vaezi G, Hojati V, Shiravi A (2019) Hydrogen sulfide protects hippocampal neurons against methamphetamine neurotoxicity via inhibition of apoptosis and neuroinflammation. J Mol Neurosci 67(1):133–141

    Article  CAS  PubMed  Google Scholar 

  28. Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates: hard cover edition. Academic Press, Cambridge

    Google Scholar 

  29. Mohseni F, Garmabi B, Khaksari M (2021) Apelin-13 attenuates spatial memory impairment by anti-oxidative, anti-apoptosis, and anti-inflammatory mechanism against ethanol neurotoxicity in the neonatal rat hippocampus. Neuropeptides 87:102130

    Article  CAS  PubMed  Google Scholar 

  30. Marino MD, Cronise K, Lugo JN Jr, Kelly SJ (2002) Ultrasonic vocalizations and maternal–infant interactions in a rat model of fetal alcohol syndrome. Dev Psychobiol J Int Soc Dev Psychobiol 41(4):341–351

    Article  Google Scholar 

  31. Shah SA, Yoon GH, Kim MO (2015) Protection of the developing brain with anthocyanins against ethanol-induced oxidative stress and neurodegeneration. Mol Neurobiol 51(3):1278–1291

    Article  CAS  PubMed  Google Scholar 

  32. Swart PC, Currin CB, Russell VA, Dimatelis JJ (2017) Early ethanol exposure and vinpocetine treatment alter learning-and memory-related proteins in the rat hippocampus and prefrontal cortex. J Neurosci Res 95(5):1204–1215

    Article  CAS  PubMed  Google Scholar 

  33. Riley EP, McGee CL (2005) Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain and behavior. Exp Biol Med 230(6):357–365

    Article  CAS  Google Scholar 

  34. Lopatynska-Mazurek M, Komsta L, Gibula-Tarlowska E, Kotlinska JH (2021) Aversive learning deficits and depressive-like behaviors are accompanied by an increase in oxidative stress in a rat model of fetal alcohol spectrum disorders: the protective effect of rapamycin. Int J Mol Sci 22(13):7083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rasmussen C (2005) Executive functioning and working memory in fetal alcohol spectrum disorder. Alcohol Clin Exp Res 29(8):1359–1367

    Article  PubMed  Google Scholar 

  36. Tran TD, Cronise K, Marino MD, Jenkins WJ, Kelly SJ (2000) Critical periods for the effects of alcohol exposure on brain weight, body weight, activity and investigation. Behav Brain Res 116(1):99–110

    Article  CAS  PubMed  Google Scholar 

  37. Pascual M, Blanco AM, Cauli O, Miñarro J, Guerri C (2007) Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur J Neurosci 25(2):541–550

    Article  PubMed  Google Scholar 

  38. Komada M, Hara N, Kawachi S, Kawachi K, Kagawa N, Nagao T et al (2017) Mechanisms underlying neuro-inflammation and neurodevelopmental toxicity in the mouse neocortex following prenatal exposure to ethanol. Sci Rep 7(1):1–12

    Article  CAS  Google Scholar 

  39. Gong J, Mullins CB (2008) Selective oxidation of ethanol to acetaldehyde on gold. J Am Chem Soc 130(49):16458–16459

    Article  CAS  PubMed  Google Scholar 

  40. Crews F, Nixon K, Kim D, Joseph J, Shukitt-Hale B, Qin L et al (2006) BHT blocks NF-κB activation and ethanol-induced brain damage. Alcohol Clin Exp Res 30(11):1938–1949

    Article  CAS  PubMed  Google Scholar 

  41. Zelová H, Hošek J (2013) TNF-α signalling and inflammation: interactions between old acquaintances. Inflamm Res 62(7):641–651

    Article  PubMed  Google Scholar 

  42. Moreno E, Yan M, Basler K (2002) Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. Curr Biol 12(14):1263–1268

    Article  CAS  PubMed  Google Scholar 

  43. Kempuraj D, Thangavel R, Natteru P, Selvakumar G, Saeed D, Zahoor H et al (2016) Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine 1(1):1003

    PubMed  PubMed Central  Google Scholar 

  44. Lee YW, Hennig B, Yao J, Toborek M (2001) Methamphetamine induces AP-1 and NF-κB binding and transactivation in human brain endothelial cells. J Neurosci Res 66(4):583–591

    Article  CAS  PubMed  Google Scholar 

  45. Zeng T, Zhang C-L, Zhao N, Guan M-J, Xiao M, Yang R et al (2018) Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved in chronic ethanol-induced fatty liver. Redox Biol 14:295–304

    Article  CAS  PubMed  Google Scholar 

  46. Brooks PJ (1997) DNA damage, DNA repair, and alcohol toxicity—a review. Alcohol Clin Exp Res 21(6):1073–1082

    CAS  PubMed  Google Scholar 

  47. Kadiiska M, Gladen B, Baird D, Germolec D, Graham L, Parker C et al (2005) Biomarkers of oxidative stress study II: are oxidation products of lipids, proteins, and DNA markers of CCl4 poisoning? Free Radical Biol Med 38(6):698–710

    Article  CAS  Google Scholar 

  48. Brocardo PS, Gil-Mohapel J, Wortman R, Noonan A, McGinnis E, Patten AR et al (2017) The effects of ethanol exposure during distinct periods of brain development on oxidative stress in the adult rat brain. Alcohol Clin Exp Res 41(1):26–37

    Article  CAS  PubMed  Google Scholar 

  49. Heaton MB, Paiva M, Madorsky I, Mayer J, Moore DB (2003) Effects of ethanol on neurotrophic factors, apoptosis-related proteins, endogenous antioxidants, and reactive oxygen species in neonatal striatum: relationship to periods of vulnerability. Dev Brain Res 140(2):237–252

    Article  CAS  Google Scholar 

  50. Mehri S, Abnous K, Khooei A, Mousavi SH, Shariaty VM, Hosseinzadeh H (2015) Crocin reduced acrylamide-induced neurotoxicity in Wistar rat through inhibition of oxidative stress. Iran J Basic Med Sci 18(9):902

    PubMed  PubMed Central  Google Scholar 

  51. Asadi F, Jamshidi AH, Khodagholi F, Yans A, Azimi L, Faizi M et al (2015) Reversal effects of crocin on amyloid β-induced memory deficit: modification of autophagy or apoptosis markers. Pharmacol Biochem Behav 139:47–58

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran

    Lida Farhadi, Vida Hojati & Golamhassan Vaezi

  2. Addiction Research Center, Shahroud University of Medical Sciences, Shahroud, Iran

    Mehdi Khaksari

Authors
  1. Lida Farhadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vida Hojati
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mehdi Khaksari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Golamhassan Vaezi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mehdi Khaksari.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Farhadi, L., Hojati, V., Khaksari, M. et al. Neuroprotective Effects of Crocin Against Ethanol Neurotoxicity in the Animal Model of Fetal Alcohol Spectrum Disorders. Neurochem Res 47, 1001–1011 (2022). https://doi.org/10.1007/s11064-021-03501-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-021-03501-z

Keywords

Search

Navigation