Abstract
Rationale
Cortical and hippocampal neuronal apoptosis and neuroinflammation are associated with behavioral deficits following traumatic brain injury (TBI).
Objectives
The present study was designed to investigate the potential protective effects of flavonoid chrysin against TBI-induced vestibulomotor impairment, exploratory/locomotor dysfunctions, recognition memory decline, and anxiety/depression-like behaviors, as well as the verified possible involved mechanisms.
Methods
Chrysin (25, 50, or 100 mg/kg/day; P.O.) was administered to rats immediately after diffuse TBI induction, and it was continued for 3 or 14 days. Behavioral functions were assessed by employing standard behavioral paradigms at scheduled points in time. Three days post-TBI, inflammation status was assayed in both cerebral cortex and hippocampus using ELISA kits. Moreover, apoptosis and expression of Bcl-2 family proteins were examined by TUNEL staining and immunohistochemistry, respectively.
Results
The results indicated that treatment with chrysin improved vestibulomotor dysfunction, ameliorated recognition memory deficit, and attenuated anxiety/depression-like behaviors in the rats with TBI. Chrysin treatment also modulated inflammation status, reduced apoptotic index, and regulated Bcl-2 family proteins expression in the brains of rats with TBI.
Conclusions
In conclusion, the results suggest that chrysin could be beneficial for protection against TBI-associated behavioral deficits, owing to its anti-apoptotic and anti-inflammatory properties.
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Change history
22 April 2023
A Correction to this paper has been published: https://doi.org/10.1007/s00213-023-06359-x
References
Alderfer BS, Arciniegas DB, Silver JM (2005) Treatment of depression following traumatic brain injury. J Head Trauma Rehabil 20:544–562
Almeida-Suhett CP, Prager EM, Pidoplichko V, Figueiredo TH, Marini AM, Li Z, Eiden LE, Braga MF (2014) Reduced GABAergic inhibition in the basolateral amygdala and the development of anxiety-like behaviors after mild traumatic brain injury. PLoS One 9:e102627
Anand KV, Anandhi R, Pakkiyaraj M, Geraldine P (2011) Protective effect of chrysin on carbon tetrachloride (CCl4)—induced tissue injury in male Wistar rats. Toxicol Ind Health 27:923–933
Arciniegas DB, Silver JM (2006) Pharmacotherapy of posttraumatic cognitive impairments. Behav Neurol 17:25–42
Arciniegas DB, Anderson CA, Topkoff J, McAllister TW (2005) Mild traumatic brain injury: a neuropsychiatric approach to diagnosis, evaluation, and treatment. Neuropsychiatr Dis Treat 1(4):311–327
Baratz R, Tweedie D, Rubovitch V, Luo W, Yoon JS, Hoffer BJ, Greig NH, Pick CG (2011) Tumor necrosis factor-α synthesis inhibitor, 3, 6′-dithiothalidomide, reverses behavioral impairments induced by minimal traumatic brain injury in mice. J Neurochem 118:1032–1042
Barha CK, Ishrat T, Epp JR, Galea LA, Stein DG (2011) Progesterone treatment normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus after traumatic brain injury. Exp Neurol 231:72–81
Barker GR, Warburton EC (2011) When is the hippocampus involved in recognition memory? J Neurosci 31:10721–10731
Borges Filho C, Jesse CR, Donato F, Del Fabbro L, de Gomes MG, Goes ATR, Souza LC, Boeira SP (2016) Chrysin promotes attenuation of depressive-like behavior and hippocampal dysfunction resulting from olfactory bulbectomy in mice. Chem Biol Interact 260:154–162
Broadbent NJ, Gaskin S, Squire LR, Clark RE (2010) Object recognition memory and the rodent hippocampus. Learn Mem 17:5–11
Brown E, Hurd NS, McCall S, Ceremuga TE (2007) Evaluation of the anxiolytic effects of chrysin, a Passiflora incarnata extract, in the laboratory rat. AANA J 75:333–337
Cernak I, Chapman SM, Hamlin GP, Vink R (2002) Temporal characterisation of pro-and anti-apoptotic mechanisms following diffuse traumatic brain injury in rats. J Clin Neurosci 9:565–572
Cheng T, Wang W, Li Q, Han X, Xing J, Qi C, Lan X, Wan J, Potts A, Guan F, Wang J (2016) Cerebroprotection of flavanol (−)-epicatechin after traumatic brain injury via Nrf2-dependent and-independent pathways. Free Radic Biol Med 92:15–28
Chua KS, Ng Y-S, Yap SG, Bok CW (2007) A brief review of traumatic brain injury rehabilitation. Ann Acad Med Singapore 36:31
Daumas S, Halley H, Francés B, Lassalle J-M (2005) Encoding, consolidation, and retrieval of contextual memory: differential involvement of dorsal CA3 and CA1 hippocampal subregions. Learn Mem 12:375–382
DeKosky ST, Blennow K, Ikonomovic MD, Gandy S (2013) Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers. Nat Rev Neurol. 9:192
El Khashab IH, Abdelsalam RM, Elbrairy AI, Attia AS (2019) Chrysin attenuates global cerebral ischemic reperfusion injury via suppression of oxidative stress, inflammation and apoptosis. Biomed Pharmacother 112:108619
Ennaceur A, Neave N, Aggleton JP (1997) Spontaneous object recognition and object location memory in rats: the effects of lesions in the cingulate cortices, the medial prefrontal cortex, the cingulum bundle and the fornix. Exp Brain Res 113:509–519
Farbood Y, Rashno M, Ghaderi S, Khoshnam SE, Sarkaki A, Rashidi K, Rashno M, Badavi M (2019) Ellagic acid protects against diabetes-associated behavioral deficits in rats: Possible involved mechanisms. Life Sci 225:8–19
Filho CB, Jesse CR, Donato F, Giacomeli R, Del Fabbro L, Antunes MS, Gomes MG, Goes ATR, Boeira SP, Prigol M, Souza LC (2015) Chronic unpredictable mild stress decreases BDNF and NGF levels and Na+,K+ATPase activity in the hippocampus and prefrontal cortex of mice: antidepressant effect of chrysin. Neuroscience 268:367–380
Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629
Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312
Griffiths S, Scott H, Glover C, Bienemann A, Ghorbel MT, Uney J, Brown MW, Warburton EC, Bashir ZI (2008) Expression of long-term depression underlies visual recognition memory. Neuron 58:186–194
Guo B, Zheng C, Cai W, Cheng J, Wang H, Li H, Sun Y, Cui W, Wang Y, Han Y, Zhang Z (2016) Multifunction of chrysin in Parkinson’s model: anti-neuronal apoptosis, neuroprotection via activation of MEF2D, and inhibition of monoamine oxidase-B. J Agric Food Chem 64:5324–5333
Gupta S (2002) A decision between life and death during TNF-α-induced signaling. J Clin Immunol 22:185–194
Habr SF, Bernardi MM, Conceição IM, Freitas TA, Felicio LF (2011) Open field behavior and intra-nucleus accumbens dopamine release in vivo in virgin and lactating rats. Psychol Neurosci 4:115–121
Hardman JM, Manoukian A (2002) Pathology of head trauma. Neuroimaging Clin N Am 12(175–87):vii
Hicks R, Smith D, Lowenstein D, MARIE RS, McIntosh TK (1993) Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. J Neurotrauma 10:405–414
Jiang Y, Gong F-L, Zhao G-B, Li J (2014) Chrysin suppressed inflammatory responses and the inducible nitric oxide synthase pathway after spinal cord injury in rats. Int J Mol Sci 15:12270–12279
Kamm K, VanderKolk W, Lawrence C, Jonker M, Davis AT (2006) The effect of traumatic brain injury upon the concentration and expression of interleukin-1β and interleukin-10 in the rat. J Trauma 60:152–157
Kosari-Nasab M, Shokouhi G, Ghorbanihaghjo A, Abbasi MM, Salari A-A (2018a) Hesperidin attenuates depression-related symptoms in mice with mild traumatic brain injury. Life Sci. 213:198–205
Kosari-Nasab M, Shokouhi G, Ghorbanihaghjo A, Abbasi MM, Salari A-A (2018b) Anxiolytic-and antidepressant-like effects of Silymarin compared to diazepam and fluoxetine in a mouse model of mild traumatic brain injury. Toxicol Appl Pharmacol 338:159–173
Krishnamoorthy A, Sevanan M, Mani S, Balu M, Balaji S, Ramajayan P (2019) Chrysin restores MPTP induced neuroinflammation, oxidative stress and neurotrophic factors in an acute Parkinson’s disease mouse model. Neurosci Lett 709:134382
Lim S-W, Sung K-C, Shiue Y-L, Wang C-C, Chio C-C, Kuo J-R (2017) Hyperbaric oxygen effects on depression-like behavior and neuroinflammation in traumatic brain injury rats. World Neurosurg 100:128–137
Liu H, Rose ME, Culver S, Ma X, Dixon CE, Graham SH (2016) Rosiglitazone attenuates inflammation and CA3 neuronal loss following traumatic brain injury in rats. Biochem Biophys Res Commun 472:648–655
Lucas SM, Rothwell NJ, Gibson RM (2006) The role of inflammation in CNS injury and disease. Br J Pharmacol 147:S232–S240
Marmarou A, Foda MAA-E, Van Den Brink W, Campbell J, Kita H, Demetriadou K (1994) A new model of diffuse brain injury in rats: Part I: Pathophysiology and biomechanics. J Neurosurg 80:291–300
McQuade JMS, Vorhees CV, Xu M, Zhang J (2002) DNA fragmentation factor 45 knockout mice exhibit longer memory retention in the novel object recognition task compared to wild-type mice. Physiol Behav 76:315–320
Mitkovski M, Dahm L, Heinrich R, Monnheimer M, Gerhart S, Stegmüller J, Hanisch U-K, Nave K-A, Ehrenreich H (2015) Erythropoietin dampens injury-induced microglial motility. J Cereb Blood Flow Metab 35:1233–1236
Mychasiuk R, Hehar H, Candy S, Ma I, Esser M (2016) The direction of the acceleration and rotational forces associated with mild traumatic brain injury in rodents effect behavioural and molecular outcomes. J Neurosci Methods 257:168–178
Ng C-F, Ko C-H, Koon C-M, Chin W-C, Kwong HCST, Lo AW-I, Wong H-L, Fung K-P, Bik-San Lau C, Lam P-K, Poon WS, Leung PC (2016) The aqueous extract of rhizome of Gastrodia elata Blume attenuates locomotor defect and inflammation after traumatic brain injury in rats. J Ethnopharmacol. 185:87–95
Pavlides C, Miyashita E, Asanuma H (1993) Projection from the sensory to the motor cortex is important in learning motor skills in the monkey. J Neurophysiol. 70:733–741
Pawlak A, Gładkowski W, Kutkowska J, Mazur M, Obmińska-Mrukowicz B, Rapak A (2018) Enantiomeric trans β-aryl-δ-iodo-γ-lactones derived from 2, 5-dimethylbenzaldehyde induce apoptosis in canine lymphoma cell lines by downregulation of anti-apoptotic Bcl-2 family members Bcl-xL and Bcl-2. Bioorg Med Chem Lett 28:1171–1177
Rao JS, Kellom M, Kim H-W, Rapoport SI (2012) Neuroinflammation and synaptic loss. Neurochem Res 37:903–910
Rashno M, Sarkaki A, Farbood Y, Rashno M, Khorsandi L, Naseri MKG, Dianat M (2019) Therapeutic effects of chrysin in a rat model of traumatic brain injury: a behavioral, biochemical, and histological study. Life Sci 228:285–294
Rimel RW, Giordani B, Barth JT, Boll TJ, Jane JA (1981) Disability caused by minor head injury. Neurosurgery 9:221–228
Sarkaki A, Farbood Y, Mansouri SMT, Badavi M, Khorsandi L, Dehcheshmeh MG, Shooshtari MK (2019) Chrysin prevents cognitive and hippocampal long-term potentiation deficits and inflammation in rat with cerebral hypoperfusion and reperfusion injury. Life Sci. 226:202–209
Schaue D, Kachikwu EL, McBride WH (2012) Cytokines in radiobiological responses: a review. Radiat Res 178:505–523
Schwab N, Tator C, Hazrati L-N (2019) DNA damage as a marker of brain damage in individuals with history of concussions. Lab Invest:1
Shi W, Zhao W, Shen A, Shao B, Wu X, Yang J, Ni L, Wu Q, Chen J (2011) Traumatic brain injury induces an up-regulation of Hs1-associated protein X-1 (Hax-1) in rat brain cortex. Neurochem Res 36:375–382
Shijo K, Ghavim S, Harris NG, Hovda DA, Sutton RL (2015) Glucose administration after traumatic brain injury exerts some benefits and no adverse effects on behavioral and histological outcomes. Brain Res 1614:94–104
Shlosberg D, Benifla M, Kaufer D, Friedman A (2010) Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 6:393
Silver JM, McAllister TW, Arciniegas DB (2009) Depression and cognitive complaints following mild traumatic brain injury. Am J Psychiatry 166:653–661
Sullivan P, Rabchevsky A, Waldmeier P, Springer JE (2005) Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death? J Neurosci Res. 79:231–239
Tabatabaei SRF, Rashno M, Ghaderi S, Askaripour M (2016) The aqueous extract of Portulaca oleracea ameliorates neurobehavioral dysfunction and hyperglycemia related to streptozotocin-diabetes induced in ovariectomized rats. Iran J Pharm Res 15:561
Tabatabaei SRF, Ghaderi S, Bahrami-Tapehebur M, Farbood Y, Rashno M (2017) Aloe vera gel improves behavioral deficits and oxidative status in streptozotocin-induced diabetic rats. Biomed Pharmacother. 96:279–290
Tao L, Li D, Liu H, Jiang F, Xu Y, Cao Y, Gao R, Chen G (2018) Neuroprotective effects of metformin on traumatic brain injury in rats associated with NF-κB and MAPK signaling pathway. Brain Res Bull 140:154–161
Thangarajan S, Ramachandran S, Krishnamurthy P (2016) Chrysin exerts neuroprotective effects against 3-Nitropropionic acid induced behavioral despair—Mitochondrial dysfunction and striatal apoptosis via upregulating Bcl-2 gene and downregulating Bax—Bad genes in male wistar rats. Biomed Pharmacother 84:514–525
Thau-Zuchman O, Shohami E, Alexandrovich AG, Trembovler V, Leker RR (2012) The anti-inflammatory drug carprofen improves long-term outcome and induces gliogenesis after traumatic brain injury. J Neurotrauma 29:375–384
Turtzo LC, Lescher J, Janes L, Dean DD, Budde MD, Frank JA (2014) Macrophagic and microglial responses after focal traumatic brain injury in the female rat. J Neuroinflammation 11:82
Villapol S, Byrnes KR, Symes AJ (2014) Temporal dynamics of cerebral blood flow, cortical damage, apoptosis, astrocyte–vasculature interaction and astrogliosis in the pericontusional region after traumatic brain injury. Front Neurol 5:82
Walker KR, Tesco G (2013) Molecular mechanisms of cognitive dysfunction following traumatic brain injury. Front Aging Neurosci 5:29
Weber JT (2012) Altered calcium signaling following traumatic brain injury. Front Pharmacol. 3:60
Wu Z, Zhang J, Nakanishi H (2005) Leptomeningeal cells activate microglia and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation. J Neuroimmunol. 167:90–98
Youdim KA, Dobbie MS, Kuhnle G, Proteggente AR, Abbott NJ, Rice-Evans C (2003) Interaction between flavonoids and the blood–brain barrier: in vitro studies. J Neurochem 85:180–192
Zhang M, Shan H, Gu Z, Wang D, Wang T, Wang Z, Tao L (2012) Increased expression of calcium/calmodulin-dependent protein kinase type II subunit delta after rat traumatic brain injury. J Mol Neurosci. 46:631–643
Zhang Z, Rasmussen L, Saraswati M, Koehler RC, Robertson C, Kannan S (2018) Traumatic injury leads to inflammation and altered tryptophan metabolism in the juvenile rabbit brain. J Neurotrauma 36:74–86
Zink BJ, Szmydynger-Chodobska J, Chodobski A (2010) Emerging concepts in the pathophysiology of traumatic brain injury. Psychiatr Clin North Am 33:741–756
Zogg CK, Haring RS, Canner JK, AlSulaim HA, Scully R, Wolf L, Engineer LD, Haider AH, Schneider EB (2016) Burden of pediatric traumatic brain injury beyond the emergency department: the untold story of the silent epidemic. Journal of the American College of Surgeons 223:S158
Acknowledgments
The authors would like to thank Mr. Baback Dadizadeh for proofreading this article.
Funding
This research was supported financially by a grant (APRC-9704) from Ahvaz Physiology Research Center, funded by the Vice Chancellor of Research, Ahvaz Jundishapur University of Medical Sciences (Iran).
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Rashno, M., Ghaderi, S., Nesari, A. et al. Chrysin attenuates traumatic brain injury-induced recognition memory decline, and anxiety/depression-like behaviors in rats: Insights into underlying mechanisms. Psychopharmacology 237, 1607–1619 (2020). https://doi.org/10.1007/s00213-020-05482-3
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DOI: https://doi.org/10.1007/s00213-020-05482-3