Advertisement
Research Article| Volume 32, ISSUE 3, 106945, March 2023

Caryocar brasiliense peel ethanolic extract has neuroprotective potential and reduces the activation of ERK1/2 in the ischemia and reperfusion brain acute phase in the rat

      Highlights

      • CBPE reduces ischemic cortical neurons of rats subject to ischemia and reperfusion;
      • CBPE reduces glial cell apoptotic activation after ischemia and reperfusion injury;
      • CBPE reduces neuronal ERK 1/2 activation after ischemia and reperfusion injury.

      Abstract

      Oxidative stress induced by ischemia and reperfusion (I/R) injury results in cell death by necrosis or apoptosis and triggers the activation of different intracellular pathways, such as mitogen-activated protein activated kinases. Pequi (Caryocar brasiliense) peel, residue of a fruit from Brazilian savannah-like vegetation, has phenolic compounds that have been demonstrated to have antioxidant effects in vitro. The present study aimed to evaluate the neuroprotective effects of C. brasiliense peel ethanolic extract (CBPE) against transient global I/R injury in the rat brain. Global ischemia for 5, 20, and 45 min followed by 2 h of reperfusion caused a significant time-dependent increase in the number of ischemic neurons (p ≤ 0.05); increased immunoreactivity of cleaved caspase-3 (CASP3); and activated extracellular signal-regulated kinase (ERK) 1/2. Pretreatment with CBPE (600 mg/kg, oral) or vitamin E (0.6 mg, oral) for 30 days showed significant protection against acute brain injury induced by 20 and 45 min or 5 min of ischemia, respectively, by reducing the cortical ischemic neuron count (p ≤ 0.05) and p-ERK1/2 immunoreactivity. In addition, active c-Jun N-terminal kinase (JNK) immunoreactivity was reduced in animals not subjected to ischemia. Therefore, we suggest an association between vitamin E and CBPE, which may generate a better neuroprotective response. Interestingly, mainly in the hippocampus and oligodendrocytes, high dose CBPE increase the number of isquemic neurons and of CASP3 immunoreactive cells in animals subjected or not to ischemia, which was not verified in the vitamin E group. Therefore, additional studies are recommended to verify the safety of the continuous use of CBPE.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Stroke and Cerebrovascular Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Benjamin E.J.
        • Virani S.S.
        • Callaway C.W.
        • Chamberlain A.M.
        • Chang A.R.
        • Cheng S.
        • Chiuve S.E.
        • Cushman M.
        • Delling F.N.
        • Deo R.
        • De Ferranti S.D.
        • Ferguson J.F.
        • Fornage M.
        • Gillespie C.
        • Isasi C.R.
        • Jiménez M.C.
        • Jordan L.C.
        • Judd S.E.
        • Lackland D.
        • Lichtman J.H.
        • Lisabeth L.
        • Liu S.
        • Longenecker C.T.
        • Lutsey P.L.
        • MacKey J.S.
        • Matchar D.B.
        • Matsushita K.
        • Mussolino M.E.
        • Nasir K.
        • O'Flaherty M.
        • Palaniappan L.P.
        • Pandey A.
        • Pandey D.K.
        • Reeves M.J.
        • Ritchey M.D.
        • Rodriguez C.J.
        • Roth G.A.
        • Rosamond W.D.
        • Sampson U.K.A.
        • Satou G.M.
        • Shah S.H.
        • Spartano N.L.
        • Tirschwell D.L.
        • Tsao C.W.
        • Voeks J.H.
        • Willey J.Z.
        • Wilkins J.T.
        • Wu J.H.Y.
        • Alger H.M.
        • Wong S.S.
        • Muntner P.
        Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association.
        Circulation. 2018; 137: E67-E492https://doi.org/10.1161/CIR.0000000000000558
        • Chu C.T.
        • Levinthal D.J.
        • Kulich S.M.
        • Chalovich E.M.
        • DeFranco D.B.
        Oxidative neuronal injury. The dark side of ERK1/2.
        Eur J Biochem. 2004; 271: 2060-2066https://doi.org/10.1111/J.1432-1033.2004.04132.X
        • Colbourne F.
        • Auer R.N.
        Transient Global Cerebral Ischemia Produces Morphologically Necrotic, Not Apoptotic Neurons.
        Acute Neuronal Inj Role Excit Program Cell Death Mech. 2010; : 121-130https://doi.org/10.1007/978-0-387-73226-8_8
        • Conroy B.P.
        • Grafe M.R.
        • Jenkins L.W.
        • Vela A.H.
        • Lin C.Y.
        • DeWitt D.S.
        • Johnston W.E.
        Histopathologic consequences of hyperglycemic cerebral ischemia during hypothermic cardiopulmonary bypass in pigs.
        Ann Thorac Surg. 2001; 71: 1325-1334https://doi.org/10.1016/S0003-4975(01)02401-8
        • De Lima A.
        • Silva A.M.D.O.
        • Trindade R.A.
        • Torres R.P.
        • Mancini-Filho J.
        Composição química e compostos bioativos presentes na polpa e na amêndoa do pequi (Caryocar brasiliense, Camb.).
        Rev Bras Frutic. 2007; 29: 695-698https://doi.org/10.1590/S0100-29452007000300052
        • Fujikawa D.G.
        The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus.
        Brain Res. 1996; 725: 11-22https://doi.org/10.1016/0006-8993(96)00203-X
        • Fujikawa D.G.
        • Shinmei S.S.
        • Cai B.
        Kainic acid-induced seizures produce necrotic, not apoptotic, neurons with internucleosomal DNA cleavage: implications for programmed cell death mechanisms.
        Neuroscience. 2000; 98: 41-53https://doi.org/10.1016/S0306-4522(00)00085-3
        • Gao K.
        • Liu M.
        • Ding Y.
        • Yao M.
        • Zhu Y.
        • Zhao J.
        • Cheng L.
        • Bai J.
        • Wang F.
        • Cao J.
        • Li J.
        • Tang H.
        • Jia Y.
        • Wen A.
        A phenolic amide (LyA) isolated from the fruits of Lycium barbarum protects against cerebral ischemia-reperfusion injury via PKCε/Nrf2/HO-1 pathway.
        Aging (Albany NY). 2019; 11: 12361-12374https://doi.org/10.18632/AGING.102578
        • Gauberti M.
        • Lapergue B.
        • De Lizarrondo S.M.
        • Vivien D.
        • Richard S.
        • Bracard S.
        • Piotin M.
        • Gory B.
        Ischemia-Reperfusion Injury After Endovascular Thrombectomy for Ischemic Stroke.
        Stroke. 2018; 49: 3071-3074https://doi.org/10.1161/STROKEAHA.118.022015
        • Jiang Q.
        Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy. Free Radic.
        Biol Med. 2014; 72: 76-90https://doi.org/10.1016/J.FREERADBIOMED.2014.03.035
        • Khazdair M.R.
        • Anaeigoudari A.
        • Hashemzehi M.
        • Mohebbati R.
        Neuroprotective potency of some spice herbs, a literature review.
        J Tradit Complement Med. 2019; 9: 98-105https://doi.org/10.1016/J.JTCME.2018.01.002
        • Khoshnam S.E.
        • Winlow W.
        • Farzaneh M.
        • Farbood Y.
        • Moghaddam H.F.
        Pathogenic mechanisms following ischemic stroke.
        Neurol Sci. 2017; 38 (2017 387): 1167-1186https://doi.org/10.1007/S10072-017-2938-1
        • Khouri J.
        • Resck I.S.
        • Poças-Fonseca M.
        • Sousa T.M.M.
        • Pereira L.O.
        • Oliveira A.B.B.
        • Grisolia C.K.
        Anticlastogenic potential and antioxidant effects of an aqueous extract of pulp from the pequi tree (Caryocar brasiliense Camb).
        Genet Mol Biol. 2007; 30: 442-448https://doi.org/10.1590/S1415-47572007000300024
        • Kim Y.C.
        Neuroprotective phenolics in medicinal plants.
        Arch Pharm Res. 2010; 33: 1611-1632https://doi.org/10.1007/S12272-010-1011-X
        • Lee R.H.C.
        • Lee M.H.H.
        • Wu C.Y.C.
        • Couto E Silva A.
        • Possoit H.E.
        • Hsieh T.H.
        • Minagar A.
        • Lin H.W.
        Cerebral ischemia and neuroregeneration.
        Neural Regen Res. 2018; 13: 373-385https://doi.org/10.4103/1673-5374.228711
        • Lennmyr F.
        • Karlsson S.
        • Gerwins P.
        • Ata K.A.
        • Terént A.
        Activation of mitogen-activated protein kinases in experimental cerebral ischemia.
        Acta Neurol Scand. 2002; 106: 333-340https://doi.org/10.1034/J.1600-0404.2002.01313.X
        • Li J.
        • Han B.
        • Ma X.
        • Qi S.
        The effects of propofol on hippocampal caspase-3 and Bcl-2 expression following forebrain ischemia-reperfusion in rats.
        Brain Res. 2010; 1356: 11-23https://doi.org/10.1016/J.BRAINRES.2010.08.012
        • Liu Q.
        • Gonzales R.J.
        Targeting mitogen-activated protein kinase in acute ischaemic stroke.
        Acta Physiol. 2017; 219: 712-714https://doi.org/10.1111/APHA.12848
        • Maddahi A.
        • Edvinsson L.
        Cerebral ischemia induces microvascular pro-inflammatory cytokine expression via the MEK/ERK pathway.
        J Neuroinflammation. 2010; 7https://doi.org/10.1186/1742-2094-7-14
        • Mandalaneni K.
        • Rayi A.
        • Jillella D.V.
        Stroke Reperfusion Injury.
        StatPearls, 2021
        • Massieu L.
        • Morán J.
        • Christen Y.
        Effect of Ginkgo biloba (EGb 761) on staurosporine-induced neuronal death and caspase activity in cortical cultured neurons.
        Brain Res. 2004; 1002: 76-85https://doi.org/10.1016/J.BRAINRES.2003.12.018
        • Mostajeran M.
        • Edvinsson L.
        • Warfvinge K.
        • Singh R.
        • Ansar S.
        Inhibition of mitogen-activated protein kinase 1/2 in the acute phase of stroke improves long-term neurological outcome and promotes recovery processes in rats.
        Acta Physiol (Oxf). 2017; 219: 814-824https://doi.org/10.1111/APHA.12632
        • Nascimento-Silva N.R.R.Do
        • Naves M.M.V.
        Potential of Whole Pequi (Caryocar spp.) Fruit-Pulp, Almond, Oil, and Shell-as a Medicinal Food.
        J Med Food. 2019; 22: 952-962https://doi.org/10.1089/JMF.2018.0149
        • Passos X.S.
        • Da Costa Santos S.
        • Ferri P.H.
        • De Fátima Lisboa Fernandes O.
        • De Freitas Paula T.
        • Ferreira Garcia A.C.
        • Rodrigues Silva M.do R.
        Atividade antifúngica de Caryocar brasiliensis (Caryocaraceae) sobre Cryptococcus neoformans.
        Rev Soc Bras Med Trop. 2002; 35: 623-627https://doi.org/10.1590/S0037-86822002000600013
        • Plotnikov M.B.
        • Chernysheva G.A.
        • Aliev O.I.
        • Smol'iakova V.I.
        • Fomina T.I.
        • Osipenko A.N.
        • Rydchenko V.S.
        • Anfinogenova Y.J.
        • Khlebnikov A.I.
        • Schepetkin I.A.
        • Atochin D.N.
        Protective Effects of a New C-Jun N-terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats.
        Molecules. 2019; 24https://doi.org/10.3390/MOLECULES24091722
        • Qi J.P.
        • Wu A.P.
        • Wang D.S.
        • Wang L.F.
        • Li S.X.
        • Xu F.L.
        Correlation between neuronal injury and Caspase23 after focal ischemia in human hippocampus.
        Chinese Medical Journal. 2004; 117: 1507-1512
        • Raval A.P.
        • Liu C.
        • Hu B.R.
        Rat Model of Global Cerebral Ischemia: The Two-Vessel Occlusion (2VO) Model of Forebrain Ischemia.
        Anim Model Acute Neurol Inj. 2009; : 77-86https://doi.org/10.1007/978-1-60327-185-1_7
        • Repici M.
        • Centeno C.
        • Tomasi S.
        • Forloni G.
        • Bonny C.
        • Vercelli A.
        • Borsello T.
        Time-course of c-Jun N-terminal kinase activation after cerebral ischemia and effect of D-JNKI1 on c-Jun and caspase-3 activation.
        Neuroscience. 2007; 150: 40-49https://doi.org/10.1016/J.NEUROSCIENCE.2007.08.021
        • Roesler R.
        • Malta L.G.
        • Carrasco L.C.
        • Holanda R.B.
        • Sousa C.A.S.
        • Pastore G.M.
        Atividade antioxidante de frutas do cerrado.
        Food Sci Technol. 2007; 27: 53-60https://doi.org/10.1590/S0101-20612007000100010
        • Sawe N.
        • Steinberg G.
        • Zhao H.
        Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke.
        J Neurosci Res. 2008; 86: 1659-1669https://doi.org/10.1002/JNR.21604
        • Shi K.
        • Tian D.C.
        • Li Z.G.
        • Ducruet A.F.
        • Lawton M.T.
        • Shi F.D.
        Global brain inflammation in stroke.
        Lancet Neurol. 2019; 18: 1058-1066https://doi.org/10.1016/S1474-4422(19)30078-X
        • Silva da
        • Martins da S.
        • Rosa da
        Phenolic compounds and antioxidant activity of extracts of pequi peel (Caryocar brasiliense Camb.). Int.
        Food Res J. 2015; 22: 1985-1992
        • Souza M.R.
        • de Carvalho R.K.
        • de Carvalho L.S.
        • de Sá S.
        • Andersen M.L.
        • de Araújo E.G.
        • Mazaro-Costa R.
        Effects of subchronic exposure to Caryocar brasiliense peel ethanolic extract on male reproductive functions in Swiss mice.
        Reprod Toxicol. 2019; 87: 118-124https://doi.org/10.1016/J.REPROTOX.2019.06.004
        • Sugino T.
        • Nozaki K.
        • Takagi Y.
        • Hattori I.
        • Hashimoto N.
        • Moriguchi T.
        • Nishida E.
        Activation of mitogen-activated protein kinases after transient forebrain ischemia in gerbil hippocampus.
        J Neurosci. 2000; 20: 4506-4514https://doi.org/10.1523/JNEUROSCI.20-12-04506.2000
        • Sun J.
        • Nan G.
        The Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway as a Discovery Target in Stroke.
        J Mol Neurosci. 2016; 59: 90-98https://doi.org/10.1007/S12031-016-0717-8
        • Wahlgren N.
        • Moreira T.
        • Michel P.
        • Steiner T.
        • Jansen O.
        • Cognard C.
        • Mattle H.P.
        • van Zwam W.
        • Holmin S.
        • Tatlisumak T.
        • Petersson J.
        • Caso V.
        • Hacke W.
        • Mazighi M.
        • Arnold M.
        • Fischer U.
        • Szikora I.
        • Pierot L.
        • Fiehler J.
        • Gralla J.
        • Fazekas F.
        • Lees K.R.
        Mechanical thrombectomy in acute ischemic stroke: Consensus statement by ESO-Karolinska Stroke Update 2014/2015, supported by ESO, ESMINT, ESNR and EAN.
        Int J Stroke. 2016; 11: 134-147https://doi.org/10.1177/1747493015609778
        • Yamaguchi K.K.L.
        • Lamarão C.V.
        • Aranha E.S.P.
        • Souza R.O.S.
        • Oliveira P.D.A.
        • Vasconcellos M.C.
        • Lima E.S.
        • Veiga-Junior V.F.
        HPLC-DAD profile of phenolic compounds, cytotoxicity, antioxidant and anti-inflammatory activities of the amazon fruit Caryocar villosum.
        Quim Nova. 2017; 40: 483-490https://doi.org/10.21577/0100-4042.20170028
        • Zheng J.
        • Dai Q.
        • Han K.
        • Hong W.
        • Jia D.
        • Mo Y.
        • Lv Y.
        • Tang H.
        • Fu H.
        • Geng W.
        JNK-IN-8, a c-Jun N-terminal kinase inhibitor, improves functional recovery through suppressing neuroinflammation in ischemic stroke.
        J Cell Physiol. 2020; 235: 2792-2799https://doi.org/10.1002/JCP.29183
        • Zingg J.M.
        Vitamin E: Regulatory Role on Signal Transduction.
        IUBMB Life. 2019; 71: 456-478https://doi.org/10.1002/IUB.1986