Abstract
Systemic injection of LPS changes neuronal excitability and increase susceptibility for convulsions. Carvacrol exerts neuroprotective and antiepileptic effects in animal models. Herein, we investigated the anticonvulsive effect of carvacrol on LPS induced seizure severity and possible involvement of the hippocampal COX-1 and -2 activities in this effect. Adult male wistar rats were used. LPS was injected (400 μg/kg; i.p.) four hours before the PTZ (80 mg/kg; i.p.) injection. Carvacrol was injected (100 mg/kg; i.p.) immediately after the LPS injection. Following the PTZ injection, behavioral seizures were observed for 30 min. Latency and duration for each stage were recorded for analysis. Rats divided into seven groups: (1) PTZ, (2) LPS + PTZ, (3) carvacrol + PTZ, (4) LPS + carvacrol + PTZ, (5) LPS, (6) carvacrol, (7) intact. At the end of the experimental procedure the hippocampus of all animals were extracted to measure COX- 1 and 2 levels using the ELISA. LPS injection four hours before the PTZ injection were significantly reduced latency to seizure stages 3–5 and increased duration of the stage 5 in compare with PTZ group (p < 0.05). Carvacrol significantly reduced these effects of LPS on seizure susceptibility (p < 0.05). However, injection of carvacrol alone before the PTZ injection did not significantly affect seizure indexes in compare with PTZ group. Additionally, LPS significantly increased hippocampal level COX-2 but not COX-1 (p < 0.01) and carvacrol significantly attenuates this effect of LPS (p < 0.001). Carvacrol prevents the proconvulsant effect of LPS possibly through the inhibition of the COX-2 increased activity.
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References
Aid S, Bosetti F (2011) Targeting cyclooxygenases-1 and -2 in neuroinflammation: therapeutic implications. Biochimie 93:46–51. https://doi.org/10.1016/j.biochi.2010.09.009
Akarsu ES, Ozdayi S, Algan E, Ulupinar F (2006) The neuronal excitability time-dependently changes after lipopolysaccharide administration in mice: possible role of cyclooxygenase-2 induction. Epilepsy Res 71:181–187. https://doi.org/10.1016/j.eplepsyres.2006.06.009
Aristatile B, Al-Assaf AH, Pugalendi KV (2013) Carvacrol suppresses the expression of inflammatory marker genes in D-galactosamine-hepatotoxic rats. Asian Pac J Trop Med 6:205–211. https://doi.org/10.1016/S1995-7645(13)60024-3
Barbalho PG, Lopes-Cendes I, Maurer-Morelli CV (2016) Indomethacin treatment prior to pentylenetetrazole-induced seizures downregulates the expression of il1b and cox2 and decreases seizure-like behavior in zebrafish larvae. BMC Neurosci 17:12. https://doi.org/10.1186/s12868-016-0246-y
Citraro R, Leo A, Marra R, De Sarro G, Russo E (2015) Antiepileptogenic effects of the selective COX-2 inhibitor etoricoxib, on the development of spontaneous absence seizures in WAG/Rij rats. Brain Res Bull 113:1–7. https://doi.org/10.1016/j.brainresbull.2015.02.004
Claycomb RJ, Hewett SJ, Hewett JA (2012) Neuromodulatory role of endogenous interleukin-1beta in acute seizures: possible contribution of cyclooxygenase-2. Neurobiol Dis 45:234–242. https://doi.org/10.1016/j.nbd.2011.08.007
Dati LM, Ulrich H, Real CC, Feng ZP, Sun HS, Britto LR (2017) Carvacrol promotes neuroprotection in the mouse hemiparkinsonian model. Neuroscience 356:176–181. https://doi.org/10.1016/j.neuroscience.2017.05.013
Deng W, Lu H, Teng J (2013) Carvacrol attenuates diabetes-associated cognitive deficits in rats. J Mol Neurosci 51:813–819. https://doi.org/10.1007/s12031-013-0069-6
Dey A, Kang X, Qiu J, Du Y, Jiang J (2016) Anti-inflammatory small molecules to treat seizures and epilepsy: from bench to bedside. Trends Pharmacol Sci 37:463–484. https://doi.org/10.1016/j.tips.2016.03.001
Engblom D, Ek M, Saha S, Ericsson-Dahlstrand A, Jakobsson PJ, Blomqvist A (2002) Prostaglandins as inflammatory messengers across the blood-brain barrier. J Mol Med (Berl) 80:5–15. https://doi.org/10.1007/s00109-001-0289-z
Font-Nieves M et al (2012) Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes. J Biol Chem 287:6454–6468. https://doi.org/10.1074/jbc.M111.327874
Ho YH, Lin YT, Wu CW, Chao YM, Chang AY, Chan JY (2015) Peripheral inflammation increases seizure susceptibility via the induction of neuroinflammation and oxidative stress in the hippocampus. J Biomed Sci 22:46. https://doi.org/10.1186/s12929-015-0157-8
Holtman L, van Vliet EA, van Schaik R, Queiroz CM, Aronica E, Gorter JA (2009) Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. Epilepsy Res 84:56–66. https://doi.org/10.1016/j.eplepsyres.2008.12.006
Holtman L, van Vliet EA, Edelbroek PM, Aronica E, Gorter JA (2010) Cox-2 inhibition can lead to adverse effects in a rat model for temporal lobe epilepsy. Epilepsy Res 91:49–56. https://doi.org/10.1016/j.eplepsyres.2010.06.011
Hotta M, Nakata R, Katsukawa M, Hori K, Takahashi S, Inoue H (2010) Carvacrol, a component of thyme oil, activates PPARalpha and gamma and suppresses COX-2 expression. J Lipid Res 51:132–139. https://doi.org/10.1194/jlr.M900255-JLR200
Khalil A, Kovac S, Morris G, Walker MC (2017) Carvacrol after status epilepticus (SE) prevents recurrent SE, early seizures, cell death, and cognitive decline. Epilepsia 58:263–273. https://doi.org/10.1111/epi.13645
Kovacs Z, Dobolyi A, Juhasz G, Kekesi KA (2014) Lipopolysaccharide induced increase in seizure activity in two animal models of absence epilepsy WAG/Rij and GAERS rats and long Evans rats. Brain Res Bull 104:7–18. https://doi.org/10.1016/j.brainresbull.2014.03.003
Landa P, Kokoska L, Pribylova M, Vanek T, Marsik P (2009) In vitro anti-inflammatory activity of carvacrol: inhibitory effect on COX-2 catalyzed prostaglandin E(2) biosynthesis. Arch Pharm Res 32:75–78. https://doi.org/10.1007/s12272-009-1120-6
Li Z, Hua C, Pan X, Fu X, Wu W (2016) Carvacrol exerts neuroprotective effects via suppression of the inflammatory response in middle cerebral artery occlusion rats. Inflammation 39:1566–1572. https://doi.org/10.1007/s10753-016-0392-5
Lima Mda S, Quintans-Junior LJ, de Santana WA, Martins Kaneto C, Pereira Soares MB, Villarreal CF (2013) Anti-inflammatory effects of carvacrol: evidence for a key role of interleukin-10. Eur J Pharmacol 699:112–117. https://doi.org/10.1016/j.ejphar.2012.11.040
Mishra RK, Baker MT (2014) Seizure prevention by the naturally occurring phenols, carvacrol and thymol in a partial seizure-psychomotor model. Bioorg Med Chem Lett 24:5446–5449. https://doi.org/10.1016/j.bmcl.2014.10.028
Pernot F et al (2011) Inflammatory changes during epileptogenesis and spontaneous seizures in a mouse model of mesiotemporal lobe epilepsy. Epilepsia 52:2315–2325. https://doi.org/10.1111/j.1528-1167.2011.03273.x
Pires LF et al (2015) Neuropharmacological effects of carvacryl acetate on delta-aminolevulinic dehydratase, Na+, K+-ATPase activities and amino acids levels in mice hippocampus after seizures. Chem Biol Interact 226:49–57. https://doi.org/10.1016/j.cbi.2014.12.001
Sayyah M, Javad-Pour M, Ghazi-Khansari M (2003) The bacterial endotoxin lipopolysaccharide enhances seizure susceptibility in mice: involvement of proinflammatory factors: nitric oxide and prostaglandins. Neuroscience 122:1073–1080
Simmons DL, Botting RM, Hla T (2004) Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56:387–437. https://doi.org/10.1124/pr.56.3.3
Temp FR, Marafiga JR, Milanesi LH, Duarte T, Rambo LM, Pillat MM, Mello CF (2017) Cyclooxygenase-2 inhibitors differentially attenuate pentylenetetrazol-induced seizures and increase of pro- and anti-inflammatory cytokine levels in the cerebral cortex and hippocampus of mice. Eur J Pharmacol 810:15–25. https://doi.org/10.1016/j.ejphar.2017.05.013
VelÍŠKovÁ J (2006) CHAPTER 48 - behavioral characterization of seizures in rats A2 - Pitkänen, Asla. In: Schwartzkroin PA, Moshé SL (eds) Models of seizures and epilepsy. Academic Press, Burlington, pp 601–611. https://doi.org/10.1016/B978-012088554-1/50050-5
Vezzani A, Friedman A (2011) Brain inflammation as a biomarker in epilepsy. Biomark Med 5:607–614. https://doi.org/10.2217/bmm.11.61
Vezzani A, Aronica E, Mazarati A, Pittman QJ (2013) Epilepsy and brain inflammation. Exp Neurol 244:11–21. https://doi.org/10.1016/j.expneurol.2011.09.033
Xiang NL, Liu J, Liao YJ, Huang YW, Wu Z, Bai ZQ, Lin X, Zhang JH (2016) Abrogating ClC-3 inhibits LPS-induced inflammation via blocking the TLR4/NF-kappaB pathway. Sci Rep 6:27583. https://doi.org/10.1038/srep27583
Zareie P, Sadegh M, Palizvan MR, Moradi-Chameh H (2018) Anticonvulsive effects of endocannabinoids; an investigation to determine the role of regulatory components of endocannabinoid metabolism in the Pentylenetetrazol induced tonic- clonic seizures. Metab Brain Dis 33:939–948. https://doi.org/10.1007/s11011-018-0195-5
Zhang YH, Lu J, Elmquist JK, Saper CB (2003) Specific roles of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide-induced fever and Fos expression in rat brain. J Comp Neurol 463:3–12. https://doi.org/10.1002/cne.10743
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This research was supported by Arak University of Medical Sciences. There are no conflicts of interests for the authors.
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Sadegh, M., Sakhaie, M.H. Carvacrol mitigates proconvulsive effects of lipopolysaccharide, possibly through the hippocampal cyclooxygenase-2 inhibition. Metab Brain Dis 33, 2045–2050 (2018). https://doi.org/10.1007/s11011-018-0314-3
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DOI: https://doi.org/10.1007/s11011-018-0314-3