Oral administration of carvacrol/β-cyclodextrin complex protects against 6-hydroxydopamine-induced dopaminergic denervation
Date
2019-02-28
2019-02-28
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Abstract
Carvacrol (CARV) presents valuable biological properties such as anti-inflammatory and antioxidant activities. However, pharmacological uses of CARV are largely limited due to disadvantages related to solubility, bioavailability, preparation and storage processes. The complexation of monoterpenes with β-cyclodextrin (β-CD) increases their stability, solubility and oral bioavailability. Here, the protective effect of oral treatment with CARV/β-CD complex (25 μg/kg/day) against dopaminergic (DA) denervation induced by unilateral intranigral injection of 6-hydroxydopamine (6-OHDA - 10 μg per rat) was analyzed, in order to evaluate a putative application in the development of neuroprotective therapies for Parkinson's disease (PD). Pretreatment with CARV/β-CD for 15 days prevented the loss of DA neurons induced by 6-OHDA in adult Wistar rats. This effect may occur through CARV anti-inflammatory and antioxidant properties, as the pretreatment with CARV/β-CD inhibited the release of IL-1β and TNF-α; besides, CARV prevented the increase of mitochondrial superoxide production induced by 6-OHDA in cultured SH-SY5Y cells. Importantly, hepatotoxicity or alterations in blood cell profile were not observed with oral administration of CARV/β-CD. Therefore, this study showed a potential pharmacological application of CARV/β-CD in PD using a non-invasive route of drug delivery, i.e., oral administration.
Referencias:
Baluchnejadmojarad, t., Hassanshahi, J., Roghani, M., mansouri, M., Raoufi, S., 2014. Protective Effect of Carvacrol in 6-hydroxydopamine Hemi-parkinsonian Rat Model. Shahed University. Belarbi, K., Cuvelier, E., Destee, A., Gressier, B., Chartier-Harlin, M.C., 2017. NADPH oxidases in Parkinson's disease: a systematic review. Mol Neurodegener 12, 84. Block, M.L., Hong, J.S., 2007. Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochem Soc Trans 35, 1127-1132. Bordt, E.A., Polster, B.M., 2014. NADPH oxidase- and mitochondria-derived reactive oxygen species in proinflammatory microglial activation: a bipartisan affair? Free Radic Biol Med 76, 34-46. Bowie, A., O'Neill, L.A., 2000. Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem Pharmacol 59, 13-23. Carvey, P.M., Zhao, C.H., Hendey, B., Lum, H., Trachtenberg, J., Desai, B.S., Snyder, J., Zhu, Y.G., Ling, Z.D., 2005. 6-Hydroxydopamine-induced alterations in blood-brain barrier permeability. Eur J Neurosci 22, 1158-1168. Costantini, E., D'Angelo, C., Reale, M., 2018. The Role of Immunosenescence in Neurodegenerative Diseases. Mediators Inflamm 2018, 6039171. Cui, Z., Xie, Z., Wang, B., Zhong, Z., Chen, X., Sun, Y., Sun, Q., Yang, G., Bian, L., 2015. Carvacrol protects neuroblastoma SH-SY5Y cells against Fe2+- induced apoptosis by suppressing activation of MAPK/JNK-NF-κB signaling pathway, Acta Pharmacol Sin. Vol. 36, pp. 1426-1436. Dati, L.M., Ulrich, H., Real, C.C., Feng, Z.P., Sun, H.S., Britto, L.R., 2017. Carvacrol promotes neuroprotection in the mouse hemiparkinsonian model. Neuroscience 356, 176-181. Dauer, W., Przedborski, S., 2003. Parkinson's disease: mechanisms and models. Neuron 39, 889-909. Deng, W., Lu, H., Teng, J., 2013. Carvacrol attenuates diabetes-associated cognitive deficits in rats. J Mol Neurosci 51, 813-819. Drechsel, D.A., Patel, M., 2008. Role of Reactive Oxygen Species in the Neurotoxicity of Environmental Agents Implicated in Parkinson’s disease. Free Radic Biol Med 44, 1873-1886. Gasparotto, J., Ribeiro, C.T., Bortolin, R.C., Somensi, N., Rabelo, T.K., Kunzler, A., Souza, N.C., Pasquali, M.A.B., Moreira, J.C.F., Gelain, D.P., 2017. Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA-induced dopaminergic denervation. Sci Rep 7, 8795. Gholijani, N., Gharagozloo, M., Farjadian, S., Amirghofran, Z., 2016. Modulatory effects of thymol and carvacrol on inflammatory transcription factors in lipopolysaccharide-treated macrophages. J Immunotoxicol 13, 157-164. Glinka, Y., Tipton, K.F., Youdim, M.B., 1996. Nature of inhibition of mitochondrial respiratory complex I by 6-Hydroxydopamine. J Neurochem 66, 2004-2010. Guimaraes, A.G., Oliveira, G.F., Melo, M.S., Cavalcanti, S.C., Antoniolli, A.R., Bonjardim, L.R., Silva, F.A., Santos, J.P., Rocha, R.F., Moreira, J.C., Araujo, A.A., Gelain, D.P., Quintans-Junior, L.J., 2010. Bioassay-guided evaluation of antioxidant and antinociceptive activities of carvacrol. Basic Clin Pharmacol Toxicol 107, 949-957. Guimaraes, A.G., Oliveira, M.A., Alves Rdos, S., Menezes Pdos, P., Serafini, M.R., Araujo, A.A., Bezerra, D.P., Quintans Junior, L.J., 2015. Encapsulation of carvacrol, a monoterpene present in the essential oil of oregano, with betacyclodextrin, improves the pharmacological response on cancer pain experimental protocols. Chem Biol Interact 227, 69-76. Guimaraes, A.G., Xavier, M.A., de Santana, M.T., Camargo, E.A., Santos, C.A., Brito, F.A., Barreto, E.O., Cavalcanti, S.C., Antoniolli, A.R., Oliveira, R.C., Quintans-Junior, L.J., 2012. Carvacrol attenuates mechanical hypernociception and inflammatory response. Naunyn Schmiedebergs Arch Pharmacol 385, 253- 263. Huang, X.J., Choi, Y.K., Im, H.S., Yarimaga, O., Yoon, E., Kim, H.S., 2006. Aspartate Aminotransferase (AST/GOT) and Alanine Aminotransferase (ALT/GPT) Detection Techniques, Sensors (Basel). Vol. 6, pp. 756-782. Jitendra, Sharma, P.K., Bansal, S., Banik, A., 2011. Noninvasive Routes of Proteins and Peptides Drug Delivery, Indian J Pharm Sci. Vol. 73, pp. 367-375. Jordan A. McKenzie, L.J.S., Caitlin B. Pointer, Jessica R. Lowry, Ekta Bajwa, Carolyn W. Lee and Andis Klegeris*, 2018. Neuroinflammation as a Common Mechanism Associated with the Modifiable Risk Factors for Alzheimer’s and Parkinson’s Diseases. Curr Aging Sci 10, 158-176. Kurkov, S.V., Loftsson, T., 2013. Cyclodextrins. Int J Pharm 453, 167-180. 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. Lima Mda, S., Quintans-Junior, L.J., de Santana, W.A., Martins Kaneto, C., Pereira Soares, M.B., Villarreal, C.F., 2013. Anti-inflammatory effects of carvacrol: evidence for a key role of interleukin-10. Eur J Pharmacol 699, 112- 117. Lima, M.M., Martins, E.F., Delattre, A.M., Proenca, M.B., Mori, M.A., Carabelli, B., Ferraz, A.C., 2012. Motor and non-motor features of Parkinson's disease - a review of clinical and experimental studies. CNS Neurol Disord Drug Targets 11, 439-449. Lins, L., Souza, M.F., Bispo, J.M.M., Gois, A.M., Melo, T.C.S., Andrade, R.A.S., Quintans-Junior, L.J., Ribeiro, A.M., Silva, R.H., Santos, J.R., Marchioro, M., 2018. Carvacrol prevents impairments in motor and neurochemical parameters in a model of progressive parkinsonism induced by reserpine. Brain Res Bull 139, 9-15. Marques, H.M.C., 2010. A review on cyclodextrin encapsulation of essential oils and volatiles. Flavour and Fragrance Journal 25, 313-326. Mechan, A.O., Fowler, A., Seifert, N., Rieger, H., Wohrle, T., Etheve, S., Wyss, A., Schuler, G., Colletto, B., Kilpert, C., Aston, J., Elliott, J.M., Goralczyk, R., Mohajeri, M.H., 2011. Monoamine reuptake inhibition and mood-enhancing potential of a specified oregano extract. Br J Nutr 105, 1150-1163. Melo, F.H., Moura, B.A., de Sousa, D.P., de Vasconcelos, S.M., Macedo, D.S., Fonteles, M.M., Viana, G.S., de Sousa, F.C., 2011. Antidepressant-like effect of carvacrol (5-Isopropyl-2-methylphenol) in mice: involvement of dopaminergic system. Fundam Clin Pharmacol 25, 362-367. Melo, F.H., Venancio, E.T., de Sousa, D.P., de Franca Fonteles, M.M., de Vasconcelos, S.M., Viana, G.S., de Sousa, F.C., 2010. Anxiolytic-like effect of Carvacrol (5-isopropyl-2-methylphenol) in mice: involvement with GABAergic transmission. Fundam Clin Pharmacol 24, 437-443. National Research Council Committee for the Update of the Guide for the Care and Use of Laboratory, A., 2011. The National Academies Collection: Reports funded by National Institutes of Health, Guide for the Care and Use of Laboratory Animals,National Academies Press (US)National Academy of Sciences., Washington (DC). Olmedo-Diaz, S., Estevez-Silva, H., Oradd, G., Af Bjerken, S., Marcellino, D., Virel, A., 2017. An altered blood-brain barrier contributes to brain iron accumulation and neuroinflammation in the 6-OHDA rat model of Parkinson's disease. Neuroscience 362, 141-151. Oz, M., Lozon, Y., Sultan, A., Yang, K.H., Galadari, S., 2015. Effects of monoterpenes on ion channels of excitable cells. Pharmacol Ther 152, 83-97. Paxinos, G., Watson, C., 2005. The rat brain in stereotaxic coordinates, 5 ed. Boston: Elsevier Academic Press Amsterdam Poewe, W., Seppi, K., Tanner, C.M., Halliday, G.M., Brundin, P., Volkmann, J., Schrag, A.-E., Lang, A.E., 2017. Parkinson disease. Nature Reviews Disease Primers 3, 17013. Qin, X.Y., Zhang, S.P., Cao, C., Loh, Y.P., Cheng, Y., 2016. Aberrations in Peripheral Inflammatory Cytokine Levels in Parkinson Disease: A Systematic Review and Meta-analysis. JAMA Neurol 73, 1316-1324. Rodriguez-Pallares, J., Parga, J.A., Munoz, A., Rey, P., Guerra, M.J., Labandeira-Garcia, J.L., 2007. Mechanism of 6-hydroxydopamine neurotoxicity: the role of NADPH oxidase and microglial activation in 6-hydroxydopamineinduced degeneration of dopaminergic neurons. J Neurochem 103, 145-156. Santos, E.H., Kamimura, J.A., Hill, L.E., Gomes, C.L., 2015. Characterization of carvacrol beta-cyclodextrin inclusion complexes as delivery systems for antibacterial and antioxidant applications. LWT - Food Science and Technology 60, 583-592. Silva, J.C., Almeida, J., Quintans, J.S.S., Gopalsamy, R.G., Shanmugam, S., Serafini, M.R., Oliveira, M.R.C., Silva, B.A.F., Martins, A., Castro, F.F., Menezes, I.R.A., Coutinho, H.D.M., Oliveira, R.C.M., Thangaraj, P., Araujo, A.A.S., Quintans-Junior, L.J., 2016. Enhancement of orofacial antinociceptive effect of carvacrol, a monoterpene present in oregano and thyme oils, by betacyclodextrin inclusion complex in mice. Biomed Pharmacother 84, 454-461. Soto-Otero, R., Mendez-Alvarez, E., Hermida-Ameijeiras, A., Munoz-Patino, A.M., Labandeira-Garcia, J.L., 2000. Autoxidation and neurotoxicity of 6- hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson's disease. J Neurochem 74, 1605- 1612. Stott, S.R., Barker, R.A., 2014. Time course of dopamine neuron loss and glial response in the 6-OHDA striatal mouse model of Parkinson's disease. Eur J Neurosci 39, 1042-1056. Suntres, Z.E., Coccimiglio, J., Alipour, M., 2015. The bioactivity and toxicological actions of carvacrol. Crit Rev Food Sci Nutr 55, 304-318. Tieu, K., 2011. A guide to neurotoxic animal models of Parkinson's disease. Cold Spring Harb Perspect Med 1, a009316. Tobon-Velasco, J.C., Cuevas, E., Torres-Ramos, M.A., 2014. Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress. CNS Neurol Disord Drug Targets 13, 1615-1626. Trabace, L., Zotti, M., Morgese, M.G., Tucci, P., Colaianna, M., Schiavone, S., Avato, P., Cuomo, V., 2011. Estrous cycle affects the neurochemical and neurobehavioral profile of carvacrol-treated female rats. Toxicology and Applied Pharmacology 255, 169-175. Vairetti, M., Ferrigno, A., Rizzo, V., Ambrosi, G., Bianchi, A., Richelmi, P., Blandini, F., Armentero, M.T., 2012. Impaired hepatic function and central dopaminergic denervation in a rodent model of Parkinson's disease: a selfperpetuating crosstalk? Biochim Biophys Acta 1822, 176-184. Walsh, S., Finn, D.P., Dowd, E., 2011. Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat. Neuroscience 175, 251-261. Wang, P., Luo, Q., Qiao, H., Ding, H., Cao, Y., Yu, J., Liu, R., Zhang, Q., Zhu, H., Qu, L., 2017. The Neuroprotective Effects of Carvacrol on Ethanol-Induced Hippocampal Neurons Impairment via the Antioxidative and Antiapoptotic Pathways. Oxid Med Cell Longev 2017, 4079425. Wang, Q., Liu, Y., Zhou, J., 2015. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target, Transl Neurodegener. Vol. 4. Xiao, Y., Joint Department, T.H., Tianjin 300211, P.R. China, Li, B., Joint Department, T.H., Tianjin 300211, P.R. China, Liu, J., Joint Department, T.H., Tianjin 300211, P.R. China, Ma, X., Joint Department, T.H., Tianjin 300211, P.R. China, 2019. Carvacrol ameliorates inflammatory response in interleukin1β-stimulated human chondrocytes. Molecular Medicine Reports 17, 3987- 3992. Yu, H., Zhang, Z.L., Chen, J., Pei, A., Hua, F., Qian, X., He, J., Liu, C.F., Xu, X., 2012. Carvacrol, a food-additive, provides neuroprotection on focal cerebral ischemia/reperfusion injury in mice. PLoS One 7, e33584. Zotti, M., Colaianna, M., Morgese, M., Tucci, P., Schiavone, S., Avato, P., Trabace, L., 2013. Carvacrol: From Ancient Flavoring to Neuromodulatory Agent. Molecules 18, 6161-6172.
Baluchnejadmojarad, t., Hassanshahi, J., Roghani, M., mansouri, M., Raoufi, S., 2014. Protective Effect of Carvacrol in 6-hydroxydopamine Hemi-parkinsonian Rat Model. Shahed University. Belarbi, K., Cuvelier, E., Destee, A., Gressier, B., Chartier-Harlin, M.C., 2017. NADPH oxidases in Parkinson's disease: a systematic review. Mol Neurodegener 12, 84. Block, M.L., Hong, J.S., 2007. Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochem Soc Trans 35, 1127-1132. Bordt, E.A., Polster, B.M., 2014. NADPH oxidase- and mitochondria-derived reactive oxygen species in proinflammatory microglial activation: a bipartisan affair? Free Radic Biol Med 76, 34-46. Bowie, A., O'Neill, L.A., 2000. Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem Pharmacol 59, 13-23. Carvey, P.M., Zhao, C.H., Hendey, B., Lum, H., Trachtenberg, J., Desai, B.S., Snyder, J., Zhu, Y.G., Ling, Z.D., 2005. 6-Hydroxydopamine-induced alterations in blood-brain barrier permeability. Eur J Neurosci 22, 1158-1168. Costantini, E., D'Angelo, C., Reale, M., 2018. The Role of Immunosenescence in Neurodegenerative Diseases. Mediators Inflamm 2018, 6039171. Cui, Z., Xie, Z., Wang, B., Zhong, Z., Chen, X., Sun, Y., Sun, Q., Yang, G., Bian, L., 2015. Carvacrol protects neuroblastoma SH-SY5Y cells against Fe2+- induced apoptosis by suppressing activation of MAPK/JNK-NF-κB signaling pathway, Acta Pharmacol Sin. Vol. 36, pp. 1426-1436. Dati, L.M., Ulrich, H., Real, C.C., Feng, Z.P., Sun, H.S., Britto, L.R., 2017. Carvacrol promotes neuroprotection in the mouse hemiparkinsonian model. Neuroscience 356, 176-181. Dauer, W., Przedborski, S., 2003. Parkinson's disease: mechanisms and models. Neuron 39, 889-909. Deng, W., Lu, H., Teng, J., 2013. Carvacrol attenuates diabetes-associated cognitive deficits in rats. J Mol Neurosci 51, 813-819. Drechsel, D.A., Patel, M., 2008. Role of Reactive Oxygen Species in the Neurotoxicity of Environmental Agents Implicated in Parkinson’s disease. Free Radic Biol Med 44, 1873-1886. Gasparotto, J., Ribeiro, C.T., Bortolin, R.C., Somensi, N., Rabelo, T.K., Kunzler, A., Souza, N.C., Pasquali, M.A.B., Moreira, J.C.F., Gelain, D.P., 2017. Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA-induced dopaminergic denervation. Sci Rep 7, 8795. Gholijani, N., Gharagozloo, M., Farjadian, S., Amirghofran, Z., 2016. Modulatory effects of thymol and carvacrol on inflammatory transcription factors in lipopolysaccharide-treated macrophages. J Immunotoxicol 13, 157-164. Glinka, Y., Tipton, K.F., Youdim, M.B., 1996. Nature of inhibition of mitochondrial respiratory complex I by 6-Hydroxydopamine. J Neurochem 66, 2004-2010. Guimaraes, A.G., Oliveira, G.F., Melo, M.S., Cavalcanti, S.C., Antoniolli, A.R., Bonjardim, L.R., Silva, F.A., Santos, J.P., Rocha, R.F., Moreira, J.C., Araujo, A.A., Gelain, D.P., Quintans-Junior, L.J., 2010. Bioassay-guided evaluation of antioxidant and antinociceptive activities of carvacrol. Basic Clin Pharmacol Toxicol 107, 949-957. Guimaraes, A.G., Oliveira, M.A., Alves Rdos, S., Menezes Pdos, P., Serafini, M.R., Araujo, A.A., Bezerra, D.P., Quintans Junior, L.J., 2015. Encapsulation of carvacrol, a monoterpene present in the essential oil of oregano, with betacyclodextrin, improves the pharmacological response on cancer pain experimental protocols. Chem Biol Interact 227, 69-76. Guimaraes, A.G., Xavier, M.A., de Santana, M.T., Camargo, E.A., Santos, C.A., Brito, F.A., Barreto, E.O., Cavalcanti, S.C., Antoniolli, A.R., Oliveira, R.C., Quintans-Junior, L.J., 2012. Carvacrol attenuates mechanical hypernociception and inflammatory response. Naunyn Schmiedebergs Arch Pharmacol 385, 253- 263. Huang, X.J., Choi, Y.K., Im, H.S., Yarimaga, O., Yoon, E., Kim, H.S., 2006. Aspartate Aminotransferase (AST/GOT) and Alanine Aminotransferase (ALT/GPT) Detection Techniques, Sensors (Basel). Vol. 6, pp. 756-782. Jitendra, Sharma, P.K., Bansal, S., Banik, A., 2011. Noninvasive Routes of Proteins and Peptides Drug Delivery, Indian J Pharm Sci. Vol. 73, pp. 367-375. Jordan A. McKenzie, L.J.S., Caitlin B. Pointer, Jessica R. Lowry, Ekta Bajwa, Carolyn W. Lee and Andis Klegeris*, 2018. Neuroinflammation as a Common Mechanism Associated with the Modifiable Risk Factors for Alzheimer’s and Parkinson’s Diseases. Curr Aging Sci 10, 158-176. Kurkov, S.V., Loftsson, T., 2013. Cyclodextrins. Int J Pharm 453, 167-180. 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. Lima Mda, S., Quintans-Junior, L.J., de Santana, W.A., Martins Kaneto, C., Pereira Soares, M.B., Villarreal, C.F., 2013. Anti-inflammatory effects of carvacrol: evidence for a key role of interleukin-10. Eur J Pharmacol 699, 112- 117. Lima, M.M., Martins, E.F., Delattre, A.M., Proenca, M.B., Mori, M.A., Carabelli, B., Ferraz, A.C., 2012. Motor and non-motor features of Parkinson's disease - a review of clinical and experimental studies. CNS Neurol Disord Drug Targets 11, 439-449. Lins, L., Souza, M.F., Bispo, J.M.M., Gois, A.M., Melo, T.C.S., Andrade, R.A.S., Quintans-Junior, L.J., Ribeiro, A.M., Silva, R.H., Santos, J.R., Marchioro, M., 2018. Carvacrol prevents impairments in motor and neurochemical parameters in a model of progressive parkinsonism induced by reserpine. Brain Res Bull 139, 9-15. Marques, H.M.C., 2010. A review on cyclodextrin encapsulation of essential oils and volatiles. Flavour and Fragrance Journal 25, 313-326. Mechan, A.O., Fowler, A., Seifert, N., Rieger, H., Wohrle, T., Etheve, S., Wyss, A., Schuler, G., Colletto, B., Kilpert, C., Aston, J., Elliott, J.M., Goralczyk, R., Mohajeri, M.H., 2011. Monoamine reuptake inhibition and mood-enhancing potential of a specified oregano extract. Br J Nutr 105, 1150-1163. Melo, F.H., Moura, B.A., de Sousa, D.P., de Vasconcelos, S.M., Macedo, D.S., Fonteles, M.M., Viana, G.S., de Sousa, F.C., 2011. Antidepressant-like effect of carvacrol (5-Isopropyl-2-methylphenol) in mice: involvement of dopaminergic system. Fundam Clin Pharmacol 25, 362-367. Melo, F.H., Venancio, E.T., de Sousa, D.P., de Franca Fonteles, M.M., de Vasconcelos, S.M., Viana, G.S., de Sousa, F.C., 2010. Anxiolytic-like effect of Carvacrol (5-isopropyl-2-methylphenol) in mice: involvement with GABAergic transmission. Fundam Clin Pharmacol 24, 437-443. National Research Council Committee for the Update of the Guide for the Care and Use of Laboratory, A., 2011. The National Academies Collection: Reports funded by National Institutes of Health, Guide for the Care and Use of Laboratory Animals,National Academies Press (US)National Academy of Sciences., Washington (DC). Olmedo-Diaz, S., Estevez-Silva, H., Oradd, G., Af Bjerken, S., Marcellino, D., Virel, A., 2017. An altered blood-brain barrier contributes to brain iron accumulation and neuroinflammation in the 6-OHDA rat model of Parkinson's disease. Neuroscience 362, 141-151. Oz, M., Lozon, Y., Sultan, A., Yang, K.H., Galadari, S., 2015. Effects of monoterpenes on ion channels of excitable cells. Pharmacol Ther 152, 83-97. Paxinos, G., Watson, C., 2005. The rat brain in stereotaxic coordinates, 5 ed. Boston: Elsevier Academic Press Amsterdam Poewe, W., Seppi, K., Tanner, C.M., Halliday, G.M., Brundin, P., Volkmann, J., Schrag, A.-E., Lang, A.E., 2017. Parkinson disease. Nature Reviews Disease Primers 3, 17013. Qin, X.Y., Zhang, S.P., Cao, C., Loh, Y.P., Cheng, Y., 2016. Aberrations in Peripheral Inflammatory Cytokine Levels in Parkinson Disease: A Systematic Review and Meta-analysis. JAMA Neurol 73, 1316-1324. Rodriguez-Pallares, J., Parga, J.A., Munoz, A., Rey, P., Guerra, M.J., Labandeira-Garcia, J.L., 2007. Mechanism of 6-hydroxydopamine neurotoxicity: the role of NADPH oxidase and microglial activation in 6-hydroxydopamineinduced degeneration of dopaminergic neurons. J Neurochem 103, 145-156. Santos, E.H., Kamimura, J.A., Hill, L.E., Gomes, C.L., 2015. Characterization of carvacrol beta-cyclodextrin inclusion complexes as delivery systems for antibacterial and antioxidant applications. LWT - Food Science and Technology 60, 583-592. Silva, J.C., Almeida, J., Quintans, J.S.S., Gopalsamy, R.G., Shanmugam, S., Serafini, M.R., Oliveira, M.R.C., Silva, B.A.F., Martins, A., Castro, F.F., Menezes, I.R.A., Coutinho, H.D.M., Oliveira, R.C.M., Thangaraj, P., Araujo, A.A.S., Quintans-Junior, L.J., 2016. Enhancement of orofacial antinociceptive effect of carvacrol, a monoterpene present in oregano and thyme oils, by betacyclodextrin inclusion complex in mice. Biomed Pharmacother 84, 454-461. Soto-Otero, R., Mendez-Alvarez, E., Hermida-Ameijeiras, A., Munoz-Patino, A.M., Labandeira-Garcia, J.L., 2000. Autoxidation and neurotoxicity of 6- hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson's disease. J Neurochem 74, 1605- 1612. Stott, S.R., Barker, R.A., 2014. Time course of dopamine neuron loss and glial response in the 6-OHDA striatal mouse model of Parkinson's disease. Eur J Neurosci 39, 1042-1056. Suntres, Z.E., Coccimiglio, J., Alipour, M., 2015. The bioactivity and toxicological actions of carvacrol. Crit Rev Food Sci Nutr 55, 304-318. Tieu, K., 2011. A guide to neurotoxic animal models of Parkinson's disease. Cold Spring Harb Perspect Med 1, a009316. Tobon-Velasco, J.C., Cuevas, E., Torres-Ramos, M.A., 2014. Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress. CNS Neurol Disord Drug Targets 13, 1615-1626. Trabace, L., Zotti, M., Morgese, M.G., Tucci, P., Colaianna, M., Schiavone, S., Avato, P., Cuomo, V., 2011. Estrous cycle affects the neurochemical and neurobehavioral profile of carvacrol-treated female rats. Toxicology and Applied Pharmacology 255, 169-175. Vairetti, M., Ferrigno, A., Rizzo, V., Ambrosi, G., Bianchi, A., Richelmi, P., Blandini, F., Armentero, M.T., 2012. Impaired hepatic function and central dopaminergic denervation in a rodent model of Parkinson's disease: a selfperpetuating crosstalk? Biochim Biophys Acta 1822, 176-184. Walsh, S., Finn, D.P., Dowd, E., 2011. Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat. Neuroscience 175, 251-261. Wang, P., Luo, Q., Qiao, H., Ding, H., Cao, Y., Yu, J., Liu, R., Zhang, Q., Zhu, H., Qu, L., 2017. The Neuroprotective Effects of Carvacrol on Ethanol-Induced Hippocampal Neurons Impairment via the Antioxidative and Antiapoptotic Pathways. Oxid Med Cell Longev 2017, 4079425. Wang, Q., Liu, Y., Zhou, J., 2015. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target, Transl Neurodegener. Vol. 4. Xiao, Y., Joint Department, T.H., Tianjin 300211, P.R. China, Li, B., Joint Department, T.H., Tianjin 300211, P.R. China, Liu, J., Joint Department, T.H., Tianjin 300211, P.R. China, Ma, X., Joint Department, T.H., Tianjin 300211, P.R. China, 2019. Carvacrol ameliorates inflammatory response in interleukin1β-stimulated human chondrocytes. Molecular Medicine Reports 17, 3987- 3992. Yu, H., Zhang, Z.L., Chen, J., Pei, A., Hua, F., Qian, X., He, J., Liu, C.F., Xu, X., 2012. Carvacrol, a food-additive, provides neuroprotection on focal cerebral ischemia/reperfusion injury in mice. PLoS One 7, e33584. Zotti, M., Colaianna, M., Morgese, M., Tucci, P., Schiavone, S., Avato, P., Trabace, L., 2013. Carvacrol: From Ancient Flavoring to Neuromodulatory Agent. Molecules 18, 6161-6172.
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