Abstract
Methylphenidate (MPH), a psychotropic medication is commonly used for children with attention deficit hyperactivity disorder (ADHD). In this study we elucidated the neuroprotective and anti-inflammatory effects of MPH and Rosmarinus officinalis (rosemary) extract, an ancient aromatic herb with several applications in traditional medicine. Briefly, six groups of mice (n = 8 each group), were specified for the study and behavioral analysis was performed to analyze spatial memory followed by histological assessment and gene expression analysis of synaptic (Syn I, II and III) and inflammatory markers (IL-6, TNFα and GFAP) via qRT-PCR, in an AlCl3-induced mouse model for neurotoxicity. The behavioral analysis demonstrated significant cognitive decline, memory defects and altered gene expression in AlCl3-treated group. Rosemary extract significantly decreased the expression of inflammatory and synaptic markers to the similar levels as that of MPH. The present findings suggested the neuroprotective potential of Rosmarinus officinalis extract. However, further characterization of its anti-inflammatory and neuroprotective properties and MPH is required to strategize future treatments for several neurological and neurodegenerative disorders, including Alzheimer’s disease.
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References
García-Avilés Á, Albert-Gascó H, Arnal-Vicente I, Elhajj E, Sanjuan-Arias J, Sanchez-Perez AM, Olucha-Bordonau F (2015) Acute oral administration of low doses of methylphenidate targets calretinin neurons in the rat septal area. Front Neuroanat 9:33. https://doi.org/10.3389/fnana.2015.00033
Repantis D, Schlattmann P, Laisney O, Heuser I (2010) Modafinil and methylphenidate for neuroenhancement in healthy individuals: a systematic review. Pharmacol Res 62:187–206. https://doi.org/10.1016/j.phrs.2010.04.002
Medina JA, Netto TL, Muszkat M, Medina AC, Botter D, Orbetelli R, Scaramuzza LF, Sinnes EG, Vilela M, Miranda MC (2010) Exercise impact on sustained attention of ADHD children, methylphenidate effects. Atten Defic Hyperact Disord 2:49–58. https://doi.org/10.1007/s12402-009-0018-y
Lyketsos CG, Carrillo MC, Ryan JM, Khachaturian AS, Trzepacz P, Amatniek J, Cedarbaum J, Brashear R, Miller DS (2011) Neuropsychiatric symptoms in Alzheimer’s disease. Alzheimers Dement 7:532–539. https://doi.org/10.1016/j.jalz.2011.05.2410
Schmitz F, Pierozan P, Rodrigues AF, Biasibetti H, Grunevald M, Pettenuzzo LF, Scaini G, Streck EL, Netto CA, Wyse ATS (2017) Methylphenidate causes behavioral impairments and neuron and astrocyte loss in the hippocampus of juvenile rats. Mol Neurobiol 54:4201–4216. https://doi.org/10.1007/s12035-016-9987-y
Kennedy DO, Wightman EL (2011) Herbal extracts and phytochemicals: plant secondary metabolites and the enhancement of human brain function. Adv Nutr 2:32–50. https://doi.org/10.3945/an.110.000117
Santos RR, Costa DC, Cavaleiro C, Costa HS, Albuqueurque TG, Castilho MC, Ramos F, Melo NR, Sanches-Silva A (2015) A novel insight on an ancient aromatic plant: the rosemary (Rosmarinus officinalis L.). Trends Food Sci Technol 45:355–368. https://doi.org/10.1016/j.tifs.2015.07.015
Nabavi SF, Tenore GC, Daglia M, Tundis R, Loizzo MR, Nabavi SM (2015) The cellular protective effects of rosmarinic acid: from bench to bedside. Curr Neurovasc Res 12:98–105. https://doi.org/10.2174/1567202612666150109113638
Wu CR, Tsai CW, Chang SW, Lin CY, Huang LC, Tsai CW (2015) Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson's disease: involvement of antioxidative enzymes induction. Chem Biol Interact 225:40–46. https://doi.org/10.1016/j.cbi.2014.11.011
Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D (2010) Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy. Alzheimers Res Ther 2:1. https://doi.org/10.1186/alzrt24
Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer disease—a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2:a006346. https://doi.org/10.1101/cshperspect.a006346
Lee YJ, Han SB, Nam SY, Oh KW, Hong JT (2010) Inflammation and Alzheimer’s disease. Arch Pharm Res 33:1539–1556. https://doi.org/10.1007/s12272-010-1006-7
Cameron B, Landreth GE (2010) Inflammation, microglia, and Alzheimer's disease. Neurobiol dis 37:503–509. https://doi.org/10.1016/j.nbd.2009.10.006
Fornasiero EF, Raimondi A, Guarnieri FC, Orlando M, Fesce R, Benfenati F, Valtorta F (2012) Synapsins contribute to the dynamic spatial organization of synaptic vesicles in an activity-dependent manner. J Neurosci 32:12214–12227. https://doi.org/10.1523/JNEUROSCI.1554-12.2012
Zhang B, Shao H, Wang XH, Chen X, Li ZS, Cao P, Zhu D, Yang YG, Xiao JW, Li B (2017) Acrylamide-induced subacute neurotoxic effects on the cerebral cortex and cerebellum at the synapse level in rats. Biomed Environ Sci 30:432–443. https://doi.org/10.3967/bes2017.057
Zhang XL, Guariglia SR, McGlothan JL, Stansfield KH, Stanton PK, Guilarte TR (2015) Presynaptic mechanisms of lead neurotoxicity: effects on vesicular release, vesicle clustering and mitochondria number. PLoS ONE 10:e0127461. https://doi.org/10.1371/journal.pone.0127461
Gothwal A, Kumar H, Nakhate KT, Ajazuddin DA, Borah A, Gupta U (2019) Lactoferrin coupled lower generation PAMAM dendrimers for brain targeted delivery of memantine in aluminum-chloride-induced Alzheimer's disease in mice. Bioconjug chem 30:2573–2583. https://doi.org/10.1021/acs.bioconjchem.9b00505
Olajide OJ, Yawson EO, Gbadamosi IT, Arogundade TT, Lambe E, Obasi K, Lawal IT, Ibrahim A, Ogunrinola KY (2017) Ascorbic acid ameliorates behavioural deficits and neuropathological alterations in rat model of Alzheimer's disease. Environ Toxicol Pharmacol 50:200–211. https://doi.org/10.1016/j.etap.2017.02.010
Justin Thenmozhi A, Dhivyabharathi M, William Raja TR, Manivasagam T, Essa MM (2016) Tannoid principles of Emblica officinalis renovate cognitive deficits and attenuate amyloid pathologies against aluminum chloride induced rat model of Alzheimer's disease. Nutr Neurosci 19:269–278. https://doi.org/10.1179/1476830515Y.0000000016
Ahmad Rathar M, Justin-Thenmozhi A, Manivasagam T, Saravanababu C, Guillemin GJ, Essa MM (2019) Asiatic acid attenuated aluminum chloride-induced tau pathology, oxidative stress and apoptosis via AKT/GSK-3β signaling pathway in Wistar rats. Neurotox Res 35:955–968. https://doi.org/10.1007/s12640-019-9999-2
Rui D, Yongjian Y (2010) Aluminum chloride induced oxidative damage on cells derived from hippocampus and cortex of ICR mice. Brain Res 9(1324):96–102. https://doi.org/10.1016/j.brainres.2010.02.024
Amber S, Ali Shah SA, Ahmed T, Zahid S (2018) Syzygium aromaticum ethanol extract reduces AlCl3-induced neurotoxicity in mice brain through regulation of amyloid precursor protein and oxidative stress gene expression. Asian Pac J Trop Med 11:123–130. https://doi.org/10.4103/1995-7645.225019
Sadasivan S, Pond BB, Pani AK, Qu C, Jiao Y, Smeyne RJ (2012) Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. PLoS ONE 7:e33693
Machado DG, Bettio LE, Cunha MP, Capra JC, Dalmarco JB, Pizzolatti MG, Rodrigues AL (2009) Antidepressant-like effect of the extract of Rosmarinus officinalis in mice: involvement of the monoaminergic system. Prog Neuropsychopharmacol Biol Psychiatry 33:642–650
Bromley-Brits K, Deng Y, Song W (2011) Morris water maze test for learning and memory deficits in Alzheimer's disease model mice. J Vis Exp 20:2920. https://doi.org/10.3791/2920
Conrad CD, Galea LA, Kuroda Y, McEwen BS (1996) Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine treatment. Behav Neurosci 110:1321–1334. https://doi.org/10.1037/0735-7044.110.6.1321
Gage GJ, Kipke DR, Shain W (2012) Whole animal perfusion fixation for rodents. J Vis Exp 65:e3564. https://doi.org/10.3791/3564
Ahmed S, Mahmood Z, Javed A, Hashmi SN, Zerr I, Zafar S, Zahid S (2017) Effect of metformin on adult hippocampal neurogenesis: comparison with donepezil and links to cognition. J Mol Neurosci 62:88–98
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Walton JR (2007) An aluminum-based rat model for Alzheimer’s disease exhibits oxidative damage, inhibition of PP2A activity, hyperphosphorylated tau, and granulovacuolar degeneration. J Inorg Biochem 101:1275–1284. https://doi.org/10.1016/j.jinorgbio.2007.06.001
Shati A, Elsaid FH (2011) Biochemical and molecularaspects of aluminum chlroide induced neurotoxicityin mice and the protective role of Crocus sativus L. extraction and honey syrup. Neuroscience 175:66–74. https://doi.org/10.1016/j.neuroscience.2010.11.043
Cao Z, Yang X, Zhang H, Wang H, Huang W, Xu F et al (2016) Aluminum chloride induces neuroinflammation, loss of neuronal dendritic spine and cognition impairment in developing rat. Chemosphere 151:289–295. https://doi.org/10.1016/j.chemosphere2016.02.092
Motaghinejad M, Motevalian M, Shabab B, Fatima S (2017) Effects of acute doses of methylphenidate on inflammation and oxidative stress in isolated hippocampus and cerebral cortex of adult rats. J Neural Transm 124:121–131. https://doi.org/10.1007/s00702-016-1623-5
Kita T, Wagner GC, Nakashima T (2003) Current research on methamphetamine-induced neurotoxicity: animal models of monoamine disruption. J Pharmacol Sci 92:178–195. https://doi.org/10.1254/jphs.92.178
Thomas DM, Walker PD, Benjamins JA, Geddes TJ, Kuhn DM (2004) Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation. J Pharmacol Exp Ther 311:1–7. https://doi.org/10.1124/jpet.104.070961
Oakes HV, Ketchem S, Hall AN, Ensley T, Archibald KM, Pond BB (2019) Chronic methylphenidate induces increased quinone production and subsequent depletion of the antioxidant glutathione in the striatum. Pharmacol Rep 71:1289–1292. https://doi.org/10.1016/j.pharep.2019.08.003
Schmitz F, Scherer EB, da Cunha MJ, da Cunha AA, Lima DD, Delwing D et al (2012) Chronic methylphenidate administration alters antioxidant defenses and butyrylcholinesterase activity in blood of juvenile rats. Mol Cell Biochem 361:281–288. https://doi.org/10.1007/s11010-011-1113-x
Nieto G, Huvaere K, Skibsted LH (2011) Antioxidant activity of rosemary and thyme by-products and synergism with added antioxidant in a liposome system. Eur Food Res Technol 233:11–18. https://doi.org/10.1007/s00217-011-1486-9
Rasoolijazi H, Mehdizadeh M, Soleimani M, Nikbakhte F, Eslami Farsani M, Ababzadeh S (2015) The effect of rosemary extract on spatial memory, learning and antioxidant enzymes activities in the hippocampus of middle-aged rats. Med J Islam Repub Iran 29:187
Rašković A, Milanović I, Pavlović N, Ćebović T, Vukmirović S, Mikov M (2014) Antioxidant activity of rosemary (Rosmarinus officinalis L.) essential oil and its hepatoprotective potential. BMC Complement Altern Med 14:225. https://doi.org/10.1186/1472-6882-14-225
Alawdi SH, El-Denshary ES, Safar MM, Eidi H, David MO, Abdel-Wahhab MA (2017) Neuroprotective effect of nanodiamond in Alzheimer’s disease rat model: a pivotal role for modulating NF-κB and STAT3 signaling. Mol Neurobiol 54:1906–1918. https://doi.org/10.1007/s12035-016-9762-0
Ozarowski M, Mikolajczak PL, Bogacz A, Gryszczynska A, Kujawska M, Jodynis-Liebert J et al (2013) Rosmarinus officinalis L. leaf extract improves memory impairment and affects acetylcholinesterase and butyrylcholinesterase activities in rat brain. Fitoterapia 91:261–271. https://doi.org/10.1016/j.fitote.2013.09.012
Jang H, Boltz D, McClaren J, Pani AK, Smeyne M, Korff A, Webster R, Smeyne RJ (2012) Inflammatory effects of highly pathogenic H5N1 influenza virus infection in the CNS of mice. J Neurosci 32:1545–1559. https://doi.org/10.1523/JNEUROSCI.5123-11.2012
Schiffer WK, Volkow ND, Fowler JS, Alexoff DL, Logan J, Dewey SL (2006) Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine. Synapse 59:243–251. https://doi.org/10.1002/syn.20235
Allan SM, Rothwell NJ (2001) Cytokines and acute neurodegeneration. Nat Rev Neurosci 2:734–744. https://doi.org/10.1038/35094583
Motaghinejad M, Motevalian M, Shabab B (2016) Effects of chronic treatment with methylphenidate on oxidative stress and inflammation in hippocampus of adult rats. Neurosci Lett 619:106–113. https://doi.org/10.1016/j.neulet.2015.12.015
Cavaliere C, Cirillo G, Bianco MR, Adriani W, De Simone A, Leo D et al (2012) Methylphenidate administration determines enduring changes in neuroglial network in rats. Eur Neuropsychopharmacol 22:53–63. https://doi.org/10.1016/j.euroneuro.2011.04.003
Brahmachari S, Fung YK, Pahan K (2006) Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide. J Neurosci 26:4930–4939. https://doi.org/10.1523/JNEUROSCI.5480-05.2006
Issy AC, Salum C, Del Bel EA (2009) Nitric oxide modulation of methylphenidate-induced disruption of prepulse inhibition in Swiss mice. Behav Brain Res 205:475–481. https://doi.org/10.1016/j.bbr.2009.08.003
Xiang Q, Liu Z, Wang Y, Xiao H, Wu W, Xiao C, Liu X (2013) Carnosic acid attenuates lipopolysaccharide-induced liver injury in rats via fortifying cellular antioxidant defense system. Food Chem Toxicol 53:1–9. https://doi.org/10.1016/j.fct.2012.11.001
O'Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer's disease. Annu Rev Neurosci 34:185–204. https://doi.org/10.1146/annurev-neuro-061010-113613
Sayorwan W, Ruangrungsi N, Priyapunyporn T, Hongratanaworakit T, Kotchabhakdi N, Siripornpanich V (2013) Effects of inhaled rosemary oil on subjective feelings and activities of the nervous system. Sci Pharm 81:531–542. https://doi.org/10.3797/scipharm.1209-05
Acknowledgements
This work was supported by National University of Sciences and Technology (NUST), Islamabad, Pakistan and through research grant number 5974 awarded to Saadia Zahid under National Research Grants Program for Universities, Higher Education Commission, Pakistan. The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Funding
This work was supported by National University of Sciences and Technology (NUST), Islamabad, Pakistan and through research Grant Number 5974 awarded to Saadia Zahid under National Research Grants Program for Universities, Higher Education Commission, Pakistan. The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
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SZ, substantial contribution to conception and design of the study, drafting and finalization of the manuscript; AJ, gene expression data analysis; SA and SK, mouse model development and animal behavior analysis; MA, histological assessment; FJM plant extract preparation; AK and UAA all experimental work, analysis and data interpretation.
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The animal protocols were conducted in agreement with the rules of the Institute of Laboratory of Animal Research, Division on Earth and Life Sciences, National Institute of Health, USA (Guide for the Care and Use of Laboratory Animals). The ethical approval for this study was obtained from the Internal Review Board (IRB), Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST).
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Khalid, A., Abbasi, U.A., Amber, S. et al. Methylphenidate and Rosmarinus officinalis improves cognition and regulates inflammation and synaptic gene expression in AlCl3-induced neurotoxicity mouse model. Mol Biol Rep 47, 7861–7870 (2020). https://doi.org/10.1007/s11033-020-05864-y
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DOI: https://doi.org/10.1007/s11033-020-05864-y