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Immunohistochemical increase in cyclooxygenase-2 without apoptosis in different brain areas of subchronic nicotine- and d-amphetamine-treated rats

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

Cyclooxygenase-2 (COX-2) upregulation has been related to both neurodegeneration and physiological processes. To clarify whether nicotine-induced upregulation of COX-2 occurs, and to analyse its significance, a comparative immunohistochemical and Western blot study was performed on the frontoparietal cortex, hippocampus and cerebellar cortex of rats treated (14 days) with nicotine, d(+)amphetamine (0.35 and 1.16 mg free base/kg/day, respectively), or both drugs simultaneously. None of these treatments promoted neuronal apoptosis. Lipid peroxidation increased in the hippocampus of the nicotine-treated rats and in all the brain regions examined in the d(+)amphetamine rats, but not in the double-treated animals. Both molecules increased the COX-2 content (as determined by the number of immunopositive neurons and the intensity of their immunodeposits) in an area-, layer- and neuron type-dependent manner, in all brain regions in which a large number of COX-2 immunopositive neurons were observed in controls (the somatosensory cortical areas, CA-1, CA-3, the gyrus dentatus, the ectorhinal/perirhinal areas, and the gyrus cingularis). No increase was seen in the motor cortical areas, while a reduction was recorded in the cerebellar cortex; these regions had only a few immunopositive neurons in controls. Western blot analysis revealed a 50–80% increase in COX-2 in the brain cortex and hippocampus of nicotine-treated rats, and similar increases (150–200%) in the cortex of the d(+)amphetamine- and nicotine + d(+)amphetamine-treated rats. Nicotine-induced upregulation of COX-2 seems to be related to neuronal plasticity rather than neurodegeneration. Nicotine agonists might be useful in the treatment of cognitive disorders.

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References

  • Albuquerque EX, Pereira EF, Mike A, Eisenberg HM, Maelicke A, Alkondon M (2000) Neuronal nicotinic receptors in synaptic functions in humans and rats: physiological and clinical relevance. Behav Brain Res 113:131–141

    Article  PubMed  CAS  Google Scholar 

  • Andersson KI, Savonenko A, Vidensky S, Goellner JJ, Zhang Y, Shaffer A, Kaufmann WE, Worley PF, Isakson P, Markowska AL (2001) Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice. J Neurosci 21:8198–8209

    Google Scholar 

  • Barch DM, Carter CS (2005) Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers. Schizophr Res 77:43–58

    Article  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Breder CD, Dewitt D, Kraig RP (1995) Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol 355:296–315

    Article  PubMed  CAS  Google Scholar 

  • Brown RW, Kolb B (2001) Nicotine sensitization increases dendritic length and spine density in the nucleus accumbens and cingulate cortex. Brain Res 899:94–100

    Article  PubMed  CAS  Google Scholar 

  • Carlson J, Noguchi K, Ellison G (2001) Nicotine produces selective degeneration in the medial habenula and fasciculus retroflexus. Brain Res 906:127–134

    Article  PubMed  CAS  Google Scholar 

  • Chang YC, Tsai CH, Yang SH, Liu CM, Chou MY (2003) Induction of cyclooxygenase-2 mRNA and protein expression in human gingival fibroblasts stimulated with nicotine. J Periodontal Res 38(5):496–501

    Article  PubMed  CAS  Google Scholar 

  • Chang YW, Jakobi R, McGinty A, Foschi M, Dunn MJ, Sorokin A (2000) Cyclooxygenase 2 promotes cell survival by stimulation of dynein light chain expression and inhibition of neuronal nitric oxide synthase activity. Mol Cell Biol 20:8571–8579

    Article  PubMed  CAS  Google Scholar 

  • Choi JS, Kim HY, Chun MH, Chung JW, Lee MY (2006a) Differential regulation of cycloxygenase-2 in the rat hippocampus after cerebral isquemia and ischemic tolerance. Neurosci Let 393:231–236

    Article  CAS  Google Scholar 

  • Choi SH, Langenbach R, Bosetti F (2006b) Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-kappa B pathway and downstream enzymes involved in prostaglandin biosynthesis. J Neurochem 98:801–811

    Article  PubMed  CAS  Google Scholar 

  • Chong ZZ, Li F, Maiese K (2005) Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol 75:207–246

    Article  PubMed  CAS  Google Scholar 

  • Consilvio C, Vicent AM, Feldman EL (2004) Neuroinflammation, COX-2, and ALS. A dual role? Exp Neurol 187:1–10

    Article  PubMed  CAS  Google Scholar 

  • Cui JG, Kuroda H, Chandrasekharan NV, Pelaez RP, Simmons DL, Bazan NG, Lukiw WJ (2004) Cyclooxygenase-3 gene expression in Alzheimer hippocampus and in stressed human neural cells. Neurochem Res 29:1731–1737

    Article  PubMed  CAS  Google Scholar 

  • Dani JA, Ji D, Zhou FM (2001) Synaptic plasticity and nicotine addiction. Neuron 31:349–352

    Article  PubMed  CAS  Google Scholar 

  • Dash PK, Mach SA, Moore AN (2000) Regional expression and role cyclooxygenase-2 following experimental traumatic brain injury. J Neurotrauma 17:69–81

    Article  PubMed  CAS  Google Scholar 

  • Davidson C, Gow AJ, Lee TH, Ellinwood EH (2001) Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Rev 36:1–22

    Article  PubMed  CAS  Google Scholar 

  • De Simone R, Ajmone-Cat MA, Carnevale D, Minghetti L (2005) Activation of alpha7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures. J Neuroinflammation 25:4

    Article  CAS  Google Scholar 

  • Deininger MH, Bekure-Nemariam K, Trautmann K, Morgalla M, Meyermann R, Schlucsener HJ (2003) Cyclooxygenase-1 and -2 in brains of patients who died with sporadic Creutzfeldt–Jakob disease. J Mol Neurosci 20:25–30

    Article  PubMed  CAS  Google Scholar 

  • Eikelenboom P, Van Gool WA (2004) Neuroinflammatory perspectives on the two faces of Alzheimer’s disease. J Neural Transm 111:281–294

    Article  PubMed  CAS  Google Scholar 

  • Featherstone RE, Kapur S, Fletcher PJ (2007) The amphetamine-induced sensitized state as a model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiat 31:1556–1571

    Article  CAS  Google Scholar 

  • Fujimi K, Noda K, Sasaki K, Wakisaka Y, Tanizaki Y, Iida M, Kiyohara Y, Kanba S, Iwaki T (2007) Altered expression of COX-2 in subdivisions of the hippocampus during aging and in Alzheimer’s disease: The Hisayama study. Dement Geriatr Cogn Disord 23:423–431

    Article  PubMed  CAS  Google Scholar 

  • Gahring LC, Persiyanov K, Days EL, Rogers SW (2005) Age-related loss of neuronal nicotinic receptor expression in the aging mouse hippocampus corresponds with cyclooxygenase-2 and PPAR gamma expression and is altered by long-term NS398 administration. J Neurobiol 62:453–468

    Article  PubMed  CAS  Google Scholar 

  • Giovannini MG, Scali C, Prosperi C, Bellucci A, Pepeu G, Casamenti F (2003) Experimental brain inflammation and neurodegenerations as model of Alzheimer’s disease: protective effects of selective COX-2 inhibitors. Int J Immunopathol Pharmacol 16:S31–S40

    Google Scholar 

  • Gunne LM (1977) Effects of amphetamine in humans. In: Martin WR (eds) Drug addiction II: amphetamine, psychotogen, and marihuana dependence. Springerg, Berlin, pp 247–275

    Google Scholar 

  • Gutala R, Wang J, Hwang YY, Haq R, Li MD (2006) Nicotine modulates expression of amyloid precursor protein and amyloid precursor-like protein 2 in mouse brain and in SH-SY5Y neuroblastoma cells. Brain Res 1093:12–19

    Article  PubMed  CAS  Google Scholar 

  • Harvey JA (1987) Behavioral pharmacology of central nervous system stimulants. Neuropharmacology 26:887–892

    Article  PubMed  CAS  Google Scholar 

  • Hassoun EA, Al-Ghafri M, Abushaban A (2003) The role of antioxidant enzymes in TCDD-induced oxidative stress in various brain regions of rats after subchronic exposure. Free Radic Biol Med 35:1028–1036

    Article  PubMed  CAS  Google Scholar 

  • Hejmadi MV, Dajas-Bailador F, Barns SM, Jones B, Wonnacott S (2003) Neuroprotection by nicotine against hypoxia-induced apoptosis in cortical cultures involves activation of multiple nicotinic acetylcholine receptor subtypes. Mol Cell Neurosci 24:779–786

    Article  PubMed  CAS  Google Scholar 

  • Hewett SJ, Bell SC, Hewett JA (2006) Contributions of cyclooxygenase-2 to neuroplasticity and neuropathology of the central nervous system. Pharmacol Ther 112:335–357

    Article  PubMed  CAS  Google Scholar 

  • Hoozemans JJ, Rozemuller AJ, Veerhuis R, Eikelenboom P (2001) Immunological aspects of Alzheimer´s disease: therapeutic implication. Bio Drug 15:325–337

    CAS  Google Scholar 

  • Hoozemans JJ, van Haastert ES, Veerhuis R, Arendt T, Scheper W, Eikelenboom P, Rozemuller AJ (2005) Maximal COX-2 and ppRb expression in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia in Alzheimer’s disease. J Neuroinflammation 21;2:27

    Article  CAS  Google Scholar 

  • Hoozemans JJ, Veerhuis R, Rozemuller JM, Eikelenboom P (2006) Neuroinflammation and regeneration in the early stages of Alzheimer’s disease pathology. Int J Dev Neurosci 24:157–165

    Article  PubMed  CAS  Google Scholar 

  • Iversen SD (1998) The pharmacology of memory. C R Acad Sci III 321:209–215

    PubMed  CAS  Google Scholar 

  • Jonnala RR, Buccafusco JJ (2001) Relationship between the increased cell surface alpha7 nicotinic receptor expression and neuroprotection induced by several nicotinic receptor agonists. J Neurosci Res 66:565–572

    Article  PubMed  CAS  Google Scholar 

  • Kaufman WE, Andreasson KI, Isakson PC, Worley PF (1997) Cyclooxygenases and the central nervous system. Prostaglandins 54:601–624

    Article  Google Scholar 

  • Kihara T, Shimohama S, Urushitani M, Sawada H, Kimura J, Kume T, Maeda T, Akaike A (1997) Nicotine receptor stimulation protects neurons against beta-amyloid toxicity. Ann Neurol 42:159–163

    Article  PubMed  CAS  Google Scholar 

  • Kovacic P, Cooksy AL (2005) Unifying mechanism for toxicity and addiction by abused drugs: electron transfer and reactive oxygen species. Med Hypotheses 64:357–366

    Article  PubMed  CAS  Google Scholar 

  • Kunz T, Marklund N, Hillered L, Oliw EH (2002) Cyclooxygenase-2, prostaglandin synthases, and prostaglandin H2 metabolism in traumatic brain injury in the rat. J Neurotrauma 19:1051–1064

    Article  PubMed  Google Scholar 

  • Le Magueresse C, Safiulina V, Changeux JP, Cherubini E (2006) Nicotinic modulation of network and synaptic transmission in the immature hippocampus investigated with genetically modified mice. J Physiol 576:533–546

    Article  PubMed  CAS  Google Scholar 

  • Levin ED, Simon BB (1998) Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology 138:217–230

    Article  PubMed  CAS  Google Scholar 

  • Levin ED, Bradley A, Addy N, Sigurani N (2002) Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory. Neuroscience 109:757–765

    Article  PubMed  CAS  Google Scholar 

  • Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl) 184:523–539

    Article  CAS  Google Scholar 

  • Li Y, Papke RL, He YL, Millard WJ, Meyer EM (1999) Characterization of the neuroprotective and toxic effects of alpha-7 nicotinic receptor activation in PC12 cells. Brain Res 830:218–225

    Article  PubMed  CAS  Google Scholar 

  • Li L, Prabhakaran K, Shou Y, Borowitz JL, Isom GE (2002) Oxidative stress and cyclooxygenase-2 induction cyanide-induced apoptosis of cortical cells. Toxicol Appl Pharmacol 185:55–63

    Article  PubMed  CAS  Google Scholar 

  • Liu Q, Zhao B (2004) Nicotine attenuates beta-amyloid peptide-induced neurotoxicity, free radical and calcium accumulation in hippocampal neuron culturs. Br J Pharmacol 141:746–754

    Article  PubMed  CAS  Google Scholar 

  • Martínez-Murillo R, Martínez-Rodríguez R, Arenas G, Franic L, Hernández A, Estrada F (1985) Succinic and malic dehydrogenase histochemical activities in cerebral, cerebellar and neostriatum sections incubated in presence of d-amphetamine. Acta Neuropathol 67:81–85

    Article  PubMed  Google Scholar 

  • Martínez-Rodríguez R, Martínez-Murillo R (1984) In vitro d-amphetamine action on oxido-reductase activity of several rat nervous centres. Acta Histochem 74:85–90

    PubMed  Google Scholar 

  • Martínez-Rodríguez R, Toledano A, Álvarez MI, Turégano L, Colman O, Rosés P, Gómez de Segura I, De Miguel E (2003) Chronic nicotine administration increases NGF-like immunoreactivity in frontoparietal cerebral cortex. J Neurosci Res 73:708–716

    Article  PubMed  CAS  Google Scholar 

  • Mazurov A, Hauser T, Miller CH (2006) Selective alpha7 nicotinic acetylcholine receptor ligands. Curr Med Chem 13:1567–1584

    Article  PubMed  CAS  Google Scholar 

  • Miettinen S, Fusco FR, Yrjanheikki J, Keinanen R, Hirvonen T, Roivainen R, Narhi M, Hokfelt T, Koistinaho J (1997) Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-d-aspartic acid-receptors and phospholipase A2. Proc Natl Acad Sci USA 94:6500–6505

    Article  PubMed  CAS  Google Scholar 

  • Minghetti L, Ajmone-Cat MA, De Berardinis MA, De Simone R (2005) Microglial activation in chronic neurodegenerative diseases: roles of apoptotic neurons and chronic stimulation. Brain Res Brain Res Rev 48:251–256

    Article  PubMed  CAS  Google Scholar 

  • Morita I (2002) Distinct functions of COX-1 and COX-2. Prostaglandins Other Lipid Mediat 68–69:165–175

    Article  PubMed  Google Scholar 

  • Oliveira MT, Rego AC, Macedo TRA, Oliveira CR (2003) Drugs of abuse induce apoptotic features in PC12 cells. Ann N Y Acad Sci 1010:667–670

    Article  PubMed  CAS  Google Scholar 

  • Ornstein TJ, Iddon JL, Baldacchino AM, Sahakian BJ, London M, Everitt BJ, Robbins TW (2000) Profiles of cognitive dysfunction in chronic amphetamine and heroin abusers. Neuropsychopharmacol 23:113–126

    Article  CAS  Google Scholar 

  • Pasinetti GM, Aisen PS (1998) Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer’s disease brain. Neurosci 87:319–324

    Article  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic press. San Diego

  • Phillis JW, Horrocks LA, Farooqui AA (2006) Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res Rev 52:201–243

    Article  PubMed  CAS  Google Scholar 

  • Rondini TA, Baddini SP, Sousa LF, Bittencourt JC, Elias CF (2004) Hypothalamic cocaine- and amphetamine-regulated transcript neurons project to areas expressing gonadotropin releasing hormone immunoreactivity and to the anteroventral periventricular nucleus in male and female rats. Neuroscience 125:735–748

    Article  PubMed  CAS  Google Scholar 

  • Rosato-Siri MD, Cattaneo A, Cherubini E (2006) Nicotine-induced enhancement of synaptic plasticity at CA3-CA1 synapses requires GABAergic interneurons in adult anti NGF mice. J Physiol 576:361–377

    Article  PubMed  CAS  Google Scholar 

  • Ross BM, Brooks RJ, Kalasinsky KS, Vorce SP, Seeman M, Fletcher PJ, Turenns SD (2002) Cyclooxygenase inhibitor modulation of dopamine-related behaviours. Eur J Pharmacol 23:141–151

    Article  Google Scholar 

  • Ryan LJ, Linder JC, Martone ME, Groves PM (1990) Histological and ultrastructural evidence that d-amphetamine causes degeneration in the neostriatum and frontal cortex of rats. Brain Res 518:66–77

    Article  Google Scholar 

  • Schiltz JC, Sawchenko PE (2002) Distinct brain vascular cell types manifest inducible cyclooxygenase expression as a function of the strength and nature of immune insults. J Neurosci 22:5606–5618

    PubMed  CAS  Google Scholar 

  • Sharifzadeh M, Tavasoli M, Naghdi N, Ghanbari A, Amini M, Roghani A (2005) Post-training intrahippocampal infusion of nicotine prevents spatial memory retention deficits induced by the cyclo-oxygenase-2-specific inhibitor celecoxib in rats. J Neurochem 95:1078–1090

    Article  PubMed  CAS  Google Scholar 

  • Shen F, Meredith GE, Napier TC (2006) Amphetamine-induced place preference and conditioned motor sensitization requires activation of tyrosine kinase receptors in the hippocampus. J Neurosci 26:11041–11051

    Article  PubMed  CAS  Google Scholar 

  • Shu SY, Ju G, Fan LZ (1988) The glucose oxidase-DAB-nickel method in peroxidase histochemistry of the nervous system. Neurosci Lett 85:169–171

    Article  PubMed  CAS  Google Scholar 

  • Stumm G, Schlegel J, Schafer T, Wurz C, Mennel HD, Krieg JC, Vedder H (1999) Amphetamines induce apoptosis and regulation of bcl-x splice variants in neocortical neurons. FASEB J 13:1065–1072

    PubMed  CAS  Google Scholar 

  • Thomas DM, Kuhn DM (2005) Cyclooxygenase-2 is an obligatory factor in methamphetamine-induced neurotoxicity. J Pharmacol Exp Ther 313:870–876

    Article  PubMed  CAS  Google Scholar 

  • Toledano A, Álvarez MI, Rivas L, Lacruz C, Martínez-Rodríguez R (1999) Amyloid precursor proteins in the cerebellar cortex of Alzheimer’s disease patients devoid of cerebellar beta-amyloid deposits: immunocytochemical study of five cases. J Neural Transm 106:1151–1169

    Article  PubMed  CAS  Google Scholar 

  • Turégano L, Martínez-Rodríguez R, Álvarez MI, Gragera RR, Gómez de Segura I, De Miguel E, Toledano A (2001) Histochemical study of acute and chronic intraperitoneal effects on several glycolitic and Krebs cycle dehydrogenase activities in the frontoparietal cortex and subcortical nuclei of the rat brain. J Neurosci Res 64:626–635

    Article  PubMed  Google Scholar 

  • Weiss B, Laties VG (1962) Enhancement of human performance by caffeine and the amphetamines. Pharmacol Rev 14:1–36

    PubMed  CAS  Google Scholar 

  • Wonnacott S, Sidhpura N, Balfour DJ (2005) Nicotine: from molecular mechanisms to behaviour. Curr Opin Pharmacol 5:53–59

    Article  PubMed  CAS  Google Scholar 

  • Wood PL (2003) The cerebellum in AD. A case for arrested neuroinflammation? In: Wood PL (eds) Neuroinflammation. Mechanism and management. 2nd edn. Humana Press, Totova, pp 295–300

    Google Scholar 

  • Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF (1993) Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11:371–386

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was largely funded by the Fundación Mutua Madrileña de Investigación Médica (Spain). The support of the Fundación Alzheimer España (Spain) for the purchase of laboratory material is gratefully acknowledged.

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Authors and Affiliations

  1. Instituto Cajal, CSIC, Avda. Dr. Arce 37, 28002, Madrid, Spain

    A. Toledano & M. I. Álvarez

  2. Centro Investigación, Hospital Universitario La Paz, 28029, Madrid, Spain

    I. Caballero & E. De Miguel

  3. Instituto de Estructura de la Materia, CSIC, Serrano 121, 28006, Madrid, Spain

    P. Carmona

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  1. A. Toledano
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  2. M. I. Álvarez
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Toledano, A., Álvarez, M.I., Caballero, I. et al. Immunohistochemical increase in cyclooxygenase-2 without apoptosis in different brain areas of subchronic nicotine- and d-amphetamine-treated rats. J Neural Transm 115, 1093–1108 (2008). https://doi.org/10.1007/s00702-008-0040-9

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