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International Journal of Clinical and Experimental Neurology

ISSN (Print): 2379-7789

ISSN (Online): 2379-7797

Editor-in-Chief: Zhiyou Cai, MD




Cyclooxygenase Expression in Canines Following Peripheral Nerve Injury

1Department of Orthopedics and Rehabilitation Medicine, Faculty of Medical Sciences, The University of Fukui, Fukui, Japan

2Research and Education Program for Life Science, The University of Fukui, Fukui, Japan

3Department of Orthopedic Surgery, Suzuki Orthopaedic Clinics, Toki, Gifu, Japan

4Department of Orthopedic Surgery, Yamada Orthopaedic Clinics, Hamamatsu, Shizuoka, Japan

5Victor Horsley Department of Neurosurgery, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK

International Journal of Clinical and Experimental Neurology. 2015, 3(2), 26-31
doi: 10.12691/ijcen-3-2-1
Copyright © 2015 Science and Education Publishing

Cite this paper:
Shigeru Kobayashi, Yoshihiko Suzuki, Syuichi Yamada, Naji Al-Khudairi, Adam Meir. Cyclooxygenase Expression in Canines Following Peripheral Nerve Injury. International Journal of Clinical and Experimental Neurology. 2015; 3(2):26-31. doi: 10.12691/ijcen-3-2-1.

Correspondence to: Shigeru  Kobayashi, Department of Orthopedics and Rehabilitation Medicine, Faculty of Medical Sciences, The University of Fukui, Fukui, Japan. Email:


In order to investigate the mechanism of neurogenic pain, this study used a median nerve compression model in dogs. The nerve was compressed with a clip for three weeks. Immunohistochemistry was done by the avidin-biotin-peroxidase complex method to observe the changes of T cells (CD45) and macrophages (Mac-1) after compression. Antibodies against cyclooxygenase (COX)-1 and 2 were used to examine the localization and changes of these mediators caused by nerve compression. In control animals, resident T cells were detected, but there were no macrophages. COX-2 was positive in the Schwann cells and vascular endothelial cells, while COX-1 was detected in the vascular endothelial cells. After nerve compression, numerous T cells and macrophages appeared among the demyelinized nerve fibers. The macrophages were positive for COX-2. COX-2 may be deeply involved in neuritis arising from mechanical compression, and this mediator seems to be important in the manifestation of neurogenic pain.



[1]  O’Neill GP, Ford-Hutchinson AW: Expression of mRNA for cyclooxigenase-1 and cyclooxigenase-2 in human tissues. FEBS Lett, 1993, 2: 156-160.
[2]  Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, Lee L, Isakson P. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA, 1994, 91: 12013-12017.
[3]  Kobayashi S, Meir A, Baba H, Uchida K, and Hayakawa K. Imaging of intraneural edema using gadolinium-enhanced MR imaging: Experimental compression injury. AJNR Am J Neuroradiol, 2005, 26: 973-980.
[4]  Rydevik B, Lundborg, G: Permeability of intraneurial microvessels and perineurium following acute, graded experimental nerve compression. Scand J Plast Reconstr Surg, 1977, 11: 179-187.
[5]  Rydevik B, Lundborg G, Bagg U: Effects of graded compression on intraneural blood flow. J Hand Surg, 1981, 6: 3-12.
Show More References
[6]  Misko TP, Trotter JL, Cross AH: Mediation of inflammation by encephalitogenic cells: interferon-γ induction of nitric oxide synthase and cyclooxygenase 2. J Neuroimmuol, 1995, 61: 195-204.
[7]  Schweizer A, Feige U, Fontana A, Müller K, Dinarello CA: Interleukin-1 enhances pain reflexes. Medication through increased prostaglandin E2 levels. Agents Actions, 1988, 25: 246-251.
[8]  Follenfalt RL, Nakamura-Craig M, Henderson B, Higgs GA: Inhibition of neuropeptides of interleukin-1β-induced, prostaglandin-independent hyperalgesia. Br J Pharmacol, 1989, 98: 41-43.
[9]  Oka T, Aou S, Hori T: Intracerebroventricular injection of interleukin-1β induces hyperalgesia in rats. Brain Res, 1993, 624: 21-68.
[10]  Fukuoka H, Kawatani M, Hisamitsu T, Takeshige C: Cutaneous hyperalgesia induced by peripheral injection of interleukin-1β in the rat. Brain Res, 1994, 657: 133-140.
[11]  DeLeo JA, Colburn RW: The role of cytokines in nociception and chronic pain. In: Weinstein JN, Gordon SL. Ed., Low Back Pain. A Scientific and Clinical Overview. American Academy of Orthopaedic Surgeons, Illinois, 1995: 163-185.
[12]  Jeanjean AP, Moussaoui SM, Maloteaux JM, Laduron PM: Interleukin-1β induces long-term increase of axonally transported opiate receptors and substance P. Neuroscience, 1955, 68: 151-157.
[13]  Kobayashi S, Baba H, Uchida K, Shimada S, Negoro K, Takeno K, Yayama T, Yamada S, Yoshizawa H: Localization and changes of intraneural inflammatory cytokines and inducible-nitric oxide induced by mechanical compression. J Orthop Res, 2005, 23: 771-778.
[14]  Cunha FQ, Poole S, Lorenzetti BB, Ferreira SH: The pivotal role of tumor necrosis factor α in the development of inflammatory hyperalgesia. Br J Pharmacol, 1992, 107: 660-664.
[15]  Watkins LR, Goehler LE, Relton J, Brewer MT, Maier SF: Mechanisms of tumor necrosis factor-α (TNF-α) hyperalgesia. Brain Res, 1995, 692: 244-250.
[16]  Duarte IDG, Lorenzetti BB, Ferreria SH: Peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. Eur J Pharmacol, 1990, 186: 289-293.
[17]  Khail Z, Helme RD: The quantitative contribution of nitric oxide and sensory nerves to bradykinin-induced inflammation in rat skin microvasculature. Brain Res, 1992, 582: 102-108.
[18]  Lalenti A, Lanaro A, Moncada S, Rosa MD: Modulation of acute inflammation by endoeneous nitric oxide. Eur J Pharmacol, 1992, 211: 177-182
[19]  Kawabata A, Manabe S, Manabe T, Takagi H: Effect of topical administration of L-arginine on formalin-induced nociception in the mouse: A dual role of peripherally formed NO in the pain modulation. Br J Pharmacol, 1994, 112: 547-550.
[20]  Choi Y, Raja SN, Moore LC, Tobin JR: Neuropathic pain in rats is associated with altered nitric oxide synthase activity in neural tissue. J Neurol Sci, 1996, 138: 14-20.
[21]  Meller ST, Pechman PS, Gebhart GF, Maves TJ: Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. Neuroscience, 1992, 50: 7-10.
[22]  Dewitt DL: Prostaglandin endoperoxide synthase: Regulation of enzyme expression. Biochim Biophys Acta, 1991, 1083: 121-134.
[23]  Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL: Expression of a mitogen responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acid Sci USA, 1991, 88: 2692-2696.
[24]  Hla T, Neilson, K: Human cyclooxigenase-2 cDNA. Proc Natl Acad Sci USA, 1992, 89: 7384-7388.
[25]  Talmor M, Patel MP, Spann MD, Barden C, Specht M, McLean A, Hoffman LA, Nolanm WB: Cox-2 up-regulation in idiopathic carpal tunnel syndrome. Plast Reconstr Surg, 2003, 112: 1807-1814.
[26]  Yayama T, Kobayashi S, Nakanishi Y, Uchida K, Kokubo Y, Miyazaki T, Takeno K, Awara K., Mwaka ES, Iwamoto Y, Baba H: Effects of graded mechanical compression of rabbit sciatic nerve on nerve blood flow and electrophysiological properties. J Clin Neurosci, 2010, 17, 501-505.
[27]  Kobayashi S, Hayakawa K., Nakane T, Meir A, Mwaka ES, Yayama T, Shimada S, Inukai T, Nakajima H, Baba H: Visualization of intraneural edema using gadolinium-enhanced magnetic resonance imaging in carpal tunnel syndrome. J Orthop Sci, 2009, 14, 24-34.
[28]  Gupta R, Rowshan K, Chao T, Mozaffar, T, Steward O: Chronic nerve compression induces local demyelination and remyelination in a rat model of carpal tunnel syndrome. Exp Neurol, 2004, 187,500-508.
[29]  Yayama T, Kobayashi S, Awara, K, Takeno K, Miyazaki T, Kubota, M, Negoro K, Baba H: Intraneural blood flow analysis during an intraoperative Phalen's test in carpal tunnel syndrome. J Orthop Res 28: 1022-1025, 2010.
[30]  Lacroix S, Rivest S: Effect of acute systemic inflammatory response and cytokines on the transcription of the genes encoding cyclooxygenase enzymes (COX-1 and COX-2) in the rat brain. J Neurochem, 1998, 70: 452-466.
[31]  Nogawa S, Forster C, Zhang F, Nagayama M, Ross ME, Iadecola C: Interaction between inducible nitric oxide synthesis and cyclooxigenase-2 after cerebral ischemia. Proc Natl Acad Sci USA, 1988, 95: 10966-10971.
[32]  Tonai T, Taketani Y, Ueda N, Nishisho T, Ohmoto Y, Sakata, Y, Muraquchi M, Wada K, Yamamoto S: Possible involvement of interleukin-1 in cyclooxigenase-2 induction after spinal cord injury in rats. J Neurochem, 1999, 72: 302-309.
[33]  Ma W, Eisenach JC: Morphological and pharmacological evidence for the role of peripheral prostaglandins in the pathogenesis of neuropathic pain. Eur J Neurosci, 2002, 15: 1037-1047.
[34]  Durrenberger PF, Facer P, Gray RA, Chessell IP, Naylor A, Bountra C, Banati RB, Birch R, Anand P: Cyclooxygenase-2 (Cox-2) in injured human nerve and a rat model of nerve injury. J Peripher Nerv Syst, 2004, 9: 15-25.
[35]  Ma W, Eisenach JC: Cyclooxygenase 2 in infiltrating inflammatory cells in injured nerve is universally up-regulated following various types of peripheral nerve injury. Neuroscience, 2003, 121: 691-704.
[36]  Lee SH, Soyoola E, Chanmugam P, Hart S, Sun W, Zhong H, Liou S, Simmons D, Hwang D: Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. J Biol Chem, 1992, 267: 25934-25938.
[37]  Schiltz JC, Sawchenko PE: Distinct brain vascular cell types manifest inducible cyclooxygenase expression as a function of the strength and nature of immune insults. J Neurosci, 2002, 22: 5606-5618.
Show Less References


Behavioral and Neurochemical Characteristics of Two Months Old WAG/Rij Rats with Genetic Absence Epilepsy

1Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia

2State Zakusov Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, Russia

International Journal of Clinical and Experimental Neurology. 2015, 3(2), 32-44
doi: 10.12691/ijcen-3-2-2
Copyright © 2015 Science and Education Publishing

Cite this paper:
E. A. Fedosova, K. Yu. Sarkisova, V. S. Kudrin, V. B. Narkevich, A. S. Bazyan. Behavioral and Neurochemical Characteristics of Two Months Old WAG/Rij Rats with Genetic Absence Epilepsy. International Journal of Clinical and Experimental Neurology. 2015; 3(2):32-44. doi: 10.12691/ijcen-3-2-2.

Correspondence to: A.  S. Bazyan, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia. Email:


WAG/Rij rats are genetic animal model of absence epilepsy with comorbidity of depression. The first spike-wave discharges (SWDs) in WAG/Rij rats begin to appear at the age of 2-3 months and are fully manifested by 5-6 months. Occurrence of SWDs in the EEG is the main index of absence epilepsy. Previously it has been shown that the extensive absence epilepsy in 5-6 months old WAG/Rij rats is accompanied by decrease of dopamine and its metabolites concentrations in the meso-cortico-limbic and nigro-striatal dopaminergic brain systems, resulting in the expression of depression-like behavioral symptoms, and impairments of the learning and memory processes. In 36 days old WAG/Rij rats, SWDs are not manifested, deficiency of the mesolimbic dopamine is not revealed, and symptoms of depression-like behavior are not expressed. In this study, behavior in the open field, light-dark choice, forced swimming tests, monoamines and their metabolites concentrations in 5 brain structures (prefrontal cortex, nucleus accumbens, hypothalamus, striatum, hippocampus) were investigated in two months old WAG/Rij rats in comparison with age-matched Wistar rats. Reduced concentration of the dopamine and its metabolites, and increased concentration of the serotonin was found in WAG/Rij rats compared with Wistar rats only in the prefrontal cortex, indicating that the prefrontal cortex is the brain structure where neurochemical abnormalities appear first. No substantial changes in the monoamine and their metabolites concentrations have been revealed in other brain structures. Two months old WAG/Rij rats didn’t exhibit depression-like behavior in the forced swimming test, and learning/memory deficits in the passive avoidance test, but they showed behavioral changes, indicating increase anxiety/stress-reactivity, and alterations in learning/memory in the active avoidance test. Results suggest that two month-old WAG/Rij rats are at the stage of so called “pre-pathology” (increased anxiety and stress reactivity) preceding the development of depression-like behavior and substantial cognitive impairments which are co-morbid to fully expressed absence epilepsy in 5-6 months old rats of this strain.



[1]  Barson JR, Morganstern I, Leibowitz SF (2011). Similarities in hypothalamic and mesocorticolimbic circuits regulating the overconsumption of food and alcohol. Physiol Behav; 104 (1): 128-137.
[2]  Bazyan AS (1999). Neuromodulators and integrative mechanisms of emotional and motivation states. Neurochemical Journal; 16 (2): 88-103.
[3]  Bazyan AS, Orlova NV, Getsova VM (2000). Modulation of the activity of monoaminergic brain systems and emotional condition by dalargin in rats during development of emotional resonance response. Zh Vyssh Nerv Deiat Im I P Pavlova; 50(3): 500-508.
[4]  Bazyan AS (2001). Divergent and convergent mechanisms of the integrative activity of the mammalian brain. Zh Vyssh Nerv Deiat Im I P Pavlova; 51(4): 514-528.
[5]  Bazyan AS, Segal OL (2009). Synaptic and paracrine nonsynaptic systems of the mammalian brain. Neurochemical Journal; 3(2): 77-86.
Show More References
[6]  Bazyan AS, Grigir'ian GA, Ioffe ME, 2011. Regulation of motor behaviour. Usp Fiziol Nauk; 42(3): 65-80.
[7]  Bazyan AS, and van Luijtelaar G (2013). Review article. Neurochemical and behavioral features in genetic absence epilepsy and in acutely induced absence seizures. ISRN Neurology. Art. ID 875834.
[8]  Bechara A, Damasio AR (2005). The somatic marker hypothesis: a neural theory of economic decision. Games and Econom. Behav; 52 (2): 336-372.
[9]  Braw Y, Malkesman O, Dagan M, Bercovich A, Lavi-Avnon Y, Schroeder M, Overstreet DH, Weller A (2006). Anxiety-like behaviors in pre-pubertal rats of the Flinders Sensitive Line (FSL) and Wistar-Kyoto (WKY) animal models of depression. Behav. Brain Res; 167 (2): 261-269.
[10]  Calatayud F, Belzung C, Aubert A (2004). Ethological validation and the assessment of anxiety-like behaviors: methodological comparison of classical analysis and structural approaches. Behav Processes; 67(2): 195-206.
[11]  Carlezon WAJr, Thomas MJ (2009). Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis. Neuropharmacol; 56 (1): 122-132.
[12]  Costall B, Jones BJ, Kelly ME, Neylor RJ, Tomkins DM, (1989). Exploration of mice in a black and white test box: validation as a model of anxiety. Pharmacol Biochem Behav; 32(3): 777-785.
[13]  Cryan JF, Lucki I (2000). Antidepressant-like behavioral effects mediated by 5-hydroxytryptamine (2C) receptors. Pharmacol. Exp. Ther; 295(3): 1120-1126.
[14]  Deneve S, (2012). Making decisions with unknown sensory reliability. Front Neurosci. 6:75.
[15]  Espejo EF (1997). Selective dopamine depletion within the medial prefrontal cortex induces anxiogenic-like effects in rats placed on the elevated plus maze. Brain Res; 762(1-2): 281-284.
[16]  Garcia-Cairasco N, Oliveira JAC, Wakamatsu H, Bueno ST, Guimaraes FS (1998). Reduced exploratory activity of audiogenic seizure susceptible Wistar rats. Physiol Behav; 64(5): 671-674.
[17]  Gonzalez C, Kramar C, Garagoli F, Rossato JI, Weisstaub N, Cammarota M, Medina JH (2013). Medial prefrontal cortex is a crucial node of a rapid learning system that retrieves recent and remote memories. Neurobiol. Learn. Mem; 103: 19-25.
[18]  Griebel G., Rodgers R., Perrault C.H, Sanger D.J., 1997. Risk assessment behavior: evaluation of utility in the study of 5-HT-related drugs in the rat elevated plus-maze test. Pharmacol Biochem Behav. 57(4): 817-827.
[19]  Gruber A.J., McDonald R.J. 2012. Context, emotion, and the strategic pursuit of goals: interactions among multiple brain systems controlling motivated behavior. Front Behav Neurosci; 6: 50.
[20]  Hascoët M., Bourin M., Nic Dhonnchadha B.Á., 2001. The mouse ligth-dark paradigm: A review. Prog. Neuropsychopharmacol. Bio. Psychiatry; 25(1): 141-166.
[21]  Ho S.S., Gonzalez R.D., Abelson J.L., Liberzon I., 2012. Neurocircuits underlying cognition-emotion interaction in a social decision making context. Neuroimage; 63(2): 843-537.
[22]  Jüngling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, Okamura N, Duangdao DM, Xu Y-L, Reinscheid RK, Pape H-C (2008). Neuropeptide S-mediated control of fear expression and extinction: Role of intercalated GABAergic neurons in the amygdala. Neuron; 59(2): 298–310.
[23]  King D, Zigmond MJ, Finlay JM (1997). Effects of dopamine depletion in the medial prefrontal cortex on the stress-induced increases in extracellular dopamine in the nucleus accumbens and shell. Neurology; 77(1): 141-153.
[24]  Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D, Henn F, Malinow R (2011). Synaptic potentiation onto habenula neurons in learned helplessness model of depression. Nature; 470(7335): 535-539.
[25]  Lucki I (1997). The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav. Pharmacol; 8(6-7): 523-532.
[26]  Matveeva MI, Shtemberg AS, Timoshenko GN, Krasavin EA, Narkevich VB, Klodt PM, Kudrin VS, Bazyan AS (2013). The effects of irradiation by 12C carbon ions on monoamine exchange in several rat brain structures. Neurochemical Journal; 7(4): 303–307.
[27]  Mink JW (2003). The basal ganglia. Fundamental neuroscience. 2nd/Ed. Scuire LR, Bloom FT, McConnell SC, Roberts JL, Spitzer NC, Zigmond MJ. Elsevier Sci.: Acad. Press; 815-839.
[28]  Morrow A.L., Porcu P., Boyd K.N., Grant K.A., 2006. Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior. Dialogues Clin. Neurosci; 8(4): 463-477.
[29]  Naitoh H, Nomura S, Kunimi Y, Yamaoka K (1992). "Swimming-induced head twitching" in rats in the forced swimming test induced by overcrowding stress: a new marker in the animal model of depression? Keio J Med; 41(4): 221-224.
[30]  Nozek K, Dennis K, Andrus BM, Ahmadiyeh N, Baum AE, Woods LC, Redei EE (2008). Context and stress-dependent behavioral response to stress. Behav. Brain Functions; 4:23.
[31]  Porsolt RD, Lenegre A (1992). Behavioral models of depression. In Elliot J.M., Heal D.J., Marsden C.A. (Eds) Experimental approaches to anxiety and depression. Willey, New York; 73-85.
[32]  Prut L, Belzung C (2003). The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol; 463(1-3): 3-33.
[33]  Przybycien-Szymanska MM, Gillespie RA, Pak TR (2012). 17β-Estradiol is required for the sexually dimorphic effects of repeated binge-pattern alcohol exposure on the HPA axis during adolescence. PLoS One; 7 (2):e32263.
[34]  Sarkisova KYu, Kolomeitseva IA, Kulikov MA (1996). Effects of substance P on behavioral measures in the open field and forced swimming tests in rats with different type of behavior. Bull Exp Biol Med; 121: 244-247.
[35]  Sarkisova KYu, Kulikov MA, (1994). Individual differences in reaction to acute stress associated with type of behavior. Prediction of the resistance to stress. Bull Exp Biol Med; 117: 89-92.
[36]  Sarkisova KYu, Kulikov MA (2001). Prophylactic action of the antioxidant agent AEKOL on behavioral (psycho-emotional) disturbances induced by chronic stress in rats. Neurosci Behav Physiol; 31(5): 503-508.
[37]  Sarkisova KYu, Midzyanovskaya IS, Kulikov MA (2003). Depressive-like behavioral alterations and c-fos expression in the dopaminergic brain regions in WAG/Rij rats with genetic absence epilepsy. Behav Brain Res; 144(1-2): 211-226.
[38]  Sarkisova KYu, Kulikov MA (2006). Behavioral characteristics of WAG/Rij rats susceptible and non-susceptible to audiogenisc seizures. Behav Brain Res; 166(1): 9-18.
[39]  Sarkisova KYu, Kulikov MA, Midzyanovskaya IS, Folomkina AA (2008). Dopamine-dependent nature of depression-like behavior in WAG/Rij rats with genetic absence epilepsy. Neurosci Behav Physiol; 38(2): 119-128.
[40]  Sarkisova KYu, Kulikov MA, Folomkina AA (2011). Does antiabsence drug ethosuximide exert antidepressant effect? Zh Vyssh Nerv Deiat Im I P Pavlova: 61(2):227-235.
[41]  Sarkisova K, van Luijtelaar G (2011). Review article. The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry; 5(4): 854-876.
[42]  Sarkisova KYu, Kulikov MA, Kudrin VS, Narkevich VB, Midzyanovskaya I.S., Birioukova LM, Folomkina AA, Bazyan A.S (2013a). Neurochemical mechanisms of depression-like behavior in WAG/Rij rats. Zh. Vyssh. Nerv. Deiat. Im I P Pavlova; 63(3): 303-315.
[43]  Sarkisova KYu, Kulikov MA, Midzyanovskaya IS, Birioukova LM, Kudrin VS (2013b). Neurochemical mechanisms of depression in absence epilepsy. Abstracts IX International interdisciplinary congress "Neuroscience for medicine and psychology", Sudak, Crimea, Ukraine, June 3-13, P. 279-280.
[44]  Shumake J, Ilango A, Scheich H, Wetzel W, Ohl FW (2010). Differential neuromodulation of acquisition and retrieval of avoidance learning by the lateral habenula and ventral tegmental area. J Neurosci; 30(17): 5876-5883.
[45]  Tanji J, Hoshi E (2008). Role of the lateral prefrontal cortex in executive behavioral control. Physiol Rev; 88(1): 37-57.
[46]  Takao K., Miyakawa T., 2006. Light/dark transition test for mice. J Vis Exp. Nov; 13(1): 104.
[47]  Zaitsev AV, Lewis DA (2013). Functional properties and short-term dynamics of unidirectional and reciprocal synaptic connections between layer 2/3 pyramidal cells and fast-spiking interneurons in juvenile rat prefrontal cortex. Eur J Neurosci; 38(7): 2988-2998.
[48]  Zhou WL, Antic SD (2012). Rapid dopaminergic and GABAergic modulation of calcium and voltage transients in dendrites of prefrontal cortex pyramidal neurons. J Physiol; 590(16): 3891-3911.
Show Less References


Neuropsychiatric Symptoms of Urbach-Wiethe Disease

1School of Psychology, Kean University, Union, NJ, USA

2Department of Nursing, Kean University, Union, NJ, USA

International Journal of Clinical and Experimental Neurology. 2015, 3(2), 45-50
doi: 10.12691/ijcen-3-2-3
Copyright © 2015 Science and Education Publishing

Cite this paper:
Richard P. Conti, Jacqueline M. Arnone. Neuropsychiatric Symptoms of Urbach-Wiethe Disease. International Journal of Clinical and Experimental Neurology. 2015; 3(2):45-50. doi: 10.12691/ijcen-3-2-3.

Correspondence to: Richard  P. Conti, School of Psychology, Kean University, Union, NJ, USA. Email:


Urbach–Wiethe (or lipoid proteinosis) disease (UWD) is a rare autosomal recessive disorder characterized by dermatological, psychiatric, and neurological symptoms. Presentation occurs during childhood, but can be observed from birth. While benign, the disease is progressive and chronic with no known cure. Treatment modalities are palliative for symptoms. The extant literature consists mainly of anecdotal reports and case studies that are limited by small sample sizes and paucity of controlled studies. Incidence and prevalence rates are unknown. There are less than 500 documented cases reported worldwide, and of those, less than 50 cases demonstrate neurological and neuropsychiatric conditions. Worldwide occurrence of the disease is documented, with the largest cohort living in a remote area of South Africa. The affected individuals are mainly Caucasian, born to consanguineous parents, and from Dutch or German heritage. Patients affected have been reported in China, Pakistan and Iran. Current and earlier studies focus primarily on the most visible signs of disease, dystonia and dermatological symptoms, while other studies have reported calcification in the amygdala, hippocampus, parahippocampal gyrus, and the striatum. While central nervous system involvement can lead to a wide range of clinical manifestations such as epilepsy and neuropsychiatric symptoms, there is not a consensus of reported cases with amygdala calcifications accompanied by neurological symptoms. Quantitative research is warranted to further identify the role and relationship between amygdala calcification and neurologic and neuropsychiatric symptoms, while qualitative research will afford insights into the lived experience of individuals and families living with UWD.



[1]  Siebert M., Markowitsch H.J., and Bartel P. “Amygdala, affect and cognition: evidence from 10 patients with Urbach-Wiethe disease,” Brain, 2003; 126: 2627-2637.
[2]  Thornton H.B., Nel D., Thornton D., van Honk J., Baker G.A., and Stein D.J. “The neuropsychiatry and neuropsychology of lipoid proteinosis,” J Neuropsychiatry Clin Neurosci, 2008; 20: 86-92.
[3]  Goncalves F.G., de Melo M.B., de L. Matos V., Barra F.R., and Figueroa R.E. “Amygdalae and striatum calcification in lipoid proteinosis,” Am J Neuroradiol, 2010; 31: 88-90.
[4]  Appenzeller S., Chaloult E., Velho P., et al. “Amygdalae calcifications associated with disease duration in lipoid proteinosis.” J Neuroimag, 2006; 16: 154-156.
[5]  Aziz M.T., Mandour M.A., El-Ghazzawi I.F., Belal A.-E.-A., and Talaat A.M. “Urbach-Wiethe disease in ORL practice (A clinical and histochemical study of the laryngeal lesions),” J Laryngol Otol, 1980; 94: 1309-1319.
Show More References
[6]  Yakout Y.M., Elwany S., Abdel-Kreem A., and Seif S.A. “Radiological finding in lipoid proteinosis,” J Laryngol Otol, 1985; 99: 259-265.
[7]  Urbach E., and Wiethe C. “Lipoidosis cutis et mucosa,” Virchows Archiv Pathol, 1929; 27: 286-319.
[8]  Hamada T., McLean W.H.I., Ramsay M., Ashton G.H.S., Nanda A., Jenkins T., Edelstein I., South A.P., Bleck O., Wessagowit V., Mallipeddi R., and Orchard G.E. “G. Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1),” Hum Molec. Genet, 2002; 11: 833-840.
[9]  Hamada T., Wessagowit V., South A.P., Ashton G.H.S., Chan I., Oyama N., Siriwattana A., and McGrath J.A. “Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correllation,” J Invest Dermatol, 2003; 120: 345-350.
[10]  Kachewar, S.G., and Kulkarni, D.S. “A novel association of the additional intracranial calcification in lipid proteinosis: A case report.” J Clin and Diag Res, 2012; 9: 1579-1581.
[11]  Morgan B., Terburg D., Thornton H.B., Stein D.J., and van Honk J. “Paradoxical facilitation of working memory after basolateral amygdala damage,” Plos One, 2012; 7(6): e38116.
[12]  Emsley R.A., and Paster L. “Lipoid proteinosis presenting with neuropsychiatric manifestations,” J Neurol Neurosurg Psychiatry, 1985; 48:1290-1292.
[13]  Holme S.A., Lenane P., and Krafchik B.R. “What syndrome is this? Urbach-Weithe syndrome (Lipoid proteinosis),” Pediatr Dermatol, 2005; 22(3): 266-267.
[14]  Kachewar S., Singh B.H., Sasane A.G., and Bhadane S. “Full blown case of lipoid proteinosis,” Med J Armed Forces of India, 2011; 67: 90-91.
[15]  Nanda A., Alsaleh Q.A., Al-Sabah H., Ali A.M., and Anim J.T. “Lipoid Proteinosis: Report of four siblings and brief review of the literature,” Pediatr Dermatol, 2001; 18(1): 21-26.
[16]  Sainani M.P., Muralidhar R., Parthiban K., and Vijayalakshmi P. “Lipoid proteinosis of Urbach and Wiethe: A case report,” Int Opthalmol, 2011; 31: 141-143.
[17]  Hofer P.A. “Urbach-Wiethe disease (lipoglycoproteinosis; lipoid proteinosis; hyalinoses cutis et mucosae). A review,” Acta Dermato Venereologica Supplementum, 1973; 53: 1-52.
[18]  Toosi S., and Ehsani A.H. “Treatment of lipoid proteinosis with acitretin: A case report,” J Eur Acad Dermatol, 2009; 23: 482-483.
[19]  Wong C.K., and Lin C.S. “Remarkable response of lipid proteinosis to oral dimethylsulphoxide,” Brit J Dermatol, 1988; 119: 541-544.
[20]  Zhang R., Liu Y., Xue Y., Wang Y., Wang X., Shi S., Cai T., and Wang Q. “Treatment of lipoid proteinosis due to the p.C220G mutation in ECM1, a major allele in Chinese patients,” J Transl Med, 2014; 12(85).
[21]  Hamann S.B., Ely T.D., Hoffman J.M., and Kilts C.D. “Ecstasy and Agony: Activation of the human amygdala in positive and negative emotion,” Psychol Sci, 2002; 13(2): 135-141.
[22]  Markowitsch, H.J., and Staniloiu A. “Amygdala in action: Relaying biological and social significance to autobiographical memory,” Neuropsychologia, 2011; 49 (4): 718-733.
[23]  Terburg D., Morgan B. E., Montoya E. R., Hooge I.T., Thornton H.B., Hariri A.R., ... and van Honk J. “Hypervigilance for fear after basolateral amygdala damage in humans,” Transl Psychiatry, 2012; 2e115.
[24]  Bach, D. R., Talmi, D., Hurlemann, R., Patin, A., and Dolan, R. J. “Automatic relevance detection in the absence of a functional amygdala,” Neuropsychologia, 2011; 49(5): 1302-1305.
[25]  Yang, T. T., Menon, V., Eliez, S., Blasey, C., White, C. D., Reid, A. J.... and Reiss, A. L. “Amygdalar activation associated with positive and negative facial expressions,” Neuroreport, 2002; 13(14): 1737-1741.
[26]  Tranel, D., Gullickson, G., Koch, M., and Adolphs, R. “Altered experience of emotion following bilateral amygdala damage,” Cogn Neuropsychiatry, 2006; 11(3): 219-232.
[27]  Chan I., Liu L., Hamada T., Sethuraman G., and McGrath J.A. “The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein,” Exp Dermatol, 2007; 16: 881-890.
[28]  Boudouresque J., Cosset A., and Sayag J. “Maladie d’Urbach-Whiethe: Crises temporales avec phenomenes extatiques et calcification des deux lobes temporaux,” Bull Acad Med Paris, 1972; 156: 416-442.
[29]  Claeys K.G., Claes L.R.F., Van Goethem J.W.M., et al. “Epilepsy and migraine in a patient with Urbach–Wiethe disease,” Seizure, 2007; 16: 465-468.
[30]  Omrani H.G., Tajdini M., Ghelichnia B., et al. “Should we think of Urbach–Wiethe disease in refractory epilepsy? Case report and review of the literature,” J Neurol Sci, 2012; 320: 149-152.
[31]  Matthies S., Rüsch N., Weber M., et al. “Small amygdala–high aggression? The role of the amygdala in modulating aggression in healthy subjects,” World J Biol Psychiatry, 2012; 13(1): 75-78.
[32]  Newton F.H., Rosenberg R.N., Lampert P.W., and O'Brien J.S. “Neurologic involvement in Urbach‐Wiethe's disease (lipoid proteinosis) A clinical, ultrastructural, and chemical study,” Neurol, 1971; (12), 1205-1213.
[33]  Lupo I., Cefalu A.B., Bongiorno M.R., et al. “A novel mutation of the extracellular matrix protein 1 gene (ECM1) in a patient with lipoid proteinosis (Urbach-Wiethe disease) from Sicily,” Brit J Dermatol, 2005; 153(5): 1019-1022.
[34]  Kleinert R., Cervos-Navarro J., Kleinert G., et al. “Predominantly cerebral manifestation in Urbach-Wiethe's syndrome (lipoid proteinosis cutis et mucosae): A clinical and pathomorphological study,” Clin Neuropathol, 1986; 6(1): 43-45.
[35]  Adolphs R., Tranel D., Damasio H., and Damasio A. “Impaired recognition of emotion in facial expression following bilateral damage to the human amygdala,” Nature, 1994; 372: 669-672.
[36]  Adolphs R., Tranel D., Damasio H., and Damasio A.R. “Fear and the human amygdala,” J Neurosci, 1995; 15: 5879-5891.
[37]  Paul L.K., Corsello C., Tranel D., and Adolphs R. “Does bilateral damage to the human amygdala produce autistic symptoms?,” J Neurodev Disord, 2010; 2(3): 165-173.
[38]  Adolphs, R., and Tranel, D. “Impaired judgments of sadness but not happiness following bilateral amygdala damage,” J Cogn Neurosci, 2004; 16(3): 453-462.
[39]  Adolphs R., Gosselin F., Buchanan T.W., Tranel D., Schyns P.G, and Damasio A. “A mechanism for impaired fear recognition after amygdala damage,” Nature, 2005; 433: 68-72.
[40]  Adolphs R., Spezio M.L., Parlier M., and Piven J. “Distinct face-processing strategies in parents of autistic children,” Curr Biol, 2008; 18: 1090-1093.
[41]  Böhme M., and Wahlgren C.F. “Lipoid proteinosis in three children,” Acta Paediatrica, 1996; 85(8): 1003-1005.
[42]  Bahadir S., Cobanoglu U., Kapicioglu Z., et al. “Lipoid proteinosis: A case with ophthalmological and psychiatric findings,” J Dermatol, 2006; 33(3): 215-218.
[43]  Salih M.A., Abu-Amero K.K., Alrasheed S., et al. “Molecular and neurological characterizations of three Saudi families with lipoid proteinosis,” BMC Med Genet, 2011; 12(3).
[44]  Markowitsch H.J., Calabrese P., Würker M., Durwen H.F., et al. “The amygdala's contribution to memory-a study on two patients with Urbach-Wiethe disease,” Neuroreport, 1994; 5(11): 1349-1352.
[45]  Cahill L., Haier R.J., Fallon J., Alkire M.T., Tang C., Keator D., et al. “Amygdala activity at encoding correlated with long‐term, free recall of emotional information,” Proc Natl Acad Sci USA, 1996; 93(15): 8016-8021.
[46]  Adolphs R, Cahill L., Schul R., and Babinsky R. “Impaired declarative memory for emotional material following bilateral amygdala damage in humans,” Learn Memory, 1997; 4(3): 291-300.
[47]  Hurlemann R., Wagner M., Hawellek B., et al. “Amygdala control of emotion-induced forgetting and remembering: Evidence from Urbach-Wiethe disease,” Neuropsychologia. 2007; 45(5): 877-884.
[48]  Claeys K.G., Claes L.R.F., Van Goethem J.W.M., et al. “Epilepsy and migraine in a patient with Urbach–Wiethe disease,” Seizure, 2007; 16(5): 465-468.
[49]  Wiest G., Lehner-Baumgartner E., and Baumgartner C. “Panic attacks in an individual with bilateral selective lesions of the amygdala,” Arch Neurol, 2006; 63(12): 1798-1801.
[50]  Brand M., Grabenhorst F., Starcke K., Vandekerckhove M.M., and Markowitsch H.J. “Role of the amygdala in decisions under ambiguity and decisions under risk: evidence from patients with Urbach-Wiethe disease,” Neuropsychologia, 2007; 45(6): 1305-1317.
[51]  Becker, B., Mihov, Y., Scheele, D., Kendrick, K. M., Feinstein, J. S., Matusch, A.,... and Hurlemann, R. “Fear processing and social networking in the absence of a functional amygdala,” Biol Psychiatry, 2012; 72(1): 70-77.
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