The activity of antiparkinsonian drug hemantane in models of peripheral inflammation and lipopolysaccharide-induced neuroinflammation
ABSTRACT
A large body of literature supports the idea that inflammation exacerbates neurodegenerative pathology. This idea is also supported by the fact that intracerebral or intraperitoneal injection of lipopolysaccharide (LPS) induces symptoms of Parkinson’s disease in rats. The aim of this study is to evaluate the anti-inflammatory effects of the novel antiparkinsonian drug hemantane (N-2(adamantyl)hexamethylenimine hydrochloride), which is currently undergoing clinical trials, in models of peripheral inflammation and neuroinflammation and to investigate its ulcerogenic action, which is a common side effect of nonselective nonsteroidal anti-inflammatory drugs. Acetic acid-induced peritonitis in mice was used as a model of peripheral inflammation. Effect on the stomach was investigated in rats were deprived of food for 16 hours and then were treated with 0.2 LD50 of hemantane or the comparator drug diclofenac sodium per os. Injection of LPS in the left substantia nigra pars compacta in rats was chosen as a model of neuroinflammation. LPS-induced body weight loss, forelimb akinesia and behavioral changes caused by irritating odor were registered in rats. Hemantane in the dosage range of 10 - 40 mg/kg demonstrates anti-inflammatory activity and significantly decreases the intensity of exudative reaction in a model of acetic acid-induced peritonitis in mice. Additionally, at the dose of 0.2 LD50 orally it did not damage the gastric mucosa of rats. In a model of neuroinflammation induced by a unilateral injection of LPS, hemantane (10 mg/kg) prevents weight loss, development of forepaw akinesia contralateral to the operation, and smell disturbance in rats. Effectiveness of hemantane in the animal models of peripheral inflammation and neuroinflammation make it possible to suggest a new application of hemantane as a safe anti-inflammatory drug.
A large body of literature supports the idea that inflammation exacerbates neurodegenerative pathology. This idea is also supported by the fact that intracerebral or intraperitoneal injection of lipopolysaccharide (LPS) induces symptoms of Parkinson’s disease in rats. The aim of this study is to evaluate the anti-inflammatory effects of the novel antiparkinsonian drug hemantane (N-2(adamantyl)hexamethylenimine hydrochloride), which is currently undergoing clinical trials, in models of peripheral inflammation and neuroinflammation and to investigate its ulcerogenic action, which is a common side effect of nonselective nonsteroidal anti-inflammatory drugs. Acetic acid-induced peritonitis in mice was used as a model of peripheral inflammation. Effect on the stomach was investigated in rats were deprived of food for 16 hours and then were treated with 0.2 LD50 of hemantane or the comparator drug diclofenac sodium per os. Injection of LPS in the left substantia nigra pars compacta in rats was chosen as a model of neuroinflammation. LPS-induced body weight loss, forelimb akinesia and behavioral changes caused by irritating odor were registered in rats. Hemantane in the dosage range of 10 - 40 mg/kg demonstrates anti-inflammatory activity and significantly decreases the intensity of exudative reaction in a model of acetic acid-induced peritonitis in mice. Additionally, at the dose of 0.2 LD50 orally it did not damage the gastric mucosa of rats. In a model of neuroinflammation induced by a unilateral injection of LPS, hemantane (10 mg/kg) prevents weight loss, development of forepaw akinesia contralateral to the operation, and smell disturbance in rats. Effectiveness of hemantane in the animal models of peripheral inflammation and neuroinflammation make it possible to suggest a new application of hemantane as a safe anti-inflammatory drug.
Cite this paper
Ivanova, E., Kapitsa, I., Valdman, E. and Voronina, T. (2013) The activity of antiparkinsonian drug hemantane in models of peripheral inflammation and lipopolysaccharide-induced neuroinflammation. Advances in Parkinson's Disease, 2, 11-17. doi: 10.4236/apd.2013.21003.
Ivanova, E., Kapitsa, I., Valdman, E. and Voronina, T. (2013) The activity of antiparkinsonian drug hemantane in models of peripheral inflammation and lipopolysaccharide-induced neuroinflammation. Advances in Parkinson's Disease, 2, 11-17. doi: 10.4236/apd.2013.21003.
References
[1] Phani, S., Loike, J.D. and Przeborski, S. (2012) Neurodegeneration and inflammation in Parkinson desease. Parkinsonism & Related Disorders, 18, S207-S209. doi:10.1016/S1353-8020(11)70064-5 [2] Streit, W.J., Mrak, R.E. and Griffin, W.S.T. (2004) Microglia and neuroinflammation: A pathological perspective. Journal of Neuroinflammation, 1, 14. http://www.jneuroinflammation.com/content/1/1/14 doi:10.1186/1742-2094-1-14 [3] McGeer, P.L., Schwab, C., Parent, A. and Doudet, D. (2003) Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Annals of Neurology, 54, 599-604.doi:10.1002/ana.10728 [4] Nagatsu, T., Mogi, M., Ichinose, H. and Togari, A. (2000) Cytokines in Parkinson’s disease. Journal of Neural Transmission. Supplement, 58, 143-151. [5] Blum-Degen, D., Muller, T., Kuhn, W., Gerlach, M., Przuntek, H. and Riederer, P. (1995) Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neuroscience Letters, 202, 17-20. doi:10.1016/0304-3940(95)12192-7 [6] Mogi, M., Harada, M., Riederer, P., Narabyashi, H., Fujita. J. and Nagatsu, T. (1994) Interleukin-1 beta growth factor and transforming growth factor-alpha are elevated in the brain from Parkinsonian patients. Neuroscience Letters, 180, 147-150. doi:10.1016/0304-3940(94)90508-8 [7] Muller, T., Blum-Degen, D., Przuntek, H. and Kuhn, W. (1998) Interleukin-6 levels in cerebrospinal fluid inversely correlate to severity of Parkinson’s disease. Acta Neurologica Scandinavica, 98, 142-144. doi:10.1111/j.1600-0404.1998.tb01736.x [8] Knott, C., Stern, G. and Wilkin, G.P. (2000) Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenase-1 and -2. Molecular and Cellular Neuroscience, 16, 724-739. doi:10.1006/mcne.2000.0914 [9] Gao, X., Chen, H., Schwarzchild, M.A. and Ascherio, A. (2011) Use of ibuprofen and risk of Parkinson’s disease. Neurology, 76, 863-869. doi:10.1212/WNL.0b013e31820f2d79 [10] Hirsch, E.C. and Hunnot, S. (2009) Neuroinflammation in Parkinson’s disease: A target for neuroprotection? The Lancet Neurology, 8, 382-397. doi:10.1016/S1474-4422(09)70062-6 [11] Qin, L., Wu, X., Block, M.L., Liu, Y., Breese, G.R., Hong, J.S., et al. (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia, 55, 453-462.doi:10.1002/glia.20467 [12] Kim, W.G., Mohney, R.P., Wilson, B., Jeohn, G.H., Liu, B. and Hong, J.S. (2000) Regional difference in susceptibility to lipopolysacchride-induced neurotoxicity in the rat brain: Role of microglia. The Journal of Neuroscience, 20, 6309-6316. [13] Lieberman, A.P., Pitha, P.M., Shin, H.S. and Shin, M.L. (1989) Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proceedings of the National Academy of Sciences of the United States of America, 86, 6348-6352. doi:10.1073/pnas.86.16.6348 [14] Chang, Y.C., Kim, H.-W., Rapoport, S.I. and Rao, J.S. (2008) Chronic NMDA administration increases neuroinflammatory markers in rat frontal cortex: Cross-talk between excitotoxicity and neuroinflammation. Neurochemical Research, 33, 2318-2323. doi:10.1007/s11064-008-9731-8 [15] Val’dman, E.A. (2001) Application-specific protocol. FSBI Zakusov Institute of Pharmacology, Moscow. [16] Wober, W. (1999) Comparative efficacy and safety of nimesulide and diclofenac in patients with acute shoulder, and a meta-analysis of controlled studies of nimesulide. Rheumatology (Oxford), 38, 33-38. doi:10.1093/rheumatology/38.suppl_1.33 [17] Caldwell, J.R. (1986) Efficacy and safety of diclofenac sodium in rheumatoid arthritis experience in the United States. The American Journal of Medicine, 80, 43-47. [18] Akriviadis, E., Hatzigavriel, M., Kapnias, D., Kirimlidis, J., Markantas, A. and Garyfallos, A. (1997) Treatment of biliary colic with diclofenac: A randomized, double-blind, placebo-controlled study. Gastroenterology, 113, 225-231. doi:10.1016/S0016-5085(97)70099-4 [19] Jorge, L.L., Feres, C.C. and Teles, V.E. (2011) Topical preparations for pain relief: Efficacy and patient adherence. Journal of Pain Research, 4, 11-24. [20] Davies, N.M. and Anderson, K.E. (1997) Clinical pharmacokinetics of diclofenac. Therapeutic insights and pitfalls. Clinical Pharmacokinetics, 33, 184-213. doi:10.2165/00003088-199733030-00003 [21] Henry, D., Lim, L.L., Garcia Rodriguez, L.A., Perez Gutthann, S., Carson, J.L., Griffin, M., et al. (1996) Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: Results of a collaborative meta-analysis. British Medical Journal, 312, 1563-1566. doi:10.1136/bmj.312.7046.1563 [22] Laporte, J., Ibanez, L., Vidal, X., Vendrell, L. and Leone, R. (2004) Upper gastrointestinal bleeding associated with the use of NSAIDs: Newer versus older agents. Drug safety, 27, 411-420. doi:10.2165/00002018-200427060-00005 [23] Shvarts, G.Ya. and Syabaev, R.D. (2005) Methodological instructions on the study of new nonsteroidal anti-inflammatory drugs. In: Chabriev, R.U. Ed., Guidance on experimental (preclinical) study of new pharmacological substances, Meditsina Publishers, Moscow, 695-709. [24] Bhandage, A., Shevkar, K. and Undale, V. (2009) Evaluation of antinociceptive activity of roots of Glycyrrhiza glabra Linn. Journal of Pharmacy Research, 2, 803-807. [25] Barkatullah, Ibrar, M., Ali, N., Muhammad, N. and Ehsan, M. (2012) In-vitro pharmacological study and preliminary phytochemical profile of Viola canescens Wall. Ex Roxb. African Journal of Pharmacy and Pharmacology, 6, 1142 -1146. doi:10.5897/AJPP12.061 [26] Purnima, A., Koti, B.C., Thippeswamy, A.H.M., Jaji, M.S., Vishwantha Swamy, A.H.M., Kurhe, Y.V., et al. (2010) Antiinflammatory, analgesic and antipyretic activities of Mimusops elengi Linn. Indian Journal of Pharmaceutical Sciences, 72, 480-485. doi:10.4103/0250-474X.73908 [27] Ivanova, E., Nepoklonov, A., Kokshenev, I., Kapitsa, I., Voronina, T. and Val’dman, E. (2012) Study of anticataleptic activity of hemantane using different routs of drug administration and in combination with levodopa. Biomedicine, 1, 74-81. [28] Castrano, A., Hererra, A.J., Cano, J., and Machado, A. (1998) Lipopolysaccharide intranigral injection induces inflammatory reaction damage in nigrostriatal dopaminergic system. Journal of Neurochemistry, 70, 1584-1592. doi:10.1046/j.1471-4159.1998.70041584.x [29] Bures, J., Petran, M. and Zachar, J. (1960) Electrophysiological methods in biological research. Academic Press, New York. [30] Schallert, T. and Jones, T.A. (1993) “Exuberant” neuronal growth after brain damage in adult rats: The essential role of behavioral experience. Journal of Neural Transplantation & Plasticity, 4, 193-198. doi:10.1155/NP.1993.193 [31] Kapitsa, I., Ivanova, E., Nepoklonov, A., Kokshenev, I., Voronina, T. and Val’dman, E. (2011) Comparative study of amantadine and hemantane effects on development of levodopa-induced dyskinesia in rat model of parkinsonian syndrome. Eksperimental’naia I Klinicheskaia Farmakologiia, 7, 9-12. [32] Schallert, T., Fleming, S.M., Leasure, J.L., Tillerson, J.L. and Bland, S.T. (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology, 39, 777-787. doi:10.1016/S0028-3908(00)00005-8 [33] Kirik, D., Rosenblad, C., Bjorklund, A. and Mandel, R.J. (2000) Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson’s model: Intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system. The Journal of Neuroscience, 20, 4686-4700. [34] Lemasson, M., Delbe, C., Gheusi, G., Vincent, J.D. and Lledo, P.M. (2005) Use of ultrasonic vocalizations to assess olfactory detection in mouse pups treated with 3- methylindole. Behavioural Processes, 68, 13-23. doi:10.1016/j.beproc.2004.09.001 [35] Liu, Y., Qin, L., Li, G., Zhang, W., An, L., Liu, B., et al. (2003) Dextromethorplan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. The Journal of Pharmacology and Experimental Therapeutics, 305, 212-218. doi:10.1124/jpet.102.043166 [36] Lam, F.F.Y. and Ng, E.S.K. (2010) Substance P and glutamate receptor antagonists improve the antiarthritic actions of dexamethasone in rats. British Journal of Pharmacology, 159, 958-969. doi:10.1111/j.1476-5381.2009.00586.x [37] Fiebich, B.L., Schleicher, S., Spleiss, O., Czygan, M. and Hüll, M. (2001) Neuroinflammatory circuits in Alzheimer’s disease: Interleukin-1 induces cyclooxygenase 2 in human neuroblastoma cells. Proceedings of Meeting of the Volkswagen Foundation and the GEBIN on Psycho Neuro Endocrino Immunology, Regensburg, 15-17 November 2001, 15-16. [38] Ofman, J.J., MacLean, C.H., Straus, W.L., Morton, S.C., Berger, M.L., Roth, E.A., et al. (2002) A metaanalysis of severe upper gastrointestinal complications of nonsteroidal antiinflammatory drugs. The Journal of Rheumatology, 29, 804-812. [39] Gao, H.M., Jiang, J., Wilson, B., Zhang, W., Hong, J.S. and Liu, B. (2002) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: Relevance to Parkinson’s disease. Journal of Neurochemistry, 81, 1285-1297. doi:10.1046/j.1471-4159.2002.00928.x [40] Iravani, M.M., Leung, C.C., Sedeghian, M., Haddon, C.O., Rose, S. and Jenner, P. (2005) The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation. European Journal of Neuroscience, 22, 317-330. doi:10.1111/j.1460-9568.2005.04220.x [41] Wisse, B.E., Ogimoto, K., Tang, J., Harris, M.K.J., Raines, E.W. and Schwartzm, M.W. (2007) Evidence that LPS-induced anorexia depends upon central, rather than peripheral, inflammatory signals. Endocrinology, 148, 5230-5237.doi:10.1210/en.2007-0394 [42] Tolosa, E., Gaig, C., Santamaria, J. and Compta, Y. (2009) Diagnosis and the premotor phase of Parkinson disease. Neurology, 72, S12-S20. doi:10.1212/WNL.0b013e318198db11 [43] Tolosa, E., Compta, Y. and Gaig, C. (2007) The premotor phase of Parkinson’s disease. Parkinsonism & Related Disorders, 13, S2-S7. doi:10.1016/j.parkreldis.2007.06.007 [44] Hawkes, C.H., Shephard, B.C. and Daniel, S.E. (1999) Is Parkinson’s disease a primary olfactory disorder? International Journal of Medicine, 56, 33-39. [45] Tissingh, G., Berendse, H.W., Bergmans, P., DeWaard, R., Drukarch B., Stoof, J.C., et al. (2001) Loss of olfaction in de novo and treated Parkinson’s disease: Possible implications for early diagnosis. Movement Disorders, 6, 41-46. doi:10.1002/1531-8257(200101)16:1<41::AID-MDS1017>3.0.CO;2-M [46] Müller, A., Reichmann, H., Livermore, A. and Hummel, T. (2002) Olfactory function in idiopathic Parkinson’s disease (IPD): Results from cross-sectional studies in IPD patients and long-term follow-up of de novo IPD patients. Journal of Neural Transmission, 109, 805-811. doi:10.1007/s007020200067 [47] Pearce, R.K.B., Hawkes, C.H. and Daniel, S.E. (1995) The anterior olfactory nucleus in Parkinson’s disease. Movement Disorders, 10, 283-287. doi:10.1002/mds.870100309 [48] Sobel, N., Thomason, M.E., Stappen, I., Tanner, C.M., Tetrud, J.W., Bower, J.M., et al. (2011) An impairment in sniffing contributes to the olfactory impairment in Parkinson’s disease. Proceedings of the National Academy of Sciences of the United States of America, 98, 4154-4159. doi:10.1073/pnas.071061598 [49] Aguilar, E., Mullol, J., Clementi, V., Perez, V. and Marin C. (2011) Odor discrimination impairment in 6-OHDA- lesioned rats: A tool for hyposmia research in Parkinson’s disease. Neurodegenerative Diseases, 8. [50] Furuyashiki, T., Holland, P.C. and Gallagher, M. (2008) Rat orbitofrontal cortex separately encodes response and outcome information during performance of goal-directed behavior. The Journal of Neuroscience, 28, 5127-5138. doi:10.1523/JNEUROSCI.0319-08.2008
[1] Phani, S., Loike, J.D. and Przeborski, S. (2012) Neurodegeneration and inflammation in Parkinson desease. Parkinsonism & Related Disorders, 18, S207-S209. doi:10.1016/S1353-8020(11)70064-5 [2] Streit, W.J., Mrak, R.E. and Griffin, W.S.T. (2004) Microglia and neuroinflammation: A pathological perspective. Journal of Neuroinflammation, 1, 14. http://www.jneuroinflammation.com/content/1/1/14 doi:10.1186/1742-2094-1-14 [3] McGeer, P.L., Schwab, C., Parent, A. and Doudet, D. (2003) Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Annals of Neurology, 54, 599-604.doi:10.1002/ana.10728 [4] Nagatsu, T., Mogi, M., Ichinose, H. and Togari, A. (2000) Cytokines in Parkinson’s disease. Journal of Neural Transmission. Supplement, 58, 143-151. [5] Blum-Degen, D., Muller, T., Kuhn, W., Gerlach, M., Przuntek, H. and Riederer, P. (1995) Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neuroscience Letters, 202, 17-20. doi:10.1016/0304-3940(95)12192-7 [6] Mogi, M., Harada, M., Riederer, P., Narabyashi, H., Fujita. J. and Nagatsu, T. (1994) Interleukin-1 beta growth factor and transforming growth factor-alpha are elevated in the brain from Parkinsonian patients. Neuroscience Letters, 180, 147-150. doi:10.1016/0304-3940(94)90508-8 [7] Muller, T., Blum-Degen, D., Przuntek, H. and Kuhn, W. (1998) Interleukin-6 levels in cerebrospinal fluid inversely correlate to severity of Parkinson’s disease. Acta Neurologica Scandinavica, 98, 142-144. doi:10.1111/j.1600-0404.1998.tb01736.x [8] Knott, C., Stern, G. and Wilkin, G.P. (2000) Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenase-1 and -2. Molecular and Cellular Neuroscience, 16, 724-739. doi:10.1006/mcne.2000.0914 [9] Gao, X., Chen, H., Schwarzchild, M.A. and Ascherio, A. (2011) Use of ibuprofen and risk of Parkinson’s disease. Neurology, 76, 863-869. doi:10.1212/WNL.0b013e31820f2d79 [10] Hirsch, E.C. and Hunnot, S. (2009) Neuroinflammation in Parkinson’s disease: A target for neuroprotection? The Lancet Neurology, 8, 382-397. doi:10.1016/S1474-4422(09)70062-6 [11] Qin, L., Wu, X., Block, M.L., Liu, Y., Breese, G.R., Hong, J.S., et al. (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia, 55, 453-462.doi:10.1002/glia.20467 [12] Kim, W.G., Mohney, R.P., Wilson, B., Jeohn, G.H., Liu, B. and Hong, J.S. (2000) Regional difference in susceptibility to lipopolysacchride-induced neurotoxicity in the rat brain: Role of microglia. The Journal of Neuroscience, 20, 6309-6316. [13] Lieberman, A.P., Pitha, P.M., Shin, H.S. and Shin, M.L. (1989) Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proceedings of the National Academy of Sciences of the United States of America, 86, 6348-6352. doi:10.1073/pnas.86.16.6348 [14] Chang, Y.C., Kim, H.-W., Rapoport, S.I. and Rao, J.S. (2008) Chronic NMDA administration increases neuroinflammatory markers in rat frontal cortex: Cross-talk between excitotoxicity and neuroinflammation. Neurochemical Research, 33, 2318-2323. doi:10.1007/s11064-008-9731-8 [15] Val’dman, E.A. (2001) Application-specific protocol. FSBI Zakusov Institute of Pharmacology, Moscow. [16] Wober, W. (1999) Comparative efficacy and safety of nimesulide and diclofenac in patients with acute shoulder, and a meta-analysis of controlled studies of nimesulide. Rheumatology (Oxford), 38, 33-38. doi:10.1093/rheumatology/38.suppl_1.33 [17] Caldwell, J.R. (1986) Efficacy and safety of diclofenac sodium in rheumatoid arthritis experience in the United States. The American Journal of Medicine, 80, 43-47. [18] Akriviadis, E., Hatzigavriel, M., Kapnias, D., Kirimlidis, J., Markantas, A. and Garyfallos, A. (1997) Treatment of biliary colic with diclofenac: A randomized, double-blind, placebo-controlled study. Gastroenterology, 113, 225-231. doi:10.1016/S0016-5085(97)70099-4 [19] Jorge, L.L., Feres, C.C. and Teles, V.E. (2011) Topical preparations for pain relief: Efficacy and patient adherence. Journal of Pain Research, 4, 11-24. [20] Davies, N.M. and Anderson, K.E. (1997) Clinical pharmacokinetics of diclofenac. Therapeutic insights and pitfalls. Clinical Pharmacokinetics, 33, 184-213. doi:10.2165/00003088-199733030-00003 [21] Henry, D., Lim, L.L., Garcia Rodriguez, L.A., Perez Gutthann, S., Carson, J.L., Griffin, M., et al. (1996) Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: Results of a collaborative meta-analysis. British Medical Journal, 312, 1563-1566. doi:10.1136/bmj.312.7046.1563 [22] Laporte, J., Ibanez, L., Vidal, X., Vendrell, L. and Leone, R. (2004) Upper gastrointestinal bleeding associated with the use of NSAIDs: Newer versus older agents. Drug safety, 27, 411-420. doi:10.2165/00002018-200427060-00005 [23] Shvarts, G.Ya. and Syabaev, R.D. (2005) Methodological instructions on the study of new nonsteroidal anti-inflammatory drugs. In: Chabriev, R.U. Ed., Guidance on experimental (preclinical) study of new pharmacological substances, Meditsina Publishers, Moscow, 695-709. [24] Bhandage, A., Shevkar, K. and Undale, V. (2009) Evaluation of antinociceptive activity of roots of Glycyrrhiza glabra Linn. Journal of Pharmacy Research, 2, 803-807. [25] Barkatullah, Ibrar, M., Ali, N., Muhammad, N. and Ehsan, M. (2012) In-vitro pharmacological study and preliminary phytochemical profile of Viola canescens Wall. Ex Roxb. African Journal of Pharmacy and Pharmacology, 6, 1142 -1146. doi:10.5897/AJPP12.061 [26] Purnima, A., Koti, B.C., Thippeswamy, A.H.M., Jaji, M.S., Vishwantha Swamy, A.H.M., Kurhe, Y.V., et al. (2010) Antiinflammatory, analgesic and antipyretic activities of Mimusops elengi Linn. Indian Journal of Pharmaceutical Sciences, 72, 480-485. doi:10.4103/0250-474X.73908 [27] Ivanova, E., Nepoklonov, A., Kokshenev, I., Kapitsa, I., Voronina, T. and Val’dman, E. (2012) Study of anticataleptic activity of hemantane using different routs of drug administration and in combination with levodopa. Biomedicine, 1, 74-81. [28] Castrano, A., Hererra, A.J., Cano, J., and Machado, A. (1998) Lipopolysaccharide intranigral injection induces inflammatory reaction damage in nigrostriatal dopaminergic system. Journal of Neurochemistry, 70, 1584-1592. doi:10.1046/j.1471-4159.1998.70041584.x [29] Bures, J., Petran, M. and Zachar, J. (1960) Electrophysiological methods in biological research. Academic Press, New York. [30] Schallert, T. and Jones, T.A. (1993) “Exuberant” neuronal growth after brain damage in adult rats: The essential role of behavioral experience. Journal of Neural Transplantation & Plasticity, 4, 193-198. doi:10.1155/NP.1993.193 [31] Kapitsa, I., Ivanova, E., Nepoklonov, A., Kokshenev, I., Voronina, T. and Val’dman, E. (2011) Comparative study of amantadine and hemantane effects on development of levodopa-induced dyskinesia in rat model of parkinsonian syndrome. Eksperimental’naia I Klinicheskaia Farmakologiia, 7, 9-12. [32] Schallert, T., Fleming, S.M., Leasure, J.L., Tillerson, J.L. and Bland, S.T. (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology, 39, 777-787. doi:10.1016/S0028-3908(00)00005-8 [33] Kirik, D., Rosenblad, C., Bjorklund, A. and Mandel, R.J. (2000) Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson’s model: Intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system. The Journal of Neuroscience, 20, 4686-4700. [34] Lemasson, M., Delbe, C., Gheusi, G., Vincent, J.D. and Lledo, P.M. (2005) Use of ultrasonic vocalizations to assess olfactory detection in mouse pups treated with 3- methylindole. Behavioural Processes, 68, 13-23. doi:10.1016/j.beproc.2004.09.001 [35] Liu, Y., Qin, L., Li, G., Zhang, W., An, L., Liu, B., et al. (2003) Dextromethorplan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. The Journal of Pharmacology and Experimental Therapeutics, 305, 212-218. doi:10.1124/jpet.102.043166 [36] Lam, F.F.Y. and Ng, E.S.K. (2010) Substance P and glutamate receptor antagonists improve the antiarthritic actions of dexamethasone in rats. British Journal of Pharmacology, 159, 958-969. doi:10.1111/j.1476-5381.2009.00586.x [37] Fiebich, B.L., Schleicher, S., Spleiss, O., Czygan, M. and Hüll, M. (2001) Neuroinflammatory circuits in Alzheimer’s disease: Interleukin-1 induces cyclooxygenase 2 in human neuroblastoma cells. Proceedings of Meeting of the Volkswagen Foundation and the GEBIN on Psycho Neuro Endocrino Immunology, Regensburg, 15-17 November 2001, 15-16. [38] Ofman, J.J., MacLean, C.H., Straus, W.L., Morton, S.C., Berger, M.L., Roth, E.A., et al. (2002) A metaanalysis of severe upper gastrointestinal complications of nonsteroidal antiinflammatory drugs. The Journal of Rheumatology, 29, 804-812. [39] Gao, H.M., Jiang, J., Wilson, B., Zhang, W., Hong, J.S. and Liu, B. (2002) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: Relevance to Parkinson’s disease. Journal of Neurochemistry, 81, 1285-1297. doi:10.1046/j.1471-4159.2002.00928.x [40] Iravani, M.M., Leung, C.C., Sedeghian, M., Haddon, C.O., Rose, S. and Jenner, P. (2005) The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation. European Journal of Neuroscience, 22, 317-330. doi:10.1111/j.1460-9568.2005.04220.x [41] Wisse, B.E., Ogimoto, K., Tang, J., Harris, M.K.J., Raines, E.W. and Schwartzm, M.W. (2007) Evidence that LPS-induced anorexia depends upon central, rather than peripheral, inflammatory signals. Endocrinology, 148, 5230-5237.doi:10.1210/en.2007-0394 [42] Tolosa, E., Gaig, C., Santamaria, J. and Compta, Y. (2009) Diagnosis and the premotor phase of Parkinson disease. Neurology, 72, S12-S20. doi:10.1212/WNL.0b013e318198db11 [43] Tolosa, E., Compta, Y. and Gaig, C. (2007) The premotor phase of Parkinson’s disease. Parkinsonism & Related Disorders, 13, S2-S7. doi:10.1016/j.parkreldis.2007.06.007 [44] Hawkes, C.H., Shephard, B.C. and Daniel, S.E. (1999) Is Parkinson’s disease a primary olfactory disorder? International Journal of Medicine, 56, 33-39. [45] Tissingh, G., Berendse, H.W., Bergmans, P., DeWaard, R., Drukarch B., Stoof, J.C., et al. (2001) Loss of olfaction in de novo and treated Parkinson’s disease: Possible implications for early diagnosis. Movement Disorders, 6, 41-46. doi:10.1002/1531-8257(200101)16:1<41::AID-MDS1017>3.0.CO;2-M [46] Müller, A., Reichmann, H., Livermore, A. and Hummel, T. (2002) Olfactory function in idiopathic Parkinson’s disease (IPD): Results from cross-sectional studies in IPD patients and long-term follow-up of de novo IPD patients. Journal of Neural Transmission, 109, 805-811. doi:10.1007/s007020200067 [47] Pearce, R.K.B., Hawkes, C.H. and Daniel, S.E. (1995) The anterior olfactory nucleus in Parkinson’s disease. Movement Disorders, 10, 283-287. doi:10.1002/mds.870100309 [48] Sobel, N., Thomason, M.E., Stappen, I., Tanner, C.M., Tetrud, J.W., Bower, J.M., et al. (2011) An impairment in sniffing contributes to the olfactory impairment in Parkinson’s disease. Proceedings of the National Academy of Sciences of the United States of America, 98, 4154-4159. doi:10.1073/pnas.071061598 [49] Aguilar, E., Mullol, J., Clementi, V., Perez, V. and Marin C. (2011) Odor discrimination impairment in 6-OHDA- lesioned rats: A tool for hyposmia research in Parkinson’s disease. Neurodegenerative Diseases, 8. [50] Furuyashiki, T., Holland, P.C. and Gallagher, M. (2008) Rat orbitofrontal cortex separately encodes response and outcome information during performance of goal-directed behavior. The Journal of Neuroscience, 28, 5127-5138. doi:10.1523/JNEUROSCI.0319-08.2008