ABSTRACT The aim of this study was to investigate the potential protective effect of tetramethylpyrazine (TMP), one of available blood-activating and stasis-eliminating components from traditional Chinese medicines, on glutamate-induced neurotoxicity in mice and its possible mechanism. Mice, except for controls, received simultaneously intragastric (ig) administration of monosodium glutamate [MSG, 4.0 g/(kg·d)] or/and intraperitoneal (ip) administration of TMP [10, 20, 40 mg/(kg·d)] for 10 d, and then behavioral tests, as well as histopathological and immunohistochemical examination of hippocampi were performed to analyze the glutamate-induced functional and morphological changes and the possible protective effect of TMP. The results showed that ip administration of TMP countered the effects of ig administration of MSG on behavior and histopathology, suggesting that TMP was a neuroprotective agent. This study provides evidence that TMP possesses obviously neuroprotection against glutamate-induced neurotoxicity, and the neuroprotection effect may result from its inhibiting expression of NMDARs, consequently blocking-up Ca2+ influx through the receptor’s associated ion channel, which can be neurotoxic.
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Y. Zhang, Z. Huang, L. Yu and L. Zhang, "Protective Effects of Tetramethylpyrazine on Glutamate-Induced Neurotoxicity in Mice," Journal of Behavioral and Brain Science, Vol. 2 No. 3, 2012, pp. 326-332. doi: 10.4236/jbbs.2012.23037.
 J. W. Olney, O. L. Ho and V. Rhee, “Cytotoxic Effects of Acidic and Sulphur Containing Amino Acids on the Infant Mouse Central Nervous System,” Experimental Brain Research, Vol. 14, No. 1, 1971, pp. 61-76.
 M. Jiang, H. Sun and Y. Q. Zhang. “Excitotoxic Effect of Glutamate on the Afferent Neurons in Guinea Pig,” Journal of Central South University (Medical Sciences), Vol. 29, No. 2, 2004, pp. 170-173.
 H. Y. Zhang, Z. R. He, J. Yi, J. Gu, W. C. Liu, et al, “Morphological Study on Excitotoxic Neurodegeneration of Exogenous Glutamate in New Born Rat Brain,” Chinese Journal of Anatomy, Vol. 25, No. 4, 2002, pp. 345-349.
 L. Alberghina and A. M. Colangelo, “The Modular Systems Biology Approach to Investigate the Control of Apoptosis in Alzheimer’s Disease Neurodegeneration,” BMC Neuroscience, Vol. 7, No. 1, 2006, pp. 27-32.
 Y. Nishizawa, “Glutamate Release and Neuronal Damage in Ischemia,” Life Science, Vol. 69, No. 4, 2001, pp. 369-381. doi:10.1016/S0024-3205(01)01142-0
 Q. Mao, Z. Huang, S. Ip and C. Che, “Antidepressant-Like Effect of Ethanol Extract from Paeonia Lactiflora in Mice,” Phytotherapy Research, Vol. 22, No. 11, 2008, pp. 1496-1499. doi:10.1002/ptr.2519
 Y. P. Zhang, L. J. Yu, R. D. Ma, L. Bao, R. Zeng, et al., “Potent Protective Effects of Ferulic Acid on Glutamate-Induced Neurotoxicity in Adult Mice,” Chinese Journal of Neuromedicine, Vol. 7, No. 6, 2008, pp. 596-606.
 L. J. Yu, X. D. Jiang, Y. P. Zhang, M. N. Liao, R. D. Ma, et al., “Antidepressant-Like Activity of Tetramethylpyrazine Measured by Chronic Experimental Method in Rat Model of Depression,” Pharmacology & Pharmacy, Vol. 3, No. 1, 2012, pp. 52-57. doi:10.4236/pp.2012.31008
 G. Liu, “Chinese Herbal Mdicine,” Hua Xia Publishing House, Beijing, 2001, pp. 227-228.
 H. B. Li and F. Chen, “Preparative Isolation and Purification of Chuanxiongzine from the Medicinal Plant Ligusticum Chuanxiong by High-Speed Counter-Current Chromatography,” Journal of Chromatography A, Vol. 1047, No. 2, 2004, pp. 249-253.
 M. Su, Y. Zhou and G. Yang, “Effects of Tetramethylpyrazine on L-Type Calcium-Channel Current and the Intracellular Calcium Concentration in Primary Cultured Hippocampal Neuronal Cells,” Chinese Journal of Rehabilitation, Vol. 23, No. 1, 2008, pp. 17-19.
 Y. B. Ji, “Pharmacological Action and Application of Blood-Activating and Stasis-Eliminating Available Composition of Traditional Chinese Medicine,” Heilongjiang Science and Technique Press, Harbin, 1999, pp. 118-121.
 L. Yu, X. Jiang, M. Liao, R. Ma and T. Yu, “Antidepressant-Like Effect of Tetramethylpyrazine in Mice and Rats,” Neuroscience & Medicine, Vol. 2, No. 6, 2011, pp. 142-148. doi:10.4236/nm.2011.22020
 The Ministry of Science and Technology of the People’s Republic of China, “Guidance Suggestions for the Care and Use of Laboratory Animals,” 2006.
 T. X. Yu, Y. Zhao, W. C. Shi, R. D. Ma and L. J. Yu, “Effects of Maternal Oral Administration of Monosodium Glutamate at a Late Stage of Pregnancy on Developing Mouse Fetal Brain,” Brain Research, Vol. 747, No. 2, 1997, pp. 195-206. doi:10.1016/S0006-8993(96)01181-X
 J. Podhorna and R. E. Brown, “Strain Differences in Activity and Emotionality Do Not Account for Differences in Learning and Memory Performance between C57BL/6 and DBA/2 Mice,” Genes Brain and Behavior, Vol. 1, No. 2, 2002, pp. 96-110.
 B. H. Xu, H. F. Duan and R. Y. Liu, “The Effect on Learing and Memory of Application of RNAase to Hippocampus of Rats,” Chinese Science Bulletin, Vol. 24, No. 2, 1979, pp. 182-185.
 J. Q. Chen, W. H. Zhan, Y. L. He, J. S. Peng, J. P. Wang, et al., “Expression of Heparanase Gene, CD44v6, MMP-7 and nm23 Protein and Their Relationship with the Invasion and Metastasis of Gastric Carcinomas,” World Journal of Gastroenteroenterology, Vol. 10, No. 6, 2004, pp. 776-782.
 Z. R. Shi, S. H. Itzkowitz and Y. S. Kim, “A Comparison of Three Immunoperoxidase Techniques for Antigen Detection in Colorectal Carcinoma Tissues,” Journal of Histochemistry and Cytochemistry, Vol. 36, No. 3, 1988, pp. 317-322. doi:10.1177/36.3.3278057
 D. W. Choi, “Methods for Antagonizing Glutamate Neurotoxicity,” Cerebrovascular & Brain Metabolism Reviews, Vol. 2, No. 2, 1990, pp. 105-147.
 D. W. Choi, “Excitotoxic Cell Death,” Journal of Neurobiology, Vol. 23, No. 9, 1992, pp. 1261-1276.
 D. W. Choi, “Glutamate Neurotoxicity and Diseases of the Nervous System,” Neuron, Vol. 1, No. 8, 1988, pp. 623-634. doi:10.1016/0896-6273(88)90162-6
 W. O. Whetsell Jr., “Current Concepts of Excitotoxicity,” Journal of Neuropathology & Experimental Neurology, Vol. 55, No. 1, 1996, pp. 1-13.
 R. Pellicciari, G. Costantino, M. Marinozz and B. Natalini, “Modulation of Glutamate Receptor Pathways in the Search for New Neuroprotective Agents,” Farmaco, Vol. 53, No. 4, 1998, pp. 255-261.
 L. Yu, Y. Zhang, R. Ma, L. Bao, J. Fang, et al., “Potent Protection of Ferulic Acid against Excitotoxic Effects of Maternal Intragastric Administration of Monosodium Glutamate at a Late Stage of Pregnancy on Developing Mouse Fetal Brain,” European Neuropsychopharmacology, Vol. 16, No. 3, 2006, pp. 170-177.
 B. Cheng and M. P. Mattson, “IGF-I and IGF-II Protect Cultured Hippocampal and Septal Neurons against Calcium-Mediated Hypoglycemic Damage,” Journal of Neuroscience, Vol. 12, No. 4, 1992, pp. 558-566.
 D. W. Choi and S. M. Rothan, “The Role of Gutamate Neurotoxicity in Hipoxic-Ischemic Neuronal Death,” Annual Review of Neuroscience, Vol. 13, 1990, pp. 171-182. doi:10.1146/annurev.ne.13.030190.001131
 R. J. Gagliadi, “Neuroprotection, Excitotoxicity and NM-DA Antagonists,” Arquivos de Neuro-Psiquiatria, Vol. 58, No. 2B, 2000, pp. 583-588.
 P. H. Chan, “Role of Oxidants in Ischemic Brain Damage,” Stroke, Vol. 27, No. 6, 1996, pp. 1124-1128.
 E. R. Stadtman and B. S. Berlett, “Reactive Oxygen-Mediated Protein Oxidation in Aging and Disease,” Drug Metabolism Reviews, Vol. 30, No. 2, 1998, pp. 225-243. doi:10.3109/03602539808996310
 D. E. Pellegrini-Giampietro, G. Cherici, M. Alesiani, et al., “Excitatory Amino Acid Release and Free Radical Formation may Cooperate in the Genesis of IschemiaInduced Neuronal Damage,” Journal of Neuroscience, Vol. 10, No. 3, 1990, pp. 1035-1041.
 S. A. Lipton and P. A. Rosenberg, “Mechanisms of Disease: Excitatory Amino Acids as a Final Common Pathway in Neurologic Disorders,” The New England Journal of Medicine, Vol. 330, No. 9, 1994, pp. 613-622.
 R. L. Sacco, J. T. DeRosa, E. C. Haley, et al., “Glycine Antagonist in Neuroprotection for Patients with Acute Stroke: GAIN Americas: A Randomized Controlled Trial,” Journal of the American Medical Association, Vol. 285, No. 13, 2001, pp. 1719-1728.