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Tissue kallikrein alleviates glutamate-induced neurotoxicity by activating ERK1.
J Neurosci Res. 2009 Dec; 87(16):3576-90.JN

Abstract

Glutamate-induced neurotoxicity consequent to N-methyl-D-aspartic acid (NMDA) and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propionic acid (AMPA) receptor activation underlies the pathogenesis of a wide range of central nervous system disorders, including brain ischemia. Prevention of ischemia/reperfusion (I/R)-induced neuronal injury has long been regarded as an effective therapeutic strategy for ischemia. Human tissue kallikrein (TK) gene transfer has been shown to protect neurons against cerebral I/R-induced apoptosis and oxidative stress, via activation of the brandykinin B2 receptor (B2R). However, little is known about the role of TK on glutamate-induced neurotoxicity. Here we report that pretreatment of cultured cortical neurons with TK largely prevented glutamate-induced morphological changes and cell death. We found that TK pretreatment alleviated glutamate-induced oxidative stress by inhibiting neuronal nitric oxide synthase (nNOS) activity, thereby reducing the generation of nitric oxide (NO) and reactive oxygen species (ROS). Blockage of NMDA and AMPA receptors by their specific antagonists MK801 and CNQX had effects similar to those of TK administration. Furthermore, we found that the extracellular signal-regulated kinase 1/2 cascade (ERK1/2), particularly ERK1, and nuclear factor-kappaB (NF-kappaB) were involved in TK neuroprotection against glutamate-induced neurotoxicity. TK pretreatment activated ERK1 and NF-kappaB, leading to enhanced expression of brain-derived neurotrophic factor (BDNF) mRNA and antiapoptotic gene Bcl-2 protein. Collectively, these findings demonstrate that TK attenuates glutamate-induced apoptosis through an intracellular signaling pathway including activation of B2R, ERK1/2, and NF-kappaB and up-regulation of BDNF and Bcl-2 expression. Thus, TK represents a promising therapeutic strategy for ischemic stroke.

Authors+Show Affiliations

Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, People's Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19598250

Citation

Liu, Ling, et al. "Tissue Kallikrein Alleviates Glutamate-induced Neurotoxicity By Activating ERK1." Journal of Neuroscience Research, vol. 87, no. 16, 2009, pp. 3576-90.
Liu L, Zhang R, Liu K, et al. Tissue kallikrein alleviates glutamate-induced neurotoxicity by activating ERK1. J Neurosci Res. 2009;87(16):3576-90.
Liu, L., Zhang, R., Liu, K., Zhou, H., Tang, Y., Su, J., Yu, X., Yang, X., Tang, M., & Dong, Q. (2009). Tissue kallikrein alleviates glutamate-induced neurotoxicity by activating ERK1. Journal of Neuroscience Research, 87(16), 3576-90. https://doi.org/10.1002/jnr.22151
Liu L, et al. Tissue Kallikrein Alleviates Glutamate-induced Neurotoxicity By Activating ERK1. J Neurosci Res. 2009;87(16):3576-90. PubMed PMID: 19598250.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tissue kallikrein alleviates glutamate-induced neurotoxicity by activating ERK1. AU - Liu,Ling, AU - Zhang,Renliang, AU - Liu,Kui, AU - Zhou,Houguang, AU - Tang,Yuping, AU - Su,Jinjin, AU - Yu,Xiaoyan, AU - Yang,Xuelian, AU - Tang,Min, AU - Dong,Qiang, PY - 2009/7/15/entrez PY - 2009/7/15/pubmed PY - 2010/1/6/medline SP - 3576 EP - 90 JF - Journal of neuroscience research JO - J Neurosci Res VL - 87 IS - 16 N2 - Glutamate-induced neurotoxicity consequent to N-methyl-D-aspartic acid (NMDA) and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propionic acid (AMPA) receptor activation underlies the pathogenesis of a wide range of central nervous system disorders, including brain ischemia. Prevention of ischemia/reperfusion (I/R)-induced neuronal injury has long been regarded as an effective therapeutic strategy for ischemia. Human tissue kallikrein (TK) gene transfer has been shown to protect neurons against cerebral I/R-induced apoptosis and oxidative stress, via activation of the brandykinin B2 receptor (B2R). However, little is known about the role of TK on glutamate-induced neurotoxicity. Here we report that pretreatment of cultured cortical neurons with TK largely prevented glutamate-induced morphological changes and cell death. We found that TK pretreatment alleviated glutamate-induced oxidative stress by inhibiting neuronal nitric oxide synthase (nNOS) activity, thereby reducing the generation of nitric oxide (NO) and reactive oxygen species (ROS). Blockage of NMDA and AMPA receptors by their specific antagonists MK801 and CNQX had effects similar to those of TK administration. Furthermore, we found that the extracellular signal-regulated kinase 1/2 cascade (ERK1/2), particularly ERK1, and nuclear factor-kappaB (NF-kappaB) were involved in TK neuroprotection against glutamate-induced neurotoxicity. TK pretreatment activated ERK1 and NF-kappaB, leading to enhanced expression of brain-derived neurotrophic factor (BDNF) mRNA and antiapoptotic gene Bcl-2 protein. Collectively, these findings demonstrate that TK attenuates glutamate-induced apoptosis through an intracellular signaling pathway including activation of B2R, ERK1/2, and NF-kappaB and up-regulation of BDNF and Bcl-2 expression. Thus, TK represents a promising therapeutic strategy for ischemic stroke. SN - 1097-4547 UR - https://www.unboundmedicine.com/medline/citation/19598250/Tissue_kallikrein_alleviates_glutamate_induced_neurotoxicity_by_activating_ERK1_ L2 - https://doi.org/10.1002/jnr.22151 DB - PRIME DP - Unbound Medicine ER -