title: Tissue kallikrein protects cortical neurons against in vitro ischemia-acidosis/reperfusion-induced injury through the ERK1/2 pathway.
abstract: Human tissue kallikrein (hTK) gene transfer has been shown to protect neurons against cerebral ischemia/reperfusion (I/R) injury, and exogenous tissue kallikrein (TK) administration can enhance neurogenesis and angiogenesis following focal cortical infarction. Previous studies have reported that acidosis is a common feature of ischemia and plays a critical role in brain injury. However, little is known about the role of TK in ischemia-acidosis-induced injury, which is partially caused by the activation of acid-sensing ion channels (ASICs). Here we report that pretreatment of cultured cortical neurons with TK reduced cell death induced by either acidosis or oxygen and glucose deprivation-acidosis/reoxygenation (OGD-A/R). Immunocytochemical staining revealed that TK largely prevented OGD-A/R-induced neuronal morphological changes. We also observed that TK treatment protected cultured neurons from acidosis and OGD-A/R insults. TK exerted the neuroprotective effects by reducing production of reactive oxygen species (ROS), stabilizing the mitochondrial membrane potential (MMP) and inhibiting caspase-3 activation, and thereby attenuating oxidative stress and apoptosis. In addition, we found that activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signaling cascade but not the PI3K/Akt signaling pathway was required for the survival-promoting effect of TK on neurons exposed to OGD-A/R. Moreover, blockade of ASICs had effects similar to TK administration, suggesting direct or indirect involvement of ASICs in TK protection. In conclusion, TK has antioxidant characteristics and is capable of alleviating ischemia-acidosis/reperfusion-induced injury, inhibiting apoptosis and promoting cell survival in vitro through activating the ERK1/2 signaling pathways. Therefore, TK represents a promising therapeutic strategy for ischemic stroke.
authors: Department of Neurology, Huashan Hospital, Fudan University, 12# Middle Wulumuqi Road, Shanghai 200040, People's Republic of China.
authors: Ling
authors: L
authors: Liu
authors: Renliang
authors: R
authors: Zhang
authors: Kui
authors: K
authors: Liu
authors: Houguang
authors: H
authors: Zhou
authors: Xuelian
authors: X
authors: Yang
authors: Xinfeng
authors: X
authors: Liu
authors: Min
authors: M
authors: Tang
authors: Jinjin
authors: J
authors: Su
authors: Qiang
authors: Q
authors: Dong
mesh_terms: D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000188:drug therapy; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000633:toxicity; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000188:drug therapy; D020287:In Situ Nick-End Labeling / Q000379:methods; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010852:Picrotoxin / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D020840:Tissue Kallikreins / Q000494:pharmacology*; D014556:Urine / Q000737:chemistry
chemical_list: D062565:Acid Sensing Ion Channels; D053148:Caspase 3; D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D005947:Glucose; D007770:L-Lactate Dehydrogenase; D008869:Microtubule-Associated Proteins; D048052:Mitogen-Activated Protein Kinase 3; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010852:Picrotoxin; D017382:Reactive Oxygen Species; D015222:Sodium Channels; D020840:Tissue Kallikreins; C489787:MAP2 protein, rat