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.