Abstract
Cerebral ischemia, a common cerebrovascular disease, is characterized by functional deficits and apoptotic cell death. Autophagy, a type of programmed cell death, plays critical roles in controlling neuronal damage and metabolic homeostasis, and has been inextricably linked to cerebral ischemia. We previously identified a short peptide aptamer from collapsin response mediator protein 2 (CRMP2), designated the Ca2+ channel-binding domain 3 (CBD3) peptide, that conferred protection against excitotoxicity and traumatic brain injury. ST2-104, a nona-arginine (R9)-fused CBD3 peptide, exerted beneficial effects on neuropathic pain and was neuroprotective in a model of Alzheimer’s disease; however, the effect of ST2-104 on cerebral ischemia and its mechanism of action have not been studied. In this study, we modeled cerebral ischemia–reperfusion injury in rats with the middle cerebral artery occlusion (MCAO) as well as challenged SH-SY5Y neuroblastoma cells with glutamate to induce toxicity to interrogate the effects of ST2-104 on autophagy following ischemic/excitotoxic insults. ST2-104 reduced the infarct volume and improved the neurological score of rats subjected to MCAO. ST2-104 protected SH-SY5Y cells from death following glutamate exposure via blunting apoptosis and autophagy as well as limiting excessive calcium entry. 3-Methyladenine (3-MA), an inhibitor of autophagy, promoted the effects of ST2-104 in inhibiting apoptosis triggered by glutamate while rapamycin, an activator of autophagy, failed to do so. ST2-104 peptide reversed glutamate-induced apoptosis via inhibiting Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ)-mediated autophagy, which was partly enhanced by STO-609 (an inhibitor of CaMKKβ). ST2-104 attenuated neuronal apoptosis by inhibiting autophagy through CaMKKβ/AMPK/mTOR pathway. Our results suggest that the neuroprotective effect of ST2-104 are due to actions on the crosstalk between apoptosis and autophagy via the CaMKKβ/AMPK/mTOR signaling pathway. The findings present novel insights into the potential neuroprotection of ST2-104 in cerebral ischemia.
Highlights
Cerebral ischemia is a cerebrovascular disorder and the second leading cause of death globally, killing approximately 5.5 million people annually [1]
R9‐channel-binding domain 3 (CBD3), a collapsin response mediator protein 2 (CRMP2)‐derived peptide (i.e., ST2‐104), decreases brain infarction and enhances neurological function in middle cerebral artery occlusion (MCAO) rats Twenty-four hours following MCAO, we evaluated the extent of cerebral damage using triphenyl tetrazolium chloride (TTC), which distinguishes between ischemic and non-ischemic areas (Fig. 1a)
These results indicate that pretreatment with ST2-104 peptide could modulate infarct size and attenuate the neurological deficits inflicted by cerebral ischemia‐reperfusion injury
Summary
Cerebral ischemia is a cerebrovascular disorder and the second leading cause of death globally, killing approximately 5.5 million people annually [1]. It is characterized by key molecular events including excitotoxicity, calcium overload, and overproduction of free radicals—all. The recognition that brief periods of ischemia trigger complex cellular events leading to progressive apoptotic necrotic neuronal cell death has motivated intense research efforts to identify compounds/biologics to curb apoptosis to manage cerebral ischemia. Decades of research has implicated apoptosis as a prime regulator of neuronal death following cerebral ischemia [5]; the potential mechanisms have not been fully elucidated. Cytoplasmic proteins are sequestered into double-membrane vesicles called autophagosomes, fuse with lysosomes to produce single-membraned autophagolysosomes, and degraded by lysosomal hydrolases; autophagy contributes to both the maintenance of normal cellular metabolism and renewal of organelles [7]
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