Abstract
Hippocampal neuronal apoptosis is a devastating consequence of cardiac arrest (CA) and subsequent cardiopulmonary resuscitation (CPR). In this study, we assessed the contribution of cytotoxic T lymphocyte (CTL)-derived toxic mediator granzyme B (Gra-b) to the hippocampal neuronal apoptosis following CA/CPR in rats. Rats that experienced CA/CPA presented with cytosomal shrinkage, dense cytoplasm, and intensive eosinophilic staining in the CA1 region of dorsal hippocampus. CA/CPR rats also exhibited inability in spatial navigation and a local infiltration of peripheral CD8+ T cells into the hippocampus. The protein levels of Gra-b, cleaved Caspase-3, and cleaved PARP1 were significantly elevated in rats undergoing CA/CPR. Pretreatment with Gra-b inhibitor suppressed Gra-b release, attenuated hippocampal neuronal apoptosis, as well as improved cognitive impairment. Together, this study indicates that CTL-derived Gra-b is involved in the CA/CPR-induced neuronal apoptosis, and pharmacological manipulation of Gra-b may represent a novel avenue for the treatment of brain injury following CA/CPR.
Highlights
Cardiac arrest (CA), an abrupt loss of heart function in individuals with or without heart disease, is a leading cause of cardiovascular and cerebral hypoxia and ischemia, resulting in disability and mortality [1]
Our present study confirmed that cardiac arrest (CA)/cardiopulmonary resuscitation (CPR) could increase the permeability of Blood-brain barrier (BBB), allowing blood CD8+ cytotoxic T lymphocyte (CTL) to infiltrate into the brain tissue and secrete granzyme B (Gra-b) protein, and leading to neuronal apoptosis and death, probably via the Caspase-3 signaling pathway
Administration of Gra-b inhibitor annulled the upregulation of Gra-b, cleaved Caspase-3, and cleaved PARP1 levels, ameliorating neuronal apoptosis as well as behavioral and cognitive impairment
Summary
Cardiac arrest (CA), an abrupt loss of heart function in individuals with or without heart disease, is a leading cause of cardiovascular and cerebral hypoxia and ischemia, resulting in disability and mortality [1]. Sustained CA and hypoxia induced ischemic brain injury with the onset of secondary neuroinflammation, including glial activation, peripheral immune cell recruitment, and pro-/antiinflammatory factor release, resulting in pyrexia, hypophagia, hyperalgesia, and cognitive. Studies of the central nervous system (CNS) evidenced an elevation of CD8+ cytotoxic T lymphocytes (CTLs) in a number of pathogen-induced neurological disorders [7,8,9], wherein activated CTLs can generate a series of serine proteases, granzymes (Gra), which can induce cellular apoptosis, leading to neuronal death in ischemic brain regions [10,11,12]. Despite the de facto infiltration of CTLs into the CNS after CA/CPR, the precise contributions of CTL-derived Gra-b to neuronal apotosis remain elusive.
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