Effects of compound 21, a non‑peptide angiotensin II type 2 receptor agonist, on general anesthesia‑induced cerebral injury in neonatal rats

Abstract

General anesthesia has a great impact on neurodevelopment. However, the mechanisms underlying this effect and therapeutic methods to address it remain limited. The present study aimed to investigate the effects of compound (C)21, a non-peptide angiotensin II type 2 receptor agonist, on general anesthesia-induced cerebral injury in neonatal rats. Neonatal Sprague Dawley rats (postnatal day 7) were randomly divided into three groups (n=6 per group): The control, isoflurane and C21+ isoflurane (C21) group. General anesthesia was induced through inhalation of 1.3% isoflurane. Apoptosis and synaptic structure were analyzed. The levels of peroxisome proliferator-activated receptor (PPAR)-α were detected using an enzyme-linked immunosorbent assay. BCL2, apoptosis regulator (Bcl-2) expression was also measured. Compared with the control group, the cerebral cortex, hippocampus, amygdala and hypothalamus in the isoflurane group had significantly more apoptotic cells (P<0.05). The nuclei of the control group were round and transparent, while shrunken nuclei and condensed chromatin were visible in the isoflurane group. A reduction in synapse number was observed in the isoflurane group compared with the control. By contrast, nuclei shrinkage and the decrease in synaptic number was improved in the C21 group. PPAR-α and Bcl-2 expression, at the mRNA and protein levels, was significantly reduced in the isoflurane group compared with the control (P<0.05). C21 treatment reduced the decrease in PPAR-α and Bcl-2 in the cerebral cortex, hippocampus, amygdala and hypothalamus (P<0.05). Collectively, it was demonstrated that C21 prevented apoptosis and synaptic loss induced by general anesthesia in neonatal rats by enhancing the expression of PPAR-α and Bcl-2.

The Angiotensin AT2Receptor: From a Binding Site to a Novel Therapeutic Target

“…A more recent study demonstrated that peripheral administration of C21 after unilateral cortical traumatic brain injury in mice elicited a significant reduction in neurologic deficits, an effect that was associated with decreased inflammation and apoptosis within the peri-contusional area of the brain (Ismael and Ishrat, 2021). Beneficial effects of AT 2 R agonism in brain injury are not restricted to traumatic brain injury, as C21 treatment lessens the neuronal apoptosis and synaptic loss induced by isoflurane anesthesia of neonatal rats (Yong et al, 2018). Collectively, these findings suggest that AT 2 R activation can be beneficial in brain injury situations in adults and developing animals and that this area bears further investigation.…”

Role of PPARs in Progression of Anxiety: Literature Analysis and Signaling Pathways Reconstruction

“…(i) Gamma is not expressed in the structures of the olfactory bulb, in the part of the olfactory cortex, part of the neocortex, some structures of the thalamus, nuclei of the solitary tract, dorsal motor nuclei of the vagus, and Purkinje cells (ii) Alpha is not expressed in the hypothalamus [24] All 3 isoforms are actively expressed in the basal ganglia to which amygdala belongs [24,136,137]. Thus, PPARs in high concentration are located in the brain areas involved in the formation of anxiety, including those that are widely represented in the hippocampus and amygdala.…”

Overexpression of miR‑133b protects against isoflurane‑induced learning and memory impairment

“…Isoflurane is one of the most commonly used inhaled anesthetics, and has been reported to contribute to long-term memory deficits (4). Anesthesia-associated neuronal apoptosis is considered to be an important mechanism involved in the neurological impairment induced by anesthesia (5,6). Notably, exposure of the developing brain to isoflurane can cause severe damage to neurological functions, which may result in persistent learning deficits and cognitive impairment (3,7).…”