Effects of stem cell-derived exosomes on neuronal apoptosis and inflammatory cytokines in rats with cerebral ischemia-reperfusion injury via PI3K/AKT pathway-mediated mitochondrial apoptosis

Abstract

Objective

This study aimed to investigate the effects of stem cell-derived exosomes (SC-Exos) on learning, memory, and neuronal apoptosis in rats with cerebral ischemia-reperfusion injury and to determine whether SC-Exos exert their effects via phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway-mediated mitochondrial pathways of apoptosis.

Materials and methods

Eighty rats were randomly allocated to control, model, SC-Exos, and PI3K inhibitor groups. A model of focal cerebral ischemia-reperfusion was established using the improved Longa method. Expression of interleukin-1α (IL-1α), interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were compared in the brains and serum of each group. The expressions of Bcl-2, Bax, cleaved-caspase-3, cleaved-caspase-9, cytochrome C (CytC), PI3K, and AKT-related genes and proteins were evaluated by real-time quantitative polymerase chain reaction and western blotting.

Results

The SC-Exos-group exhibited more novel entries, less latency for the novel arm, and fewer entries into the starting arm and other arms than the model group (p<.05). Lower expression of the inflammatory cytokines IL-1α, IL-2, and TNF-α and higher expression of IFN-γ were observed in the SC-Exos group than in the model group. TdT-mediated dUTP nick end labeling (TUNEL) assay showed that lower neural cell apoptosis rate and expression of Bax, cleaved-caspase-3, cleaved-caspase-9, CytC, PI3K, and AKT mRNA and proteins and higher expression of Bcl-2 mRNA and protein were observed in the SC-Exos group than in the model group (p<.05).

Conclusions

SC-Exos can significantly ameliorate brain injury caused by cerebral ischemia-reperfusion. The mechanism may be a novel therapeutic target for ischemia-reperfusion injury.

Keywords:

• Phosphatidylinositol-3-kinase/protein kinase B
• stem cell-derived exosome cerebral ischemia-reperfusion injury
• inflammatory cytokine
• neuronal apoptosis
• novel therapeutic target

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Ministry of Science and Technology of China under Grant No. 2016YFA0100902 and National Natural Science Foundation of China under Grant No. 81501508.