A New Therapeutic Trend: Natural Medicine for Ameliorating Ischemic Stroke via PI3K/Akt Signaling Pathway

Abstract

Ischemic stroke (IS) is an acute cerebrovascular disease caused by sudden arterial occlusion, which is characterized by a high morbidity, mortality, and disability rate. It is one of the most important causes of nervous system morbidity and mortality in the world. In recent years, the search for new medicine for the treatment of IS has become an attractive research focus. Due to the extremely limited time window of traditional medicine treatment, some side effects may occur, and accompanied by the occurrence of adverse reactions, the frequency of exploration with natural medicine is significantly increased. Phosphatidylinositol-3-kinase/Protein kinase B (PI3K/Akt) signaling pathway is a classical pathway for cell metabolism, growth, apoptosis, and other physiological activities. There is considerable research on medicine that treats various diseases through this pathway. This review focuses on how natural medicines (including herbs and insects) regulate important pathophysiological processes such as inflammation, oxidative stress, apoptosis, and autophagy through the PI3K/Akt signaling pathway, and the role it plays in improving IS. We found that many kinds of herbal medicine and insect medicine can alleviate the damage caused by IS through the PI3K/Akt signaling pathway. Moreover, the prescription after their combination can also achieve certain results. Therefore, this review provides a new candidate category for medicine development in the treatment of IS.

Keywords: PI3K/Akt signaling pathway; ischemic stroke; natural medicine; new trend; treatment.

Figure 1

Relationship between PI3K/Akt signaling pathway and apoptosis, inflammation, autophagy, and oxidative stress. After the activation of PI3K/AKT signaling pathway: (1) it can act on the downstream targets such as NF-κB, mammalian target of rapamycin (mTOR), and down-regulate the expression of cysteinyl aspartate specific proteinase-9 (Caspase-9), cysteinyl aspartate specific proteinase-3 (Caspase-3), and apoptosis-related protein B lymphocyte tumor-2 (Bcl-2) associated x protein (Bax), ultimate anti-apoptosis; (2) it up-regulates the expression of low complexity communications codec II/I (LC3-II/LC3-I), Beclin-1, interleukin-1 (IL-1), and toll-like receptor 4 (TLR4) to achieve the effect of anti-autophagy; (3) it inhibits the expression of pro-inflammatory factors induced by NF-κB to achieve the effect of anti-inflammation; (4) activated Akt further activates Nrf2, to achieve the effect of anti-oxidative stress.

Figure 2

Relationship between ischemic stroke and apoptosis, inflammation, autophagy, and oxidative stress. After cerebral ischemia, the activity of Na⁺/K⁺−ATP enzyme in ischemic penumbra decreases and the imbalance of ion homeostasis leads to cell membrane depolarization and Ca²⁺ influx, resulting in excessive release of glutamate and excitotoxicity. With the influx of a large amount of Ca²⁺, the adhesion factors of endothelial cells increase, which leads to white blood cell recruitment, increases the contents of ROS and nitric oxide (NO), and causes oxidative stress. Then, NF-κB and MAPK signaling pathways are activated, causing cell apoptosis. Microglial and astrocytic cells are also activated, which up-regulate tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), finally causing an inflammatory reaction. Meanwhile, microglia cell-mediated down-regulation of Toll-like receptor-4 (TLR-4) induce autophagy.