The Potential Effects Of Natural Compounds On Regulating Autophagy And Stroke

Abstract

Stroke is considered a leading cause of death and neurological disability, placing a huge burden on individuals and communities. To date, the complex pathological mechanisms of stroke have limited effective treatment. Autophagy refers to the intracellular degradation process in which lysosomes participate. Autophagy plays a key role in maintaining cellular homeostasis and survival by eliminating damaged or non-essential cellular components. A growing body of evidence supports autophagy to protect neuronal cells from ischemic damage. In some cases, however, auto-phagy activation induces cell death and exacerbates ischemic brain injury. A variety of naturally derived compounds, such as cistanche, have been found to regulate autophagy and play a neuroprotective role against stroke. In our present work, we review recent advances in naturally derived compounds that regulate autophagy and discuss their potential applications in stroke therapy.

1. Introduction

Ischemic stroke is characterized by a rapid decrease in blood supply to areas of the brain, resulting in neuronal death, severe neurological deficits, disability, and even death. Ischemic stroke is considered to be one of the leading causes of neurological impairment and death worldwide. To date, recombinant tissue plasminogen activator (rtPA) is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of ischemic stroke. However, this strategy is limited to a 3e4.5 hour time window after an ischemic attack and increases the risk of cerebral hemorrhage, resulting in only a small number of patients (5%) benefiting from this strategy. In addition to thrombolysis, many neuroprotectants that are effective preclinically have been found to be ineffective against stroke in humans. This difference may be related to the complex mechanism of cerebral ischemia. Therefore, a better understanding of cutting-edge research in ischemic neuronal injury will provide opportunities for the development of novel anti-stroke drugs.

Pic: Faw Cistanche

In an ischemic brain, nutrients and oxygen are scarce, which may activate autophagy, the intracellular catabolic mechanism through lysosomes. Normally, autophagy is activated in response to starvation, such as nutritional deficiencies. Thus, autophagy leads to the clearance of organelles and proteins to compensate for hunger. Autophagy has been shown to play a key role in a wide range of human diseases, including cerebral ischemia.

Natural products come from different natural sources. A growing body of evidence highlights the beneficial role of these naturally derived compounds in the prevention and treatment of human diseases, including stroke. While an epidemiological study has shown a direct association between a diet rich in natural products and neuroprotection and reduced risk and severity of stroke, little is known about the role of natural products as autophagy regulators in the treatment of ischemic stroke. It was found that total cistanche glycosides in mice with right common carotid artery ligature increased SOD activity, stroke index, percentage of cerebral infarction area, MDA content in brain tissue, and nitric oxide synthase (nitric oxide synthase) in cerebral ischemia reperfusion model. NOS line method blocked the middle cerebral artery in rats to create cerebral infarction range, improve neurological symptoms, increase the activity of GSH-Px and SOD in brain tissue, and reduce the content of MDA. It can also reduce the content of glutamate in brain tissue of SD rats after cerebral ischemia reperfusion, which may be related to the increase of excitatory amino acid in brain tissue. These results suggest that total glycosides of cistanche have a good protective effect on cerebral ischemia reperfusion injury.

Pic: Cistaches Extract

2. Autophagy is also regulated independently of the mTOR signaling pathway.

In a nutrient-rich environment, beclin 1 binds to B-cell lymphoma 2 (BCL-2), an anti-apoptotic protein in the BCL-2 family. During nutrient deprivation, BCL-2 is phosphorylated by Jun N-terminal kinase 1 (JNK1), thereby separating from beclin 1 and thus facilitating autophagosome initiation. Notably, beclin 1 May also play a role in autophagosome maturation. In addition, two downstream cascades of RAS, namely RASePtdIns3K and RASeRAF-1eERK1/2 pathway, are influential factors in the reverse regulation of autophagy. These signaling pathways provide another way to detect growth factor or amino acid deletions in a way independent of mTOR

3. Various stress factors may be involved in autophagy activation of ischemic neurons after ischemic stroke.

These factors may include, but are not limited to, production of reactive oxygen species (ROS), aggregation of misfolded proteins, intracellular calcium overload, bioenergy crisis, and dramatic loss of amino acids. Unfolded proteins induce ER stress, which triggers autophagy through several signaling pathways. In protein response to ER stress, protein kinase R (PKR) -like ER kinase (PERK), creatine requirement enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) act as sensor proteins that are typically bound and inhibited by ER chaperone glucose regulatory protein (GRP-78) 66. GRP-78 separates from these sensor proteins during endoplasmic reticulum stress and interacts with the misfolded protein, thereby activating the sensor. Specifically, PERK phosphorylates eukaryotic translation initiation Factor (eIF2a) during ischemia and upregulates autophagy related proteins such as ATG12. In addition, ischemia triggers downstream pathways of TRAF2 and IRE1. After translocation and cleavage of the Golgi apparatus, ATF6 is activated and further induces transcription of ER chaperone and other components to degrade proteins critical to ER.

Pic: Protection of cerebral ischemia

In ischemic neurons, CaMKK and LKB1 are activated, and AMPK15 is phosphorylated due to calcium overload and ATP depletion. AMPK phosphorylates Raptor or TSC2, thereby inhibiting autophagy induced by the mTOR pathway. In addition, scaffold protein b-arrestin 1, which enables Vps34 to interact with beclin 1, is up-regulated during cerebral ischemia. B-statin 1 knockout enhances vulnerability to ischemic brain injury in mice, which may be related to autophagy deficiency.

4. Role of Autophagy in cerebral ischemia

Activation of autophagy has been demonstrated in several animal models of cerebral ischemia, although the role of autophagy remains controversial. The contribution of autophagy to ischemic stroke may depend on the activity of autophagy. Overactivated autophagy can promote neuronal cell death. Autophagy has also been found in brains damaged by ischemia/reperfusion (I/R). In a focal cerebral ischemia model, autophagy activation was observed at the injury boundary, and treatment with the autophagy inhibitor 3-methylladenine significantly reduced infarct volume even after 3 hours of ischemia. Recently, the autophagy process of mitochondria in ischemic neurons has been revealed. Cistanche can protect against cerebral ischemia and cerebral ischemia-reperfusion injury. Therefore, autophagy has a neuroprotective effect in both in vitro and in vivo ischemia models. Moreover, it is agreed that autophagy does not simply "randomly" pick its cargo. In contrast, several types of selective autophagy have been identified in the ischemic brain.

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5: Conclusion

The role of autophagy in cerebral ischemia is still controversial. Due to the lack of knowledge in this area, there are no clinical trials related to the regulation of autophagy in the treatment of stroke. However, autophagy is thought to be an endogenous strategy to protect neuronal response to ischemia. It is worth noting that some natural compounds act as neuroprotectants, at least in part by autophagy regulation. It is important to note that it cannot be ruled out that other mechanisms, such as anti-oxidation and anti-apoptosis, may also contribute greatly to the potential neuroprotective effects of these natural compounds. The use of natural compounds may lay the foundation for new pharmacological approaches to stroke treatment. For example, echinoside in cistanche can reduce the expression number of apoptotic nerve cells in hippocampus of rats with focal cerebral ischemia injury model established by middle cerebral artery occlusion method (MCAO), and the mechanism may be related to anti-apoptotic effect. Echinoside can also reduce the contents of NE, 5-HT, DOPAC, DA, HVA and 5-hydroxyindoleacetic acid (HIAA) in the extracellular fluid of striatum in rats with cerebral ischemia, and its mechanism may be related to the increase of monoamine transmitters after cerebral ischemia. These results suggest that echinoside has a protective effect on the brain tissue of cerebral ischemia rats. Given the neuroprotective effects of these compounds on other neurological diseases, their potential effects on stroke would be promising and would certainly require further study.

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