Astragaloside IV Supplementation Promotes A Neuroprotective Effect in Experimental Models of Neurological Disorders: A Systematic Review

Abstract

Background: Neurological disorders constitute a growing worldwide concern due to the progressive aging of the population and the risky behavior they represent. Herbal medicines have scientific relevance in the treatment of these pathologies. One of these substances, Astragaloside IV (AS-IV), is the main active compound present in the root of Astragalus membranaceus (Fisch.) Bge, a Chinese medicinal herb with neuroprotective properties.

Objective: In the present study we performed a systematic review that sought to comprehend the neuroprotective effect presented by AS-IV in experimental models of neurological disorders.

Methods: This study is a systematic review, where an electronic search in United States National Library of Medicine (PubMed), Science Direct, Cochrane Library, Scientific Electronic Library Online (SciELO), Scopus, Web of Science, Medline via Proquest and Periodicos Capes databases covering the years between 2007 and 2017, using "Astragaloside IV" and "Neurodegenerative diseases"; "Astragaloside IV" and " Neurological disorders" as reference terms was made.

Results: A total of 16 articles were identified, in which the efficacy of AS-IV was described in experimental models of Parkinson's disease, Alzheimer's disease, cerebral ischemia and autoimmune encephalomyelitis, by improving motor deficits and/or neurochemical activity, especially antioxidant systems, reducing inflammation and oxidative stress.

Conclusion: The findings of the present study indicate that the administration of AS-IV can improve behavioral and neurochemical deficits largely due to its antioxidant, antiapoptotic and antiinflammatory properties, emerging as an alternative therapeutic approach for the treatment of neurological disorders.

Keywords: Alzheimer's disease; Neurological disorders; Parkinson's disease; astragaloside IV; brain; cerebral ischemia..

Fig. (1)

Chemical structure of Astragaloside IV.

Fig. (2)

Flowchart showing the selection process of the studies used in this systematic review.

Fig. (3)

Potential mechanisms proposed for the AS-IV action in experimental models of neurological disorders. In step A, the protective effect of AS-IV (10 and 20 mg/kg) observed in an experimental I/R model as outlined prevented the accumulation of CD11b/CD18 positive neutrophils and reduced the expression of the intracellular adhesion molecule-1 (ICAM-1), which was partially achieved by the strong attenuation of TNF-α and IL-1β anti-inflammatory mechanism production by the suppression of these molecules related to neutrophil adhesion. Another proposed action mechanism reduced BBB permeability and decreased lymphocyte infiltration due to anti-inflammatory action, resulting in in decreased neuroinflammation. In step B, the AS-IV acted on the ischemic region, decreasing the metabolism of glucose and resulting in the reduction of clot area, attenuating the volume of cerebral infarction. The anti-edema action of AS-IV was also correlated with AQP4 regulation, which mediates the flow of water in the CNS with a consequent decrease of the cerebral edema and reduction of microglial activation, followed by reduced BBB interruption and MMP9 (Matrix metaloproteinase) related to vasogenic edema, which was inhibited by AS-IV which also decreased lymphocyte infiltration. In step C, the effect of the AS-IV was observed in a culture of dopaminergic neurons when 100 μM was administered. This model of 6-OHDA showed cell death in the SNpc (substantia nigra pars compacta), while the group treated with AS-IV notably increased cell survival, attenuating the loss of dopaminergic neurons since it presented intact germination; and in step D, the AS-IV prevented mitochondrial dysfunction by increasing the enzyme action of the SOD and GSH antioxidant defense system to convert hydrogen peroxide into H₂O and O₂, thereby preventing lipid peroxidation and mitochondrial damage. The AS-IV inhibited the apoptotic pathway between both action mechanisms proposed for neurodegenerative diseases. These action mechanisms were briefly summarized and evaluated in the reviewed studies, reporting that AS-IV reduced the activation of the BAX channel (which accelerates programmed cell death) and increased Bcl-2 that represses apoptosis. Furthermore, AS-IV prevented the activation of the procaspases that activate the effector caspase 3, thus preventing oxidative stress, apoptosis and a decrease malondialdehyde (MDA) which catalyzes the formation of numerous ROS. AS-IV also increased mitochondrial potential and ATP generation, inhibiting the membrane pore opening and consequently reverting the mitochondrial oxidation. In step E, AS-IV action in the experimental model induced by Aβ-amyloid illustrated, since it inhibits Aβ-amyloid formation by the APP, thus inhibiting the BACE-1 which cleaves this protein by generating the toxic amyloid, and it also inhibited presenilin-1 expression. In step F the TH enzyme of dopamine, NO and NOS synthesis increased, which elevated dopamine release in the striatum. (The color version of the figure is available in the electronic copy of the article).