Cycloastragenol, a Triterpenoid Saponin, Regulates Oxidative Stress, Neurotrophic Dysfunctions, Neuroinflammation and Apoptotic Cell Death in Neurodegenerative Conditions

Abstract

Here, we have unveiled the effects of cycloastragenol against Aβ (Amyloid-beta)-induced oxidative stress, neurogenic dysfunction, activated mitogen-activated protein (MAP) kinases, and mitochondrial apoptosis in an Aβ-induced mouse model of Alzheimer’s disease (AD). The Aβ-induced mouse model was developed by the stereotaxic injection of amyloid-beta (5 μg/mouse/intracerebroventricular), and cycloastragenol was given at a dose of 20 mg/kg/day/p.o for 6 weeks daily. For the biochemical analysis, we used immunofluorescence and Western blotting. Our findings showed that the injection of Aβ elevated oxidative stress and reduced the expression of neurogenic markers, as shown by the reduced expression of brain-derived neurotrophic factor (BDNF) and the phosphorylation of its specific receptor tropomyosin receptor kinase B (p-TrKB). In addition, there was a marked reduction in the expression of NeuN (neuronal nuclear protein) in the Aβ-injected mice brains (cortex and hippocampus). Interestingly, the expression of Nrf2 (nuclear factor erythroid 2–related factor 2), HO-1 (heme oxygenase-1), p-TrKB, BDNF, and NeuN was markedly enhanced in the Aβ + Cycloastragenol co-treated mice brains. We have also evaluated the expressions of MAP kinases such as phospho c-Jun-N-terminal kinase (p-JNK), p-38, and phospho-extracellular signal-related kinase (ERK1/2) in the experimental groups, which suggested that the expression of p-JNK, p-P-38, and p-Erk were significantly upregulated in the Aβ-injected mice brains; interestingly, these markers were downregulated in the Aβ + Cycloastragenol co-treated mice brains. We also checked the expression of activated microglia and inflammatory cytokines, which showed that cycloastragenol reduced the activated microglia and inflammatory cytokines. Moreover, we evaluated the effects of cycloastragenol against mitochondrial apoptosis and memory dysfunctions in the experimental groups. The findings showed significant regulatory effects against apoptosis and memory dysfunction as revealed by the Morris water maze (MWM) test. Collectively, the findings suggested that cycloastragenol regulates oxidative stress, neurotrophic processes, neuroinflammation, apoptotic cell death, and memory impairment in the mouse model of AD.

Astragalus mongholicus Bunge (Fabaceae): Bioactive Compounds and Potential Therapeutic Mechanisms Against Alzheimer’s Disease

“…These results have proven that AS-IV prevents Aβ-induced apoptosis of SK-N-SH cells by suppressing the opening of mPTP, the production of intracellular ROS, and increasing the level of anti-apoptosis molecules ( Sun et al, 2014 ). In vivo study by Ikram et al (2021) showed similar results. Increased oxidative stress was observed in Aβ injected mice, accompanied by significant neuronal loss and increased levels of Bax, casp-3, and Bim.…”

“…These data suggest that the PPARγ signaling pathway is the key target of AS-IV in suppressing the inflammatory reaction as well as other molecular changes in the hippocampus. In another study by Ikram et al (2021) , Aβ was stereotaxically injected into the lateral ventricle of mice to induce the Alzheimer’s disease model, followed by 6 weeks treatment of cycloastragenol, a triterpenoid saponin present in AR. It was found that Aβ injection reduced the number of neurons, levels of BDNF, phosphorylated receptor tropomyosin receptor kinase B (p-TrKB), nuclear factor erythroid 2-related factor 2 (Nrf-2), hemo oxygenase-1 (HO-1), and increased oxidative stress markers, which might be mediated by the MAP kinases (MAPK) as expression levels of p-JNK, p-P-38, p-Erk were increased.…”

Novel Antioxidant Collagen Peptides of Siberian Sturgeon (Acipenserbaerii) Cartilages: The Preparation, Characterization, and Cytoprotection of H2O2-Damaged Human Umbilical Vein Endothelial Cells (HUVECs)

“…However, synthetic antioxidants have shown a potential toxicity risk and their applications are strictly regulated [ 13 , 14 ]. Therefore, researchers are focusing their research interests on natural active molecules and their derivatives, such as flavonoids, triterpenoid, quinones, and alkaloids [ 12 , 15 , 16 , 17 ]. Remarkably, antioxidant peptide (AP) originated from food proteins, which captured worldwide interest because of their advantages in environmental protection and in sustainability, and their small molecular weight (MW) and low toxic side effects [ 1 , 9 , 12 ].…”

The role of Cycloastragenol at the intersection of Nrf-2/ARE, telomerase, and proteasome activity

“…In the literature, there are several studies describing CA as a neuroprotective compound against several neurotoxic agents such as Aβ1-42 peptide (Ikram et al, 2021) and 6-OHDA (6-hydroxydopamine) (Nesil et al, 2011). As our data clearly revealed that CA increased Nrf-2, telomerase, and proteasome activity, which reportedly alleviate neurotoxicity, CA-mediated protection against 6-OHDA was next investigated in the context of the involvement of Nrf-2 and hTERT.…”