TY - JOUR
T1 - Cycloastragenol, a Triterpenoid Saponin, Regulates Oxidative Stress, Neurotrophic Dysfunctions, Neuroinflammation and Apoptotic Cell Death in Neurodegenerative Conditions
AU - Ikram, M.
AU - Jo, M.H.
AU - Choe, K.
AU - Khan, A.
AU - Ahmad, S.
AU - Saeed, K.
AU - Kim, M.W.
AU - Kim, M.O.
N1 - Funding Information:
Funding: This research was supported by the Neurological Disorder Research Program of the National Research Foundation (NRF) funded by the Korean Government (MSIT) (2020M3E5D9080660).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Here, we have unveiled the effects of cycloastragenol against A beta (Amyloid-beta)-induced oxidative stress, neurogenic dysfunction, activated mitogen-activated protein (MAP) kinases, and mitochondrial apoptosis in an A beta-induced mouse model of Alzheimer's disease (AD). The A beta-induced mouse model was developed by the stereotaxic injection of amyloid-beta (5 mu g/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 A beta 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 A beta-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 A beta + 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 A beta-injected mice brains; interestingly, these markers were downregulated in the A beta + 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.
AB - Here, we have unveiled the effects of cycloastragenol against A beta (Amyloid-beta)-induced oxidative stress, neurogenic dysfunction, activated mitogen-activated protein (MAP) kinases, and mitochondrial apoptosis in an A beta-induced mouse model of Alzheimer's disease (AD). The A beta-induced mouse model was developed by the stereotaxic injection of amyloid-beta (5 mu g/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 A beta 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 A beta-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 A beta + 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 A beta-injected mice brains; interestingly, these markers were downregulated in the A beta + 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.
KW - Alzheimer's disease
KW - Amyloid-beta
KW - neurogenesis
KW - neuroprotection
KW - neurodegeneration
KW - ADULT HIPPOCAMPAL NEUROGENESIS
KW - ASTRAGALOSIDE IV
KW - DISEASE
KW - INHIBITION
KW - ACTIVATION
KW - RECEPTORS
KW - MEMORY
KW - ROLES
KW - CREB
U2 - 10.3390/cells10102719
DO - 10.3390/cells10102719
M3 - Article
C2 - 34685699
SN - 2073-4409
VL - 10
JO - Cells
JF - Cells
IS - 10
M1 - 2719
ER -