Ambroxol confers neuroprotection against scopolamine-induced Alzheimer’s-like pathology by modulating oxidative stress, neuroinflammation, and cognitive deficits via Nrf-2/JNK/GSK-3β signaling pathways
Alzheimer’s disease (AD) is the most common and costly chronic progressive neurodegenerative disorder, with the highest impact on public health worldwide. Pathological hallmarks of AD include progressive cognitive decline and memory impairment, dominantly mediated by oxidative neurodegeneration. Oxi...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1607289/full |
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| author | Waqas Ahmad Kyonghwan Choe Kyonghwan Choe Riaz Ahmad Tae Ju Park Myeong Ok Kim Myeong Ok Kim |
| author_facet | Waqas Ahmad Kyonghwan Choe Kyonghwan Choe Riaz Ahmad Tae Ju Park Myeong Ok Kim Myeong Ok Kim |
| author_sort | Waqas Ahmad |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is the most common and costly chronic progressive neurodegenerative disorder, with the highest impact on public health worldwide. Pathological hallmarks of AD include progressive cognitive decline and memory impairment, dominantly mediated by oxidative neurodegeneration. Oxidative stress is commonly recognized as a key factor in the pathophysiological progression of AD. Despite significant advancements, a definitive and effective therapeutic intervention for AD remains elusive. In this study, we investigate the neuroprotective potential of ambroxol (Amb), known for its potent anti-inflammatory and antioxidant properties. Given ambroxol’s potential neuroprotective effects, we explore the underlying molecular mechanisms, explicitly examining its role in attenuating scopolamine-induced oxidative stress-mediated activation of the c-Jun N-terminal kinase (JNK) pathway, as well as its modulation of Akt and glycogen synthase kinase-3 beta (GSK-3β) signaling, which is a key contributor to neuroinflammation, synaptic dysfunction and neurodegeneration. AD pathology is induced by scopolamine administration, leading to excessive lipid peroxidation (LPO) and reactive oxygen species (ROS) generation, which leads to a decline in critical antioxidant proteins, including nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1). However, ambroxol treatment effectively attenuated oxidative stress by reducing the production of reactive oxidative species while restoring the expression of key antioxidant proteins. Similarly, ambroxol attenuated oxidative stress-induced JNK activation and modulated Akt and GSK-3β alterations. Immunofluorescence and western blot analyses revealed that ambroxol attenuated reactive gliosis by suppressing the expression of GFAP and Iba-1, alongside the downregulation of key pro-inflammatory mediators, such as IL-1β, TNF-α, and phosphorylated NF-κB (p-p65). Scopolamine also compromised synaptic integrity and induced deficits in memory formation and spatial learning. In contrast, ambroxol promoted synaptic integrity by upregulating the expression of SNAP-23 and PSD-95, thereby ameliorating scopolamine-induced impairments in spatial learning and memory. |
| format | Article |
| id | doaj-art-045675a7dbd74bc8a2712a24633c936b |
| institution | DOAJ |
| issn | 1663-4365 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj-art-045675a7dbd74bc8a2712a24633c936b2025-08-20T03:14:23ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652025-07-011710.3389/fnagi.2025.16072891607289Ambroxol confers neuroprotection against scopolamine-induced Alzheimer’s-like pathology by modulating oxidative stress, neuroinflammation, and cognitive deficits via Nrf-2/JNK/GSK-3β signaling pathwaysWaqas Ahmad0Kyonghwan Choe1Kyonghwan Choe2Riaz Ahmad3Tae Ju Park4Myeong Ok Kim5Myeong Ok Kim6Division of Life Science and Applied Life Science (BK 21 Four), College of Natural Sciences, Gyeongsang National University, Jinju, South KoreaDivision of Life Science and Applied Life Science (BK 21 Four), College of Natural Sciences, Gyeongsang National University, Jinju, South KoreaDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, NetherlandsDivision of Life Science and Applied Life Science (BK 21 Four), College of Natural Sciences, Gyeongsang National University, Jinju, South KoreaDepartment of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, United StatesDivision of Life Science and Applied Life Science (BK 21 Four), College of Natural Sciences, Gyeongsang National University, Jinju, South KoreaAlz-Dementia Korea Co., Jinju, South KoreaAlzheimer’s disease (AD) is the most common and costly chronic progressive neurodegenerative disorder, with the highest impact on public health worldwide. Pathological hallmarks of AD include progressive cognitive decline and memory impairment, dominantly mediated by oxidative neurodegeneration. Oxidative stress is commonly recognized as a key factor in the pathophysiological progression of AD. Despite significant advancements, a definitive and effective therapeutic intervention for AD remains elusive. In this study, we investigate the neuroprotective potential of ambroxol (Amb), known for its potent anti-inflammatory and antioxidant properties. Given ambroxol’s potential neuroprotective effects, we explore the underlying molecular mechanisms, explicitly examining its role in attenuating scopolamine-induced oxidative stress-mediated activation of the c-Jun N-terminal kinase (JNK) pathway, as well as its modulation of Akt and glycogen synthase kinase-3 beta (GSK-3β) signaling, which is a key contributor to neuroinflammation, synaptic dysfunction and neurodegeneration. AD pathology is induced by scopolamine administration, leading to excessive lipid peroxidation (LPO) and reactive oxygen species (ROS) generation, which leads to a decline in critical antioxidant proteins, including nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1). However, ambroxol treatment effectively attenuated oxidative stress by reducing the production of reactive oxidative species while restoring the expression of key antioxidant proteins. Similarly, ambroxol attenuated oxidative stress-induced JNK activation and modulated Akt and GSK-3β alterations. Immunofluorescence and western blot analyses revealed that ambroxol attenuated reactive gliosis by suppressing the expression of GFAP and Iba-1, alongside the downregulation of key pro-inflammatory mediators, such as IL-1β, TNF-α, and phosphorylated NF-κB (p-p65). Scopolamine also compromised synaptic integrity and induced deficits in memory formation and spatial learning. In contrast, ambroxol promoted synaptic integrity by upregulating the expression of SNAP-23 and PSD-95, thereby ameliorating scopolamine-induced impairments in spatial learning and memory.https://www.frontiersin.org/articles/10.3389/fnagi.2025.1607289/fullAlzheimer’s diseasescopolamineambroxoloxidative stressneuroinflammationsynaptic dysfunction. |
| spellingShingle | Waqas Ahmad Kyonghwan Choe Kyonghwan Choe Riaz Ahmad Tae Ju Park Myeong Ok Kim Myeong Ok Kim Ambroxol confers neuroprotection against scopolamine-induced Alzheimer’s-like pathology by modulating oxidative stress, neuroinflammation, and cognitive deficits via Nrf-2/JNK/GSK-3β signaling pathways Frontiers in Aging Neuroscience Alzheimer’s disease scopolamine ambroxol oxidative stress neuroinflammation synaptic dysfunction. |
| title | Ambroxol confers neuroprotection against scopolamine-induced Alzheimer’s-like pathology by modulating oxidative stress, neuroinflammation, and cognitive deficits via Nrf-2/JNK/GSK-3β signaling pathways |
| title_full | Ambroxol confers neuroprotection against scopolamine-induced Alzheimer’s-like pathology by modulating oxidative stress, neuroinflammation, and cognitive deficits via Nrf-2/JNK/GSK-3β signaling pathways |
| title_fullStr | Ambroxol confers neuroprotection against scopolamine-induced Alzheimer’s-like pathology by modulating oxidative stress, neuroinflammation, and cognitive deficits via Nrf-2/JNK/GSK-3β signaling pathways |
| title_full_unstemmed | Ambroxol confers neuroprotection against scopolamine-induced Alzheimer’s-like pathology by modulating oxidative stress, neuroinflammation, and cognitive deficits via Nrf-2/JNK/GSK-3β signaling pathways |
| title_short | Ambroxol confers neuroprotection against scopolamine-induced Alzheimer’s-like pathology by modulating oxidative stress, neuroinflammation, and cognitive deficits via Nrf-2/JNK/GSK-3β signaling pathways |
| title_sort | ambroxol confers neuroprotection against scopolamine induced alzheimer s like pathology by modulating oxidative stress neuroinflammation and cognitive deficits via nrf 2 jnk gsk 3β signaling pathways |
| topic | Alzheimer’s disease scopolamine ambroxol oxidative stress neuroinflammation synaptic dysfunction. |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1607289/full |
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