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Umuhengerin Neuroprotective Effects in Streptozotocin-Induced Alzheimer's Disease Mouse Model via Targeting Nrf2 and NF-Kβ Signaling Cascades.

ABSTRACT: Alzheimer's disease (AD) is the most common type of dementia and is characterized by advanced cognitive deterioration, deposition of Aβ (amyloid-beta), and the formation of neurofibrillary tangles. Administration of streptozotocin (STZ) via the intracerebroventricular (ICV) route is a reliable model resembling sporadic AD (SAD) associated neuropathological changes. The present study was undertaken to explore the neuroprotective effects of the methoxy flavonoid, umuhengerin, in an STZ-induced SAD mouse model as a potential therapy for AD. Mice were injected once with STZ (3 mg/kg, ICV), followed by daily administration of umuhengerin (orally, 30 mg/kg) or the positive control donepezil (orally, 2.5 mg/kg) for 21 days. The pharmacological activity of umuhengerin was assessed through estimation of oxidative stress and inflammatory markers via mouse ELISA kits, Western blot analysis, and brain histopathological examination. Morris water maze test was also conducted to investigate umuhengerin-induced cognitive enhancement. The results showed that umuhengerin attenuated STZ-produced neuroinflammation and oxidative stress with a notable rise in the expression of Nrf2 (nuclear factor erythroid 2-related factor 2). In contrast, it downregulated Keap-1 (Kelch-like ECH associated protein 1), as well as elevated brain contents of GSH (reduced glutathione) and HO-1 (heme oxygenase-1). STZ-injected animals receiving umuhengerin showed marked downregulation of the nuclear factor kappa beta (NF-Kβp65) and noticeable increment in the expression of its inhibitor kappa beta alpha protein (IKβα), as well as prominent reduction in malondialdehyde (MDA), H₂O₂ (hydrogen peroxide), and TNF-α (tumor-necrosis factor-alpha) contents. Β-secretase protein expression and acetylcholinesterase (AchE) activity were also diminished upon umuhengerin injection in the STZ group, leading to decreased Aβ formation and cognitive improvement, respectively. In conclusion, umuhengerin neuroprotective effects were comparable to the standard drug donepezil; thus, it could be an alternative approach for AD management.

SUBMITTER: Sirwi A

PROVIDER: S-EPMC8698785 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Alzheimer's disease (AD) as an age-related, irreversible neurodegenerative disease, characterized by cognitive dysfunction, has become progressively serious with a global rise in life expectancy. As the failure of drug elaboration, considerable research effort has been devoted to developing therapeutic strategies for treating AD. TCM is gaining attention as a potential treatment for AD. Gastrodia elata Blume, Polygala tenuifolia Willd., Cistanche deserticola Ma, Rehmannia lutinosa (Gaertn.)DC., Acorus gramineus Aiton, and Curcuma longa L. (GPCRAC) are all well-known Chinese herbs with neuroprotective benefits and are widely used in traditional Chinese decoction for AD therapy. However, the efficacy and further mechanisms of GPCRAC extracts in AD experimental models are still unclear. The purpose of this study was to investigate the synergistic protective efficacy of GPCRAC extracts (composed of extracts from these six Chinese medicines), and the protein targets mediated by GPCRAC extracts in treating AD. Methods: Scopolamine-induced cognitive impairment mouse model was established to determine the neuroprotective effects of GPCRAC extracts in vivo, as shown by behavioral tests and cerebral cholinergic function assays. To identify the potential molecular mechanism of GPCRAC extracts against AD, label-free quantitative proteomics coupled with tandem mass spectrometry (LC-MS/MS) were performed. The integrated bioinformatics analysis was applied to screen the core differentially expressed proteins in vital canonical pathways. Critical altered proteins were validated by qPCR and Western blotting. Results: Administration of GPCRAC extracts significantly recovered scopolamine-induced cognitive impairment, as evidenced by the improved learning and memory ability, increased Ach content and ChAT activity, as well as decreased AchE activity in the hippocampus of mice. In total, 390 proteins with fold-change>1.2 or <0.83 and p < 0.05 were identified as significant differentially expressed proteins, of which 110 were significantly up-regulated and 25 were significantly down-regulated between control and model group. By mapping the significantly regulated proteins, we identified five hub proteins: PPP2CA, Gsk3β, PP3CC, PRKACA, and BCL-2 that were associated with dopaminergic synapse and apoptosis signaling pathway, respectively. Western blotting and QPCR demonstrate that the expression levels of these core proteins could be significantly improved by the administration of GPCRAC extracts. These pathways and some of the identified proteins are implicated in AD pathogenesis. Conclusion: Administration of GPCRAC extracts was effective on alleviating scopolamine-induced cognitive impairment, which might be through modulation of dopaminergic synapse and apoptosis signaling pathway. Consequently, our quantitative proteome data obtained from scopolamine-treated model mice successfully characterized AD-related biological alterations and proposed novel protein biomarkers for AD.

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Umuhengerin Neuroprotective Effects in Streptozotocin-Induced Alzheimer's Disease Mouse Model via Targeting Nrf2 and NF-Kβ Signaling Cascades.

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