The citrus flavonoid “Nobiletin” impedes STZ-induced Alzheimer’s disease in a mouse model through regulating autophagy mastered by SIRT1/FoxO3a mechanism

Abstract

The prominence of autophagy in the modulation of neurodegenerative disorders has sparked interest to investigate its stimulation in Alzheimer's disease (AD). Nobiletin possesses several bioactivities such as anti-inflammation, antioxidation, and neuroprotection. Consequently, the study's aim was to inspect the possible neurotherapeutic impact of Nobiletin in damping AD through autophagy regulation. Mice were randomly assigned into: Group I which received DMSO, Groups II, III, and IV obtained STZ (3 mg/kg) intracerebroventricularly once with Nobiletin (50 mg/kg/day; i.p.) in Group III and Nobiletin with EX-527 (2 mg/kg, i.p.) in Group IV. Interestingly, Nobiletin ameliorated STZ-induced AD through enhancing the motor performance and repressing memory defects. Moreover, Nobiletin de-escalated hippocampal acetylcholinesterase (AChE) activity and enhanced acetylcholine level while halting BACE1 and amyloid-β levels. Meanwhile, Nobiletin stimulated the autophagy process through activating the SIRT1/FoxO3a, LC3B-II, and ATG7 pathway. Additionally, Nobiletin inhibited Akt pathway and controlled the level of NF-κB and TNF-α. Nobiletin amended the oxidative stress through enhancing GSH and cutting down MDA levels. However, EX527, SIRT1 inhibitor, counteracted the neurotherapeutic effects of Nobiletin. Therefore, the present study provides a strong verification for the therapeutic influence of Nobiletin in AD. This outcome may be assigned to autophagy stimulation through SIRT1/FoxO3a, inhibiting AChE activity, reducing neuroinflammation and oxidative stress. Graphical abstract

Multi-Omics Integration and Causal Inference Identify HSD17B1 as a Potential Nobiletin Target Linking Neurosteroid Metabolism to Alzheimer’s Disease

“…Importantly, the cell-based validation complements the computational, transcriptomic, and genetic evidence presented above. These findings are also consistent with recent experimental studies showing that nobiletin can modulate neuroinflammatory and AD-like pathological responses in cellular and animal models [ 50 , 51 ]. At the same time, the findings do not imply that HSD17B1 fully mediates all effects of nobiletin; rather, they support HSD17B1 as one component of a broader protective molecular network.…”

Multi-Omics Integration and Causal Inference Identify HSD17B1 as a Potential Nobiletin Target Linking Neurosteroid Metabolism to Alzheimer’s Disease

“…Importantly, the cell-based validation complements the computational, transcriptomic, and genetic evidence presented above. These findings are also consistent with recent experimental studies showing that nobiletin can modulate neuroinflammatory and AD-like pathological responses in cellular and animal models [ 50 , 51 ]. At the same time, the findings do not imply that HSD17B1 fully mediates all effects of nobiletin; rather, they support HSD17B1 as one component of a broader protective molecular network.…”

Evaluation of the In Vitro Blood–Brain Barrier Transport of Ferula persica L. Bioactive Compounds

“…That study revealed some compounds significantly correlated with both ROS scavenging capacity and AChE inhibition, among which nobiletin and isofraxidin were identified. As presented above, these compounds have also demonstrated high PAMPA-BBB permeability in AerExt and RootExt, and both compounds have already shown interesting neuroprotective properties [ 46 , 47 , 48 , 49 ]. Other low molecular weight compounds, such as ferulic acid, have been also reported to exhibit favorable BBB permeability, as demonstrated in both in vivo studies and PAMPA-BBB models [ 50 ].…”

Optimization and Chemical Characterization of Extracts Obtained from Ferula persica var. latisecta Aerial Parts and Roots and Their Neuroprotective Evaluation

“…Among them, 8 compounds (guaiol acetate, selina-3,7(11)-diene, 2-hydroxypalmitic acid, kaempferol, stearic acid, palmitic acid, palmitoleic acid, and α-cyperone) were correlated with both activities (Table 5). Some of these compounds, such as isofraxidin [76,77] β-asarone [3], nobiletin [78,79], α-cyperone [70], and kaempferol [43], have already demonstrated interesting neuroprotective properties.…”

Multi-Omics Integration and Causal Inference Identify HSD17B1 as a Potential Nobiletin Target Linking Neurosteroid Metabolism to Alzheimer’s Disease

“…Importantly, the cell-based validation complements the computational, transcriptomic, and genetic evidence presented above. These findings are also consistent with recent experimental studies showing that nobiletin can modulate neuroinflammatory and AD-like pathological responses in cellular and animal models [ 50 , 51 ]. At the same time, the findings do not imply that HSD17B1 fully mediates all effects of nobiletin; rather, they support HSD17B1 as one component of a broader protective molecular network.…”

Evaluation of the In Vitro Blood–Brain Barrier Transport of Ferula persica L. Bioactive Compounds

“…That study revealed some compounds significantly correlated with both ROS scavenging capacity and AChE inhibition, among which nobiletin and isofraxidin were identified. As presented above, these compounds have also demonstrated high PAMPA-BBB permeability in AerExt and RootExt, and both compounds have already shown interesting neuroprotective properties [ 46 , 47 , 48 , 49 ]. Other low molecular weight compounds, such as ferulic acid, have been also reported to exhibit favorable BBB permeability, as demonstrated in both in vivo studies and PAMPA-BBB models [ 50 ].…”

Optimization and Chemical Characterization of Extracts Obtained from Ferula persica var. latisecta Aerial Parts and Roots and Their Neuroprotective Evaluation

“…Among them, 8 compounds (guaiol acetate, selina-3,7(11)-diene, 2-hydroxypalmitic acid, kaempferol, stearic acid, palmitic acid, palmitoleic acid, and α-cyperone) were correlated with both activities (Table 5). Some of these compounds, such as isofraxidin [76,77] β-asarone [3], nobiletin [78,79], α-cyperone [70], and kaempferol [43], have already demonstrated interesting neuroprotective properties.…”

Multi-Omics Integration and Causal Inference Identify HSD17B1 as a Potential Nobiletin Target Linking Neurosteroid Metabolism to Alzheimer’s Disease

“…Importantly, the cell-based validation complements the computational, transcriptomic, and genetic evidence presented above. These findings are also consistent with recent experimental studies showing that nobiletin can modulate neuroinflammatory and AD-like pathological responses in cellular and animal models [ 50 , 51 ]. At the same time, the findings do not imply that HSD17B1 fully mediates all effects of nobiletin; rather, they support HSD17B1 as one component of a broader protective molecular network.…”

Evaluation of the In Vitro Blood–Brain Barrier Transport of Ferula persica L. Bioactive Compounds

“…That study revealed some compounds significantly correlated with both ROS scavenging capacity and AChE inhibition, among which nobiletin and isofraxidin were identified. As presented above, these compounds have also demonstrated high PAMPA-BBB permeability in AerExt and RootExt, and both compounds have already shown interesting neuroprotective properties [ 46 , 47 , 48 , 49 ]. Other low molecular weight compounds, such as ferulic acid, have been also reported to exhibit favorable BBB permeability, as demonstrated in both in vivo studies and PAMPA-BBB models [ 50 ].…”

Optimization and Chemical Characterization of Extracts Obtained from Ferula persica var. latisecta Aerial Parts and Roots and Their Neuroprotective Evaluation

“…Among them, 8 compounds (guaiol acetate, selina-3,7(11)-diene, 2-hydroxypalmitic acid, kaempferol, stearic acid, palmitic acid, palmitoleic acid, and α-cyperone) were correlated with both activities (Table 5). Some of these compounds, such as isofraxidin [76,77] β-asarone [3], nobiletin [78,79], α-cyperone [70], and kaempferol [43], have already demonstrated interesting neuroprotective properties.…”