Neuroprotective Mechanisms of Citrus Flavonoids in Neurodegenerative Diseases

Citrus flavonoids, notably polymethoxylated and flavanone subclasses such as nobiletin, hesperetin and hesperidin, have emerged as multi‐target agents capable of attenuating the complex pathology of neurodegenerative diseases. These compounds display potent antioxidant activity by upregulating endogenous defence systems, primarily via activation of the Nrf2 pathway, thereby neutralising reactive oxygen species and reducing lipid peroxidation. Concurrently, they exert anti‐inflammatory effects through modulation of TLR4/NF-κB signalling, limiting the release of pro-inflammatory cytokines and glial activation in both cortex and hippocampus. Beyond cytoprotection, citrus flavonoids enhance synaptic plasticity and promote neurogenesis in key memory‐related regions, restoring levels of synaptic proteins such as PSD-95 and boosting long-term potentiation. In models of Alzheimer’s disease they mitigate amyloidogenesis by inhibiting beta-secretase activity and tau hyperphosphorylation, while in Parkinson’s models they preserve dopaminergic neurons by inhibiting apoptotic cascades. The convergence of antioxidant, anti‐inflammatory and pro‐regenerative actions underpins their neuroprotective profile and supports their translation as dietary supplements or adjunctive therapies in neurodegenerative disorders globally.

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Neuroprotective Mechanisms of Citrus Flavonoids in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in neuroprotective mechanisms of citrus flavonoids in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Flavonoid: A class of polyphenolic compounds in citrus fruits with diverse bioactive properties, including antioxidant and anti‐inflammatory effects.

Neuroinflammation: Inflammatory response in the central nervous system characterised by activation of glial cells and release of cytokines.

Oxidative stress: Cellular damage resulting from an imbalance between reactive oxygen species production and antioxidant defences.

Neurogenesis: The process of generating new neurons from neural stem or progenitor cells, especially in the adult hippocampus.

TLR4/NF-κB signalling: An innate immune pathway activated by toll‐like receptor 4 that leads to nuclear translocation of NF-κB and transcription of inflammatory genes.

Nrf2 pathway: A cellular defence mechanism in which the transcription factor Nrf2 induces expression of antioxidant and cytoprotective enzymes.

References

1. Nobiletin Mitigates D-Galactose-Induced Memory Impairment via Improving Hippocampal Neurogenesis in Mice. Nutrients (2023).
2. Dapagliflozin/Hesperidin Combination Mitigates Lipopolysaccharide-Induced Alzheimer’s Disease in Rats. Pharmaceuticals (2023).
3. Hesperetin, a Citrus Flavonoid, Attenuates LPS-Induced Neuroinflammation, Apoptosis and Memory Impairments by Modulating TLR4/NF-κB Signaling. Nutrients (2019).
4. Potential Benefits of Nobiletin, A Citrus Flavonoid, against Alzheimer’s Disease and Parkinson’s Disease. International Journal of Molecular Sciences (2019).