The scientific community has universally recognized the chemopreventive power of the class of molecules known to the public as polyphenols or bioflavonoids. This term indicates aromatic molecules, endowed with very powerful biological actions, which exert protective effects against the damage of oxidizing free radicals (ROS). Aside from neutralizing ROS, polyphenols are known to have very specific cellular targets. These are usually enzymes implied in inflammatory processes (e.g. lipo-oxygenases), the catabolism of nitrogenous substances (eg. xanthine oxidase), enzymes that degrade supporting structures (such as collagenase) and intracellular signaling proteins at the head of the dialogue network that allows the cell to decipher all exogenous signals. Some of them are used to trigger inflammation signals, others to stimulate cell proliferation, others to signal the presence of external stresses, others still serve to cellular specializations in different tissues.
Not all flavonoids have, anyway, the same degree of enzymatic affinity towards the same enzyme, or the same degree of bioavailability dictated mostly by the degree of hydro- / liposolubility, not to mention the absorption capacity through the intestinal mucosa dictated by various physiological or pathologic situations. A very popular source of flavonoids are citrus fruits (lemon, orange, tangerine, grapefruit and all their varieties or similar fruits of the genus Citrus). Their concentration in the fruit pulp reaches appreciable quantities, but it is in the peels that they are often represented in greater amounts. Almost a dozen of them are known and what differentiates them from the more common polyphenols known in vegetables, vegetables and regular fruit, is their greater fat solubility. The flavonoids of citrus fruits, in fact, possess a higher degree of methylation than most of the others, and are categorized as “poly-methoxylates”. This chemical characteristic allows them to dissolve better at the body level, in fatty structures such as nervous (myelin).
One of these flavonoids is nobiletin, which is highly represented in oranges and tangerines. Finally, there are studies that prove that nobiletin was found to be neuroprotective in experimental animal models. Administered before a cerebral ischemic insult, it allows the infarcted tissue to recover and reduce oxidative stress. It also positively affects the cellular responses of glutamate triggered by the NMDA receptor, promoting the genesis of cellular neurites. It has good specificity for components of the MAP-kinase pathway (c-Raf, MEK1, PI-3K) activated in pathological contexts. In the case of pathological activation by the NMDAR receptor and beta-amyloid, the sustained activation of MAP-kinases can contribute to neuronal toxicity and the neurodegenerative process. Nobiletin has an important additional cellular target, i.e. mitochondria, where it enhances with the activity of complex I of cellular respiration, reducing the production of oxidative by-products (superoxide) and therefore cell peroxides.
This completes its neuroprotective spectrum, as oxidative stress and mitochondrial dysfunction are central phenomena in neurological and neurodegenerative diseases such as multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis and many more. A second flavonoid much studied in the neuropathological field is hesperitin, typically present in the peel of oranges, which has biological properties and molecular targets somewhat different from those of nobiletin. It has been found to be a powerfully anti-inflammatory and neuroprotective, because it suppresses the activation of ERK and p38 MAP-kinases in the brain microglìa, that reacts to cell damage, to the accumulation of beta-amyloid and produces cytokines that support the inflammatory background, and becoming a subclinical neuroinflammation. About these phenomena, hesperitin interferes with neuroinflammation because it acts on the pathway of the inflammasome, of the tolerance receptors and the transcription factor NF-kB (TLRs / NLRP3 / NF-kB).
Toll-like receptors (TLR) play a critical role in recognizing microbial and bacterial components in the brain, initiating the immune response. A TLR-mediated signaling pathway removes bacteria from the biological system but can damage the brain cells. Brain microglial cells express TLR4, which recognizes LPS and is associated with the release of inflammatory mediators during NF-κB signaling. Indeed, several studies have suggested that dominant, nongrowing bacteria contribute to Alzheimer dementia, releasing inflammatory elements like lipopolysaccharide (LPS). LPS is found in Gram-negative bacteria that activate the immune system, which through ROS generation and oxidative damage in neural cells lead to behavioral and memory impairments. In this regard, hesperitin promotes neuronal survival and trophism, through PI3K-Akt and MAPK pathways and enhances antioxidant defenses by affecting the Nrf-2 transcription factor.
Beside its direct antioxidant activity, hesperitin may affect the redox-sensitive Nrf-2 factor, which up-regulates either defensive proteins (e.g. Hsp70) and antioxidant enzymes (thoredoxin, TxR1, GPX-1, NQO-1, HO-1, SOD2, etc.), Growing concerns are centered around the entry of flavonoids through the blood–brain barrier (BBB). Furthermore, changes in nervous system function may be simply caused by aging, which could exacerbate motor and cognitive modifications. Some studies have analyzed the ability of flavonoids to penetrate through the BBB, which enhanced the laboratory findings conducted thus far. In the case of hesperetin, studies on brain endothelial cells and in vivo show that citrus flavonoids, such as hesperetin, are taken up by brain cells. It is far likely that nobiletin and other poly-methoxy-flavonoids (hepta-methoxy-flavone, tangeretin, sudachitin, etc.) would have more probability than hesperitin (less methoxy-groups) to cross BBB due to their higher lipophilic nature.
Before Alzheimer and other forms of senile dementias, citrus flavonoids could benefit multiple sclerosis, which is far common and prone to practical drug interventions. There are no direct data ont he effects of Citrus flavonoids in man or patients with the disease. Yet, lab experiment confirm that hesperitin and nobiletin both work well in the experimental model of this condition (EAE) by affecting the differentiation of Th17 lymphocytes. In a very recetly published research, either prophylactic and therapeutic use of nobiletin inhibited EAE-induced increase of TNF-α, IL-1β and IL-6 activities, to alleviate inflammatory response in brain and spinal cord of lab animals experimentally induced with EAE. Moreover, nobiletin supplement dramatically increased the IL-10, TGF-β and IFNγ expressions in prophylaxis and treatment animal groups compared with the EAE group in the brain and spinal cord. Overall, citrus polyphenols can represent a good alternative to be exploited for the complementary treatment of conditions such as senile cognitive decline and multiple sclerosis.
As there are no clinical trials on the effect of these substances in the human context, it is not possible to anticipate efficacy, timing and other evaluable clinical parameters. Assuming that the murine counterpart reflects the vast majority of the times what will appear in the human counterpart, the only recommendation that can be given is to consume fresh citrus fruits with meals, when possible, or citrus extracts that also include the skins rich in these active ingredients. The rationale for their use holds anyway.
- edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
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