Fisetin: biopharmaceutical properties and the interaction between cellular aging and neuroprotection

As we age, the function of the brain gradually diminishes. In addition, age is also one of the risk factors for many neurological diseases such as Alzheimer’s disease. The average age in many Western countries is increasing, so identifying ways to reduce the effects of aging on brain function has become even more urgent. Dr. Osama Elsallabi, from the D ‘Annandzia University and the Karolinska Institute of Medicine in Kyrgie-Pescara, And Dr. Antonia Patruno, Dr. Mirko Pesce, Dr. Amelia Cataldi, Prof. Simone Carradori and Prof. Marialucia Gallorini of the D ‘Annunzia University of Kyrgie-Pescara at the Molecules The journal published articles reviewing the latest research results on the antioxidant and neuroprotective effects of fisetin and comprehensively describing the silicon pharmacokinetics, pharmacodynamics and toxicity of fisetin and its related metabolites.

Nutrients from plants have been shown to prevent brain changes that lead to neurological disorders. In 2022, two review articles identified fisetin as one of the most promising drugs. 1,2 Preclinical studies have shown that fisetin has the potential to reduce the effects of stroke, mild cognitive impairment and dementia. 1, 2,

multinutrient

Flavonoids are a group of plant compounds with health-promoting properties. Fisetin is a flavonoid with multiple biological mechanisms that support nervous system health. 2 Fisetin is found in many fruits and vegetables, but in very small amounts. Most commercially available oral fisetin has poor bioavailability. 3 Scientists overcame this problem by wrapping fisetin in a form of fiber found in fenugreek plants. This helps protect fisetin from being broken down, increasing the absorption of fisetin into the body by 25 times. 4 Promise of neurological disorders

The promise of neurological diseases

In preclinical studies, fisetin has shown promise for treating a range of neurological disorders, including: 1,2

• Alzheimer’s disease

• Brain aging and cognitive decline

• Stroke

• Neurological complications of diabetes

• Depression

• Traumatic brain injury 6

• Parkinson’s disease

• Huntington’s disease

• Amyotrophic lateral sclerosis (ALS)

• Neurotoxicity (damage to the nervous system caused by toxins)

• Schizophrenia

• Vascular dementia

• Other forms of neurodegenerative diseases

In addition, fisetin improved response to ischemic stroke treatment in a clinical trial. 5

Fighting neurological diseases

A review published in 2021 found fisetin regulates 37 different biological pathways. All of these actions can reduce the risk and severity of age-related neurological disorders. The five ways fisetin protects the brain and nervous system are:

Fisetin Prevent toxic brain deposits

The plaques and tangles deposited in the brain are made up of toxic proteins called beta-amyloid and hyperphosphorylated tau. Fisetin prevents its accumulation in preclinical models. 6,7 In another study, fisetin increased autophagy, a form of cell cleaning that helps remove existing toxic proteins from brain cells. 8

Fisetin Antioxidant activity

Oxidative stress is an important factor leading to nervous system diseases. Fisetin is a potent antioxidant that cleans up harmful compounds before they can cause damage. Preclinical models have shown that fisetin increases intracellular levels of glutathione, a free radical scavenger important for cell survival. 9

Fisetin Reduce chronic inflammation

Chronic inflammation causes most chronic diseases in the brain. In preclinical trials, two forms of fisetin blocked activation of the nuclear factor kappa B (NF-kB), a major regulator of inflammation. 10,11 This operation prevents the release of pro-inflammatory compounds. In a study of a specific strain of mice predisposed to Alzheimer’s type neurodegeneration, feeding fisetin early to middle life protected against learning and memory decline. Fisetin also limits the levels of inflammatory compounds that are elevated in Alzheimer’s disease and other neurodegenerative diseases. 12

Fisetin Memory and learning support

A protein called CREB helps brain cells adapt to experiences over time, a process known as long-term enhancement. 13 This is a key component of memory formation. Fisetin increases CREB activation and enhances long-term enhancement in preclinical studies. 13 to 15

Fisetin Blocking saccharification damage

Glycosylation occurs when glucose attaches to proteins, DNA, and lipids to form toxic compounds. Damage caused by glycation has been linked to cognitive dysfunction and neurodegenerative diseases such as Alzheimer’s disease. 16 Glycated beta-amyloid protein is more damaging to brain function than the non-glycated form. 17 In mice, fisetin has been shown to reduce glycosylation and its damaging effects. 18

A nutrient that protects the brain

As of 2022, neurological disorders are identified as the cause of more disability than any other cause and are the second leading cause of death.

• Fisetin is a small nutrient found in many fruits and vegetables.

• Oral fisetin is rapidly metabolized. Combining it with fenugreek fiber increases its bioavailability by about 25 times.

Preclinical studies have shown that fisetin may be beneficial in neurological disorders, including stroke, Alzheimer’s disease, Parkinson’s disease, brain aging, and cognitive decline. A clinical study has also been completed and other studies are underway.

Fisetin works in a number of ways and may help improve nervous system health and reduce the risk of developing neurological diseases. Two recent reviews combined most of the preclinical evidence supporting fisetin’s power. These include preventing or managing neurological conditions such as stroke, Alzheimer’s, Parkinson’s and cognitive decline.

Fisetin is a powerful anti-aging drug

The discovery of senolytics is one of the most important breakthroughs in the field of anti-aging. Senolytic compounds eliminate aging senescent cells in the brain and body. These dysfunctional cells contribute to many of the conditions of old age, including neurodegenerative diseases. 19 In preclinical studies, removal of senescent cells has been shown to improve tissue function, reduce the risk of chronic disease and extend life. 20-22 In a group of 10 flavonoids tested in mice genetically predisposed to rapid and premature aging, fisetin was the most effective anti-aging agent. 23 Senolytics like fisetin hold promise in fighting aging and age-related diseases.

Referensi:

1. Maher P. Prevention and treatment of neurological disorders with the flavonol fisetin. Brain plastic. February 9, 2021; 6(2):155-66.

2. Ravula AR, Teegala SB, Kalakotla S, et al. Fisetin, a potential flavonoid with multiple targets for the treatment of neurological diseases: a recent review. European Journal of Pharmacology. November 5, 2021; 910:174492.

3. Grynkiewicz G, Demchuk OM. Fisetin’s new perspective. Frontier Chemistry 2019; 7:697.

4. Ok. A cross-experimental pharmacokinetic study of fisetin 1000 mg and formulated fisetin 200 mg given in a single dose to healthy volunteers. Manufacturer’s study (in print for future publication). 2020.

5. Wang L, Cao D, Wu H, et al. Fisetin extends the therapeutic window for ischemic stroke with tissue plasminogen activator: a double-blind randomized placebo-controlled clinical trial. Clin Appl Thromb Hemost. From January to December 2019; 25:10 76029619871359.

6. Ahmed A, Ali T, Park HY, etc. Neuroprotective effects of Fisetin on amyloid-β-induced cognitive/synaptic dysfunction, neuroinflammation, and neurodegeneration in adult mice. Molecular neurobiology. April 2017; 54(3):2269-85.

7. Xiao S, Lu Y, Wu Q, etc. Fisetin inhibits tau aggregation by interacting with proteins and preventing the formation of beta chains. Int J Biol Macromol. 1 May 2021; 178:381-93.

8. Kim S, Choi KJ, Cho SJ, etc. Fisetin stimulates autophagy degradation of phosphorylated tau by activating TFEB and Nrf2 transcription factors. Scientific Reports April 26, 2016; 6:24,933.

9. Maher P. How fisetin reduces the effects of age and disease on central nervous system function. Front Biosci (Schol Ed). June 1, 2015; 7(1) : 58-82.

10. Molagoda IMN, Jayasingha J, Choi YH, etc. Fisetin inhibits lipopolysaccharids-induced inflammatory responses by activating beta-catenin, thereby reducing endotoxic shock. Scientific Reports 16 April 2021; 11(1):8377.

11. Xu MX, Ge CX, Li Q, etc. Fisetin nanoparticles protect against neuroinflammation caused by PM2.5 exposure by down-regulating NF-B signaling pathways associated with astrocyte activation. Journal of Functional Foods. 2020 2020/02/01/; 65:103716.

12. Currais A, Prior M, Dargusch R, et al. Regulation of p25 and inflammatory pathways by fisetin maintained cognitive function in transgenic mice with Alzheimer’s disease. Aged cells. April 2014; 13(2) : 379-90.

13. Maher P, Akaishi T, Abe K. Flavonoid fisetin promotes ERK-dependent long-term enhancement and enhances memory. Proc Natl Acad Sci US A. 31 October 2006; 103(44):16568-73.

14. He WB, Abe K, Akaishi T. Oral fisetin promotes induction of long-term hippocampal enhancement in vivo. J Pharmacol Sci. January 2018; 136(1) : 42-5.

15. Maher P. is involved in the regulation of multiple pathways by which fisetin maintains neuronal function during aging. Gene nutrition. December 2009; 4(4) : 297-307.

16. Chrysanthou M, Miro Estruch I, Rietjens I, et al. An in vitro method to investigate the role of advanced glycation end products (AGEs) in neurodegeneration. Nutrients. January 15, 2022; 14(2).

17. Chen C, Li XH, Tu Y, et al. Abeta-AGE exacerbates cognitive deficits in rats through the RAGE pathway. Neuroscience. January 17, 2014; 257:1-10.

18. Thangthaeng N, Poulose SM, Miller MG, et al. Preserving brain function during aging: anti-glycation potential of berry fruits. Neuromolecular Medicine. September 2016; 18(3) : 465-73.

19. Kritsilis M, S VR, Koutsoudaki PN, etc. Senescence, cellular senescence and neurodegenerative diseases. International Journal of Molecular Science. September 27, 2018; 19(10) : 2937.

20. Kirkland JL, Tchkonia T. Cellular aging: Transforming Perspectives. Electronic biomedicine. July 2017; 21:21-8.

21. Kirkland JL, Tchkonia T, Zhu Y, etc. Clinical potential of Senolytic drugs. J Am Geriatr Soc. October 2017; 65(10) : 2297-301.

22. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles Heel of senescent cells: from the transcriptome to aging drugs. Aged cells. August 2015; 14(4) : 644-58.

23. Yousefzadeh MJ, Zhu Y, McGowan SJ et al. Fisetin is a geriatric therapy that can extend health and longevity. Electronic biomedicine. October 2018; 36:18-28.

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