Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review

Ravula, Arun Reddy; Teegala, Suraj Benerji; Shanker, Kalakotla; Pasangulapati, Jagadeesh Prasad; Perumal, Venkatesan; Boyina, Hemanth Kumar

doi:10.1016/j.ejphar.2021.174492

Cited by 58 publications

(33 citation statements)

References 178 publications

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“…Fisetin, also known as 3,3′,4′,7-tetrahydroxyflavone, is a flavonol compound and was first extracted from Cotinus coggygria by Jacob Schmid in 1886 [ 105 ], and its structure was elucidated by Joseph Hergig in 1891. In addition, fisetin is also found in many vegetables and fruits, such as onions, cucumbers, persimmon, strawberries, and apples [ 106 ]. Emerging evidence indicates that fisetin acting as a potent antioxidant possesses multiple biological activities, including anti-inflammatory, antiviral, anticarcinogenic, and other effects [ 107 ].…”

Section: The Potential Therapy Of Phytochemicals As Nrf2 Activators I...mentioning

confidence: 99%

Targeting Nrf2-Mediated Oxidative Stress Response in Traumatic Brain Injury: Therapeutic Perspectives of Phytochemicals

Yong

Pan

et al. 2022

Oxidative Medicine and Cellular Longevity

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Traumatic brain injury (TBI), known as mechanical damage to the brain, impairs the normal function of the brain seriously. Its clinical symptoms manifest as behavioral impairment, cognitive decline, communication difficulties, etc. The pathophysiological mechanisms of TBI are complex and involve inflammatory response, oxidative stress, mitochondrial dysfunction, blood-brain barrier (BBB) disruption, and so on. Among them, oxidative stress, one of the important mechanisms, occurs at the beginning and accompanies the whole process of TBI. Most importantly, excessive oxidative stress causes BBB disruption and brings injury to lipids, proteins, and DNA, leading to the generation of lipid peroxidation, damage of nuclear and mitochondrial DNA, neuronal apoptosis, and neuroinflammatory response. Transcription factor NF-E2 related factor 2 (Nrf2), a basic leucine zipper protein, plays an important role in the regulation of antioxidant proteins, such as oxygenase-1(HO-1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), and glutathione peroxidase (GPx), to protect against oxidative stress, neuroinflammation, and neuronal apoptosis. Recently, emerging evidence indicated the knockout (KO) of Nrf2 aggravates the pathology of TBI, while the treatment of Nrf2 activators inhibits neuronal apoptosis and neuroinflammatory responses via reducing oxidative damage. Phytochemicals from fruits, vegetables, grains, and other medical herbs have been demonstrated to activate the Nrf2 signaling pathway and exert neuroprotective effects in TBI. In this review, we emphasized the contributive role of oxidative stress in the pathology of TBI and the protective mechanism of the Nrf2-mediated oxidative stress response for the treatment of TBI. In addition, we summarized the research advances of phytochemicals, including polyphenols, terpenoids, natural pigments, and otherwise, in the activation of Nrf2 signaling and their potential therapies for TBI. Although there is still limited clinical application evidence for these natural Nrf2 activators, we believe that the combinational use of phytochemicals such as Nrf2 activators with gene and stem cell therapy will be a promising therapeutic strategy for TBI in the future.

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Section: The Potential Therapy Of Phytochemicals As Nrf2 Activators I...mentioning

confidence: 99%

Targeting Nrf2-Mediated Oxidative Stress Response in Traumatic Brain Injury: Therapeutic Perspectives of Phytochemicals

Yong

Pan

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…A traumatic brain injury (TBI) is a sudden injury from an external force that is associated with long-term cognitive deficits relating to trauma-induced neurodegeneration [1,2]. The preclinical research indicates that TBI is caused by secondary injury mechanisms (oxidative stress, neuroinflammation, and neurodegeneration) that severely affect the quality of life of military personnel returning from combat zones [2,3]. Previous studies from our laboratory established that under mild TBI conditions, the generation of free-radical-generating enzymes, the expression of oxidative damage markers, BBB leakage, and neuroinflammation occur [4].…”

Section: Introductionmentioning

confidence: 99%

Transferrin-Grafted Albumin Nanoparticles for the Targeted Delivery of Apocynin and Neuroprotection in an In Vitro Model of the BBB

Perumal

Ravula

Agas

et al. 2023

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Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide, affecting over 10 million people annually, with an estimated cost of $76.5 billion. Although apocynin freely transverses the blood–brain barrier (BBB), its application is limited due to its rapid elimination, low terminal half-life (t1/2 = 6.7 min), narrow dose–response relationship, and cytotoxicity, thereby requiring repeated dosages. With this study, we aimed to develop transferrin-functionalized nanoparticles encapsulating apocynin to treat neuroinflammation for targeted drug delivery to sites of brain injury. As a preliminary approach, we endeavored to optimize the formulation parameters of apocynin-loaded albumin nanoparticles prepared through the desolvation method. The nanoparticles were characterized for their size, polydispersity, surface charge, drug loading and in vitro drug release. In this study, we also investigated the anti-inflammatory and neuroprotective effects of free apocynin and nanoparticle-loaded apocynin in neuronal cells. We show that the developed formulation displayed monodispersed, nanosized particles with higher entrapment efficiency, loading, stability, and sustained release profiles. The permeability of the nanoparticles across HBMECs reached the maximum at 67%. The in vivo evaluation revealed the enhanced uptake of transferrin-anchored nanoparticles in the brain tissues when compared with unmodified nanoparticles after I.V. administration. In vivo nanoparticle localization studies using a blast TBI (bTBI) model and confocal fluorescence microscopy have shown that tf-apoANPs are successful in delivering relatively high amounts of nanoparticles to the brain parenchyma and glial cells compared to non-targeted nanoparticles. We also establish that targeted nanoparticles accumulate in the brain. In conclusion, tf-apoANPs are efficacious carriers for targeted delivery across the blood–brain barrier to potentially treat neuroinflammation in brain injury and other diseases.

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“…The average human daily intake is estimated to be around 0.4 mg [ 4 ]. It has been recently demonstrated that this natural compound could modulate different pleiotropic pathways (phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and p38, mitogen-activated protein kinases (MAPK)-dependent nuclear factor kappalight-chain-enhancer of activated B cells (NF-κB)) exerting a large plethora of biological effects including anti-inflammatory, hypolipidemic, hypoglycemic, antioxidant, neuroprotective, antiangiogenic, and antitumor ones [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection

et al. 2022

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Like other organs, brain functions diminish with age. Furthermore, for a variety of neurological disorders—including Alzheimer’s disease—age is one of the higher-risk factors. Since in many Western countries the average age is increasing, determining approaches for decreasing the effects of aging on brain function is taking on a new urgency. Neuroinflammation and oxidative stress are two convoluted key factors in brain aging and chronic neurodegenerative diseases. The diverseness of factors, causing an age-related decrease in brain functions, requires identifying small molecules that have multiple biological activities that can affect all these factors. One great source of these small molecules is related to polyphenolic flavonoids. Recently, 3,3′,4′,7-tetrahydroxyflavone (fisetin) has been reported as a potent senotherapeutic capable of extending lifespan by reducing peroxidation levels and enhancing antioxidant cell responses. The neuroprotective effects of fisetin have been shown in several in vitro and in vivo models of neurological disorders due to its actions on multiple pathways associated with different neurological disorders. The present work aims to collect the most recent achievements related to the antioxidant and neuroprotective effects of fisetin. Moreover, in silico pharmacokinetics, pharmacodynamics, and toxicity of fisetin are also comprehensively described along with emerging novel drug delivery strategies for the amelioration of this flavonol bioavailability and chemical stability.

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Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review

Cited by 58 publications

References 178 publications

Targeting Nrf2-Mediated Oxidative Stress Response in Traumatic Brain Injury: Therapeutic Perspectives of Phytochemicals

Targeting Nrf2-Mediated Oxidative Stress Response in Traumatic Brain Injury: Therapeutic Perspectives of Phytochemicals

Transferrin-Grafted Albumin Nanoparticles for the Targeted Delivery of Apocynin and Neuroprotection in an In Vitro Model of the BBB

Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection

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