Neuroprotective Effects of Citrus Flavonoids Hwang, Sam-Long; Shih, Ping-Hsiao; Yen, Gow-Chin
Journal of agricultural and food chemistry,
02/2012, Letnik:
60, Številka:
4
Journal Article
Recenzirano
Recent attention has been given to the influence of dietary factors on health and mental well-being. Oxidative stress is associated with many diseases including neurodegenerative disorders. Dietary ...flavonoids exert cardioprotective, chemopreventive, and neuroprotective effects. The biological activities of flavonoids have been attributed to their antioxidant, anti-inflammatory, and signaling properties. A clear understanding of the mechanisms of action, as either antioxidants or signaling molecules, is crucial for the application of flavonoids as interventions in neurodegeneration and as brain foods. Citrus flavonoids exert little adverse effect and have low or no cytotoxicity to healthy, normal cells. The main citrus flavonoids can also traverse the blood–brain barrier; hence, they are promising candidates for intervention in neurodegeneration and as constituents in brain foods. In this review, we discuss the bioactivity, multiple neuroprotection mechanisms, and antioxidant and signaling properties of citrus flavonoids. Receptor-mediated neuroprotective actions and parallel signaling pathways are also explored. Finally, the induction of cellular defense proteins against oxidative stress and neurotoxicity by hesperetin, a main and widespread citrus flavonoid, are also discussed. It is suggested that citrus fruits, which are rich in abundant sources of hesperetin and other flavonoids, are promising for the development of general food-based neuroprotection and brain foods.
The citrus flavanones hesperidin, hesperetin, and neohesperidin are known to exhibit antioxidant activities and could traverse the blood-brain barrier. H2O2 formation induces cellular oxidative ...stress associated with neurodegenerative diseases. In this study, protective effects of pretreatments (6 h) with hesperidin, hesperetin, and neohesperidin (0.8, 4, 20, and 50 µM) on H2O2-induced (400 µM, 16 h) neurotoxicity in PC12 cells were evaluated. The results showed that hesperetin, hesperidin, and neohesperidin, at all test concentrations, significantly (p < 0.05) inhibited the decrease of cell viability (MTT reduction), prevented membrane damage (LDH release), scavenged ROS formation, increased catalase activity, and attenuated the elevation of intracellular free Ca2+, the decrease of mitochondrial membrane potential (except those of 0.8 µM neohesperidin-treated cells) and the increase of caspase-3 activity in H2O2-induced PC12 cells. Meanwhile, hesperidin and hesperetin attenuated decreases of glutathione peroxidase and glutathione reductase activities and decreased DNA damage in H2O2-induced PC12 cells. These results first demonstrate that the citrus flavanones hesperidin, hesperetin, and neohesperidin, even at physiological concentrations, have neuroprotective effects against H2O2-induced cytotoxicity in PC12 cells. These dietary antioxidants are potential candidates for use in the intervention for neurodegenerative diseases.
An 11 years old male Labrador cross presented with unilateral vestibular signs, ipsilateral facial paresis, moderate obtundation, ptyalism, and paraparesis. MRI of the brain revealed diffuse, ...multifocal T2/FLAIR hyperintense changes throughout various regions of the brain including the medulla, midbrain, pons, thalamus and right cerebral hemisphere with mild multifocal contrast enhancement. The patient progressed to trismus with generalized increased extensor tone and risus sardonicus. A diagnosis of generalized tetanus was made and the patient was started on antibiotics, skeletal muscle relaxants and tetanus antitoxin and made a full recovery. To the best of the authors’ knowledge, this is the first reported case of canine tetanus in which the presenting signs involved cranial nerve dysfunction as well as the first report describing MRI changes in canine tetanus within the central nervous system.
The physiological benefits of dietary flavonoids have been attributed to their antioxidant and signaling properties. Our previous study revealed that hesperetin exhibits neuroprotection in PC12 cells ...by diverse mechanisms. Biological activities of flavonoids might be determined by their chemical structures. Here, we further studied the effects of hesperetin and its structural counterparts, isorhamnetin and isosakuranetin, on kinases related to survival signaling as well as other cytoprotective actions. Pretreatment with flavonoids (0.8 or 50 μM) increased cell viability and catalase activity (CA) and decreased membrane damage, reactive oxygen species (ROS) generation, intracellular calcium level (Ca2+i), and caspase-3 activity in H2O2-treated PC12 cells. Increased CA, Ca2+i, and ROS levels, but lower caspase-3 activities, were obtained upon treatment with 50 μM isorhamnetin or isosakuranetin. Based on their structural differences and the concentrations used, these flavonoids differentially activated pro-survival signaling molecules, including Akt/protein kinase B, p38 mitogen-activated protein kinase, and inhibited the activation of c-jun N-terminal kinase, which triggers apoptosis. Our results demonstrate that signaling actions of thses flavonoids are involved in their neuroprotection against oxidative stress and that they act more as signaling molecules than antioxidants.
Hesperetin is known to activate estrogen receptors (ERs). Estrogen-mediated neuroprotection could be via both ER and tyrosine kinase receptor (Trk) signaling. This study tested whether hesperetin ...protected PC12 cells from hydrogen peroxide induced oxidative damage via ER- and/or TrkA-mediated actions. Hesperetin (0.1, 1, and 50 μM) inhibited cell viability decreases and reactive oxygen species, intracellular calcium level, and caspase-3 activity increases in H2O2-induced PC12 cells. Such actions were significantly (p < 0.05) suppressed by ICI 182,780 (an ER antagonist) or K252a (a TrkA antagonist) at low concentrations (0.1 or 1 μM) only. Hesperetin also stimulated the activation of Akt, ERK, and CREB as well as induced brain-derived neurotrophic factor, PPARγ coactivator 1α (PGC-1α), and seladin-1 (selective Alzheimer’s disease indicator-1) via both ER and TrkA in the cells. This study demonstrates that the neuroprotective effects of hesperetin, at low concentrations, are attributed to its stimulation on receptor signaling. Moreover, ER and TrkA are known to be expressed in most Alzheimer’s disease (AD) vulnerable brain regions. This study thus suggests that hesperetin might have potential for intervention in neurodegenerative disorders, particularly for AD.
Dogs with epilepsy are among the commonest neurological patients in veterinary practice and therefore have historically attracted much attention with regard to definitions, clinical approach and ...management. A number of classification proposals for canine epilepsy have been published during the years reflecting always in parts the current proposals coming from the human epilepsy organisation the International League Against Epilepsy (ILAE). It has however not been possible to gain agreed consensus, "a common language", for the classification and terminology used between veterinary and human neurologists and neuroscientists, practitioners, neuropharmacologists and neuropathologists. This has led to an unfortunate situation where different veterinary publications and textbook chapters on epilepsy merely reflect individual author preferences with respect to terminology, which can be confusing to the readers and influence the definition and diagnosis of epilepsy in first line practice and research studies.In this document the International Veterinary Epilepsy Task Force (IVETF) discusses current understanding of canine epilepsy and presents our 2015 proposal for terminology and classification of epilepsy and epileptic seizures. We propose a classification system which reflects new thoughts from the human ILAE but also roots in former well accepted terminology. We think that this classification system can be used by all stakeholders.
Ehlers–Danlos syndrome is a rare, heritable connective tissue disorder characterized by soft, hyperextensible skin, joint hypermobility, and tissue fragility, the severity of which can range from ...mild to severe. A 9-month-old male entire miniature Dachshund was presented following peracute tetraparesis. Neurological examination was suggestive of intracranial vestibular disease or high cervical myelopathy. MRI revealed atlantoaxial instability and subluxation, resulting in marked spinal cord compression at C1–C2, which was surgically stabilized. On discharge from the hospital, skin fragility was noted as the result of skin tearing during tape removal. A piece of full-thickness antebrachial skin was submitted for histopathology which showed changes consistent with Ehlers–Danlos syndrome. This case report describes the first case of atlantoaxial instability and subluxation in a dog as the result of a confirmed underlying collagenopathy.
This article outlines the consensus proposal on diagnosis of epilepsy in dogs by the International Veterinary Epilepsy Task Force. The aim of this consensus proposal is to improve consistency in the ...diagnosis of epilepsy in the clinical and research settings. The diagnostic approach to the patient presenting with a history of suspected epileptic seizures incorporates two fundamental steps: to establish if the events the animal is demonstrating truly represent epileptic seizures and if so, to identify their underlying cause. Differentiation of epileptic seizures from other non-epileptic episodic paroxysmal events can be challenging. Criteria that can be used to make this differentiation are presented in detail and discussed. Criteria for the diagnosis of idiopathic epilepsy (IE) are described in a three-tier system. Tier I confidence level for the diagnosis of IE is based on a history of two or more unprovoked epileptic seizures occurring at least 24 h apart, age at epileptic seizure onset of between six months and six years, unremarkable inter-ictal physical and neurological examination, and no significant abnormalities on minimum data base blood tests and urinalysis. Tier II confidence level for the diagnosis of IE is based on the factors listed in tier I and unremarkable fasting and post-prandial bile acids, magnetic resonance imaging (MRI) of the brain (based on an epilepsy-specific brain MRI protocol) and cerebrospinal fluid (CSF) analysis. Tier III confidence level for the diagnosis of IE is based on the factors listed in tier I and II and identification of electroencephalographic abnormalities characteristic for seizure disorders. The authors recommend performing MRI of the brain and routine CSF analysis, after exclusion of reactive seizures, in dogs with age at epileptic seizure onset <6 months or >6 years, inter-ictal neurological abnormalities consistent with intracranial neurolocalisation, status epilepticus or cluster seizure at epileptic seizure onset, or a previous presumptive diagnosis of IE and drug-resistance with a single antiepileptic drug titrated to the highest tolerable dose.This consensus article represents the basis for a more standardised diagnostic approach to the seizure patient. These recommendations will evolve over time with advances in neuroimaging, electroencephalography, and molecular genetics of canine epilepsy.
Nonalcoholic steatohepatitis (NASH) is caused by an elevation in oxidative stress, which might further lead to hepatic fibrogenesis. Importantly, both peroxisome proliferator-activated receptor ...(PPAR) and nuclear factor erythroid 2-related factor 2 (Nrf2) play roles in modulating oxidative stress-mediated hepatic dysfunction. The objective of this study was to investigate the mechanisms of the multifunctional effects of cyanidin on regulating antioxidant enzymes and oxidative stress-induced hepatotoxicity. The data indicated that cyanidin-mediated antioxidant enzyme expression involved the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways and Nrf2 activation. Furthermore, the synergistic effect of cyanidin and the PPAR agonist, troglitazone, on Nrf2-PPAR activation, was also observed. Besides, treatment of cyanidin and troglitazone abolished H2O2-induced downregulation of genes involved in lipid metabolism. In addition, H2O2-mediated cytotoxicity, which was caused by inducing ROS formation and apoptotic cell death, was also ameliorated upon cyanidin and troglitazone stimulation. In conclusion, mitogen-activated protein kinases (MAPKs) and the transcription factor Nrf2 played regulatory roles in cyanidin-mediated antioxidant enzyme activation. Furthermore, the combination of cyanidin and troglitazone activated PPARγ-Nrf2 and improved H2O2-mediated perturbation of genes involved in lipid metabolism. These data suggested that cyanidin and PPAR agonists might have synergistic benefits against metabolic dysfunction-related oxidative damage.
In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, ...2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors' experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible.
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