Acacetin Protects Dopaminergic Cells against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Neuroinflammation in Vitro and in Vivo
01 Aug 2012-Biological & Pharmaceutical Bulletin (The Pharmaceutical Society of Japan)-Vol. 35, Iss: 8, pp 1287-1294
TL;DR: It is suggested that acacetin can protect DA neurons against the neurotoxicity involved in PD via its anti-inflammatory action.
Abstract: Acacetin (5,7-dihydroxy-4′-methoxyflavone), a constituent of flavone naturally present in plants, has anti-cancer and anti-inflammatory activities. Neuroinflammation is thought to be one of the major pathological mechanisms responsible for Parkinson’s disease (PD), and has been a primary target in the development of treatment for PD. In the present study, we evaluated the neuroprotective effect of acacetin in PD induced by 1-methyl-4-phenylpyridine (MPP+)/or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and examined the related pathways in vitro and in vivo. In primary mesencephalic culture, acacetin protected dopaminergic (DA) cells and inhibited production of inflammatory factors such as nitric oxide, prostaglandin E2, and tumor necrosis factor-α against MPP+-induced toxicity in a dose-dependent manner. Then, we confirmed the effect of acacetin (10 mg/kg/d for 3 d, per os (p.o.)) in a mouse model of PD induced by MPTP (30 mg/kg/d for 5 d, intraperitoneally (i.p.)). In the behavioral test (pole test), the acacetin-treated mice showed decreased time of turning and locomotor activity, which were longer in MPTP-only treated mice. In addition, the acacetin-treated group inhibited degeneration of DA neurons and depletion of dopamine level induced by MPTP toxicity in the substantia nigra and striatum of the brain. Moreover, the acacetin-treated group inhibited microglia activation, accompanied by production of inducible nitric oxide synthases and cyclooxygenase-2. These results suggest that acacetin can protect DA neurons against the neurotoxicity involved in PD via its anti-inflammatory action.
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TL;DR: Recent progresses in the neuroimmune aspects of PD are summarized, potential therapeutic interventions targeting neuroinflammation are highlighted and inflammatory processes have been suggested as promising interventional targets.
Abstract: Parkinson’s disease (PD), the second most common age-associated neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons and the presence of α-synuclein-containing aggregates in the substantia nigra pars compacta (SNpc). Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Post-mortem analyses of human PD patients and experimental animal studies indicate that activation of glial cells and increases in pro-inflammatory factor levels are common features of the PD brain. Chronic release of pro-inflammatory cytokines by activated astrocytes and microglia leads to the exacerbation of DA neuron degeneration in the SNpc. Besides, peripheral immune system is also implicated in the pathogenesis of PD. Infiltration and accumulation of immune cells from the periphery are detected in and around the affected brain regions of PD patients. Moreover, inflammatory processes have been suggested as promising interventional targets for PD and even other neurodegenerative diseases. A better understanding of the role of inflammation in PD will provide new insights into the pathological processes and help to establish effective therapeutic strategies. In this review, we will summarize recent progresses in the neuroimmune aspects of PD and highlight the potential therapeutic interventions targeting neuroinflammation.
552 citations
TL;DR: Flavonoids are key compounds for the development of a new generation of therapeutic agents that are clinically effective in treating neurodegenerative diseases and exhibit neuroprotective properties under both normal and pathologic conditions.
184 citations
Cites background from "Acacetin Protects Dopaminergic Cell..."
...5 and 1 mg/kg (40) Acacetin 10 mg/kg per day (41) Rutin 25 mg/kg body weight (43) EGCG(1) 2 and 10 mg/kg; 200 μM, 5 mg/kg (40, 42) Genistein 10 mg/kg (44) Tangeretin 10 and 20 mg/kg (48) Huntington disease EGCG ~1 μM; 10, 20 and 40 mg/kg (54, 58) Naringin 80 mg/kg body weight (55) Quercetin 25 mg/kg body weight (57) Eriodictyol 100 μM (59) Amyotrophic lateral sclerosis EGCG ....
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...In a recent study, acacetin (5,7-dihydroxy-49-methoxyflavone), a constituent of a flavone naturally present in plants, also inhibited the degeneration of dopaminergic neurons and depletion of dopamine concentrations induced by MPTP toxicity in the substantia nigra and striatum of the brain at a dose of 10 mg/kg per day (41)....
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TL;DR: A limited number of clinical trials showed that hesperidin-enriched dietary supplements can significantly improve cerebral blood flow, cognition, and memory performance, and further clinical trials are also required for confirming neuroprotective efficacy of this natural flavonoid and evaluating its safety profile.
Abstract: Neuroprotection is the preservation of function and networks of neural tissues from damages caused by various agents, as well as neurodegenerative diseases such as Parkinson’s, Alzheimer’s, Huntington’s diseases, and multiple sclerosis. Hesperidin, a flavanone glycoside, is a natural phenolic compound with a wide range of biological effects. Mounting evidence has demonstrated that hesperidin possesses inhibitory effect against development of neurodegenerative diseases. Our review discusses neuropharmacological mechanisms for preventive and therapeutic effects of hesperidin in neurodegenerative diseases. In addition, the review examines clinical evidence confirming its neuroprotective function. Various cellular and animal models specific to neurodegenerative diseases have been conducted to evaluate the underlying neuropharmacological mechanisms of hesperidin. Neuroprotective potential of this flavonoid is mediated by improvement of neural growth factors and endogenous antioxidant defense functions, diminishing neuro-inflammatory and apoptotic pathways. Despite the various preclinical studies on the role of hesperidin in the neurodegenerative diseases, less is known about its definite effect on humans. A limited number of clinical trials showed that hesperidin-enriched dietary supplements can significantly improve cerebral blood flow, cognition, and memory performance. Further clinical trials are also required for confirming neuroprotective efficacy of this natural flavonoid and evaluating its safety profile.
180 citations
Cites background from "Acacetin Protects Dopaminergic Cell..."
...Several other flavonoids (flavonoids isolated from honey and blueberry extracts [25,26], kaempferol [27], catechin [28], naringenin [29], and acacetin [30]) potentially inhibited neuro-inflammation by controlling the pro-inflammatory biomarkers, such as nuclear factor kappa light chain enhancer of activated B cells (NF-κB) iNOS, TNF-α, NADPH oxidase, and so forth....
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TL;DR: Data about brain distribution of the metabolic derivatives of the reviewed polyphenols are crucial for the justification of their nutritional intake in neuroprotective intervention, as well as for the identification of potential targets for a novel therapeutic approach to Parkinson’s disease.
Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disorder. However, therapeutic options treating only its symptoms are very disappointing. Therefore there is an ongoing search for compounds capable of tackling the multi-dimensional features of PD. Recently natural polyphenols have gained great interest as potential therapeutic agents. Herein, we have attempted to summarize results obtained in different animal models demonstrating their neuroprotective effects. The in vivo findings presented below are supported by human subject data and reports regarding the ability of polyphenols to cross the blood-brain barrier. The beneficial effects of polyphenols are demonstrated by the results of behavioral examinations, mainly related to motor and cognitive capabilities, histopathological and immunohistochemical examination concerning the protection of dopaminergic neurons, analyses of dopamine and the concentration of its metabolites, as well as mechanistic studies regarding the modulation of oxidative stress, neuroinflammation, cellular iron management, proteinopathy, and additionally the regulation of signaling pathways. Importantly, data about brain distribution of the metabolic derivatives of the reviewed polyphenols are crucial for the justification of their nutritional intake in neuroprotective intervention, as well as for the identification of potential targets for a novel therapeutic approach to Parkinson’s disease.
112 citations
Cites background from "Acacetin Protects Dopaminergic Cell..."
...Resveratrol (RES) given orally for ten weeks reduced neural inflammation in a 6-OHDA-induced PD in rats, as was evidenced by suppression in the production of cyclooxygenase-2 (COX-2) and TNF-α in substantia nigra as well as ameliorating 6-OHDA-induced neurobehavioral deficit [30]....
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...A number of polyphenols have been shown to inhibit microglial activation accompanied with the suppressed production of TNF-α, IL-6, IL-1β, as well as COX-2, iNOS, and NO....
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...In addition, SA showed the ability to ameliorate MPTP/p-induced decrease in expressions of TH, DAT, and vesicular monoamine transporter-2 (VMAT2) and to attenuate the production of pro-inflammatory cytokines, such as TNF-α, IL-1β, and COX-2 [74]....
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...Compound, Route and Dosage Species (Sex) Neurotoxin Neuroprotective Effects References EGCG (10 mg/kg; i.g.) 14-day post-treatment C57/BL6 mice (male) MPTP ↑DA, DOPAC and HVA↑Ras expression Reznichenko et al. 2010 [44] EGCG (10 , 50 mg/kg; i.p.) 10-day pre-treatment and 4-day co-treatment C57Bl/6 mice (male) MPTP ↑TH-positive neurons ↓iNOS expression Kim et al. 2010 [45] EGCG (25 , 50 mg/kg/day; i.g.) 1-day pre-treatment and 20-day post-treatment C57BL/6 mice (male) MPTP ↓motor coordination ↑TH-positive neurons ↓CD3+CD4+/CD3+CD8+ T cells ↓TNF-α and IL-6 protein in plasma Zhou et al. 2018 [46] Acacetin (10 mg/kg; p.o) 3-day co-treatment C57BL/6 mice (male) MPTP ↓movement impairment ↑TH-positive neurons ↓damage in DAergic cells ↑DA ↓iNOS mRNA and COX-2 mRNA Kim et al. 2012 [47] Baicalein (10 mg/kg; i.g.) 5-day co-treatment C57BL/6 mice (male) MPTP ↓motor dysfunction ↓MPTP-induced glutamatergic transmission, presynaptic glutamate release and upregulation of synaptic GluR1 subunit Xue et al. 2014 [48] Baicalein (1 and 10 mg/kg; i.g.) 7-day pre-treatment C57BL/6 mice (male) MPTP ↓motor dysfunction ↑TH-positive neurons ↓GFAP, Iba1 protein ↓phosphorylated ERK and JNK↓activation Lee et al. 2014 [49] 7,8-dihydroxyflavone (5, 20, 40, and 100 mg/kg; i.p) 7-day pre-and 7-day co-treatment B57/BL mice (male) MPTP ↑TH-positive neurons ↑TrkB activity ↓caspase-3 protein Jang et al. 2010 [50] Tangeretin (10 mg/kg; i.p.) 4-day pre-treatment C57BL/6 mice (male) MPTP ↑TH-positive neurons ↑DA ↑GRP-78 protein Takano et al. 2007 [51] Nobiletin (10 mg/kg; i.p.) 1-day pre-treatment and 6-day-post-treatment Sprague Dawley (SD) rats (female) MPTP ↑TH-positive neurons ↑DA ↓Iba1 protein and IL-1β ↑GDNF protein Jeong et al. 2015 [52] Nobiletin (50 mg/kg; i.p.) 14-day post-treatment C57BL/6 mice (male) MPTP ↓motor and cognitive impairment ↑Ca2+/calmodulin-dependent protein kinase II (CaMKII) ↑DARPP-32, dopamine- and cAMP-regulated phosphoprotein-32 Yabuki et al. 2014 [53] Table 1....
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...Moreover, administration of acacetin inhibited microglial activation accompanied by decreased production of inducible nitric oxide synthase (iNOS) and COX-2 [47]....
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TL;DR: This review focuses on the various established activities of natural products in in vitro and in vivo preclinical models, and their potential neuro-therapeutic applications using the available knowledge in the literature.
Abstract: Nature has bestowed mankind with surplus resources (natural products) on land and water. Natural products have a significant role in the prevention of disease and boosting of health in humans and animals. These natural products have been experimentally documented to possess various biological properties such as antioxidant, anti-inflammatory and anti-apoptotic activities. In vitro and in vivo studies have further established the usefulness of natural products in various preclinical models of neurodegenerative disorders. Natural products include phytoconstituents, like polyphenolic antioxidants, found in herbs, fruits, nuts, vegetables and also in marine and freshwater flora. These phytoconstituents may potentially suppress neurodegeneration and improve memory as well as cognitive functions of the brain. Also, they are known to play a pivotal role in the prevention and cure of different neurodegenerative diseases, such as Alzheimer's disease, epilepsy, Parkinson's disease and other neuronal disorders. The large-scale neuro-pharmacological activities of natural products have been documented due to the result of either the inhibition of inflammatory processes, or the up-regulation of various cell survival proteins or a combination of both. Due to the scarcity of human studies on neuroprotective effects of natural products, this review focuses on the various established activities of natural products in in vitro and in vivo preclinical models, and their potential neuro-therapeutic applications using the available knowledge in the literature.
107 citations
Cites result from "Acacetin Protects Dopaminergic Cell..."
...Almost similar kind of results have been observed with hydroxysafflor yellow A (HSYA) from Carthamus tinctorius [53, 54] baicalein & baicalin [55, 56], nobiletin [57] and acacetin [58] (Table 1)....
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References
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TL;DR: Development and application of REST is explained, the usefulness of relative expression in real-time PCR using REST is discussed and the mathematical model used is based on the PCR efficiencies and the mean crossing point deviation between the sample and control group.
Abstract: Real-time reverse transcription followed by polymerase chain reaction (RT–PCR) is the most suitable method for the detection and quantification of mRNA. It offers high sensitivity, good reproducibility and a wide quantification range. Today, relative expression is increasingly used, where the expression of a target gene is standardised by a non-regulated reference gene. Several mathematical algorithms have been developed to compute an expression ratio, based on real-time PCR efficiency and the crossing point deviation of an unknown sample versus a control. But all published equations and available models for the calculation of relative expression ratio allow only for the determination of a single transcription difference between one control and one sample. Therefore a new software tool was established, named REST© (relative expression software tool), which compares two groups, with up to 16 data points in a sample and 16 in a control group, for reference and up to four target genes. The mathematical model used is based on the PCR efficiencies and the mean crossing point deviation between the sample and control group. Subsequently, the expression ratio results of the four investigated transcripts are tested for significance by a randomisation test. Herein, development and application of REST© is explained and the usefulness of relative expression in real-time PCR using REST© is discussed. The latest software version of REST© and examples for the correct use can be downloaded at http://www.wzw.tum.de/gene-quantification/.
7,196 citations
TL;DR: The spatiotemporal progression of neuronal loss related to disease duration can be drawn in the substantia nigra pars compacta for each Parkinson's disease patient: depletion begins in the main pocket (nigrosome 1) and then spreads to other nigrosomes and the matrix along rostral, medial and dorsal axes of progression.
Abstract: To achieve accuracy in studying the patterns of loss of midbrain dopamine-containing neurons in Parkinson's disease, we used compartmental patterns of calbindin D(28K) immunostaining to subdivide the substantia nigra with landmarks independent of the degenerative process. Within the substantia nigra pars compacta, we identified dopamine-containing neurons in the calbindin-rich regions ('matrix') and in five calbindin-poor pockets ('nigrosomes') defined by analysis of the three-dimensional networks formed by the calbindin-poor zones. These zones were recognizable in all of the brains, despite severe loss of dopamine-containing neurons. The degree of loss of dopamine-containing neurons in the substantia nigra pars compacta was related to the duration of the disease, and the cell loss followed a strict order. The degree of neuronal loss was significantly higher in the nigrosomes than in the matrix. Depletion was maximum (98%) in the main pocket (nigrosome 1), located in the caudal and mediolateral part of the substantia nigra pars compacta. Progressively less cell loss was detectable in more medial and more rostral nigrosomes, following the stereotyped order of nigrosome 1 > nigrosome 2 > nigrosome 4 > nigrosome 3 > nigrosome 5. A parallel, but lesser, caudorostral gradient of cell loss was observed for dopamine-containing neurons included in the matrix. This pattern of neuronal loss was consistent from one parkinsonian substantia nigra pars compacta to another. The spatiotemporal progression of neuronal loss related to disease duration can thus be drawn in the substantia nigra pars compacta for each Parkinson's disease patient: depletion begins in the main pocket (nigrosome 1) and then spreads to other nigrosomes and the matrix along rostral, medial and dorsal axes of progression.
1,547 citations
TL;DR: Recent data concerning the biochemical and molecular apoptotic mechanisms underlying the experimental models of PD are reported and correlates them to the phenomena occurring in human disease.
1,173 citations
TL;DR: Recent advances on the study of the role of microglia based on findings from animal and cell culture models in the pathogenesis of neurodegenerative diseases, with particular emphasis on Parkinson's disease are summarized.
Abstract: Evidence from postmortem analysis implicates the involvement of microglia in the neurodegenerative process of several degenerative neurological diseases, including Alzheimer's disease and Parkinson's disease. It remains to be determined, however, whether microglial activation plays a role in the initiation stage of disease progression or occurs merely as a response to neuronal death. Activated microglia secrete a variety of proinflammatory and neurotoxic factors that are believed to induce and/or exacerbate neurodegeneration. In this article, we summarize recent advances on the study of the role of microglia based on findings from animal and cell culture models in the pathogenesis of neurodegenerative diseases, with particular emphasis on Parkinson's disease. In addition, we also discuss novel approaches to potential therapeutic strategies.
1,069 citations
12 Oct 2011
TL;DR: Genetic factors clearly contribute to the pathogenesis of Parkinson’s disease, and many studies have shed light on their implication in, not only monogenic, but also sporadic forms of PD.
Abstract: The pathological hallmarks of Parkinson’s disease (PD) are marked loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), which causes dopamine depletion in the striatum, and the presence of intracytoplasmic inclusions known as Lewy bodies in the remaining cells. It remains unclear why dopaminergic neuronal cell death and Lewy body formation occur in PD. The pathological changes in PD are seen not only in the SNc but also in the locus coeruleus, pedunculo pontine nucleus, raphe nucleus, dorsal motor nucleus of the vagal nerve, olfactory bulb, parasympathetic as well as sympathetic post-ganglionic neurons, Mynert nucleus, and the cerebral cortex (Braak et al. 2003). Widespread neuropathology in the brainstem and cortical regions are responsible for various motor and non-motor symptoms of PD. Although dopamine replacement therapy improves the functional prognosis of PD, there is currently no treatment that prevents the progression of this disease. Previous studies provided possible evidence that the pathogenesis of PD involves complex interactions between environmental and multiple genetic factors. Exposure to the environmental toxin MPTP was identified as one cause of parkinsonism in 1983 (Langston & Ballard 1983). In addition to MPTP, other environmental toxins, such as the herbicide paraquat and the pesticide rotenone have been shown to contribute to dopaminergic neuronal cell loss and parkinsonism. In contrast, cigarette smoking, caffeine use, and high normal plasma urate levels are associated with lower risk of PD (Hernan et al. 2002). Recently, Braak and coworkers proposed the “Dual Hit” theory, which postulated an unknown pathogen accesses the brain through two pathways, the nose and the gut (Hawkes et al. 2007). Subsequently, a prion-like mechanism might contribute to the propagation of αsynuclein from the peripheral nerve to the central nervous system (Angot et al. 2010). Approximately 5% of patients with clinical features of PD have clear familial etiology. Therefore, genetic factors clearly contribute to the pathogenesis of PD. Over the decade, more than 16 loci and 11 causative genes have been identified, and many studies have shed light on their implication in, not only monogenic, but also sporadic forms of PD. Recent studies revealed that PD-associated genes play important roles in cellular functions, such as mitochondrial functions, the ubiquitin-proteasomal system, autophagy-lysosomal pathway, and membrane trafficking (Hatano et al. 2009). In this chapter, we review the investigations of environmental and genetic factors of PD (Figure 1).
808 citations