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1.
Neurochem Res ; 48(6): 1707-1715, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36602724

RESUMO

Various pharmacological blockers targeting K+ channel have been identified to be related to the treatment of Parkinson's disease (PD). Previous studies showed that 4-Aminopyridine (4-AP), a wide-spectrum K+ channel blocker, was able to attenuate apomorphine-induced rotation in parkinsonism rats, indicating the possible beneficial effects in attenuation of PD motor symptoms. However, it is unclear whether 4-AP exhibits neuroprotective effects against the neurodegeneration of substantia nigra (SN)-striatum system in PD. In this study, the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model was employed to evaluate the neuroprotective effects of 4-AP. Results showed that 4-AP inhibited MPTP-induced dopaminergic neuronal loss in the SN as well as dopamine depletion in the striatum. Behavior indexes of open field test and rotarod test confirmed that 4-AP attenuated MPTP-induced motor deficits. We also showed that 4-AP treatment could significantly attenuate the MPTP-induced increase in malonaldehyde (MDA) levels and decrease in superoxide dismutase (SOD) levels. Additionally, MPTP significantly reduced the Bcl-2 expression and promoted the Caspase-3 activation; 4-AP protected dopaminergic neurons against MPTP-induced neurotoxicity by reversing these changes. These results indicate that 4-AP exerts a neuroprotective effect on dopaminergic neurons against MPTP by decreasing oxidative stress and apoptosis. This provides a promising therapeutic target for the treatment of PD.


Assuntos
Intoxicação por MPTP , Fármacos Neuroprotetores , Doença de Parkinson , Animais , Camundongos , Ratos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos , Camundongos Endogâmicos C57BL , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/prevenção & controle , Intoxicação por MPTP/induzido quimicamente , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Substância Negra , 4-Aminopiridina/farmacologia
2.
Phytomedicine ; 108: 154512, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36288652

RESUMO

BACKGROUND: Feruloylated oligosaccharides (FOs) are natural esterification products of ferulic acid and oligosaccharides. STUDY DESIGN: In this study, we examined whether FOs contribute to the ensured survival of nigrostriatal dopamine neurons and inhibition of neuroinflammation in Parkinson's disease (PD). METHODS: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg) was injected intraperitoneally into mice to establish a Parkinson's disease (PD) mouse model. FOs (15 and 30 mg/kg) were orally administered daily to the MPTP-treated mice. The rotarod test, balance beam test, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR), and western blot analyses were performed to examine the neuroprotective effects of FOs on MPTP-treated mice. RESULTS: Our study indicated that FOs increased the survival of dopamine neurons in the substantia nigra pars compacta (SNc) of the MPTP-treated mice. The neuroprotective effects of FOs were accompanied by inhibited glial activation and reduced inflammatory cytokine production. The mechanistic experiments revealed that the neuroprotective effects of FOs might be mediated through the activation of the ERK/CREB/BDNF/TrkB signalling pathway. CONCLUSION: This study provides new insights into the mechanism underlying the anti-neuroinflammatory effect of phytochemicals and may facilitate the development of dietary supplements for PD patients. Our results indicate that FOs can be used as potential modulators for the prevention and treatment of PD.


Assuntos
Intoxicação por MPTP , Fármacos Neuroprotetores , Doença de Parkinson , Camundongos , Animais , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Camundongos Endogâmicos C57BL , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/prevenção & controle , Neurônios Dopaminérgicos , Modelos Animais de Doenças , Oligossacarídeos/farmacologia
3.
Can J Physiol Pharmacol ; 100(7): 594-611, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35413210

RESUMO

1,2,3,4-tetrahydroisoquinoline (TIQ) is endogenously present in the human brain, and some of its derivatives are thought to contribute to the induction of Parkinson's disease (PD)-like signs in rodents and primates. In contrast, the endogenous TIQ derivative 1-methyl-TIQ (1-MeTIQ) is reported to be neuroprotective. In the present study, we compared the effects of artificially modified 1-MeTIQ derivatives (loading an N-propyl, N-propenyl, N-propargyl, or N-butynyl group) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like signs in mice. In a behavioral study, MPTP-induced bradykinesia was significantly decreased by all compounds. However, only 1-Me-N-propargyl-TIQ showed an inhibitory effect by blocking the MPTP-induced reduction in striatal dopamine content and the number of nigral tyrosine hydroxylase-positive cells. Western blot analysis showed that 1-Me-N-propargyl-TIQ and 1-Me-N-butynyl-TIQ potently prevented the MPTP-induced decrease in dopamine transporter expression, whereas 1-MeTIQ and 1-Me-N-propyl-TIQ did not. These results suggest that although loading an N-propargyl group on 1-MeTIQ clearly enhanced neuroprotective effects, other N-functional groups showed distinct pharmacological properties characteristic of their functional groups. Thus, the number of bonds and length of the N-functional group may contribute to the observed differences in effect.


Assuntos
Intoxicação por MPTP , Fármacos Neuroprotetores , Transtornos Parkinsonianos , Tetra-Hidroisoquinolinas , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Humanos , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/prevenção & controle
4.
Int J Mol Sci ; 23(4)2022 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-35216146

RESUMO

Chicoric acid (CA), a polyphenolic acid compound extracted from chicory and echinacea, possesses antiviral, antioxidative and anti-inflammatory activities. Growing evidence supports the pivotal roles of brain-spleen and brain-gut axes in neurodegenerative diseases, including Parkinson's disease (PD), and the immune response of the spleen and colon is always the active participant in the pathogenesis and development of PD. In this study, we observe that CA prevented dopaminergic neuronal lesions, motor deficits and glial activation in PD mice, along with the increment in striatal brain-derived neurotrophic factor (BDNF), dopamine (DA) and 5-hydroxyindoleacetic acid (5-HT). Furthermore, CA reversed the level of interleukin-17(IL-17), interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-ß) of PD mice, implicating its regulatory effect on the immunological response of spleen and colon. Transcriptome analysis revealed that 22 genes in the spleen (21 upregulated and 1 downregulated) and 306 genes (190 upregulated and 116 downregulated) in the colon were significantly differentially expressed in CA-pretreated mice. These genes were functionally annotated with GSEA, GO and KEGG pathway enrichment, providing the potential target genes and molecular biological mechanisms for the modulation of CA on the spleen and gut in PD. Remarkably, CA restored some gene expressions to normal level. Our results highlighted that the neuroprotection of CA might be associated with the manipulation of CA on brain-spleen and brain-gut axes in PD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ácidos Cafeicos/uso terapêutico , Intoxicação por MPTP/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Succinatos/uso terapêutico , Transcriptoma , Animais , Anti-Inflamatórios/farmacologia , Ácidos Cafeicos/farmacologia , Colo/efeitos dos fármacos , Colo/metabolismo , Citocinas/genética , Citocinas/metabolismo , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Baço/efeitos dos fármacos , Baço/metabolismo , Succinatos/farmacologia
5.
Drug Chem Toxicol ; 45(6): 2439-2447, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34340603

RESUMO

Parkinson's disease (PD) is one of the most common neurodegenerative diseases due to the loss of dopaminergic neurons in the midbrain in the substantia nigra. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic agent causing disruptions in mitochondria of dopaminergic neurons leading to impaired oxidant-antioxidant balance. Both zebrafish and zebrafish embryos are sensitive to MPTP. In zebrafish embryos, MPTP decreases the dopaminergic cells in the diencephalon by damaging dopaminergic neurons. Morphine is an opioid pain killer and a strong analgesic that is used to treat chronic pain. Until today morphine has been shown to regulate the survival or death of neurons and both protective and destructive effects of morphine have been reported in the central nervous system. This study aimed to evaluate the effects of morphine in MPTP-exposed zebrafish embryos. Developmental parameters were monitored and documented daily during embryonic development. Locomotor activity of zebrafish embryos at 96 h postfertilization (hpf) was determined. Acetylcholinesterase (AChE) activity and oxidant-antioxidant parameters were analyzed by biochemical methods. RT-PCR was used to evaluate bdnf, dj1, lrrk and pink1 expressions. Morphine treatment improved mortality and hatching rates, locomotor activity, AChE, and antioxidant enzyme activities as well as the expressions of bdnf, dj1, lrrk and pink1 in a dose-dependent manner that were altered by MPTP. Increased lipid peroxidation supports the role of morphine to induce autophagy to prevent PD-related pathologies. Our study provided important data on the possible molecular mechanism of the therapeutic effects of morphine in PD.


Assuntos
Intoxicação por MPTP , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Animais , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/uso terapêutico , Acetilcolinesterase/metabolismo , Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Antioxidantes/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Morfina/farmacologia , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/prevenção & controle , Intoxicação por MPTP/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxidantes/metabolismo , Proteínas Quinases/metabolismo , Peixe-Zebra
6.
Mol Nutr Food Res ; 65(20): e2100339, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34378848

RESUMO

INTRODUCTION: Malnutrition in early life affects the growth and development of fetus and children, which has a long-term impact on adult health. Previous studies reveal a relationship between dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) content, brain development, and the prevalence of neurodevelopmental disorders and inflammation. However, it is unclear about the effect of n-3 PUFA-deficiency in early life on the development of Parkinson's disease (PD) in old age, as well as the neuroprotective effect of DHA- and EPA-enriched phospholipids (DHA/EPA-PLs) supplemented in old age in long-term n-3 PUFA-deficient mice. METHODS AND RESULTS: The PD mice induced by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in n-3 PUFA-adequate (N) and -deficient (DEF) group are supplemented with a DHA/EPA-PLs diet for 2 weeks (N+DPL, DEF+DPL). DHA/EPA-PLs supplementation significantly protects against MPTP-induced impairments. The DEF+DPL group shows poorer motor performance, the loss of dopaminergic neurons, mitochondrial dysfunction, and neurodevelopment delay than the N+DPL group, and still did not recover to the Control level. CONCLUSIONS: Dietary n-3 PUFA-deficiency in early life exhibits more aggravated MPTP-induced neurotoxicity in old age, than DHA/EPA-PLs supplementation recovers brain DHA levels and exerts neuroprotective effects in old age in long-term n-3 PUFA-deficient mice, which might provide a potential dietary guidance.


Assuntos
Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Ácidos Graxos Ômega-3/deficiência , Intoxicação por MPTP/prevenção & controle , Neuroproteção , Fosfolipídeos/administração & dosagem , Animais , Apoptose , Química Encefálica , Corpo Estriado/patologia , Suplementos Nutricionais , Ácidos Graxos/análise , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo
7.
Biochem Biophys Res Commun ; 556: 16-22, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33836343

RESUMO

Evidence suggests constipation precedes motor dysfunction and is the most common gastrointestinal symptom in Parkinson's disease (PD). 5-HT4 receptor (5-HT4R) agonist prucalopride has been approved to treat chronic constipation. Here, we reported intraperitoneal injection of prucalopride for 7 days increased dopamine and decreased dopamine turnover. Prucalopride administration improved motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mouse models. Prucalopride treatment also ameliorated intestinal barrier impairment and increased IL-6 release in PD model mice. However, prucalopride treatment exerted no impact on JAK2/STAT3 pathway, suggesting that prucalopride may stimulate IL-6 via JAK2/STAT3-independent pathway. In conclusion, prucalopride exerted beneficial effects in MPTP-induced Parkinson's disease mice by attenuating the loss of dopamine, improving motor dysfunction and intestinal barrier.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Destreza Motora/efeitos dos fármacos , Doença de Parkinson/prevenção & controle , Doença de Parkinson/fisiopatologia , Animais , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Janus Quinase 2/metabolismo , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/fisiopatologia , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson Secundária/fisiopatologia , Doença de Parkinson Secundária/prevenção & controle , Fator de Transcrição STAT3/metabolismo
8.
Oxid Med Cell Longev ; 2021: 8843899, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33520086

RESUMO

Polygonatum sibiricum, a well-known life-prolonging tonic in Chinese medicine, has been widely used for nourishing nerves in the orient, but the underlying molecular mechanisms remain unclear. In this study, we found that P. sibiricum polysaccharides (PSP) ameliorated 1-methyl-4-phenyl-1,2.3,6-tetrahydropyridine- (MPTP-) induced locomotor activity deficiency and dopaminergic neuronal loss in an in vivo Parkinson's disease (PD) mouse model. Additionally, PSP pretreatment inhibited N-methyl-4-phenylpyridine (MPP+) induced the production of reactive oxygen species, increasing the ratio of reduced glutathione/oxidized glutathione. In vitro experiments showed that PSP promoted the proliferation of N2a cells in a dose-dependent manner, while exhibiting effects against oxidative stress and neuronal apoptosis elicited by MPP+. These effects were found to be associated with the activation of Akt/mTOR-mediated p70S6K and 4E-BP1 signaling pathways, as well as nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (Gclc), and glutamate-cysteine ligase modulatory subunit (Gclm), resulting in antiapoptotic and antioxidative effects. Meanwhile, PSP exhibited no chronic toxicity in C57BJ/6 mice. Together, our results suggest that PSP can serve as a promising therapeutic candidate with neuroprotective properties in preventing PD.


Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Intoxicação por MPTP/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Polygonatum/química , Polissacarídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Linhagem Celular , Intoxicação por MPTP/induzido quimicamente , Intoxicação por MPTP/metabolismo , Masculino , Camundongos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/prevenção & controle , Polissacarídeos/química
9.
J Biochem Mol Toxicol ; 35(1): e22631, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32926752

RESUMO

Parkinson's disease (PD) is a complex neurodegenerative illness associated with the loss or damage to neurons of the dopaminergic system in the brain. Few therapeutic approaches and considerable side effects of conventional drugs necessitate a new therapeutic agent to treat patients with PD. Rhaponticin is a natural hydroxystilbene, found in herbal plants such as Rheum rhaponticum, and known to have desirable biological activity including anti-inflammatory properties. However, the neuroinflammation on rhaponticin levels has only been investigated partially so far. So, the current study explored whether rhaponticin could ameliorate the pathophysiology observed in both the in vitro microglial BV-2 cells and the in vivo (1-methyl-4-phenyl-1,2,3,5-tetrahydropyridine [MPTP])-mediated PD model. The results show rhaponticin significantly attenuated lipopolysaccharide (LPS)-mediated microglial activation by suppressing nitric oxide synthase in conjunction with abridged reactive oxygen species production together with proinflammatory mediator reduction. In vivo rhaponticin treatment improves motor impairments as well as the loss of dopaminergic neurons in MPTP-treated mice possibly through suppression via mediators of inflammation. Taken together, these results offer evidence that rhaponticin exerts anti-inflammatory effects and neuroprotection in an LPS-induced microglial model and the MPTP-induced mouse models of PD.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Intoxicação por MPTP/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Animais , Linhagem Celular Transformada , Neurônios Dopaminérgicos/patologia , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/patologia , Masculino , Camundongos
10.
Neurosci Lett ; 742: 135534, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33271195

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder, caused by the selective death of dopaminergic neurons in the substantia nigra pars compacta. ß-caryophyllene (BCP) is a phytocannabinoid with several pharmacological properties, producing anti-inflammatory and antihypertensive effects. In addition, BCP protects dopaminergic neurons from neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), yet it remains unclear if this effect is due to its antioxidant activity. To assess whether this is the case, the effect of BCP on the expression and activity of NAD(P)H quinone oxidoreductase (NQO1) was evaluated in mice after the administration of MPTP. Male C57BL/6 J mice were divided into four groups, the first of which received saline solution i.p. in equivalent volume and served as a control group. The second group received MPTP. The second group received MPTP hydrochloride (5 mg/kg, i.p.) daily for seven consecutive days. The third group received BCP (10 mg/kg) for seven days, administered orally and finally, the fourth group received MPTP as described above and BCP for 7 days from the fourth day of MPTP administration. The results showed that BCP inhibits oxidative stress-induced cell death of dopaminergic neurons exposed to MPTP at the same time as it enhances the expression and enzymatic activity of NQO1. Also, the BCP treatment ameliorated motor dysfunction and protected the dopaminergic cells of the SNpc from damage induced by MPTP. Hence, BCP appears to achieve at least some of its antioxidant effects by augmenting NQO1 activity, which protects cells from MPTP toxicity. Accordingly, this phytocannabinoid may represent a promising pharmacological option to safeguard dopaminergic neurons and prevent the progression of PD.


Assuntos
Antioxidantes/uso terapêutico , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/prevenção & controle , NAD(P)H Desidrogenase (Quinona)/biossíntese , Sesquiterpenos Policíclicos/uso terapêutico , Animais , Antioxidantes/farmacologia , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Sesquiterpenos Policíclicos/farmacologia , Distribuição Aleatória
11.
J Neuroimmune Pharmacol ; 16(3): 667-678, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33221984

RESUMO

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and loss of both motor and non-motor features. Several clinical and preclinical studies have provided evidence that estrogen therapy reduces the risk of PD but have limitations in terms of adverse peripheral effects. Therefore, we examined the potential beneficial effects of the brain-selective estrogen prodrug, 10ß, 17ß-dihydroxyestra-1,4-dien-3-one (DHED) on nigrostriatal dopaminergic neurodegeneration and behavioral abnormalities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Wild-type mice were treated with daily subcutaneous injections of DHED (50 and 100 µg/kg) or vehicle for four weeks. To produce PD-like symptoms, mice were injected with MPTP (18 mg/kg in saline; intraperitoneally) four times at 2-hr intervals for one day. After behavioral examination, mice were sacrificed, and the brains were isolated for neurochemical and morphological examinations. MPTP injected mice exhibited loss of dopaminergic neurons and fibers in substantia nigra and striatum respectively, along with impaired motor function at day 7 post MPTP injection. These phenotypes were associated with significantly increased oxidative stress and inflammatory responses in the striatum regions. DHED treatments significantly mitigated behavioral impairments and dopaminergic neurodegeneration induced by MPTP. We further observed that DHED treatment suppressed oxidative stress and inflammation in the striatum of MPTP treated mice when compared to vehicle treated mice. In conclusions, our findings suggest that DHED protects dopaminergic neurons from MPTP toxicity in mouse model of PD and support a beneficial effect of brain-selective estrogen in attenuating neurodegeneration and motor symptoms in PD-related neurological disorders. Graphical Abstract.


Assuntos
Intoxicação por MPTP , Doença de Parkinson , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Encéfalo , Corpo Estriado , Modelos Animais de Doenças , Neurônios Dopaminérgicos , Estrogênios/farmacologia , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Substância Negra
12.
J Ethnopharmacol ; 268: 113568, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33188898

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Isolated from Uncaria rhynchophylla (U. rhynchophylla), rhynchophylline (Rhy) has been applied for treating diseases related to central nervous system such as Parkinson's disease. Nevertheless, the molecular mechanism of the neuroprotective effect has not been well interpreted. AIM OF THE STUDY: To investigate the effects of Rhy on MPTP/MPP + -induced neurotoxicity in C57BL/6 mice or PC12 cells and study the mechanisms involved. MATERIALS AND METHODS: The neuroprotective effect of Rhy on MPTP-induced neurotoxicity was evaluated by spontaneous motor activity test, as well as a test of rota-rod on a rat model of Parkinson's disease. The numbers of TH-positive neurons in the substantia nigra pars compacta (SNpc) was assessed by immunohistological. CCK-8, lactate dehydrogenase (LDH), reactive oxygen species (ROS), the concentration of intracellular calcium ([Ca2+]i) and flow cytometry analysis were performed to evaluate the pharmacological property of Rhy on 1-methyl-4-phenylpyridinium (MPP+) induced neurotoxicity in PC12 cells. Besides, LY294002, a PI3K inhibitor was employed to determine the underlying molecular signaling pathway revealing the effect of Rhy by western-blot analysis. RESULTS: The results showed that Rhy exhibited a protective effect against the MPTP-induced decrease in tyrosine hydroxylase (TH)-positive fibers in the substantia nigra at 30 mg/kg, demonstrated by the immunohistological and behavioral outcomes. Furthermore, it has been indicated that cell viability was improved and the MPP+-induced apoptosis was inhibited after the treatment of Rhy at 20 µM, which were severally analyzed by the CCK-8 and the Annexin V/propidium iodide staining method. In addition, Rhy treatment attenuated MPP+-induced up-regulation of LDH, ([Ca2+]i), and the levels of ROS. Besides, it can be revealed from the Western blot assay that LY294002, as a selective Phosphatidylinositol 3-Kinase (PI3K) inhibitor, effectively inhibited the Akt phosphorylation caused by Rhy, which suggested that Rhy showed its protective property through the activated the PI3K/Akt signaling pathway. Moreover, the Rhy-induced decreases of Bax and caspase-3 as the proapoptotic markers and the increase of Bcl-2 as the antiapoptotic marker, were blocked by LY294002 in the MPP+-treated PC12 cells. CONCLUSIONS: Rhy exerts a neuroprotective effect is partly mediated by activating the PI3K/Akt signaling pathway.


Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Intoxicação por MPTP/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Oxindóis/uso terapêutico , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Herbicidas/toxicidade , Intoxicação por MPTP/induzido quimicamente , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Oxindóis/isolamento & purificação , Oxindóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Uncaria
13.
Oxid Med Cell Longev ; 2020: 7635291, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123315

RESUMO

BACKGROUND: Progesterone receptor (PR) modulates neuroprotective and regenerative responses in Parkinson's disease and related neurological diseases. OBJECTIVES: The present study was designed to determine whether botanical drug puerarin could exhibit neuroprotective and neurorestorative activities via PR signaling. METHODS: The neuroprotective and neurotrophic activities of puerarin were investigated in MPTP-lesioned mice and MPP+-challenged primary rat midbrain neurons. Rotarod performance test and tail suspension test were used to assess motor functions. Tyrosine hydroxylase (TH) and PR were determined by immunostaining, Western blotting, and luciferase reporter assays. Neurite outgrowth was assessed by fluorescence staining and immunostaining. RESULTS: Puerarin effectively ameliorated the MPTP-induced motor abnormalities in MPTP-lesioned mice and protected primary rat midbrain neurons against MPP+-induced toxicity via PR signaling although progesterone exhibited the neuroprotection. PR antagonist mifepristone (RU486) diminished the neuroprotection of puerarin in MPTP-lesioned mice and MPP+-induced primary rat midbrain neurons. Moreover, puerarin promoted the differentiation of primary rat midbrain neurons and potentiated NGF to induce neuritogenesis in PC12 cells. RU486 and PR-siRNA could inhibit the effect of puerarin. Puerarin and progesterone could enhance the PR promoter. CONCLUSION: Puerarin attenuated MPTP- and MPP+-induced toxicity and potentiated neurite outgrowth via PR. These results suggested that puerarin may become an alternative hormone for suppressing MPTP- and MPP+-induced toxicity in neurodegenerative diseases.


Assuntos
Isoflavonas/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores de Progesterona/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Isoflavonas/química , Isoflavonas/metabolismo , Isoflavonas/uso terapêutico , Intoxicação por MPTP/patologia , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mifepristona/farmacologia , Simulação de Acoplamento Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Progesterona/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/genética
14.
Am J Physiol Endocrinol Metab ; 319(4): E734-E743, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32865008

RESUMO

Autophagy dysfunctions are involved in the pathogenesis of Parkinson's disease (PD). In the present study, we aimed to evaluate the involvement of G protein-coupled estrogen receptor (GPER) in the inhibitory effect of insulin-like growth factor-1 (IGF-1) against excessive autophagy in PD animal and cellular models. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment significantly induced mouse movement disorder and decreased the protein level of tyrosine hydroxylase (TH) in the substantia nigra (SN) and dopamine (DA) content in striatum. Along with the dopamine neuron injury, we observed significant upregulations of microtubule-associated light chain-3 II (LC3-II) and α-synuclein as well as a downregulation of P62 in MPTP-treated mice. These changes could be restored by IGF-1 pretreatment. Cotreatment with IGF-1R antagonist JB-1 or GPER antagonist G15 could block the neuroprotective effects of IGF-1. 1-Methy-4-phenylpyridinium (MPP+) treatment could also excessively activate autophagy along with the reduction of cell viability in SH-SY5Y cells. IGF-1 could inhibit the neurotoxicity through promoting the phosphorylation of Akt and mammalian target of rapamycin (mTOR), which could also be antagonized by JB-1 or G15. These data suggest that IGF-1 inhibits MPTP/MPP+-induced autophagy on dopaminergic neurons through the IGF-1R/PI3K-Akt-mTOR pathway and GPER.


Assuntos
Autofagia/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Intoxicação por MPTP/prevenção & controle , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Intoxicação por MPTP/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Equilíbrio Postural/efeitos dos fármacos , Receptor IGF Tipo 1 , Serina-Treonina Quinases TOR/metabolismo
15.
Neurotherapeutics ; 17(4): 1861-1877, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32638217

RESUMO

Loss of dopaminergic neurons along the nigrostriatal axis, neuroinflammation, and peripheral immune dysfunction are the pathobiological hallmarks of Parkinson's disease (PD). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been successfully tested for PD treatment. GM-CSF is a known immune modulator that induces regulatory T cells (Tregs) and serves as a neuronal protectant in a broad range of neurodegenerative diseases. Due to its short half-life, limited biodistribution, and potential adverse effects, alternative long-acting treatment schemes are of immediate need. A long-acting mouse GM-CSF (mPDM608) was developed through Calibr, a Division of Scripps Research. Following mPDM608 treatment, complete hematologic and chemistry profiles and T-cell phenotypes and functions were determined. Neuroprotective and anti-inflammatory capacities of mPDM608 were assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice that included transcriptomic immune profiles. Treatment with a single dose of mPDM608 resulted in dose-dependent spleen and white blood cell increases with parallel enhancements in Treg numbers and immunosuppressive function. A shift in CD4+ T-cell gene expression towards an anti-inflammatory phenotype corresponded with decreased microgliosis and increased dopaminergic neuronal cell survival. mPDM608 elicited a neuroprotective peripheral immune transformation. The observed phenotypic shift and neuroprotective response was greater than observed with recombinant GM-CSF (rGM-CSF) suggesting human PDM608 as a candidate for PD treatment.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Intoxicação por MPTP/induzido quimicamente , Intoxicação por MPTP/prevenção & controle , Neuroproteção/efeitos dos fármacos , Neurotoxinas/toxicidade , Animais , Relação Dose-Resposta a Droga , Intoxicação por MPTP/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroproteção/fisiologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
16.
Neurochem Res ; 45(7): 1700-1710, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32356199

RESUMO

Parkinson's disease (PD) is a prevalent age-related neurodegenerative disease which is modulated by various molecules, including long non-coding RNAs (lncRNAs). LncRNA H19 has been shown to be associated with PD progression, but the mechanism is still unclear. This research aims to investigate the role of H19 in PD development and the detailed mechanisms. Our results showed that H19 was down-regulated in brain tissue of MPTP-induced PD mice (in vivo) and in MPP+ treated human neuroblastoma cells. miR-585-3p was verified to be a target of lncRNA H19 and was negatively regulated by H19. In addition, H19 could increase the expression of PIK3R3 through miR-585-3p. In vitro results indicated that H19 inhibited the apoptosis of MPP+ treated neuroblastoma cells by regulating of miR-585-3p. Moreover, in PD model mice, overexpression of H19 attenuated MPTP-induced neuronal apoptosis. In summary, our present research demonstrated that LncRNA H19 could attenuate neurons apoptosis in MPTP-induced PD mice as well as MPP+ treated neuroblastoma cells through regulating miR-585-3p/PIK3R3. The results may provide a potential theoretical experimental data for the clinical treatment of PD through targeting lncRNAs or miRNAs.


Assuntos
Apoptose/fisiologia , Intoxicação por MPTP/metabolismo , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/biossíntese , RNA Longo não Codificante/biossíntese , Animais , Linhagem Celular Tumoral , Células HEK293 , Humanos , Intoxicação por MPTP/induzido quimicamente , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Toxicology ; 426: 152256, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31381935

RESUMO

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in substantia nigra (SN). Accumulating evidences implicate the beneficial role of estrogen in the therapy of PD. METHODS: In the present study, the protective function of luteolin-7-O-glucoside (LUT-7G), a natural flavonoid, was investigated in 1-methyl-4-phenylpyridinium (MPP+) treated SH-SY5Y cells and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced mice. RESULTS: Pre-treatment of LUT-7G increased the viability and reduced the apoptosis of SH-SY5Y cells treated by MPP+. At molecular level, the Bcl-2/Bax ratio was increased, while the expression of cleaved caspase 3 was markedly lessened. Moreover, LUT-7G increased the expression of estrogen receptor (ER), ERα and ERß, and enhanced the activation of ERK1/2/STAT3/c-Fos that could be abolished by ER antagonists. Furthermore, in vivo experiment indicated that pre-treatment of LUT-7G improved the bradykinesia, and enhanced the muscle strength as well as the balancing capacity of mice treated with MPTP. And LUT-7G prevented the injury of TH positive cells in substantia nigra and increased TH positive nerve fibers in striatum. In addition, pre-treatment of LUT-7G also significantly diminished the MPTP-induced gliosis in substantia nigra. CONCLUSIONS: LUT-7G effectively protected dopaminergic neurons against MPP+ or MPTP-induced toxicity, probably by activating the ER-mediated signaling pathway. Our findings explore the therapeutic potential of LUT-7G for PD therapy.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Flavonas/farmacologia , Glucosídeos/farmacologia , Intoxicação por MPTP/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Receptores de Estrogênio/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular , Antagonistas de Estrogênios/farmacologia , Humanos , Hipocinesia/etiologia , Hipocinesia/prevenção & controle , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Intoxicação por MPTP/patologia , Intoxicação por MPTP/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Força Muscular/efeitos dos fármacos , Fator de Transcrição STAT3/efeitos dos fármacos , Substância Negra/patologia
18.
Oxid Med Cell Longev ; 2019: 6764756, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379989

RESUMO

Hyperactivation of microglia, the resident innate immune cells of the central nervous system, exacerbates various neurodegenerative disorders, including Parkinson's disease (PD). Parkinson's disease is generally characterized by a severe loss of dopaminergic neurons in the nigrostriatal pathway, with substantial neuroinflammation and motor deficits. This was experimentally replicated in animal models, using neurotoxins, i.e., LPS (lipopolysaccharides) and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Salicornia europaea L. (SE) has been used as a dietary supplement in Korea and Europe for several years, due to its nutritional and therapeutic value. In this study, we intend to investigate the antineuroinflammatory and anti-PD-like effects of the bioactive fraction/candidate of the SE extract. Initially, we screened various fractions of SE extract using an in vitro antioxidant assay. The optimal fraction was investigated for its in vitro antineuroinflammatory potential in LPS-stimulated BV-2 microglial cells and in vivo anti-PD-like potential in MPTP-intoxicated mice. Subsequently, to identify the potential candidate responsible for the elite therapeutic potential of the optimal fraction, we conducted antioxidant activity-guided isolation and purification; the bioactive candidate was structurally characterized using nuclear magnetic resonance spectroscopy and chromatographic techniques and further investigated for its in vitro antioxidative and antineuroinflammatory potential. The results of our study indicate that SE-EA and its bioactive candidate, Irilin B, effectively alleviate the deleterious effect of microglia-mediated neuroinflammation and promote antioxidative effects. Thus, they exhibit potential as therapeutic candidates against neuroinflammatory and oxidative stress-mediated PD-like neurodegenerative complications.


Assuntos
Chenopodiaceae/química , Isoflavonas/farmacologia , Intoxicação por MPTP/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/química , Acetatos/química , Animais , Antioxidantes/metabolismo , Chenopodiaceae/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Isoflavonas/uso terapêutico , Lipopolissacarídeos/farmacologia , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Espécies Reativas de Oxigênio/metabolismo
19.
Neurochem Int ; 129: 104491, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31229553

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of protein inclusions and the loss of dopaminergic neurons. Abnormal mitochondrial homeostasis is thought to be important for the pathogenesis of PD. Transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique, constitutes a promising approach for promoting recovery of various neurological conditions. However, little is known about its mechanism of action. The present study elucidated the neuroprotective effects of tDCS on the mitochondrial quality control pathway in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. We used the MPTP-induced neurotoxicity in vivo model. Mice were stimulated for 5 consecutive days with MPTP treatment. After observation of behavioral alteration using the rotarod test, mice were sacrificed for the measurement of the PD- and mitochondrial quality control-related protein levels in the substantia nigra. tDCS improved the behavioral alterations and changes in tyrosine hydroxylase levels in MPTP-treated mice. Furthermore, tDCS attenuated mitochondrial damage, as indicated by diminished mitochondrial swelling and mitochondrial glutamate dehydrogenase activity in the MPTP-induced PD mouse model. MPTP significantly increased mitophagy and decreased mitochondrial biogenesis-related proteins. These changes were attenuated by tDCS. Furthermore, MPTP significantly increased fission-related protein dynamin-related protein 1 with no effect on fusion-related protein mitofusin-2, and tDCS attenuated these changes. Our findings demonstrated the neuroprotective effect of anodal tDCS on the MPTP-induced neurotoxic mouse model through suppressing excessive mitophagy and balancing mitochondrial dynamics. The neuroprotective effect of anodal tDCS with modulation of mitochondrial dynamics provides a new therapeutic strategy for the treatment of PD.


Assuntos
Intoxicação por MPTP/prevenção & controle , Dinâmica Mitocondrial/efeitos da radiação , Estimulação Transcraniana por Corrente Contínua , Trifosfato de Adenosina/análise , Animais , Corpo Estriado/química , Corpo Estriado/efeitos da radiação , Corpo Estriado/ultraestrutura , Eletrodos , GTP Fosfo-Hidrolases/análise , Glutamato Desidrogenase/análise , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/enzimologia , Mitofagia/efeitos da radiação , Proteínas do Tecido Nervoso/análise , Biogênese de Organelas , Teste de Desempenho do Rota-Rod , Substância Negra/química , Substância Negra/efeitos da radiação , Substância Negra/ultraestrutura , Tirosina 3-Mono-Oxigenase/análise
20.
Neuropsychopharmacol Rep ; 39(3): 247-251, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31132231

RESUMO

AIMS: Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. Although diet may influence the development of PD, the precise mechanisms underlying relationship between diet and PD pathology are unknown. Here, we examined whether dietary intake of glucoraphanin (GF), the precursor of a natural antioxidant sulforaphane in cruciferous vegetables, can affect the reduction of dopamine transporter (DAT) in the mouse striatum after repeated administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). METHODS: Normal food pellet or 0.1% GF food pellet was given into male mice for 28 days from 8-week-old. Subsequently, saline (5 mL/kg × 3, 2-hour interval) or MPTP (10 mg/kg × 3, 2-hour interval) was injected into mice. Immunohistochemistry of DAT in the striatum was performed 7 days after MPTP injection. RESULTS: Repeated injections of MPTP significantly decreased the density of DAT-immunoreactivity in the mouse striatum. In contrast, dietary intake of 0.1% GF food pellet significantly protected against MPTP-induced reduction of DAT-immunoreactivity in the striatum. CONCLUSION: This study suggests that dietary intake of GF food pellet could prevent MPTP-induced dopaminergic neurotoxicity in the striatum of adult mice. Therefore, dietary intake of GF-rich cruciferous vegetables may have beneficial effects on prevention for development of PD.


Assuntos
Antioxidantes/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Glucosinolatos/uso terapêutico , Imidoésteres/uso terapêutico , Intoxicação por MPTP/tratamento farmacológico , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Suplementos Nutricionais , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Glucosinolatos/administração & dosagem , Glucosinolatos/farmacologia , Imidoésteres/administração & dosagem , Imidoésteres/farmacologia , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oximas , Sulfóxidos
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