RESUMEN
Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder. Although mounting studies have been conducted, no effective therapy is available to halt its progression. Indole-3-carbinol (I3C) is a naturally occurring compound obtained by ß-thioglucosidase-mediated autolysis of glucobrassicin in cruciferous vegetables. Besides its powerful antioxidant activity, I3C has shown neuroprotection against depression and chemically induced neurotoxicity via its anti-inflammatory and antiapoptotic effects. This study aimed to investigate the neuroprotective effects of I3C against rotenone (ROT)-induced PD in male albino rats. The possible protective mechanisms were also explored. PD was induced by subcutaneous administration of ROT (2 mg/kg) for 28 days. The effects of I3C (25, 50, and 100 mg/kg/day) were assessed by catalepsy test (bar test), spontaneous locomotor activity, rotarod test, weight change, tyrosine hydroxylase (TH) expression, α-synuclein (α-Syn) expression, striatal dopamine (DA) content, and histological examination. The highest dose of I3C (100 mg/kg) was the most effective to prevent ROT-mediated motor dysfunctions and amend striatal DA decrease, weight loss, neurodegeneration, TH expression reduction, and α-Syn expression increase in both the midbrain and striatum. Further mechanistic investigations revealed that the neuroprotective effects of I3C are partially attributed to its anti-inflammatory and antiapoptotic effects and the activation of the sirtuin 1/AMP-activated protein kinase pathway. Altogether, these results suggested that I3C could attenuate biochemical, molecular, and functional changes in a rat PD model with following repeated rotenone exposures.
Asunto(s)
Indoles/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/prevención & control , Rotenona , Sirtuina 1/metabolismo , Desacopladores , Animales , Peso Corporal/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/prevención & control , Dopamina/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Enfermedad de Parkinson Secundaria/psicología , Equilibrio Postural/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sirtuina 1/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismo , alfa-Sinucleína/biosíntesis , alfa-Sinucleína/efectos de los fármacosRESUMEN
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.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Mucosa Intestinal/efectos de los fármacos , Destreza Motora/efectos de los fármacos , Enfermedad de Parkinson/prevención & control , Enfermedad de Parkinson/fisiopatología , Animales , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Dopamina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Janus Quinasa 2/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/fisiopatología , Intoxicación por MPTP/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Neostriado/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/fisiopatología , Enfermedad de Parkinson Secundaria/prevención & control , Factor de Transcripción STAT3/metabolismoRESUMEN
BACKGROUND: Combined maneb (MB) and paraquat (PQ), two widely used pesticides, increases oxidative stress leading to Parkinsonism. Xenobiotic metabolizing enzymes, cytochrome P450 (CYP) 2D6 and its mouse ortholog Cyp2d22 protect against Parkinsonism. Resveratrol, an antioxidant, restores antioxidant defense system through the activation of nuclear factor erythroid 2- related factor 2 (Nrf2). However, a crosstalk between Cyp2d22/CYP2D6-mediated protection and resveratrol-induced Nrf2 activation leading to neuroprotection is not yet elucidated. OBJECTIVE: The study aimed to decipher the effect of resveratrol on Nrf2 activation and expression of its downstream mediators, nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 (NQO1) and thioredoxin 1 (Trx1) along with Cyp2d22/CYP2D6 activity in combined MB and PQ mouse model of Parkinsonism and differentiated neuroblastoma cells. RESULTS: MB and PQ reduced the dopamine content (mouse) and Cyp2d22/CYP2D6 activity (mouse/neuroblastoma cells) and increased the nuclear translocation of Nrf2 and expression of NQO1 and Trx1 (both). Resveratrol ameliorated pesticides-induced changes in dopamine content and Cyp2d22/CYP2D6 activity. It was found to promote nuclear translocation of Nrf2 and expression of NQO1 and Trx1 proteins. Since Cyp2d22/CYP2D6 inhibitor (ketoconazole/quinidine) per se reduced Cyp2d22/CYP2D6 activity and dopamine content, it was found to substantially increase the pesticides-induced reduction in Cyp2d22/CYP2D6 activity and dopamine content. Inhibitors normalized the pesticides induced changes in Nrf2 translocation and NQO1 and Trx1 levels in pesticides treated groups. CONCLUSION: The results suggest that resveratrol promotes the catalytic activity of xenobiotic metabolizing enzyme, Cyp2d22/CYP2D6, which partially contributes to Nrf2 activation in pesticides- induced Parkinsonism.
Asunto(s)
Antioxidantes/metabolismo , Familia 2 del Citocromo P450/biosíntesis , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Neuroprotección/efectos de los fármacos , Enfermedad de Parkinson Secundaria , Plaguicidas/toxicidad , Resveratrol/farmacología , Animales , Línea Celular Tumoral , Masculino , Ratones , NAD(P)H Deshidrogenasa (Quinona) , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/prevención & control , Tiorredoxinas/biosíntesisRESUMEN
Rotenone is a mitochondrial complex I inhibitor, which can cause the death of dopaminergic (DA) neurons and Parkinson's disease (PD). Currently, whether metformin has a protective effect on neurotoxicity induced by rotenone is unclear. The purpose of this study was to evaluate the potential protective effect of metformin against rotenone-induced neurotoxicity. PD animal model was established by unilateral rotenone injection into the right substantia nigra (SN) of C57BL/6 mice. The behavioral tests were performed by rotarod test and cylinder test. The numbers of TH-positive neurons and Iba-1 positive microglia in the SN were investigated by immunohistochemical staining. The mRNA levels of proinflammatory cytokines (TNF-α and IL-1ß) and molecules involved in endoplasmic reticulum (ER) stress (ATF4, ATF6, XBP1, Grp78, and CHOP) in the midbrain were detected by Quantitative real-time PCR. This study showed that 50 mg/kg metformin given orally daily, beginning 3 d before rotenone injection and continuing for 4 weeks following rotenone injection, significantly ameliorated dyskinesia, increased the number of TH-positive neurons, and mitigated the activation of microglia in the SN in rotenone-induced PD mice. Furthermore, 50 mg/kg metformin markedly downregulated the expression of proinflammatory cytokines (TNF-α and IL-1ß) and ER stress-related genes (ATF4, ATF6, XBP1, Grp78, and CHOP) in rotenone-induced PD mice. Metformin has a protective effect on DA neurons against rotenone-induced neurotoxicity through inhibiting neuroinflammation and ER stress in PD mouse model.
Asunto(s)
Conducta Animal/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Metformina/farmacología , Enfermedad de Parkinson Secundaria/prevención & control , Sustancias Protectoras/farmacología , Rotenona/toxicidad , Animales , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/inmunología , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/inmunología , Inflamación , Interleucina-1beta/metabolismo , Masculino , Metformina/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/inmunología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/inmunología , Sustancias Protectoras/administración & dosificación , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Bilirubin, the end product of heme redox metabolism, has cytoprotective properties and is an essential metabolite associated with cardiovascular disease, inflammatory bowel disease, type 2 diabetes, and neurodegenerative diseases including Parkinson's disease (PD). PD is characterized by progressive degeneration of nigral dopaminergic neurons and is associated with elevated oxidative stress due to mitochondrial dysfunction. In this study, using a ratiometric bilirubin probe, we revealed that the mitochondrial inhibitor, rotenone, which is widely used to create a PD model, significantly decreased intracellular bilirubin levels in HepG2 cells. Chemical screening showed that BRUP-1 was a top hit that restored cellular bilirubin levels that were lowered by rotenone. We found that BRUP-1 up-regulated the expression level of heme oxygenase-1 (HO-1), one of the rate-limiting enzyme of bilirubin production via nuclear factor erythroid 2-related factor 2 (Nrf2) activation. In addition, we demonstrated that this Nrf2 activation was due to a direct inhibition of the interaction between Nrf2 and Kelch-like ECH-associated protein 1 (Keap1) by BRUP-1. Both HO-1 up-regulation and bilirubin restoration by BRUP-1 treatment were significantly abrogated by Nrf2 silencing. In neuronal PC12D cells, BRUP-1 also activated the Nrf2-HO-1 axis and increased bilirubin production, resulted in the suppression of neurotoxin-induced cell death, reactive oxygen species production, and protein aggregation, which are hallmarks of PD. Furthermore, BRUP-1 showed neuroprotective activity against rotenone-treated neurons derived from induced pluripotent stem cells. These findings provide a new member of Keap1-Nrf2 direct inhibitors and suggest that chemical modulation of heme metabolism using BRUP-1 may be beneficial for PD treatment.
Asunto(s)
Bilirrubina/metabolismo , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/prevención & control , Animales , Silenciador del Gen , Hemo-Oxigenasa 1/metabolismo , Células Hep G2 , Humanos , Células Madre Pluripotentes Inducidas , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neurotoxinas/toxicidad , Células PC12 , Enfermedad de Parkinson Secundaria/inducido químicamente , ARN Interferente Pequeño/farmacología , Ratas , Especies Reactivas de Oxígeno/metabolismo , Rotenona/toxicidad , Desacopladores/toxicidadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Mercury sulfides (HgS) are frequently included in Ayurveda, Tibetan and Chinese medicines to assist the presumed therapeutic effects, but the ethnopharmacology remains elusive. The present study examined the protective effects of α-HgS-containing Hua-Feng-Dan and ß-HgS-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei) against Parkinson's disease mice induced by lipopolysaccharide (LPS) plus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). METHOD: A single injection of LPS (5 mg/kg ip) was given to adult male C57BL/6 mice, and 150 days later, the low dose of MPTP (15 mg/kg, ip, for 4 days) was given to produce the "two-hit" Parkinson's disease model. Together with MPTP treatment, mice were fed with clinically-relevant doses of Hua-Feng-Dan (0.6 g/kg) and 70W (0.2 g/kg) for 35 days. Rotarod test was performed to examine muscle coordination capability. At the end of the experiment, brain was transcardially perfused with paraformaldehyde, the substantia nigra was sectioned for microglia (Iba1 staining) and dopaminergic neuron (THir staining) determination. Colon bacterial DNA was extracted and subjected to qPCR analysis with 16S rRNA probes. RESULTS: The low-grade, chronic neuroinflammation produced by LPS aggravated MPTP neurotoxicity, as evidenced by decreased motor activity, intensified microglia activation and loss of dopaminergic neurons. Both Hua-Feng-Dan and 70W increased rotarod activity and ameliorated the pathological lesions in the brain. In gut microbiomes examined, LPS plus MPTP increased Verrucomicrobiaceae, Methanobacteriaceae, Pronicromonosporaceae, and Clostridaceae species were attenuated by Hua-Feng-Dan and 70W. CONCLUSIONS: α-HgS-containing Hua-Feng-Dan and ß-HgS-containing 70W at clinical doses protected against chronic LPS plus MPTP-induced toxicity to the brain and gut, suggesting HgS-containing traditional medicines could target gut microbiota as a mechanism of their therapeutic effects.
Asunto(s)
Colon/microbiología , Compuestos de Mercurio/farmacología , Enfermedad de Parkinson Secundaria/prevención & control , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Colon/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Lipopolisacáridos , Masculino , Ratones , Microglía/patología , Enfermedad de Parkinson Secundaria/inducido químicamente , Prueba de Desempeño de Rotación con Aceleración Constante , Sustancia Negra/patologíaRESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons that project from the substantia nigra pars compacta to the striatum. Evidence from human and animal studies has suggested that oxidative damage critically contributes to neuronal loss in PD. Carvacrol (CAR), a monoterpenic phenol, is the main constituents in the essential oil of many aromatic plants and possesses some properties including anti-inflammatory and anti-oxidant effects. In this study, in vitro and in vivo experiments were performed with the CAR in order to investigate its potential neuroprotective effects in models of PD. Post-treatment with CAR in vitro was found to protect rat adrenal pheochromocytoma PC12 cells from toxicity induced by 6-hydroxydopamine (6-OHDA) administration in a dose-dependent manner by (1) increasing cell viability and (2) reduction in intracellular reactive oxygen species, intracellular lipid peroxidation, and annexin-positive cells. In vivo, post-treatment with CAR (15 and 20 mg/kg) was protective against neurodegenerative phenotypes associated with systemic administration of 6-OHDA. Results indicated that CAR improved the locomotor activity, catalepsy, akinesia, bradykinesia, and motor coordination and reduced the apomorphine-caused rotation in 6-OHDA-stimulated rats. Increased level of reduced glutathione content and a decreased level of MDA (malondialdehyde) were observed in the 6-OHDA rats post-treated with CAR. These findings suggest that CAR exerts protective effects, possibly related to an anti-oxidation mechanism, in these in vitro and in vivo models of Parkinson's disease.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cimenos/farmacología , Degeneración Nerviosa/prevención & control , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/prevención & control , Animales , Anexinas/metabolismo , Supervivencia Celular/efectos de los fármacos , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Degeneración Nerviosa/inducido químicamente , Oxidopamina , Células PC12 , Enfermedad de Parkinson Secundaria/inducido químicamente , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder caused by selective dopaminergic neuronal loss. Rotenone is a neurotoxin that selectively destroys dopaminergic neurons, leading to PD-like symptoms. Quercetin possesses antioxidant, anti-inflammatory, and neuroprotective properties but a major drawback is its low bioavailability. Therefore, the present study was designed to evaluate the neuroprotective effect of quercetin in combination with piperine against rotenone- and iron supplement-induced model of PD. Rotenone was administered at a dose of 1.5 mg/kg through an intraperitoneal route with iron supplement at a dose of 120 µg/g in diet from day 1 to day 28. Pre-treatment with quercetin (25 and 50 mg/kg, p.o.), piperine (2.5 mg/kg, p.o.) alone, quercetin (25 mg/kg, p.o.) in combination with piperine (2.5 mg/kg), and ropinirole (0.5 mg/kg, i.p.) was administered for 28 days 1 h prior to rotenone and iron supplement administration. All behavioral parameters were assessed on weekly basis. On the 29th day, all animals were sacrificed and striatum was isolated for biochemical (LPO, nitrite, GSH, mitochondrial complexes I and IV), neuroinflammatory (TNF-α, IL-1ß, and IL-6), and neurotransmitter (dopamine, norepinephrine, serotonin, GABA, glutamate) estimation. Quercetin treatment attenuated rotenone- and iron supplement-induced motor deficits and biochemical and neurotransmitter alterations in experimental rats. However, combination of quercetin (25 mg/kg) with piperine (2.5 mg/kg) significantly enhanced its neuroprotective effect as compared with treatment with quercetin alone. The study concluded that combination of quercetin with piperine contributed to superior antioxidant, anti-inflammatory, and neuroprotective effect against rotenone- and iron supplement-induced PD in experimental rats.
Asunto(s)
Alcaloides/farmacología , Benzodioxoles/farmacología , Suplementos Dietéticos/efectos adversos , Hierro/efectos adversos , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/prevención & control , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Quercetina/farmacología , Rotenona/efectos adversos , Cuerpo Estriado/metabolismo , Sinergismo Farmacológico , Complejo I de Transporte de Electrón/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Glutatión/metabolismo , Indoles/farmacología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Neurotransmisores/metabolismo , Nitritos/metabolismo , Enfermedad de Parkinson Secundaria/inducido químicamente , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
This study investigated the effect of dextromethorphan (DXM) against Parkinson's disease (PD) in rats and explored the association between DXM dose and PD risk in elderly patients 65 years and older using a population-based database. The PD rat model (Sprague Dawley rats) was induced by injecting 6-hydroxydopamine (6-OHDA) into the unilateral medial forebrain bundle of the rat brain. DXM (20â¯mg/kg) was administered intraperitoneally twice daily from 7 days before the appearance of a 6-OHDA lesion to 28 days after the lesion appeared. The availability of dopamine transporter (DAT) and serotonin transporter (SERT) in the striatum of the rat brain was measured using positron emission tomography. The apomorphine-induced rotation test was performed to study the hypersensitivity of the brain regions with lesions. This animal study demonstrated that DXM significantly attenuated 6-OHDA-induced DAT and SERT loss, correlating to rotational behaviors. The population-based human study analyzed the data from the Taiwan Longitudinal Health Insurance Database 2005 between January 2005 and December 2013 and then used the DXM dose-response curve to investigate the trend of its protective effect against PD. In the human study, low cumulative doses of DXM may potentially achieve a protective effect for PD; however, high cumulative doses seem to be a risk for PD.
Asunto(s)
Dextrometorfano/administración & dosificación , Enfermedad de Parkinson Secundaria/prevención & control , Enfermedad de Parkinson/prevención & control , Sustancias Protectoras/administración & dosificación , Anciano , Anciano de 80 o más Años , Animales , Técnicas de Observación Conductual , Conducta Animal/efectos de los fármacos , Estudios de Casos y Controles , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/análisis , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Oxidopamina/toxicidad , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/patología , Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática/análisis , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Taiwán/epidemiología , Microtomografía por Rayos XRESUMEN
BACKGROUND: Parkinson's disease is a disorder growing in prevalence, disability, and deaths. Healthcare databases provide a 'real-world' perspective for millions of individuals. We envisioned helping accelerate drug discovery by using these databases. OBJECTIVES: The objectives of this study were to assess the association of marketed medications with the risk of parkinsonism in four US claims databases and to evaluate the consistency of the association of ß-adrenoreceptor modulation with parkinsonism. METHODS: The study was conducted using a self-controlled cohort design in which subjects served as their own control. The time from treatment initiation until discontinuation or end of observation was the exposed period and a similar time preceding medication was the unexposed period. Medications were studied at ingredient and class level. The incidence rate ratio (IRR) and combined IRR were calculated. RESULTS: We assessed 2181 drugs and 117,015,066 people. Diphenhydramine, isradipine, methylphenidate, armodafinil, and modafinil were associated with reduced risk for parkinsonism in at least two databases. Armodafinil, modafinil, methylphenidate, and the ß-agonist albuterol were associated with a 56%, 54%, 39%, and 17% reduction in the risk of having parkinsonism, respectively. Isradipine results were heterogeneous and no significant association was found. Propranolol was associated with a 32% increased risk, the only ß-adrenoceptor antagonist (ß-blocker) associated with an increased risk. CONCLUSIONS: Armodafinil, modafinil, and methylphenidate were associated with a decreased risk of parkinsonism, as were ß-agonists. Of the ß-blockers, only propranolol was associated with increased risk. Healthcare database analyses that incorporate scientific rigor provide insight and direction for drug discovery efforts. These findings show association not causality; however, they offer considerable support to the association between ß-adrenergic receptor modulation and risk of Parkinson's disease.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Descubrimiento de Drogas/métodos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/diagnóstico , Vigilancia de Productos Comercializados/métodos , Antagonistas Adrenérgicos beta/efectos adversos , Adulto , Estudios de Cohortes , Bases de Datos Factuales/normas , Femenino , Humanos , Masculino , Metilfenidato/efectos adversos , Modafinilo/efectos adversos , Enfermedad de Parkinson Secundaria/prevención & controlRESUMEN
Oxidative stress and neuroinflammation play key roles in the initiation and progression of Parkinson's disease (PD), a neurodegenerative disorder, associated with the loss of nigrostriatal dopaminergic pathway. Thus, compounds that can mitigate oxidative stress and neuroinflammation are being investigated as promising agents for the treatment of PD. This study was designed to evaluate the effects of methyl jasmonate (MJ), a potent antioxidant and anti-inflammatory compound on parkinsonian-like symptoms and the underlying biochemical changes induced by rotenone (Rot) in mice. To this end, the effects of graded doses of MJ (25, 50 and100â¯mg/kg, i.p.) on motor dysfunctions, cognitive and depressive-like disorders induced by Rot (2.5â¯mg/kg, i.p.) were evaluated. The specific brain regions (striatum, prefrontal cortex and hippocampus) of the animals were processed for various biochemical studies. Rot-treated mice showed reduced motor activity, postural instability, cognitive and depressive-like disorders. Rot also increased brain levels of malondialdehyde (MDA), nitrite, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and acetyl-cholinesterase (AChE) activity. Moreover, Rot reduced the concentration of glutathione (GSH) and increased immnopositive cells of NF-κB and α-synuclein expressions in these brain regions. However, pretreatment with MJ, attenuated the parkinsonian-like symptoms and reduced the brain levels of MDA/nitrite, TNF-α and IL-6 induced by Rot. MJ also reduced AChE activity and down-regulate the expressions of NF-κB and α-synuclein in the brain of Rot-treated mice. These findings suggest that MJ has anti-parkinsonian-like activity, which may be related to the inhibition of oxidative stress, release of pro-inflammatory cytokines, and down regulation of NF-κB and α-synuclein expressions.
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Acetatos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Ciclopentanos/farmacología , Citocinas/metabolismo , FN-kappa B/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Oxilipinas/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/prevención & control , Rotenona/antagonistas & inhibidores , Desacopladores/toxicidad , alfa-Sinucleína/antagonistas & inhibidores , Animales , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Masculino , Ratones , FN-kappa B/biosíntesis , Enfermedad de Parkinson Secundaria/psicología , Desempeño Psicomotor/efectos de los fármacos , Rotenona/toxicidad , alfa-Sinucleína/biosíntesisRESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with oxidative stress. Therefore, finding new antioxidant sources might be beneficial for its treatment. Avocado Persea americana is a fruit widely cultivated in tropical and subtropical climates worldwide. Although avocado by-products in the form of peel, seed coat and seeds are currently of no commercial use, they constitute a natural source of bioactive compounds. Methanolic (80%) extract obtained from lyophilized ground peels, seed coats, and seeds of the avocado Hass, Fuerte, Reed and Colinred varieties were analyzed for their total phenolic content (TPC) and their correlations with antioxidant capacity (AC) were assessed by ABTS, FRAP, and ORAC assays. For all varieties, the var. Colinred peel shows the highest TPC and AC. Further analysis showed that the var. Colinred peel presented major phenolic compounds B-type procyanidins and epicatechin according to HPLC-MS. The antioxidant effect of peel extract was evaluated upon in vivo oxidative stress (OS) model. We show for the first time that the peel extract can protect and/or prevent transgenic parkinDrosophila melanogaster fly against paraquat-induced OS, movement impairment and lipid peroxidation, as model of PD. Our findings offer an exceptional opportunity to test natural disease-modifying substances from avocado's by-products.
Asunto(s)
Peroxidación de Lípido/efectos de los fármacos , Longevidad/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson Secundaria/prevención & control , Extractos Vegetales/uso terapéutico , Animales , Animales Modificados Genéticamente , Antioxidantes/química , Antioxidantes/uso terapéutico , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Frutas/química , Técnicas de Silenciamiento del Gen , Metanol/química , Fármacos Neuroprotectores/química , Paraquat , Enfermedad de Parkinson Secundaria/inducido químicamente , Persea/química , Extractos Vegetales/química , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
The level of nicotinamide adenine dinucleotide (NAD) decreases in Parkinson's disease (PD), and its reduction has been reported to be involved in many age-associated neurodegenerative pathologies. Thus, we investigated whether NAD replenishment is beneficial in a 6-hydroxydopamine (6-OHDA)-induced mouse model of PD. Preinjection with NAD in the striatum ameliorated motor deficits and dopaminergic neuronal damage in the substantia nigra and striatum of a mouse model of PD. Moreover, preincubation with NAD protected PC12 cells against the loss of cell viability, morphological damage, oxidative stress and mitochondrial dysfunction caused by 6-OHDA. These results add credence to the beneficial role of NAD against parkinsonian neurodegeneration in mouse models of PD, provide evidence for the potential of NAD for the prevention of PD, and suggest that NAD prevents pathological changes in PD via decreasing mitochondrial dysfunctions.
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Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Actividad Motora/efectos de los fármacos , NAD/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/prevención & control , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Microinyecciones , Mitocondrias/efectos de los fármacos , NAD/administración & dosificación , Degeneración Nerviosa/prevención & control , Fármacos Neuroprotectores/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/patologíaRESUMEN
Metabolic and mitochondrial dysfunction has been implicated in Parkinson's disease, while exercise can induce essential pathways of mitochondrial biogenesis. Here, we tested whether long-term preventive treadmill training (16 weeks, 21 m/min, and 0° inclinations for 50 min/d, 5 d/week) effects the mitochondrial and neurodegeneration markers, in the striatum of rats in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease. Following 16 weeks of exercise or no exercise period (n = 16 rats per group), the animals were divided into four experimental groups (n = 8 per group): (1) no exercise and saline (SED), (2) exercise and saline (EX), (3) no exercise and 6-OHDA (SED + 6-OHDA), and (4) exercise and 6-OHDA (EX + 6-OHDA). For the model, 8 µg of 6-OHDA (2 µg/µL prepared in a solution of 0.2% ascorbic acid and 0.9% saline) was injected into the right medial forebrain bundle. Exposure to 6-OHDA resulted in a significant reduction (P < 0.05) of mitochondrial factors AMP-activated protein kinase, peroxisome proliferator-activated receptor gamma coactivator-1 alpha, and tyrosine hydroxylase, and increased expression of silent information regulator T1, mitochondrial transcription factor A, and p53 in the SED + 6-OHDA group relative to SED group. By contrast, gene and protein expressions upon exercise were higher and p53 protein level was lower in the EX + 6-OHDA group compared with SED + 6-OHDA. Further, exercise reduced the extent of weight loss associated with the 6-OHDA injection. In conclusion, exercise might be used to reduce mitochondrial disorders in Parkinson's disease.
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Encéfalo/metabolismo , Mitocondrias/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/prevención & control , Condicionamiento Físico Animal , Animales , Modelos Animales de Enfermedad , Prueba de Esfuerzo , Masculino , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/prevención & control , Ratas WistarRESUMEN
BACKGROUND: Extrapyramidal side effects (EPS) have been identified as a complication of antipsychotic treatment. Previous meta-analyses have investigated EPS prevalence and risk factors in randomized clinical trials with highly selected patients, but studies in real-world schizophrenia are missing. OBJECTIVE: To examine the prevalence and clinical correlates associated with EPS in a nonselected national multicenter sample of stabilized patients with schizophrenia. METHODS: Between 2010 and 2016, patients suffering from schizophrenia (DSM-IV-TR criteria) were recruited through the FondaMental Academic Centers of Expertise for Schizophrenia (FACE-SZ) network and data were collected during a comprehensive 1-day-long standardized evaluation. The Simpson-Angus Scale and the Abnormal Involuntary Movement Scale were used to assess drug-induced parkinsonism (DIP) and tardive dyskinesia, respectively. RESULTS: The overall prevalence of DIP and tardive dyskinesia was 13.2% and 8.3%, respectively, in this community-dwelling sample of 674 patients. DIP was associated with negative symptoms (Positive and Negative Syndrome Scale [PANSS] subscore) (adjusted odds ratio [aOR] = 1.102, P < .001), first-generation antipsychotic prescription (aOR = 2.038, P = .047), and anticholinergic drug administration (aOR = 2.103, P = .017) independently of sex, age, disorganization (PANSS disorganized factor), and antipsychotic polytherapy. Tardive dyskinesia was associated with PANSS disorganized factor (aOR = 1.103, P = .049) independently of sex, age, negative symptoms, excitation, first-generation antipsychotic prescription, and benzodiazepine and anticholinergic drug administration. CONCLUSIONS: Our results indicate the high prevalence of EPS in a nonselected community-dwelling clinically stable sample of outpatients with schizophrenia. In the monitoring of antipsychotic treatment, EPS should be systematically evaluated, especially when negative symptoms and disorganization or cognitive alteration are present. Monotherapy with a second-generation antipsychotic should be preferentially initiated for patients with these side effects.
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Antipsicóticos/efectos adversos , Discinesia Inducida por Medicamentos , Enfermedad de Parkinson Secundaria , Esquizofrenia/tratamiento farmacológico , Discinesia Tardía , Adulto , Antipsicóticos/administración & dosificación , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Discinesia Inducida por Medicamentos/diagnóstico , Discinesia Inducida por Medicamentos/epidemiología , Discinesia Inducida por Medicamentos/prevención & control , Femenino , Francia/epidemiología , Humanos , Vida Independiente/estadística & datos numéricos , Masculino , Administración del Tratamiento Farmacológico/normas , Evaluación de Necesidades , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/diagnóstico , Enfermedad de Parkinson Secundaria/epidemiología , Enfermedad de Parkinson Secundaria/prevención & control , Prevalencia , Escalas de Valoración Psiquiátrica , Factores de Riesgo , Esquizofrenia/epidemiología , Discinesia Tardía/inducido químicamente , Discinesia Tardía/diagnóstico , Discinesia Tardía/epidemiología , Discinesia Tardía/prevención & controlRESUMEN
Parkinson is the second common neurodegenerative disease. The characteristics of Parkinson's disease (PD) are the dopamin neurons loss caused by neuroinflammation responses. C alycosin, an isoflavone phytoestrogen isolated from Astragalus membranaceus, has multiple pharmacological activities, such as anti-inflammation, anti-tumor, and neuroprotective effects. However, it is unknown whether calycosin can mitigate PD symptoms. This study aims to explore whether calycosin can alleviate PD symptoms and the underlying mechanisms. PD was induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection, and calycosin was given intracerebroventricularly to these mice. A cell model of nerve inflammation was established by BV2 microglia cells injected with lipopolysaccharide (LPS). The motor states were evaluated by stepping, whisker, and cylinder experiments. The states of dopaminergic neurons and microglia were detected by immunostainning of tyrosine hydroxylase and cluster of differentiation molecule 11b (CD11b). The expression levels of inflammatory factors were detected by qPCR. Toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were investigated by western blot. We found that calycosin treatment mitigated the behavioral dysfunctions and inflammatory responses in MPTP-induced PD mice. The TLR/NF-κB and MAPK pathways in MPTP-induced PD mice were inhibited by calycosin treatment, which was coincident with experiments in LPS-induced BV2 cells. Above all, calycosin mitigates PD symptoms through TLR/NF-κB and MAPK pathways in mice and cell lines.
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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Isoflavonas/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/prevención & control , Animales , Células Cultivadas , Neuronas Dopaminérgicas/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/prevención & control , Isoflavonas/uso terapéutico , Lipopolisacáridos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Microglía/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Células PC12 , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/patología , Ratas , Receptores Toll-Like/metabolismoRESUMEN
BACKGROUND: Parkinson's disease is the most common neurodegenerative disorder, characterized by loss of dopaminergic neurons in substantia nigra and depletion of dopamine in striatum due to excitotoxicity, oxidative stress and many other factors may contribute to MPTP- and PD-related neurodegeneration. The present study deals with the neuroprotective effect of Naringenin (NGN), a bioflavonoid against MPTP-induced Parkinson's disease in the mouse model. METHODS: Healthy male C57BL/6J mice (18-22 g b wt) were pretreated with NGN [25, 50, 100 mg/kg/b.wt, p.o] once daily for 5 days. Thereafter, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) (80 mg/kg b.wt, i.p) was given in two divided doses (2 × 40 mg/kg at 16 h interval). The animals were observed for motor functions 48 h after the first MPTP injection. After completion of behaviour tasks, all animals were euthanized to dissect out the brain and used for biochemical, molecular and histopathological investigations. RESULTS: Pretreatment of NGN significantly reversed the toxic effects of MPTP by reducing LPO levels and increasing the activities of glutathione reductase and catalase along with improved behavioural performance. Interestingly, pre-treatment with NGN down-regulated iNOS expression level in MPTP intoxicated mice brain. In addition, the histopathological evaluation revealed that NGN decreased the nuclear pigmentation and cytoplasmic vacuolation in the substantia nigra and striatal regions when compared to MPTP-intoxicated mice brain. DISCUSSION: The present study showed that NGN exerts neuroprotection by suppressing oxidative stress via antioxidant mechanisms. The above finding suggests that NGN may act as a potential target in the management of PD.
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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Flavanonas/farmacología , Peroxidación de Lípido/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson Secundaria/prevención & control , Animales , Catalasa/biosíntesis , Cuerpo Estriado/patología , Relación Dosis-Respuesta a Droga , Glutatión Reductasa/biosíntesis , Masculino , Ratones , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/patología , Sustancia Negra/patologíaRESUMEN
BACKGROUND: Accumulating evidence suggests that Fluoxetine (FLX), an anti-depressant drug, has broad neurobiological functions and neuroprotective effects in central nervous system injury, but its roles in Parkinson's disease (PD) remain unclear. In this study, we aimed to evaluate whether fluoxetine attenuates rotenone-induced neurodegeneration in PD. METHODS: Male Sprague-Dawley rats were randomly allocated to control, rotenone-treated, rotenone + FLX-treated and FLX-treated groups. Behavioral tests including open field behavioral test and catalepsy measurement were taken to evaluate neurological behavioral measurements. Apoptosis was detected by TUNEL assay. Endoplasmic reticulum (ER)-related gene expressions were detected by qRT-PCR and western blot. Immunohistochemistry was performed to assess dopaminergic neuronal degeneration. RESULTS: We demonstrated that pretreatment with FLX (10.0 mg/kg, i.p.) significantly ameliorated the catalepsy symptom and increased locomotor activity. In addition, FLX markedly reversed the loss of dopaminergic neurons and suppressed the Xboxbinding protein 1 (XBP1)/caspase-3-activated ER stress. Furthermore, FLX inhibited rotenone-mediated neurodegeneration through caspase-3-mediated neuronal apoptosis. CONCLUSION: Taken together, our findings indicate that FLX has beneficial neuroprotective effects in PD and FLX might be a potential therapeutic agent for the treatment of PD. In light of its favorable properties, FLX should be evaluated in the treatment of PD as well as related neurologic disorders.
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Fluoxetina/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/prevención & control , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Esquema de Medicación , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fluoxetina/administración & dosificación , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificaciónRESUMEN
Recent researches have shown that autophagy is associated with the pathogenesis of neurodegenerative disorders, but there is no paper to investigate the effects of autophagy modulation on Parkinson's disease depression (PDD). In addition, glycyrrhizic acid (GA), the major bioactive ingredient of Radix glycyrrhizae, can induce autophagy and ease rotenone-induced Parkinson's disease (PD). However, there is also no paper to study the action and molecular mechanisms of GA on PDD. In this research, we built the injury model of SH-SY5Y cells through 6-hydroxydopamine (6-OHDA) and corticosterone (CORT). Then, our results showed that GA markedly increased the viability and decreased the apoptosis in SH-SY5Y cells after pre-treating with 6-OHDA and CORT. Moreover, GA notably decreased the expressions of α-Syn and p-S1292-LRRK2 proteins, and significantly increased the levels of CREB and BDNF proteins. Previous papers have suggested that CORT contributed to dopaminergic neurodegeneration via the glucocorticoid (GC)/glucocorticoid receptor (GR) interaction, and our results showed that GA reduced GC level and hypothalamic-pituitary-adrenal (HPA) activity in SH-SY5Y cells by regulating GR signaling pathway. Furthermore, mechanism investigations also showed that GA had the ability to up-regulate the conversion of LC3B II/I and the expression of Beclin-1, and induce autophagy in SH-SY5Y cells, which were reversed by the autophagy inhibitor 3-methyladenine (3-MA). Collectively, these findings proved that GA exerted efficient activity against neurotoxicity in SH-SY5Y cells induced by 6-OHDA and CORT via activation of autophagy, which should be developed as an efficient candidate for treating PDD in the future.
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Autofagia/efectos de los fármacos , Ácido Glicirrínico/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/prevención & control , Apoptosis/efectos de los fármacos , Beclina-1/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Corticosterona , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Transducción de Señal/efectos de los fármacos , alfa-Sinucleína/metabolismoRESUMEN
Dopamine (DA)-replacement therapy utilizing l-DOPA is the gold standard symptomatic treatment for Parkinson's disease (PD). A critical complication of this therapy is the development of l-DOPA-induced dyskinesia (LID). The endogenous opioid peptides, including enkephalins and dynorphin, are co-transmitters of dopaminergic, GABAergic, and glutamatergic transmission in the direct and indirect striatal output pathways disrupted in PD, and alterations in expression levels of these peptides and their precursors have been implicated in LID genesis and expression. We have previously shown that the opioid glycopeptide drug MMP-2200 (a.k.a. Lactomorphin), a glycosylated derivative of Leu-enkephalin mediates potent behavioral effects in two rodent models of striatal DA depletion. In this study, the mixed mu-delta agonist MMP-2200 was investigated in standard preclinical rodent models of PD and of LID to evaluate its effects on abnormal involuntary movements (AIMs). MMP-2200 showed antiparkinsonian activity, while increasing l-DOPA-induced limb, axial, and oral (LAO) AIMs by â¼10%, and had no effect on dopamine receptor 1 (D1R)-induced LAO AIMs. In contrast, it markedly reduced dopamine receptor 2 (D2R)-like-induced LAO AIMs. The locomotor AIMs were reduced by MMP-2200 in all three conditions. The N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 has previously been shown to be anti-dyskinetic, but only at doses that induce parkinsonism. When MMP-2200 was co-administered with MK-801, MK-801-induced pro-parkinsonian activity was suppressed, while a robust anti-dyskinetic effect remained. In summary, the opioid glycopeptide MMP-2200 reduced AIMs induced by a D2R-like agonist, and MMP-2200 modified the effect of MK-801 to result in a potent reduction of l-DOPA-induced AIMs without induction of parkinsonism.