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1.
An Acad Bras Cienc ; 93(suppl 4): e20210481, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34730624

RESUMO

Epidemiological studies have shown an inverse association between coffee consumption and the development of Parkinson's disease (PD). The effects of the oral treatment with green (non-roasted) coffee extracts (CE, 100 or 400 mg/kg) and caffeine (31.2 mg/kg) were evaluated on catalepsy induced by haloperidol in mice, and unilateral 6-OHDA lesion of medial forebrain bundle (MFB) or striatum in rats. Also, the in vitro antioxidant activity and the monoamine levels in the striatum were investigated. CE presented a mild antioxidant activity in vitro and its administration decreased the catalepsy index. CE at the dose of 400 mg/kg induced ipsilateral rotations 14 days after lesion; however, chronic 30-day CE and caffeine treatments did not interfere with the animals' rotation after apomorphine or methamphetamine challenges in animals with MFB lesion, nor on monoamines levels. Furthermore, CE and caffeine were effective in inhibiting the asymmetry between ipsilateral and contralateral rotations induced by methamphetamine and apomorphine in animals with lesion in the striatum but did not avoid the monoamines depletion. These results indicate that CE components indirectly modulate dopaminergic transmission, suggesting a pro-dopaminergic action of CE, and further investigation must be conducted to elucidate the mechanisms of action and the possible neuroprotective role in PD.


Assuntos
Café , Doença de Parkinson , Animais , Comportamento Animal , Modelos Animais de Doenças , Camundongos , Modelos Animais , Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos
2.
Clinics (Sao Paulo) ; 76: e3175, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34644736

RESUMO

OBJECTIVES: In addition to the classic motor symptoms of Parkinson's disease (PD), patients also present with non-motor symptoms, such as autonomic dysfunction, which is present in almost 90% of patients with PD, affecting the quality of life and mortality. Regarding sex differences in prevalence and presentation, there is increasing concern about how sex affects autonomic dysfunction. However, there are no previous data on autonomic cardiac function in females after 6-hydroxydopamine (6-OHDA) striatal injection. METHODS: Wistar female rats were ovariectomized. After 20 days, the animals received bilateral injections of 6-OHDA (total dose per animal: 48 µg) or a vehicle solution in the striatum. Thirty days after 6-OHDA injection, subcutaneous electrodes were implanted for electrocardiogram (ECG) recording. Ten days after electrode implantation, ECG signals were recorded. Analyses of heart rate variability (HRV) parameters were performed, and the 6-OHDA lesion was confirmed by analyzing the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta (SNpc). RESULTS: A high dose of 6-OHDA did not affect HRV of females, independent of ovariectomy. As expected, ovariectomy did not affect HRV or lesions in the SNpc after 6-OHDA injection. CONCLUSIONS: We suggest that females with 6-OHDA present with cardioprotection, independent of ovarian hormones, which could be related to female vagal predominance.


Assuntos
Qualidade de Vida , Animais , Modelos Animais de Doenças , Feminino , Frequência Cardíaca , Humanos , Masculino , Ovariectomia , Oxidopamina , Ratos , Ratos Wistar
3.
J Vis Exp ; (176)2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34661577

RESUMO

L-DOPA-induced dyskinesias (LIDs) refer to motor complications that arise from prolonged L-DOPA administration to patients with Parkinson's disease (PD). The most common pattern observed in the clinic is the peak-dose dyskinesia which consists of clinical manifestations of choreiform, dystonic, and ballistic movements. The 6-hydroxydopamine (6-OHDA) rat model of PD mimics several characteristics of LIDs. After repeated L-DOPA administration, 6-OHDA-lesioned rats exhibit dyskinetic-like movements (e.g., abnormal involuntary movements, AIMs). This protocol demonstrates how to induce and analyze AIMs in 6-OHDA-lesioned rats with 90%-95% dopaminergic depletion in the nigrostriatal pathway. Repeated administration (3 weeks) of L-DOPA (5 mg/kg, combined with 12.5 mg/kg of benserazide) can induce the development of AIMs. The time course analysis reveals a significant increase in AIMs at 30-90 min (peak-dose dyskinesia). Rodent models of LIDs are an important preclinical tool to identify effective antidyskinetic interventions.


Assuntos
Discinesia Induzida por Medicamentos , Doença de Parkinson , Animais , Dopamina , Discinesia Induzida por Medicamentos/etiologia , Levodopa/efeitos adversos , Oxidopamina , Doença de Parkinson/tratamento farmacológico , Ratos
4.
Molecules ; 26(19)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34641332

RESUMO

L-DOPA therapy in Parkinson's disease (PD) is limited due to emerging L-DOPA-induced dyskinesia. Research has identified abnormal dopamine release from serotonergic (5-HT) terminals contributing to this dyskinesia. Selective serotonin reuptake inhibitors (SSRIs) or 5-HT receptor (5-HTr) agonists can regulate 5-HT activity and attenuate dyskinesia, but they often also produce a loss of the antiparkinsonian efficacy of L-DOPA. We investigated vilazodone, a novel multimodal 5-HT agent with SSRI and 5-HTr1A partial agonist properties, for its potential to reduce dyskinesia without interfering with the prokinetic effects of L-DOPA, and underlying mechanisms. We assessed vilazodone effects on L-DOPA-induced dyskinesia (abnormal involuntary movements, AIMs) and aberrant responsiveness to corticostriatal drive in striatal medium spiny neurons (MSNs) measured with in vivo single-unit extracellular recordings, in the 6-OHDA rat model of PD. Vilazodone (10 mg/kg) suppressed all subtypes (axial, limb, orolingual) of AIMs induced by L-DOPA (5 mg/kg) and the increase in MSN responsiveness to cortical stimulation (shorter spike onset latency). Both the antidyskinetic effects and reversal in MSN excitability by vilazodone were inhibited by the 5-HTr1A antagonist WAY-100635, demonstrating a critical role for 5-HTr1A in these vilazodone actions. Our results indicate that vilazodone may serve as an adjunct therapeutic for reducing dyskinesia in patients with PD.


Assuntos
Discinesia Induzida por Medicamentos/prevenção & controle , Levodopa/administração & dosagem , Oxidopamina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Receptor 5-HT1A de Serotonina/metabolismo , Cloridrato de Vilazodona/administração & dosagem , Animais , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/metabolismo , Regulação da Expressão Gênica , Levodopa/efeitos adversos , Masculino , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Cloridrato de Vilazodona/farmacologia
5.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576094

RESUMO

Targeted screening using the MTT cell viability test with a mini-library of natural and synthetic 1,4-naphthoquinones and their derivatives was performed in order to increase the survival of Neuro-2a neuroblastoma cells in in vitro paraquat and 6-hydroxydopamine models of Parkinson's disease. As a result, 10 compounds were selected that could protect neuronal cells from the cytotoxic effects of both paraquat and 6-hydroxydopamine. The five most active compounds at low concentrations were found to significantly protect the activity of nonspecific esterase from the inhibitory effects of neurotoxins, defend cell biomembranes from lytic destruction in the presence of paraquat and 6-hydroxydopamine, and normalize the cell cycle. The protective effects of these compounds are associated with the suppression of oxidative stress, decreased expression of reactive oxygen species and nitric oxide formation in cells and normalization of mitochondrial function, and restoration of the mitochondrial membrane potential altered by neurotoxins. It was suggested that the neuroprotective activity of the studied 1,4-NQs is attributable to their pronounced antioxidant and free radical scavenging activity and their ability to reduce the amount of reactive oxygen species formed by paraquat and 6-hydroxydopamine action on neuronal cells. The significant correlation between the neuroprotective properties of 1,4-naphthoquinones and Quantitative Structure-Activity Relationship descriptors describing the physicochemical properties of these compounds means that the hydrophobicity, polarity, charge, and shape of the molecules can be of decisive importance in determining the biological activity of studied substances.


Assuntos
Modelos Biológicos , Naftoquinonas/farmacologia , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Oxidopamina/toxicidade , Paraquat/toxicidade , Animais , Compostos de Bifenilo/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Neuroproteção/efeitos dos fármacos , Óxido Nítrico/biossíntese , Picratos/química , Relação Quantitativa Estrutura-Atividade , Espécies Reativas de Oxigênio/metabolismo , Reprodutibilidade dos Testes
6.
Nat Commun ; 12(1): 5569, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552093

RESUMO

Deep brain stimulation (DBS) has long been used to alleviate symptoms in patients suffering from psychiatric and neurological disorders through stereotactically implanted electrodes that deliver current to subcortical structures via wired pacemakers. The application of DBS to modulate neural circuits is, however, hampered by its mechanical invasiveness and the use of chronically implanted leads, which poses a risk for hardware failure, hemorrhage, and infection. Here, we demonstrate that a wireless magnetothermal approach to DBS (mDBS) can provide similar therapeutic benefits in two mouse models of Parkinson's disease, the bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and in the unilateral 6-hydroxydopamine (6-OHDA) model. We show magnetothermal neuromodulation in untethered moving mice through the activation of the heat-sensitive capsaicin receptor (transient receptor potential cation channel subfamily V member 1, TRPV1) by synthetic magnetic nanoparticles. When exposed to an alternating magnetic field, the nanoparticles dissipate heat, which triggers reversible firing of TRPV1-expressing neurons. We found that mDBS in the subthalamic nucleus (STN) enables remote modulation of motor behavior in healthy mice. Moreover, mDBS of the STN reversed the motor deficits in a mild and severe parkinsonian model. Consequently, this approach is able to activate deep-brain circuits without the need for permanently implanted hardware and connectors.


Assuntos
Estimulação Encefálica Profunda/métodos , Nanopartículas de Magnetita/uso terapêutico , Transtornos Parkinsonianos/terapia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Temperatura Alta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/patologia , Oxidopamina/efeitos adversos , Transtornos Parkinsonianos/induzido quimicamente , Núcleo Subtalâmico/fisiologia , Canais de Cátion TRPV/metabolismo
7.
Eur J Neurosci ; 54(7): 6618-6632, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34470083

RESUMO

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) are uniquely vulnerable to neurodegeneration in Parkinson's disease (PD). We hypothesize that their large axonal arbor is a key factor underlying their vulnerability, due to increased bioenergetic, proteostatic and oxidative stress. In keeping with this model, other DAergic populations with smaller axonal arbors are mostly spared during the course of PD and are more resistant to experimental lesions in animal models. Aiming to improve mouse PD models, we examined if neonatal partial SNc lesions could lead to adult mice with fewer SNc DA neurons that are endowed with larger axonal arbors because of compensatory mechanisms. We injected 6-hydroxydopamine (6-OHDA) unilaterally in the SNc at an early postnatal stage at a dose selected to induce loss of approximately 50% of SNc DA neurons. We find that at 10 and 90 days after the lesion, the axons of SNc DA neurons show massive compensatory sprouting, as revealed by the proportionally smaller decrease in tyrosine hydroxylase (TH) in the striatum compared with the loss of SNc DA neuron cell bodies. The extent and origin of this axonal sprouting was further investigated by AAV-mediated expression of eYFP in SNc or ventral tegmental area (VTA) DA neurons of adult mice. Our results reveal that SNc DA neurons have the capacity to substantially increase their axonal arbor size and suggest that mice designed to have reduced numbers of SNc DA neurons could potentially be used to develop better mouse models of PD, with elevated neuronal vulnerability.


Assuntos
Neurônios Dopaminérgicos , Parte Compacta da Substância Negra , Animais , Dopamina , Camundongos , Oxidopamina/toxicidade , Substância Negra , Área Tegmentar Ventral
8.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443430

RESUMO

Parkinson's disease (PD) is a currently incurable neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and α-synuclein aggregation. Accumulated evidence indicates that the saponins, especially from ginseng, have neuroprotective effects against neurodegenerative disorders. Interestingly, saponin can also be found in marine organisms such as the sea cucumber, but little is known about its effect in neurodegenerative disease, including PD. In this study, we investigated the anti-Parkinson effects of frondoside A (FA) from Cucumaria frondosa and ginsenoside Rg3 (Rg3) from Panax notoginseng in C. elegans PD model. Both saponins were tested for toxicity and optimal concentration by food clearance assay and used to treat 6-OHDA-induced BZ555 and transgenic α-synuclein NL5901 strains in C. elegans. Treatment with FA and Rg3 significantly attenuated DAergic neurodegeneration induced by 6-OHDA in BZ555 strain, improved basal slowing rate, and prolonged lifespan in the 6-OHDA-induced wild-type strain with downregulation of the apoptosis mediators, egl-1 and ced-3, and upregulation of sod-3 and cat-2. Interestingly, only FA reduced α-synuclein aggregation, rescued lifespan in NL5901, and upregulated the protein degradation regulators, including ubh-4, hsf-1, hsp-16.1 and hsp-16.2. This study indicates that both FA and Rg3 possess beneficial effects in rescuing DAergic neurodegeneration in the 6-OHDA-induced C. elegans model through suppressing apoptosis mediators and stimulating antioxidant enzymes. In addition, FA could attenuate α-synuclein aggregation through the protein degradation process.


Assuntos
Caenorhabditis elegans/fisiologia , Ginsenosídeos/farmacologia , Glicosídeos/farmacologia , Doença de Parkinson/patologia , Triterpenos/farmacologia , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ginsenosídeos/química , Ginsenosídeos/toxicidade , Glicosídeos/química , Glicosídeos/toxicidade , Longevidade/efeitos dos fármacos , Degeneração Neural/complicações , Degeneração Neural/patologia , Oxidopamina , Doença de Parkinson/complicações , Proteólise/efeitos dos fármacos , Triterpenos/química , Triterpenos/toxicidade , alfa-Sinucleína/metabolismo
9.
Exp Brain Res ; 239(11): 3277-3287, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34463828

RESUMO

The purpose of this study is to clarify that exercise may improve the motor dysfunction of Parkinson's disease (PD) model rats by increasing the reuptake of glutamate (Glu) in the striatum. The neurotoxin 6-hydroxydopamine (6-OHDA) was injected into the medial forebrain bundle (MFB) of the rats' right brain to establish PD model rats with unilateral injury, and the sham operation group was given the same dose of normal saline at the same site as the control group. The reliability of the model was evaluated by apomorphine (APO)-induced rotation test combined with tyrosine hydroxylase (TH) immunohistochemical staining in the substantia nigra and striatum. The exercise group started treadmill training intervention (11 m/min, 30 min/day, 5d/week, and 4 weeks in total) 1 week after the operation. The balance bar test, suspension test, and the tail-lifting handstand test were used to evaluate exercise performance of rats; RT-PCR and western blotting were used to detect protein and mRNA expression of glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) in the striatum; and isotope labeling was used to detect the ability of Glu reuptake in the striatum. (1) Compared with PD group, the number of TH immunoreactive cells in the substantia nigra and the content of TH immunoreactive fibers in the striatum did not change significantly in PD + Ex group. (2) Compared with PD group, the latency and total time of crossing the balance beam were significantly shorter (P < 0.01), the retention time of two forepaws on the metal wire was significantly longer (P < 0.01), the maximum lifting of head and trunk was significantly increased (P < 0.01) in PD + Ex group. (3) Compared with PD group, the ability of Glu reuptake in the striatum was significantly increased (P < 0.05), the expression levels of GLT-1 and GS mRNA in the striatum were significantly increased (P < 0.05), the protein expression of GLT-1 and GS in the striatum was significantly upregulated (P < 0.05) in PD + Ex group. Exercise intervention can significantly improve the motor dysfunction of PD model rats, increase the ability of striatal Glu reuptake significantly, and upregulate the expression levels of GLT-1 and GS protein and GS mRNA significantly. Exercise intervention may increase the protein expression level of GLT-1 and increase the reuptake ability of Glu in the striatum, thereby reducing the excitotoxic effect of excessive Glu on the postsynaptic membrane, and ultimately alleviate the motor dysfunction in PD model rats.


Assuntos
Doença de Parkinson , Animais , Corpo Estriado , Modelos Animais de Doenças , Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Substância Negra
10.
Cell Death Dis ; 12(7): 674, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226513

RESUMO

Parkinson's disease is a common neurodegenerative disease. Cell transplantation is a promising therapeutic option for improving the survival and function of dopaminergic neurons, but the mechanisms underlying the interaction between the transplanted cells and the recipient neurons remain to be studied. In this study, we investigated the effects of skin precursor cell-derived Schwann cells (SKP-SCs) directly cocultured with 6-OHDA-injured dopaminergic neurons in vitro and of SKP-SCs transplanted into the brains of 6-OHDA-induced PD mice in vivo. In vitro and in vivo studies revealed that SKP-SCs could reduce the damage to dopaminergic neurons by enhancing self-autophagy and modulating neuronal autophagy. Thus, the present study provides the first evidence that cell transplantation mitigates 6-OHDA-induced damage to dopaminergic neurons by enhancing self-autophagy, suggesting that earlier transplantation of Schwann cells might help alleviate the loss of dopaminergic neurons.


Assuntos
Autofagia , Encéfalo/patologia , Neurônios Dopaminérgicos/patologia , Transtornos Parkinsonianos/prevenção & controle , Células de Schwann/transplante , Transplante de Células-Tronco , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Fenótipo , Ratos Sprague-Dawley , Células de Schwann/metabolismo , Pele/citologia , Serina-Treonina Quinases TOR/metabolismo
11.
Brain Behav ; 11(8): e2278, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34296537

RESUMO

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is a severe neurodegenerative disease with high morbidity in the elderly population. 6-OHDA-induced cell senescence is reported to be involved in the pathogenesis of PD. Ramelteon is an oral hypnotic agent that specifically targets the receptors of the suprachiasmatic nucleus in the human hypothalamus. Here, an investigation is made to see whether Ramelteon possesses a beneficial effect against 6-OHDA-induced cellular senescence in human SH-SY5Y neuronal cells. METHODS: The release of LDH was detected to assess cytotoxicity and flow cytometry was conducted to evaluate the cell cycle. The telomerase activity and the SA-ß-Gal assay were performed to determine the state of cell senescence. Oxidative stress was evaluated by detecting the release of H2 O2 . The expressions of p21, p53, and Nrf2 were measured using the qRT-PCR and Western blotting assay. siRNA technology was used to knock down the expression level of Nrf2 in SH-SY5Y neuronal cells. RESULTS: First, it was found that Ramelteon mitigated cell cycle arrest in the G0/G1 phase in 6-OHDA-challenged SH-SY5Y neuronal cells. Second, treatment with Ramelteon alleviated cellular senescence in 6-OHDA-treated SH-SY5Y neuronal cells by increasing telomerase activity and reducing the activity of SA-ß-gal. It was also found that Ramelteon reduced the expressions of p21 and p53. Notably, Ramelteon attenuated 6-OHDA-induced oxidative stress by increasing the expression of Nrf2. Silencing of Nrf2 abolished the protective effects of Ramelteon against 6-OHDA-induced cellular senescence. Based on these findings, it was concluded that Ramelteon alleviated 6-OHDA-induced cellular senescence by increasing the expression of Nrf2 in human SH-SY5Y neuronal cells. CONCLUSION: Ramelteon protected against 6-OHDA-induced cellular senescence in human SH-SY5Y neuronal cells through activating the Nrf2 signaling pathway.


Assuntos
Doenças Neurodegenerativas , Idoso , Linhagem Celular Tumoral , Senescência Celular , Humanos , Indenos , Oxidopamina/toxicidade
12.
Front Immunol ; 12: 683577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248967

RESUMO

Dyskinesia is a serious complication of Parkinson's disease during levodopa (L-DOPA) treatment. The pathophysiology of L-DOPA-induced dyskinesia (LID) is complex and not fully illuminated. At present, treatment of dyskinesia is quite limited. Recent studies demonstrated neuroinflammation plays an important role in development of LID. Thus, inhibition of neuroinflammation might open a new avenue for LID treatment. Resveratrol (RES) is the most well-known polyphenolic stilbenoid and verified to possess a large variety of biological activities. DA neurotoxicity was assessed via behavior test and DA neuronal quantification. The movement disorders of dyskinesia were detected by the abnormal involuntary movements scores analysis. Effects of RES on glial cells-elicited neuroinflammation were also explored. Data showed that RES attenuated dyskinesia induced by L-DOPA without affecting L-DOPA's anti-parkinsonian effects. Furthermore, RES generated neuroprotection against long term treatment of L-DOPA-induced DA neuronal damage. Meanwhile, RES reduced protein expression of dyskinesia molecular markers, ΔFOS B and ERK, in the striatum. Also, there was a strong negative correlation between DA system damage and ΔFOS B level in the striatum. In addition, RES inhibited microglia and astroglia activation in substantia nigra and subsequent inflammatory responses in the striatum during L-DOPA treatment. RES alleviates dyskinesia induced by L-DOPA and these beneficial effects are closely associated with protection against DA neuronal damage and inhibition of glial cells-mediated neuroinflammatory reactions.


Assuntos
Discinesias/etiologia , Discinesias/fisiopatologia , Levodopa/efeitos adversos , Resveratrol/farmacologia , Animais , Biomarcadores , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Discinesias/tratamento farmacológico , Discinesias/metabolismo , Masculino , Oxidopamina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Ratos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/fisiopatologia
13.
Sci Rep ; 11(1): 15185, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312413

RESUMO

Parkinson's disease (PD) is a progressive and chronic neurodegenerative disease of the central nervous system. Early treatment for PD is efficient; however, long-term systemic medication commonly leads to deleterious side-effects. Strategies that enable more selective drug delivery to the brain using smaller dosages, while crossing the complex brain-blood barrier (BBB), are highly desirable to ensure treatment efficacy and decrease/avoid unwanted outcomes. Our goal was to design and test the neurotherapeutic potential of a forefront nanoparticle-based technology composed of albumin/PLGA nanosystems loaded with dopamine (ALNP-DA) in 6-OHDA PD mice model. ALNP-DA effectively crossed the BBB, replenishing dopamine at the nigrostriatal pathway, resulting in significant motor symptom improvement when compared to Lesioned and L-DOPA groups. Notably, ALNP-DA (20 mg/animal dose) additionally up-regulated and restored motor coordination, balance, and sensorimotor performance to non-lesioned (Sham) animal level. Overall, ALNPs represent an innovative, non-invasive nano-therapeutical strategy for PD, considering its efficacy to circumvent the BBB and ultimately deliver the drug of interest to the brain.


Assuntos
Barreira Hematoencefálica/metabolismo , Dopamina/administração & dosagem , Dopamina/farmacocinética , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Nanotecnologia , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
14.
Physiol Behav ; 240: 113535, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34303714

RESUMO

Rats with low-level globus pallidus (GP) dopaminergic denervation can develop anxiety without any motor alterations. The aim of this study was to evaluate the effect of low-level 6-OHDA-induced unilateral and bilateral GP lesions in male Wistar rats (n = 8/group) on recognition memory, motor activity, and the number of TH+ neurons in the SNc. For unilateral- and bilateral-lesioned animals, there was a significant decrease in the number of TH+ neurons (27% and 42%, respectively) and in the object, location, and temporal order discrimination indexes of recognition memory tests. Motor activity was unaffected. Thus, GP dopamine denervation was detrimental to short-memory.


Assuntos
Denervação/efeitos adversos , Dopamina , Globo Pálido , Transtornos da Memória , Memória de Curto Prazo , Animais , Masculino , Transtornos da Memória/etiologia , Oxidopamina/toxicidade , Ratos , Ratos Wistar , Substância Negra
15.
Nutrients ; 13(5)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068460

RESUMO

Parkinson's disease (PD) is a debilitating neurodegenerative disease, which progresses over time, causing pathological depigmentation of the substantia nigra (SN) in the midbrain due to loss of dopaminergic neurons. Emerging studies revealed the promising effects of some nutrient compounds in reducing the risk of PD. One such nutrient compound that possess neuroprotective effects and prevents neurodegeneration is tocotrienol (T3), a vitamin E family member. In the present study, a single dose intracisternal injection of 250 µg 6-hydroxydopamine (6-OHDA) was used to induce parkinsonism in male Sprague Dawley (SD) rats. Forty-eight hours post injection, the SD rats were orally supplemented with alpha (α)- and gamma (γ)-T3 for 28 days. The neuroprotective effects of α- and γ-T3 were evaluated using behavioural studies and immunohistochemistry (IHC). The findings from this study revealed that supplementation of α- and γ-T3 was able to ameliorate the motor deficits induced by 6-OHDA and improve the neuronal functions by reducing inflammation, reversing the neuronal degradation, and preventing further reduction of dopaminergic neurons in the SN and striatum (STR) fibre density.


Assuntos
Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Tocotrienóis/farmacologia , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/etiologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/etiologia , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo
16.
J Med Chem ; 64(12): 8246-8262, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34107215

RESUMO

Adenosine A1/A2A receptors (A1R/A2AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H3 receptor (H3R) antagonists in combination with the "caffeine-like effects" of A1R/A2AR antagonists, we designed A1R/A2AR/H3R MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl H3R pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar H3R affinities (Ki < 55 nM). Compound 4 (ST-2001, Ki (A1R) = 11.5 nM, Ki (A2AR) = 7.25 nM) and 12 (ST-1992, Ki (A1R) = 11.2 nM, Ki (A2AR) = 4.01 nM) were evaluated in vivo. l-DOPA-induced dyskinesia was improved after administration of compound 4 (1 mg kg-1, i.p. rats). Compound 12 (2 mg kg-1, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.


Assuntos
Antagonistas do Receptor A1 de Adenosina/uso terapêutico , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A1 de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/metabolismo , Animais , Discinesias/tratamento farmacológico , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Levodopa/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Piperidinas/síntese química , Piperidinas/metabolismo , Piperidinas/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Pirrolidinas/síntese química , Pirrolidinas/metabolismo , Pirrolidinas/uso terapêutico , Ratos Sprague-Dawley , Receptor A2A de Adenosina/metabolismo , Receptores Histamínicos H3/metabolismo , Vigília/efeitos dos fármacos
17.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071302

RESUMO

The 3-hydroxyquinone derivative of the non-psychotrophic phytocannabinoid cannabigerol, so-called VCE-003.2, and some other derivatives have been recently investigated for neuroprotective properties in experimental models of Parkinson's disease (PD) in mice. The pharmacological effects in those models were related to the activity on the peroxisome proliferator-activated receptor-γ (PPAR-γ) and possibly other pathways. In the present study, we investigated VCE-004.8 (formulated as EHP-101 for oral administration), the 3-hydroxyquinone derivative of cannabidiol (CBD), with agonist activity at the cannabinoid receptor type-2 (CB2) receptor in addition to its activity at the PPAR-γ receptor. Studies were conducted in both in vivo (lesioned-mice) and in vitro (SH-SY5Y cells) models using the classic parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). Our data confirmed that the treatment with VCE-004.8 partially reduced the loss of tyrosine hydroxylase (TH)-positive neurons measured in the substantia nigra of 6-OHDA-lesioned mice, in parallel with an almost complete reversal of the astroglial (GFAP) and microglial (CD68) reactivity occurring in this structure. Such neuroprotective effects attenuated the motor deficiencies shown by 6-OHDA-lesioned mice in the cylinder rearing test, but not in the pole test. Next, we explored the mechanism involved in the beneficial effect of VCE-004.8 in vivo, by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-004.8 at a concentration of 10 µM, which was completely reversed by the addition of antagonists, T0070907 and SR144528, aimed at blocking PPAR-γ and CB2 receptors, respectively. The treatment with T0070907 alone only caused a partial reversal, whereas SR144528 alone had no effect, indicating a major contribution of PPAR-γ receptors in the cytoprotective effect of VCE-004.8 at 10 µM. In summary, our data confirmed the neuroprotective potential of VCE-004.8 in 6-OHDA-lesioned mice, and in vitro studies confirmed a greater relevance for PPAR-γ receptors rather than CB2 receptors in these effects.


Assuntos
Canabidiol/química , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Quinonas/química , Administração Oral , Animais , Benzamidas/farmacologia , Canfanos/farmacologia , Canabinoides/química , Linhagem Celular Tumoral , Sobrevivência Celular , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neuroproteção , Oxidopamina/química , PPAR gama/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Tirosina 3-Mono-Oxigenase/metabolismo
18.
Biochimie ; 189: 87-98, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34182001

RESUMO

Human mesenchymal stem cells (hMSCs) secretome has been have been at the forefront of a new wave of possible therapeutic strategies for central nervous system neurodegenerative disorders, as Parkinson's disease (PD). While within its protein fraction, several promising proteins were already identified with therapeutic properties on PD, the potential of hMSCs-secretome vesicular fraction remains to be elucidated. Such highlighting is important, since hMSCs secretome-derived vesicles can act as biological nanoparticles with beneficial effects in different pathological contexts. Therefore, in this work, we have isolated hMSCs secretome vesicular fraction, and assessed their impact on neuronal survival, and differentiation on human neural progenitors' cells (hNPCs), and in a 6-hydroxydopamine (6-OHDA) rat model of PD when compared to hMSCs secretome (as a whole) and its protein derived fraction. From the results, we have found hMSCs vesicular fraction as polydispersity source of vesicles, which when applied in vitro was able to induce hNPCs differentiation at the same levels as the whole secretome, while the protein separated fraction was not able to induce such effect. In the context of PD, although distinct effects were observed, hMSCs secretome and its derived fractions displayed a positive impact on animals' motor and histological performance, thereby indicating that hMSCs secretome and its different fractions may impact different mechanisms and pathways. Overall, we concluded that the use of the secretome collected from hMSCs and its different fractions might be active modulators of different neuroregeneration mechanisms, which could open new therapeutical opportunities for their future use as a treatment for PD.


Assuntos
Células da Medula Óssea/metabolismo , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Neurais/metabolismo , Doença de Parkinson Secundária/metabolismo , Animais , Células da Medula Óssea/patologia , Modelos Animais de Doenças , Vesículas Extracelulares/patologia , Humanos , Masculino , Células-Tronco Mesenquimais/patologia , Células-Tronco Neurais/patologia , Oxidopamina/efeitos adversos , Oxidopamina/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Ratos , Ratos Wistar
19.
Methods Mol Biol ; 2322: 95-110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34043196

RESUMO

Several animal models are employed to discover novel treatments for the symptoms of Parkinson's disease (PD). PD models can be divided into two models: neurotoxin models and genetic models. Among neurotoxins to produce PD models, 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and rotenone, which inhibit the mitochondrial complex I, are widely used. Animal models of PD using these neurotoxins are also known as mitochondrial toxin models. Here this chapter describes the preparation of these mitochondrial toxin models.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Mitocôndrias/efeitos dos fármacos , Neurotoxinas/farmacologia , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Rotenona/farmacologia , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/metabolismo , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Ratos Wistar , Roedores
20.
Neuroscience ; 467: 201-217, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34048797

RESUMO

Before the advent of L-DOPA, the gold standard symptomatic therapy for Parkinson's disease (PD), anticholinergic drugs (muscarinic receptor antagonists) were the preferred antiparkinsonian therapy, but their unwanted side effects associated with impaired extrastriatal cholinergic function limited their clinical utility. Since most patients treated with L-DOPA also develop unwanted side effects such as L-DOPA-induced dyskinesia (LID), better therapies are needed. Recent studies in animal models demonstrate that optogenetic and chemogenetic manipulation of striatal cholinergic interneurons (SCIN), the main source of striatal acetylcholine, modulate parkinsonism and LID, suggesting that restoring SCIN function might serve as a therapeutic option that avoids extrastriatal anticholinergics' side effects. However, it is still unclear how the altered SCIN activity in PD and LID affects the striatal circuit, whereas the mechanisms of action of anticholinergic drugs are still not fully understood. Recent animal model studies showing that SCINs undergo profound changes in their tonic discharge pattern after chronic L-DOPA administration call for a reexamination of classical views of how SCINs contribute to PD symptoms and LID. Here, we review the recent advances on the circuit implications of aberrant striatal cholinergic signaling in PD and LID in an effort to provide a comprehensive framework to understand the effects of anticholinergic drugs and with the aim of shedding light into future perspectives of cholinergic circuit-based therapies.


Assuntos
Discinesia Induzida por Medicamentos , Doença de Parkinson , Animais , Antiparkinsonianos , Antagonistas Colinérgicos , Corpo Estriado , Modelos Animais de Doenças , Humanos , Levodopa , Oxidopamina , Doença de Parkinson/tratamento farmacológico
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