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
Parkinson's disease is a neurodegenerative disorder while secondary-parkinsonism can be caused by infectious, inflammatory, traumatic, vascular, hereditary, paraneoplastic, or even induced by drug/metal poisoning. Here we report an uncommon subacute parkinsonism who presented with micrographia and mild cognitive impairment. The CSF examination showed inflammatory profile and positive anti-NMDAR antibody. The patient showed no improvement with levodopa/benserazide administration but satisfactory response to immunotherapy with methylprednisolone. This case indicated that autoimmune etiology should also be considered in parkinsonism to exclude a treatable condition.
Asunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato/complicaciones , Autoanticuerpos/líquido cefalorraquídeo , Disfunción Cognitiva/etiología , Escritura Manual , Inmunoterapia , Enfermedad de Parkinson Secundaria/inmunología , Adulto , Encefalitis Antirreceptor N-Metil-D-Aspartato/tratamiento farmacológico , Encefalitis Antirreceptor N-Metil-D-Aspartato/inmunología , Antiparkinsonianos/uso terapéutico , Benserazida/uso terapéutico , Combinación de Medicamentos , Fiebre de Origen Desconocido/etiología , Humanos , Inmunosupresores/uso terapéutico , Levodopa/uso terapéutico , Masculino , Metilprednisolona/uso terapéutico , Pruebas Neuropsicológicas , Enfermedad de Parkinson Secundaria/diagnóstico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/psicología , Temblor/etiologíaRESUMEN
Bisphenol A (BPA) is noted for its adversative effects by inducing oxidative stress, carcinogenicity, neurotoxicity, inflammation, etc. However, the likely act of BPA in inducing neurodegenerative phenotypes remains elusive in the available literature. Hence, the present study was conducted to decipher the neurodegenerative potential of BPA in inducing Parkinson's disease like phenotypes in zebrafish. Zebrafish were subjected to chronic waterborne exposure to BPA for 56 days. Locomotor activities and neurobehavioral response were assessed by the NTDT (novel tank diving test), OFT (open field test), and LDPT (light-dark preference test). The oxidative stress markers and histopathological observation for pyknosis and chromatin condensation were carried out. Immunohistochemistry for activated caspase-3 and targeted proteins expression study was performed. The basic findings reveal that chronic BPA exposure significantly induces locomotor dysfunction through a significant decline in mean velocity and total distance traveled. As a measure of pyknosis and chromatin condensation, pyknotic and Hoechst positive neurons in telencephalon and diencephalon significantly increased by BPA exposure. A higher concentration of BPA adversely affects the neurobehavioral response, antioxidant status, and neuromorphology in zebrafish. Parkinson-relevant targeted protein expression viz. alpha-synuclein and LRRK2, were significantly upregulated, whereas tyrosine hydroxylase, NeuN, and Nurr1 were significantly downregulated in the zebrafish brain. As an indicator of cell death by apoptosis, the expression of activated caspase-3 was significantly increased in the BPA-exposed zebrafish brain. These basic results of the current study indicate that chronic waterborne exposure to BPA induces neuropathological manifestation leading to the development of motor dysfunction and Parkinsonism-like neurodegenerative phenotypes in zebrafish.
Asunto(s)
Conducta Animal/efectos de los fármacos , Compuestos de Bencidrilo/efectos adversos , Encéfalo/metabolismo , Caspasa 3/metabolismo , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Fenoles/efectos adversos , Transducción de Señal/efectos de los fármacos , Contaminantes Químicos del Agua/efectos adversos , Proteínas de Pez Cebra/metabolismo , Pez Cebra/metabolismo , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Femenino , Locomoción/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Prueba de Campo Abierto/efectos de los fármacos , Enfermedad de Parkinson Secundaria/psicología , FenotipoRESUMEN
BACKGROUND: The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson's disease (PD), are largely unknown, although oxidative stress is recognized as a key factor. We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in PD pathology, and that acrolein scavenger hydralazine can reduce the elevated acrolein, mitigate DA neuron death, and alleviate motor deficits in a 6-hydroxydopamine (6-OHDA) rat model. As such, we hypothesize that a structurally distinct acrolein scavenger, dimercaprol (DP), can also offer neuroprotection and behavioral benefits. METHODS: DP was used to lower the elevated levels of acrolein in the basal ganglia of 6-OHDA rats. The acrolein levels and related pathologies were measured by immunohistochemistry. Locomotor and behavioral effects of 6-OHDA injections and DP treatment were examined using the open field test and rotarod test. Pain was assessed using mechanical allodynia, cold hypersensitivity, and plantar tests. Finally, the effects of DP were assessed in vitro on SK-N-SH dopaminergic cells exposed to acrolein. RESULTS: DP reduced acrolein and reversed the upregulation of pain-sensing transient receptor potential ankyrin 1 (TRPA1) channels in the substantia nigra, striatum, and cortex. DP also mitigated both motor and sensory deficits typical of PD. In addition, DP lowered acrolein and protected DA-like cells in vitro. Acrolein's ability to upregulate TRPA1 was also verified in vitro using cell lines. CONCLUSIONS: These results further elucidated the acrolein-mediated pathogenesis and reinforced the critical role of acrolein in PD while providing strong arguments for anti-acrolein treatments as a novel and feasible strategy to combat neurodegeneration in PD. Considering the extensive involvement of acrolein in various nervous system illnesses and beyond, anti-acrolein strategies may have wide applications and broad impacts on human health.
Asunto(s)
Acroleína/metabolismo , Dimercaprol/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Canal Catiónico TRPA1/metabolismo , Animales , Conducta Animal , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Hidroxidopaminas , Masculino , Actividad Motora/efectos de los fármacos , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Dolor/etiología , Dimensión del Dolor/efectos de los fármacos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/psicología , Ratas , Ratas Sprague-Dawley , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoRESUMEN
The number of functionally active synapses provides a measure of neural integrity, with reductions observed in neurodegenerative disorders. [11C]UCB-J binds to synaptic vesicle 2A (SV2A) transmembrane protein located in secretory vesicles. We aimed to assess [11C]UCB-J PET as an in vivo biomarker of regional cerebral synaptic SV2A density in rat lesion models of neurodegeneration. Healthy anesthetized rats had [11C]UCB-J PET and arterial blood sampling. We compared different models describing [11C]UCB-J brain uptake kinetics to determine its regional distribution. Blocking studies were performed with levetiracetam (LEV), an antiepileptic SV2A antagonist. Tracer binding was measured in rodent unilateral acute lesion models of Parkinsonism and Huntington's disease, induced with 6-hydroxydopamine (6-OHDA) and quinolinic acid (QA), respectively. [3H]UCB-J autoradiography was performed in postmortem tissue. Rat brain showed high and fast [11C]UCB-J uptake and washout with up to 80% blockade by LEV. [11C]UCB-J PET showed a 6.2% decrease in ipsilateral striatal SV2A binding after 6-OHDA and 39.3% and 55.1% decreases after moderate and high dose QA confirmed by autoradiography. In conclusion, [11C]UCB-J PET provides a good in vivo marker of synaptic SV2A density which can potentially be followed longitudinally along with synaptic responses to putative neuroprotective agents in models of neurodegeneration.
Asunto(s)
Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/lesiones , Glicoproteínas de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Tomografía de Emisión de Positrones/métodos , Sinapsis/metabolismo , Animales , Anticonvulsivantes/farmacología , Autorradiografía , Femenino , Enfermedad de Huntington/inducido químicamente , Enfermedad de Huntington/patología , Enfermedad de Huntington/psicología , Hidroxidopaminas/farmacocinética , Cinética , Levetiracetam/farmacología , Glicoproteínas de Membrana/antagonistas & inhibidores , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/patología , Enfermedad de Parkinson Secundaria/psicología , Ácido Quinolínico/farmacocinética , Radiofármacos , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss of nigrostriatal dopaminergic neurons leading to dopamine depletion and problems of movement, emotions, and cognition. While the pathogenesis of PD is not clear, damage of dopaminergic neurons by oxygen-derived free radicals is considered an important contributing mechanism. This study aimed to evaluate the role of treadmill exercise in male Wister rats as a single treatment and as an aid-therapy with L-dopa for rotenone-induced PD. To study the role of the Nrf2- ARE pathway as a mechanism involved in exercise-associated improvement in rotenone-induced PD in rats. METHOD: Animals were divided into 5 groups, (Control, rotenone, rotenone\exercise, rotenone\L-dopa, and rotenone\exercise\L-dopa (combination)groups). After the PD induction, rats in the rotenone\exercise and combination groups were daily treadmill exercised for 4 weeks. RESULTS: Treadmill exercise significantly improved behavioral and motor aspects of rotenone-induced PD. When treadmill exercise was introduced as a single intervention, it amended most behavioral aspects of PD, gait fully corrected, short-term memory, and motor coordination. Where L-dopa corrected locomotor activity and motor coordination but failed to improve short-term memory and only partially corrected the gait of rotenone-treated rats. When treadmill exercise was combined with L-dopa, all features of PD were corrected. It was found that exercise upregulated some of its associative genes to Nrf2 pathways such as TFAM, Nrf2 and NQO.1 mRNA expression. CONCLUSION: This study suggests that forced exercise improved parkinsonian like features by activating the Nrf2 pathway.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Conducta Animal , Trastornos del Movimiento/terapia , Factor 2 Relacionado con NF-E2/fisiología , Neostriado/fisiología , Enfermedad de Parkinson Secundaria/terapia , Condicionamiento Físico Animal/psicología , Rotenona , Transducción de Señal/fisiología , Desacopladores , Animales , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Levodopa/uso terapéutico , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Factor 2 Relacionado con NF-E2/genética , Neostriado/enzimología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/psicología , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Wistar , Tirosina 3-Monooxigenasa/metabolismo , Regulación hacia Arriba/fisiologíaRESUMEN
The hyperactivity of the lateral habenula (LHb) is closely associated with depression. At present, it is unknown how GABA transporter (GAT) in the LHb affects depressive-like behaviors, particularly in Parkinson's disease (PD)-related depression. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced depressive-like behaviors and led to hyperactivity of LHb neurons compared to sham-lesioned rats. Intra-LHb injection of GAT-1 inhibitor NO-711 produced antidepressant-like responses, decreased firing rate of LHb neurons, and increased levels of LHb extracellular GABA in sham-lesioned and the lesioned rats. Further, the dose producing behavioral effects in the lesioned rats was lower than that of sham-lesioned rats. In the lesioned rats, the duration of inhibitory effect on the firing rate and increased levels of the GABA induced by NO-711 was longer than those in sham-lesioned rats, respectively. Intra-LHb injection of GAT-3 inhibitor SNAP-5114 improved depressive-like behaviors and decreased firing rate of LHb neurons in the lesioned rats, but not in sham-lesioned rats. SNAP-5114 increased LHb GABA levels in the lesioned rats, whereas did not alter that in sham-lesioned rats. These changes were involved in the down-regulated expression of LHb GAT-1 and GAT-3 after lesioning the SNc. These findings suggest that GAT-1 plays a major role in transporting LHb GABA under physiological conditions, and depletion of dopamine increases the transport capacity of GAT-3 in the LHb. Further, the study provides evidence that GAT-1 and GAT-3 in the LHb are involved in the regulation of PD-related depression.
Asunto(s)
Depresión/tratamiento farmacológico , Depresión/psicología , Antagonistas del GABA/farmacología , Proteínas Transportadoras de GABA en la Membrana Plasmática/efectos de los fármacos , Habénula/efectos de los fármacos , Enfermedad de Parkinson Secundaria/psicología , Animales , Anisoles/farmacología , Conducta Animal/efectos de los fármacos , Depresión/etiología , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Fenómenos Electrofisiológicos , Hidroxidopaminas , Masculino , Ácidos Nipecóticos/farmacología , Oximas/farmacología , Enfermedad de Parkinson Secundaria/complicaciones , Ratas , Ratas Sprague-Dawley , Natación/psicología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders. Whether OXT administration confers neuroprotection to 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced neurotoxicity in mice are still not known. In this study, we first found that the OXT levels are decreased in MPTP mice. Supplementation with OXT effectively rescues the locomotor disabilities and anxiety-like behaviors in MPTP mice. OXT also alleviates the hyperphosphorylation of α-synuclein at S129 site and the loss of dopaminergic neurons in the substantia nigra pars compacta, as well as the oxidative stress in the MPTP mice, and alleviates both oxidative stress and cell cytotoxicity in vitro. Furthermore, we found that OXT could inhibit the miR-26a/DAPK1 signal pathway in MPTP mice. In summary, our study demonstrates protective effects of OXT in MPTP mice and that miR-26a/DAPK1 signaling pathway may play an important role in mediating the protection of OXT.
Asunto(s)
Proteínas Quinasas Asociadas a Muerte Celular/efectos de los fármacos , Intoxicación por MPTP/tratamiento farmacológico , MicroARNs/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Oxitocina/uso terapéutico , Transducción de Señal/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Línea Celular Tumoral , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Intoxicación por MPTP/psicología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/psicología , Desempeño Psicomotor/efectos de los fármacosRESUMEN
The complexity of Parkinson's disease (PD) pathogenesis is attributed to multiple pathways involved in the neurodegeneration process. Among these pathways arise the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), and mammalian target of rapamycin (mTOR) axis, where inhibition of this cascade has been implicated in the pathogenesis of PD. Crocin, a carotenoid found in saffron, has shown beneficial effects against neurodegenerative diseases via anti-apoptotic, anti-inflammatory, and antioxidant activities. However, the exact molecular pathways involved in crocin's neuroprotective effects have not been fully elucidated. This drove our attention to unravel the possible involvement of PI3k/Akt/mTOR pathway in the neuroprotective effect of crocin against rotenone (ROT)-induced PD in rats. Sixty adult male Wistar rats were divided into four groups: control, crocin (30 mg/kg/day; i.p.), ROT (1.5 mg/kg/day, i.p.) and ROT pre-treated with crocin for 30 days. Crocin administration showed a substantial behavioral improvement. At the cellular level, crocin significantly stimulated the PI3K/Akt pathway, augmented phospho-proline-rich Akt substrate 40 kDa (p-PRAS40), mTOR and p-p70S6K levels. Consequently, glycogen synthase kinase-3ß (GSK-3ß), forkhead box transcription factor of the O class (FoxO3a), and the downstream caspase-9 were decreased; thus, attenuating neurodegeneration, which was witnessed through increased tyrosine hydroxylase (TH) and dopamine (DA), and hampered α-synuclein levels. Moreover, crocin showed enhanced expression of microRNA-7 (miRNA-7) and miRNA-221, which contributed to Akt/mTOR activation. These results were verified by improved histopathological portrait and increased number of intact neurons. In conclusion, crocin showed promising neuroprotective effects in ROT-induced PD via activation of PI3K/Akt/mTOR axis and enhanced miRNA-7 and miRNA-221.
Asunto(s)
Carotenoides/farmacología , MicroARNs/biosíntesis , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Rotenona , Transducción de Señal/efectos de los fármacos , Desacopladores , Animales , Conducta Animal/efectos de los fármacos , Masculino , MicroARNs/efectos de los fármacos , MicroARNs/genética , Proteína Oncogénica v-akt/efectos de los fármacos , Enfermedad de Parkinson Secundaria/psicología , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Ratas , Ratas Wistar , Serina-Treonina Quinasas TOR/efectos de los fármacos , Pérdida de Peso/efectos de los fármacosRESUMEN
This study investigated carbonylation of proteins with oxidative modification profiling in the striatum of aging and Parkinson disease (PD) rats, as well as the long-term effects of regular aerobic exercise on the carbonylation process and the damaging effects of PD vs habitual sedentary behavior. Regular aerobic exercise improved the PD rats' rotational behavior, increased tyrosine hydroxylase expression in both the striatum and substantia nigra pars compacta, and decreased α-synuclein expression significantly. Interestingly, apoptotic nuclei and autophagosomes were increased in the aerobic exercise PD rat striatum. Carbonylated protein Ca2+/calmodulin-dependent protein kinase alpha (CAMKIIα) was present in the middle-aged and aged groups but only in the sedentary, not the exercise, PD rat striatum. Notably, CAMKIIα was characterized by a 4-hydroxynonenal adduct. Regular aerobic exercise upregulated CAMKIIα expression level, activated the CAMK signaling pathway, and promoted the expression of autophagy markers Beclin1 and microtubule-associated proteins 1 A/1B light chain 3II. Aberrant carbonylation of CAMKII initiated age-related changes and might be useful as a potential biomarker of PD. Regular aerobic exercise alleviated protein carbonylation modification of CAMKIIα and regulated the CAMK signaling pathway, thereby affecting and regulating the homeostasis of apoptosis and autophagy in the striatum to alleviate the neurodegenerative process of PD lesions.
Asunto(s)
Apoptosis , Autofagia , Proteínas de Unión al Calcio/metabolismo , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/terapia , Condicionamiento Físico Animal , Carbonilación Proteica , Envejecimiento/fisiología , Animales , Beclina-1/metabolismo , Conducta Animal , Cuerpo Estriado/crecimiento & desarrollo , Cuerpo Estriado/metabolismo , Terapia por Ejercicio , Homeostasis , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Oxidopamina , Enfermedad de Parkinson Secundaria/psicología , Ratas , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
Prolonged administration of Levodopa (L-dopa) therapy can generate L-dopa-induced dyskinesia (LID). Accumulating evidence indicates that hyper-activation of the dopamine D1 receptor (D1R) and the cAMP signaling cascade in the medium spiny neurons (MSNs) of the striatum are involved in LID. Previous studies have shown that striatal ß-arrestin2 overexpression significantly reduces LID severity and have indicated that ß-arrestin2 may play a causal role in the dyskinesia sensitization process. L-dopa-induced changes in the expression of signaling molecules and other proteins in the striatum were examined immunohistochemically and by western blot. A rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablate ß-arrestin2. We found that striatal overexpression of AAV-mediated ß-arrestin2 produced less severe AIMs (abnormal involuntary movements) in response to L-dopa, whereas selective deletion of ß-arrestin2 in the striatal neurons dramatically enhanced the severity of dyskinesia induced by L-dopa. Furthermore, no significant improvements in motor behavior (FFT: forelimb functional test) were seen with the inhibition or overexpression of ß-arrestin2. Finally, overexpression of ß-arrestin2 diminished L-dopa-induced D1R and phosphor-DARPP32/ERK levels. Viral deletion of ß-arrestin2 markedly enhanced the key biochemical markers in the direct pathway. We found that increased availability of ß-arrestin2 ameliorated dyskinesia severity with no influence on the anti-Parkinsonian action of L-dopa, suggesting a promising approach for controlling LID in Parkinson's disease. In addition, overexpression of ß-Arrestin2 prevented the development of LID by inhibiting G protein-dependent D1R and phosphor-DARPP32/ERK signaling in dyskinetic rats.
Asunto(s)
Antiparkinsonianos , Discinesia Inducida por Medicamentos/terapia , Levodopa , Neostriado/metabolismo , Enfermedad de Parkinson Secundaria/terapia , Arrestina beta 2/biosíntesis , Arrestina beta 2/genética , Adenoviridae/genética , Animales , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Discinesia Inducida por Medicamentos/psicología , Eliminación de Gen , Terapia Genética , Vectores Genéticos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Neostriado/efectos de los fármacos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/psicología , Fosfoproteínas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Factores de Transcripción/efectos de los fármacosRESUMEN
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.
Asunto(s)
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 an age-related neurodegenerative disorder that severely affects quality of life of patients and their families. The flavonoid chrysin (5,7-dihydroxylflavone) is a naturally occurring flavone with several pharmacological activities, including anti-inflammatory and anti-oxidative. We investigated the effects of a 28-day chrysin treatment (10 mg/kg/day, i.g.) on a model of PD induced by 6-OHDA in aged (20-month old) mice. We found a protective effect of chrysin on behavioral and cognitive alterations (rotational behavior, passive avoidance and Barnes maze tests), nitric oxide synthesis (NOx), lipid peroxidation (HNE), glutathione levels (GSH), reactive species levels (RS), neuroinflammation (interleukin-1 beta - IL-1ß and tumor necrosis factor alpha - TNF-α), Na+, K+-ATPase and nicotinamide adenine dinucleotide phosphate oxidase activity (NADPH oxidase) activities. In addition, chrysin protected against changes in striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. In conclusion, chrysin improved several behavioral, cognitive and neurochemical parameters in a relevant preclinical model of PD in aged mice.
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Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Flavonoides/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Encéfalo/metabolismo , Dopamina/metabolismo , Femenino , Flavonoides/farmacología , Ácido Homovanílico/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Fármacos Neuroprotectores/farmacología , Óxido Nítrico Sintasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Oxidopamina , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/psicología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Clinical epidemiological studies have shown that there is a link between Parkinson's disease (PD) and cancer, but how PD regulates cancer development remains unknown. In our study, the effect of metabotropic glutamate receptor 5 (mGlu5) on hepatoma was explored in a rotenone-induced PD model both in vitro and in vivo. We found that conditioned media derived from MN9D dopaminergic neuronal cells by rotenone-induced toxicity inhibited the growth, migration, invasion and promoted apoptosis of Hepa1-6 cells, which corresponded with decreased expression of mGlu5. Furthermore, treatment with 2-methyl-6-(phenylethynyl)pyridine (MPEP), a mGlu5 antagonist and knockdown of mGlu5, further reduced ATP levels and migration distance, and increased cleavage of caspase-3 in Hepa1-6 cells. Additionally, we found that conditioned media derived from rotenone-treated MN9D dopaminergic neuronal cells enhanced reactive oxygen species (ROS) generation and JNK phosphorylation, which could be further increased by MPEP treatment, and attenuated by mGlu5 agonist, (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG) and ROS scavenger, N-acetyl-l-cysteine (NAC). The results indicated that down-regulation of mGlu5 promoted cell apoptosis through the intracellular ROS/JNK signaling pathway in a rotenone-induced cellular PD model. These findings were confirmed in vivo in a rotenone-induced rat model of PD combined with diethylnitrosamine (DEN)-induced hepatoma. Expression of Ki67 was decreased, and the levels of caspase-3 and p-JNK were increased in this model, which was accompanied by a decrease in protein expression of mGlu5. The study suggest that negative regulation of mGlu5 may inhibit hepatoma development in a rotenone-induced PD model, and as such may help with our further understanding of the correlation between PD and cancer.
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Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/prevención & control , Síndromes de Neurotoxicidad/patología , Enfermedad de Parkinson Secundaria/patología , Receptor del Glutamato Metabotropico 5/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen , Masculino , Ratones , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/psicología , Piridinas/toxicidad , Ratas , Ratas Sprague-Dawley , Especies de Nitrógeno Reactivo/metabolismo , Receptor del Glutamato Metabotropico 5/biosíntesis , Receptor del Glutamato Metabotropico 5/genética , Rotenona , Transducción de Señal/efectos de los fármacos , DesacopladoresRESUMEN
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD). The neuropathology of LRRK2 mutation-related PD, including increased dopaminergic neurodegeneration and Lewy bodies, is indistinguishable from that of idiopathic PD. The subtle nonmotor phenotypes of LRRK2 mutation-related PD have not been fully evaluated. In the present study, we examined anxiety/depression-like behaviors and accompanying neurochemical changes in differently aged transgenic (Tg) mice expressing human mutant LRRK2 G2019S. Through multiple behavioral tests, including light-dark test, elevated plus maze, sucrose preference test, forced swimming test, and tail-suspension test, we found that anxiety/depression-like behavior appeared in middle-aged (43-52 weeks) Tg mice before the onset of PD-like motor dysfunction. These behavioral tests were performed using both male and female mice, and there were no sex-related differences in behavioral changes in the middle-aged Tg mice. Along with behavioral changes, serotonin levels also significantly declined in the hippocampus of Tg mice. Additionally, increases in the expression of the 5-HT1A receptor (5-HT1AR) grew more significant with aging and were detected in the hippocampus, amygdala, and dorsal raphe nucleus. In vitro study using the serotonergic RN46A and hippocampal HT22 cells showed that 5-HT1AR upregulation was related to enhanced expression of LRRK2 G2019S and was attenuated by the LRRK2 inhibitor LRRK2-IN-1. Wild-type LRRK2 had no significant effect on 5-HT1AR transcription. The present study provides the first in vivo and in vitro evidence demonstrating abnormal regulation of 5-HT1AR along with the manifestation of anxiety/depression-like, nonmotor symptom in PD related to LRRK2.SIGNIFICANCE STATEMENT Parkinson's disease (PD), the second most common neurodegenerative disorder, is clinically characterized by motor dysfunctions. In most cases, various nonmotor symptoms present several years before the onset of the classical motor features of PD and severely affect the quality of life of patients. Here, we demonstrate the causative role of leucine-rich repeat kinase 2 (LRRK2), a common PD-linked mutation, in the development of anxiety/depression-like behaviors. We found that age-dependent 5-HT1A receptor upregulation in the hippocampus, amygdala, and dorsal raphe nucleus is accompanied by the expression of the LRRK2 mutant phenotype. Our findings demonstrating a potential mechanism for nonmotor psychiatric symptoms produced by LRRK2 mutation suggest that directly targeting the 5-HT1A receptor can improve the therapeutic efficacy of drugs for PD-associated depression.
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Ansiedad/genética , Ansiedad/psicología , Depresión/genética , Depresión/psicología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Trastornos del Movimiento/genética , Receptor de Serotonina 5-HT1A/genética , Envejecimiento/genética , Envejecimiento/psicología , Animales , Química Encefálica/genética , Femenino , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Humanos , Masculino , Ratones , Ratones Transgénicos , Actividad Motora/fisiología , Enfermedad de Parkinson Secundaria/genética , Enfermedad de Parkinson Secundaria/psicología , Receptor de Serotonina 5-HT1A/biosíntesis , Serotonina/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
Methcathinone-induced Parkinsonism is a recently described extrapyramidal syndrome characterized by globus pallidus and substantia nigra lesions, which provides a unique model of basal ganglia dysfunction. We assessed motivated behaviour in this condition using a novel cost-benefit decision-making task, in which participants decided whether it was worth investing effort for reward. Patients showed a dissociation between reward and effort sensitivity, such that pallidonigral complex dysfunction caused them to become less sensitive to rewards, while normal sensitivity to effort costs was maintained.
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Intoxicación por Manganeso/complicaciones , Motivación/fisiología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/psicología , Propiofenonas/efectos adversos , Recompensa , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Estudios de Casos y Controles , Toma de Decisiones/fisiología , Femenino , Humanos , Masculino , Motivación/efectos de los fármacos , Enfermedad de Parkinson Secundaria/diagnóstico por imagenRESUMEN
AIM: Hyperhomocysteinemia and homocysteine (Hcy) mediated dopaminergic neurotoxicity is a matter of concern in the pathophysiology of Parkinson's disease (PD). Our previous study established the involvement of oxidative stress in the substantia nigra (SN) of Hcy rat model of PD; however, the role of antioxidants, such as melatonin, was not tested in this model. MAIN METHODS: Melatonin (10, 20 and 30mg/kg, i.p.) was administered to rats injected with Hcy in right SN (1.0µmol in 2µl saline) to investigate its potency in attenuating the behavioral abnormalities, dopamine depletion and oxidative stress prompted by Hcy. KEY FINDINGS: Treatment of melatonin protected against nigral dopamine loss and replenished the striatal dopamine loss that resulted in amelioration of rotational behavioral bias in Hcy denervated animals. Melatonin administration significantly improved mitochondrial complex-I activity and protected the SN neurons from the toxic insults of oxidative stress induced by Hcy. Amelioration of oxidative stress by melatonin in Hcy-infused SN was bought by dose-dependently scavenging of hydroxyl radicals, restoration of glutathione level and elevation in the activity of antioxidant enzymes. SIGNIFICANCE: The observations bring into light the significant neuroprotective potentials of melatonin in Hcy model of PD which is attributed to the attenuation of oxidative stress in SN.
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Antioxidantes/uso terapéutico , Conducta Animal/efectos de los fármacos , Dopamina/metabolismo , Homocisteína , Melatonina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson Secundaria/prevención & control , Enfermedad de Parkinson Secundaria/psicología , Animales , Catecolaminas/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Complejo I de Transporte de Electrón/efectos de los fármacos , Radicales Libres/metabolismo , Homocisteína/administración & dosificación , Masculino , Microinyecciones , Enfermedad de Parkinson Secundaria/inducido químicamente , Ratas , Ratas Sprague-Dawley , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoAsunto(s)
Trastornos Cerebrovasculares/fisiopatología , Trastornos Cerebrovasculares/psicología , Cognición , Enfermedad de Parkinson Secundaria/fisiopatología , Enfermedad de Parkinson Secundaria/psicología , Corteza Sensoriomotora/fisiopatología , Vías Aferentes/fisiopatología , Anciano , Anciano de 80 o más Años , Electromiografía , Potenciales Evocados Motores , Potenciales Evocados Somatosensoriales , Femenino , Humanos , Masculino , Nervio Mediano/fisiopatología , Músculo Esquelético/fisiopatología , Inhibición Neural , Plasticidad Neuronal , Pruebas Neuropsicológicas , Estimulación Magnética TranscranealRESUMEN
Parkinson's disease (PD) is a movement disorder and the second most common neurodegenerative disease worldwide in which nigrostriatal dopaminergic neurons within substantia nigra pars compacta (SNC) are lost, with clinical motor and non-motor symptoms including bradykinesia, resting tremor, rigidity, stooping posture and cognitive deficits. This study was undertaken to evaluate the neuroprotective potential of acetyl-l-carnitine (ALC) against unilateral striatal 6-hydroxydopamine (6-OHDA)-induced model of PD and to explore some involved mechanisms. In this experimental study, intrastriatal 6-OHDA-lesioned rats received ALC at doses of 100 or 200mg/kg/day for 1 week. ALC (200mg/kg) lowered apomorphine-induced rotational asymmetry and reduced the latency to initiate and the total time in the narrow beam test, reduced striatal malondialdehyde (MDA), increased catalase activity and glutathione (GSH) level, prevented reduction of nigral tyrosine hydroxylase (TH)-positive neurons and striatal TH-immunoreactivity, and lowered striatal glial fibrillary acidic protein (GFAP) and its immunoreactivity as an indicator of astrogliosis, and nuclear factor NF-kappa B and Toll-like receptor 4 (TLR4) as reliable markers of neuroinflammation. Meanwhile, ALC at both doses mitigated nigral DNA fragmentation as a valuable marker of apoptosis. The results of this study clearly suggest the neuroprotective effect of ALC in 6-OHDA-induced model of PD through abrogation of neuroinflammation, apoptosis, astrogliosis, and oxidative stress and it may be put forward as an ancillary therapeutic candidate for controlling PD.
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Acetilcarnitina/farmacología , Cuerpo Estriado/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Nootrópicos/farmacología , Enfermedad de Parkinson Secundaria/prevención & control , Sustancia Negra/efectos de los fármacos , Animales , Apomorfina/farmacología , Conducta Animal/efectos de los fármacos , Cuerpo Estriado/metabolismo , Agonistas de Dopamina/farmacología , Inflamación/inducido químicamente , Inflamación/prevención & control , Masculino , Vías Nerviosas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/psicología , Ratas , Ratas Wistar , Sustancia Negra/metabolismo , SimpaticolíticosRESUMEN
Parkinson's disease is one of the most common neurodegenerative disease found in aged peoples. Plentiful studies are being conducted to find a suitable and effective cure for this disease giving special impetus on use of herbal plants. The study aimed at investigating the effect of ethanolic extract of Mucuna pruriens (Mp) on level of nitric oxide (NO) in paraquat (PQ) induced Parkinson's disease (PD) mouse model and its subsequent contribution to lipid peroxidation. Twenty four Swiss albino mice were divided into three groups; Control, PQ and PQ+Mp. PQ doses were given intraperitoneally, twice in a week and oral dose of ethanolic extract of Mp seed was given for 9 weeks. Nitrite content and lipid peroxidation was measured in all treated groups along with respective controls. RNA was isolated from the nigrostriatal tissue of control and the treated mice and was reverse transcribed into cDNA. PCR was performed to amplify iNOS mRNA and western blot analysis was performed to check its protein level. We had also perfused the mice in all treated group and performed Tyrosine hydroxylase (TH) and iNOS immunoreactivity in substantia nigra region of mice brain. PQ-treatment increased nitrite content, expression of iNOS and lipid peroxidation compared to respective controls. Mp treatment resulted in a significant attenuation of iNOS expression, nitrite content and lipid peroxidation demonstrating that it reduces nitric oxide in PQ-induced Parkinson's disease. Interestingly; we also observed that mRNA, protein expression and immunoreactivity of iNOS was significantly decreased after Mp treatment and TH immunoreactivity was significantly improved after the treatment of Mp. Our results demonstrated that Mp protects the dopaminergic neurons from the NO injury in substantia nigra.