RESUMEN
Parkinson's disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa has remained the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia.
Asunto(s)
Antiparkinsonianos/toxicidad , Dopaminérgicos/toxicidad , Discinesia Inducida por Medicamentos/metabolismo , Levodopa/toxicidad , Trastornos Parkinsonianos/metabolismo , Receptores de Dopamina D3/metabolismo , Animales , Callithrix , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/uso terapéutico , Discinesia Inducida por Medicamentos/prevención & control , Células HEK293 , Humanos , Ligandos , Trastornos Parkinsonianos/prevención & control , Primates , Estructura Secundaria de Proteína , Quinpirol/farmacología , Quinpirol/uso terapéutico , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/químicaRESUMEN
Both dopamine (DA) loaded Solid Lipid Nanoparticles (SLN) and liposomes (Lip), designed for intranasal administration of the neurotransmitter as an innovative Parkinson disease treatment, were already characterized in vitro in some extent by us (Trapani et al., 2018a and Cometa et al., 2020, respectively). Herein, to gain insight into the structure of SLN, X-ray Photoelectron Spectroscopy Analysis was carried out and DA-SLN (SLN 1) were found to exhibit high amounts of the neurotransmitter on the surface, whereas the external side of Glycol Chitosan (GCS) containing SLN (SLN 2) possessed only few amounts. However, SLN 2 were characterized by the highest encapsulation DA efficiency (i.e., 81%). Furthermore, in view of intranasal administration, mucoadhesion tests in vitro were also conducted for SLN and Lip formulations, evidencing high muchoadesive effect exerted by SLN 2. Concerning ex-vivo studies, SLN and Lip were found to be safe for Olfactory Ensheathing Cells and fluorescent SLN 2 were taken up in a dose-dependent manner reaching the 100% of positive cells, while Lip 2 (chitosan-glutathione-coated) were internalised by 70% OECs with six-times more lipid concentration. Hence, SLN 2 formulation containing DA and GCS may constitute interesting formulations for further studies and promising dosage form for non-invasive nose-to-brain neurotransmitter delivery.
Asunto(s)
Dopaminérgicos/administración & dosificación , Dopamina/administración & dosificación , Portadores de Fármacos/química , Liposomas , Nanopartículas , Adhesividad , Administración Intranasal , Animales , Células Cultivadas , Quitosano/química , Dopamina/farmacocinética , Dopamina/toxicidad , Dopaminérgicos/farmacocinética , Dopaminérgicos/toxicidad , Relación Dosis-Respuesta a Droga , Lípidos/química , Ratones , Bulbo Olfatorio/citología , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/metabolismo , Espectroscopía de FotoelectronesRESUMEN
Methamphetamine abuse is associated with an increased risk of developing Parkinson's disease (PD). Recently, it was found that methamphetamine increases mitochondrial oxidant stress in substantia nigra pars compacta (SNc) dopaminergic neurons by releasing vesicular dopamine (DA) and stimulating mitochondrially-anchored monoamine oxidase (MAO). As mitochondrial oxidant stress is widely thought to be a driver of SNc degeneration in PD, these observations provide a potential explanation for the epidemiological linkage. To test this hypothesis, mice were administered methamphetamine (5 mg/kg) for 28 consecutive days with or without pretreatment with an irreversible MAO inhibitor. Chronic methamphetamine administration resulted in the degeneration of SNc dopaminergic neurons and this insult was blocked by pretreatment with a MAO inhibitor - confirming the linkage between methamphetamine, MAO and SNc degeneration. To determine if shorter bouts of consumption were as damaging, mice were given methamphetamine for two weeks and then studied. Methamphetamine treatment elevated both axonal and somatic mitochondrial oxidant stress in SNc dopaminergic neurons, was associated with a modest but significant increase in firing frequency, and caused degeneration after drug cessation. While axonal stress was sensitive to MAO inhibition, somatic stress was sensitive to Cav1 Ca2+ channel inhibition. Inhibiting either MAO or Cav1 Ca2+ channels after methamphetamine treatment attenuated subsequent SNc degeneration. Our results not only establish a mechanistic link between methamphetamine abuse and PD, they point to pharmacological strategies that could lessen PD risk for patients with a methamphetamine use disorder.
Asunto(s)
Dopaminérgicos/toxicidad , Neuronas Dopaminérgicas/efectos de los fármacos , Metanfetamina/toxicidad , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sustancia Negra/efectos de los fármacos , Animales , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/metabolismo , Mitocondrias/patología , Técnicas de Cultivo de Órganos , Estrés Oxidativo/fisiología , Sustancia Negra/metabolismo , Sustancia Negra/patologíaAsunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Cuerpo Estriado/efectos de los fármacos , Intoxicación por MPTP , Privación de Sueño , Sueño REM , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Dopamina/metabolismo , Dopaminérgicos/toxicidad , Neuronas Dopaminérgicas , Humanos , Ratones , Privación de Sueño/fisiopatología , Ubiquitina-Proteína LigasasRESUMEN
PURPOSE: The development of L-DOPA-induced dyskinesia (LID) is one of the most severe side effects of chronic L-DOPA treatment in Parkinson's disease patients. [11C]DASB positron emission tomography (PET) provides a prominent tool to visualize and quantify serotonin transporter (SERT) pathology in vivo in patients and in animal models. To evaluate the effect of chronic L-DOPA treatment on SERT availability in an animal model of LID, we performed a longitudinal PET study. PROCEDURES: Rats received a unilateral 6-hydroxydopamine (6-OHDA) lesion, and striatal and extrastriatal SERT expression levels were studied with [11C]DASB, a marker of SERT availability, before and after daily treatment with L-DOPA. Dyskinesias were evaluated at different time points over a period of 21 days. RESULTS: [11C]DASB binding was found to be decreased after 6-OHDA lesions in the striatum, cortex, and hippocampus 5 weeks after 6-OHDA injection in the lesioned hemisphere of the rat brain. Chronic L-DOPA priming resulted in a relative preservation of SERT availability in the lesioned and healthy hemisphere compared to baseline measurements. CONCLUSIONS: Our longitudinal PET data support a preservation of SERT availability after the induction of L-DOPA-induced dyskinesia, which is in line with previous reports in dyskinetic PD patients.
Asunto(s)
Encéfalo/patología , Radioisótopos de Carbono/farmacocinética , Discinesia Inducida por Medicamentos/diagnóstico por imagen , Actividad Motora/fisiología , Tomografía de Emisión de Positrones/métodos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Modelos Animales de Enfermedad , Dopaminérgicos/toxicidad , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/patología , Levodopa/toxicidad , Masculino , Radiofármacos/química , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
Selective blockade of serotonin 2A (5-HT2A) receptors is a promising strategy to reduce L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia and has shown efficacy in a Phase III clinical trial for dopaminergic psychosis in Parkinson's disease (PD). However, pre-clinical and clinical evidence suggest that, while this approach may be effective and well tolerated, there might be a ceiling beyond which no further therapeutic benefit might be achieved. There is mounting evidence that 5-HT2A receptors form a functional hetero-complex with metabotropic glutamate 2 (mGlu2) receptors, with antagonism of 5-HT2A receptors and activation of mGlu2 receptors producing similar effects on the Gi/Gq signalling ratio at the intra-cellular level. Based on this interaction between 5-HT2A and mGlu2 receptors, we hypothesised that activation of mGlu2 receptors would alleviate dyskinesia and psychosis in PD. LY-354,740 is a selective mGlu2/3 orthosteric agonist that was previously tested in the clinic. In experiments conducted in the 6-hydroxydopamine (6-OHDA)-lesioned rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset, we found that mGlu2/3 activation with LY-354,740 significantly reduced the expression of dyskinesia and psychosis-like behaviours, while simultaneously enhancing l-DOPA therapeutic benefit. Moreover, mGlu2/3 activation with LY-354,740 attenuated the development of dyskinesia. These data indicate that activation of mGlu2/3 receptors is a therapeutic strategy that may provide relief for both motor and-non-motor treatment-related complications in PD.
Asunto(s)
Antiparkinsonianos/efectos adversos , Conducta Animal/efectos de los fármacos , Compuestos Bicíclicos con Puentes/farmacología , Discinesia Inducida por Medicamentos/etiología , Agonistas de Aminoácidos Excitadores/farmacología , Levodopa/efectos adversos , Trastornos Parkinsonianos/tratamiento farmacológico , Psicosis Inducidas por Sustancias/etiología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Adrenérgicos/toxicidad , Animales , Compuestos Bicíclicos con Puentes/uso terapéutico , Callithrix , Dopaminérgicos/toxicidad , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Agonistas de Aminoácidos Excitadores/uso terapéutico , Intoxicación por MPTP/tratamiento farmacológico , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Psicosis Inducidas por Sustancias/tratamiento farmacológico , Ratas , Receptores de Glutamato Metabotrópico/agonistasRESUMEN
Repeated methamphetamine (METH) exposure can cause severe neurotoxicity to the central nervous system, and lead to memory deficits. L-Stepholidine (L-SPD) is a structurally identified alkaloid extract of the Chinese herb Stephania intermedia, which elicits dopamine (DA) D1-type receptors partial agonistic activity and D2-type receptors antagonistic activity. In this study, we investigated the effect of L-SPD on METH-induced memory deficits in mice and its underlying mechanisms. We found that repeated exposure to METH (10 mg/kg, i.p., once per day for 7 consecutive days) impaired memory functions in the novel object recognition experiment. Pretreatment of L-SPD (10 mg/kg, i.p.) significantly improved METH-induced memory deficits in mice. Meanwhile, the protein expression of dopaminergic D2 receptors in hippocampus area was significantly increased by repeated METH exposure, while the protein expression of dopamine transporter (DAT) was significantly reduced. Additionally, the protein expression of phospho-protein kinase A (p-PKA) was significantly increased by repeated METH exposure. The hyperpolarization-activated cyclic-nucleotide-gated non-selective cation 1 (HCN1) channel, which was a key regulator of memory functions and could be regulated by p-PKA, was also significantly increased by repeated METH exposure. These changes caused by METH could be prevented by L-SPD pretreatment. Therefore, our data firstly showed that pretreatment of L-SPD exhibited the protective effect against METH-induced memory deficits, possibly through reducing METH-induced upregulation of dopaminergic pathway and HCN1 channels.
Asunto(s)
Berberina/análogos & derivados , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/prevención & control , Metanfetamina/toxicidad , Fármacos Neuroprotectores/uso terapéutico , Animales , Berberina/uso terapéutico , Dopaminérgicos/toxicidad , Agonistas de Dopamina/uso terapéutico , Antagonistas de Dopamina/uso terapéutico , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Trastornos de la Memoria/metabolismo , Ratones , Ratones Endogámicos C57BL , Distribución AleatoriaRESUMEN
Methamphetamine (METH) abuse is known to increase the risk of Parkinson's disease (PD) due to its dopaminergic neurotoxicity. This is the rationale for the METH model of PD developed by toxic METH dosing (10 mg/kg four times every 2 h) which features robust neurodegeneration and typical motor impairment in mice. In this study, we used diffusion kurtosis imaging to reveal microstructural brain changes caused by METH-induced neurodegeneration. The METH-treated mice and saline-treated controls underwent diffusion kurtosis imaging scanning using the Bruker Avance 9.4 Tesla MRI system at two time-points: 5 days and 1 month to capture both early and late changes induced by METH. At 5 days, we found a decrease in kurtosis in substantia nigra, striatum and sensorimotor cortex, which is likely to indicate loss of DAergic neurons. At 1 month, we found an increase of kurtosis in striatum and sensorimotor cortex and hippocampus, which may reflect certain recovery processes. Furthermore, we performed tract-based spatial statistics analysis in the white matter and at 1 month, we observed increased kurtosis in ventral nucleus of the lateral lemniscus and some of the lateral thalamic nuclei. No changes were present at the early stage. This study confirms the ability of diffusion kurtosis imaging to detect microstructural pathological processes in both grey and white matter in the METH model of PD. The exact mechanisms underlying the kurtosis changes remain to be elucidated but kurtosis seems to be a valuable biomarker for tracking microstructural brain changes in PD and potentially other neurodegenerative disorders.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/patología , Dopaminérgicos/toxicidad , Metanfetamina/toxicidad , Enfermedad de Parkinson Secundaria/patología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Enfermedad de Parkinson Secundaria/diagnóstico por imagenRESUMEN
Astrocytes provide support for neurons, regulate metabolic processes, and influence neuronal communication in a variety of ways, including through the homeostatic regulation of glutamate. Following 2-h cocaine or methamphetamine self-administration (SA) and extinction, rodents display decreased levels of basal glutamate in the nucleus accumbens core (NAcore), which transitions to elevated glutamate levels during drug seeking. We hypothesized that, like cocaine, this glutamate 'overflow' during methamphetamine seeking arises via decreased expression of the astroglial glutamate transporter GLT-1, and withdrawal of perisynaptic astroglial processes (PAPs) from synapses. As expected, methamphetamine self-administration and extinction decreased the level of contact made by PAPs in the NAcore, yet did not impact glutamate uptake, GLT-1 expression, or the general structural characteristics of astrocytes. Interestingly, systemic administration of N-acetylcysteine (NAC), a drug that both upregulates GLT-1 and promotes glial-glutamate release, reduced cued methamphetamine seeking. In order to test the impact of astrocyte activation and the induction of glial glutamate release within the NAcore, we employed astrocyte-specific expression of designer receptors exclusively activated by designer drugs (DREADDs). We show here that acute activation of Gq-coupled DREADDs in this region inhibited cued methamphetamine seeking. Taken together, these data indicate that cued methamphetamine seeking following two-hour SA is not mediated by deficient glutamate clearance in the NAcore, yet can be inhibited by engaging NAcore astrocytes.
Asunto(s)
Astrocitos/efectos de los fármacos , Astrocitos/fisiología , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Metanfetamina/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Animales , Astrocitos/patología , Dopaminérgicos/administración & dosificación , Dopaminérgicos/toxicidad , Masculino , Metanfetamina/toxicidad , Núcleo Accumbens/patología , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
Puerarin (PU) has emerged as a promising herb-derived anti-Parkinsonism compound. However, the undesirable water solubility as well as the unwanted bioavailability of PU limit its application. Therefore, this study aimed to develop and characterize PU nanocrystals (PU-NCs) with enhanced oral bioavailability and improved brain accumulation for the treatment of Parkinson's disease (PD). The fabricated PU-NCs were approximately spherical, with a mean size of 83.05 ± 1.96 nm, a PDI of 0.047 ± 0.009, a drug loading of 72.7%, and a rapid dissolution rate in vitro. Molecular dynamics simulation of PU and Pluronic F68 demonstrated the interaction energy and binding energy of -88.1 kJ/mol and -40.201 ± 0.685 kJ/mol, respectively, indicating a spontaneous binding with van der Waals interactions. In addition, the cellular uptake and permeability of PU-NCs were significantly enhanced as compared to PU alone ( p < 0.01). Moreover, PU-NCs exerted a significant neuroprotective effect against the cellular damage induced by the 1-methyl-4-phenylpyridinium ion (MPP+). Besides, PU-NCs demonstrated no obvious toxic effects on zebrafish, as evidenced by the unaltered morphology, hatching, survival rate, body length, and heart rate. Fluorescence resonance energy transfer (FRET) imaging revealed that intact nanocrystals were found in the intestine and brain of adult zebrafish gavaged with DiO/DiI/PU-NCs. Increased values of Cmax and AUC0- t were observed in the plasma of rats following oral administration of PU-NCs compared to PU suspension. Likewise, brain accumulation of PU-NCs was higher than that of PU suspension. Furthermore, PU-NCs attenuated dopamine depletion, ameliorated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, and enhanced the levels of dopamine and its metabolites. Taken altogether, this study provides evidence that PU-NCs could be exploited as a potential oral delivery system to treat PD, by improving the poor bioavailability of PU and enhancing their delivery into the brain.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Encéfalo/efectos de los fármacos , Isoflavonas/administración & dosificación , Nanopartículas/química , Fármacos Neuroprotectores/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Vasodilatadores/administración & dosificación , Administración Oral , Animales , Antiparkinsonianos/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Dopaminérgicos/toxicidad , Portadores de Fármacos/química , Isoflavonas/farmacología , Intoxicación por MPTP/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Ratas , Ratas Sprague-Dawley , Vasodilatadores/farmacología , Pez CebraRESUMEN
Methamphetamine is a widely abused psychostimulant. It reverses transport through the dopamine transporter, thereby increasing the extracellular level of dopamine in the brain, which is associated with the rewarding effect. Repeated intake of methamphetamine leads to drug addiction, a chronically relapsing disorder characterized by compulsive drug taking, inability to limit intake, and intense drug cravings. The molecular and cellular mechanisms of drug addiction are not well understood, but have been proposed to involve neural plasticity and the remodeling of specific brain circuits. Accumulating evidence also indicates that patients addicted to methamphetamine exhibit impaired cognitive functions such as executive function, attention, social cognition, flexibility, and working memory. Furthermore, decision-making is altered in patients with drug addiction, including methamphetamine abusers. Cognitive impairment as well as altered decision-making in methamphetamine abusers may contribute to the high rate of relapse even after long-term withdrawal with psychosocial support. In this article, we review the effect of methamphetamine on cognition and decision-making in rodents. We also discuss possible mechanisms underlying cognition and decision-making impairments, including neuronal circuits, molecular and cellular events, and action control, as well as potential therapeutic targets.
Asunto(s)
Estimulantes del Sistema Nervioso Central/toxicidad , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/psicología , Toma de Decisiones/efectos de los fármacos , Dopaminérgicos/toxicidad , Metanfetamina/toxicidad , Animales , Estimulantes del Sistema Nervioso Central/administración & dosificación , Disfunción Cognitiva/metabolismo , Toma de Decisiones/fisiología , Dopaminérgicos/administración & dosificación , Humanos , Metanfetamina/administración & dosificaciónRESUMEN
Increasing evidence supports a close relationship between Ras-ERK1/2 activation in the striatum and L-DOPA-induced dyskinesia (LID). ERK1/2 activation by L-DOPA takes place through the crosstalk between D1R/AC/PKA/DARPP-32 pathway and NMDA/Ras pathway. Compelling genetic and pharmacological evidence indicates that Ras-ERK1/2 inhibition prevents LID onset and may even revert already established dyskinetic symptoms. However, it is currently unclear whether exacerbation of Ras-ERK1/2 activity in the striatum may further aggravate dyskinesia in experimental animal models. Here we took advantage of two genetic models in which Ras-ERK1/2 signaling is hyperactivated, the Nf1+/- mice, in which the Ras inhibitor neurofibromin is reduced, and the Ras-GRF1 overexpressing (Ras-GRF1 OE) transgenic mice in which a specific neuronal activator of Ras is enhanced. Nf1+/- and Ras-GRF1 OE mice were unilaterally lesioned with 6-OHDA and treated with an escalating L-DOPA dosing regimen. In addition, a subset of Nf1+/- hemi-parkinsonian animals was also co-treated with the Ras inhibitor lovastatin. Our results revealed that Nf1+/- and Ras-GRF1 OE mice displayed similar dyskinetic symptoms to their wild-type counterparts. This observation was confirmed by the lack of differences between mutant and wild-type mice in striatal molecular changes associated to LID (i.e., FosB, and pERK1/2 expression). Interestingly, attenuation of Ras activity with lovastatin does not weaken dyskinetic symptoms in Nf1+/- mice. Altogether, these data suggest that ERK1/2-signaling activation in dyskinetic animals is maximal and does not require further genetic enhancement in the upstream Ras pathway. However, our data also demonstrate that such a genetic enhancement may reduce the efficacy of anti-dyskinetic drugs like lovastatin.
Asunto(s)
Discinesia Inducida por Medicamentos/tratamiento farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Levodopa/toxicidad , Lovastatina/farmacología , Neurofibromina 1/fisiología , Proteínas ras/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Dopaminérgicos/toxicidad , Discinesia Inducida por Medicamentos/metabolismo , Discinesia Inducida por Medicamentos/patología , Quinasas MAP Reguladas por Señal Extracelular/genética , Femenino , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Transducción de Señal , Proteínas ras/genéticaRESUMEN
Mucuna pruriens (Mucuna) has been prescribed in Ayurveda for various brain ailments including 'kampavata' (tremors) or Parkinson's disease (PD). While Mucuna is a well-known natural source of levodopa (L-dopa), published studies suggest that other bioactive compounds may also be responsible for its anti-PD effects. To investigate this hypothesis, an L-dopa reduced (<0.1%) M. pruriens seeds extract (MPE) was prepared and evaluated for its anti-PD effects in cellular (murine BV-2 microglia and human SH-SY5Y neuroblastoma cells), Caenorhabditis elegans, and Drosophila melanogaster models. In BV-2 cells, MPE (12.5â»50 µg/mL) reduced hydrogen peroxide-induced cytotoxicity (15.7-18.6%), decreased reactive oxygen species production (29.1-61.6%), and lowered lipopolysaccharide (LPS)-induced nitric oxide species release by 8.9â»60%. MPE (12.5-50 µg/mL) mitigated SH-SY5Y cell apoptosis by 6.9-40.0% in a non-contact co-culture assay with cell-free supernatants from LPS-treated BV-2 cells. MPE (12.5-50 µg/mL) reduced 6-hydroxydopamine (6-OHDA)-induced cell death of SH-SY5Y cells by 11.85â»38.5%. Furthermore, MPE (12.5-50 µg/mL) increased median (25%) and maximum survival (47.8%) of C. elegans exposed to the dopaminergic neurotoxin, methyl-4-phenylpyridinium. MPE (40 µg/mL) ameliorated dopaminergic neurotoxin (6-OHDA and rotenone) induced precipitation of innate negative geotaxis behavior of D. melanogaster by 35.3 and 32.8%, respectively. Therefore, MPE contains bioactive compounds, beyond L-dopa, which may impart neuroprotective effects against PD.
Asunto(s)
Levodopa/farmacología , Microglía/efectos de los fármacos , Mucuna/química , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , 1-Metil-4-fenilpiridinio/toxicidad , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Dopaminérgicos/toxicidad , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/metabolismo , Humanos , Masculino , Microglía/metabolismo , Neuroblastoma/metabolismo , Oxidopamina/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Semillas/químicaRESUMEN
Protein phosphorylation is a key mediator of signal transduction, allowing for dynamic regulation of substrate activity. Whereas protein kinases obtain substrate specificity by targeting specific amino acid sequences, serine/threonine phosphatase catalytic subunits are much more promiscuous in their ability to dephosphorylate substrates. To obtain substrate specificity, serine/threonine phosphatases utilize targeting proteins to regulate phosphatase subcellular localization and catalytic activity. Spinophilin and its homologue neurabin are two of the most abundant dendritic spine-localized protein phosphatase 1 (PP1) targeting proteins. The association between spinophilin and PP1 is increased in the striatum of animal models of Parkinson's disease (PD). However, mechanisms that regulate the association of spinophilin and neurabin with PP1 are unclear. Here, we report that the association between spinophilin and PP1α or PP1γ1 was increased by CDK5 expression and activation in a heterologous cell system. This increased association is at least partially due to phosphorylation of PP1. Conversely, CDK5 expression and activation decreased the association of PP1 with neurabin. As with dopamine depletion, methamphetamine (METH) abuse causes persistent alterations in dopamine signaling which influence striatal medium spiny neuron function and biochemistry. Moreover, both METH toxicity and dopamine depletion are associated with deficits in motor control and motor learning. Pathologically, we observed a decreased association of spinophilin with PP1 in rat striatum evaluated one month following a binge METH paradigm. Behaviorally, we found that loss of spinophilin recapitulates rotarod pathology previously observed in dopamine-depleted and METH-treated animals. Together, these data have implications in multiple disease states associated with altered dopamine signaling such as PD and psychostimulant drug abuse and delineate a novel mechanism by which PP1 interactions with spinophilin and neurabin may be differentially regulated.
Asunto(s)
Cuerpo Estriado/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteína Fosfatasa 1/metabolismo , Trastornos Relacionados con Anfetaminas/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Dopaminérgicos/toxicidad , Metanfetamina/toxicidad , Ratones , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas del Tejido Nervioso/genética , Enfermedad de Parkinson/metabolismo , Fosforilación , Ratas , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
OBJECTIVE: To provide an overview of neuroleptic malignant syndrome (NMS) for the general practitioner with the most up-to-date information on etiology, workup, and management. DATA SOURCES: The search using PubMed included articles with the key words neuroleptic malignant syndrome, antipsychotics, neuroleptics, diagnosis, and treatment of neuroleptic malignant syndrome published in English from January 2000 to 2017. Single-case reports and articles dealing with the pediatric patient population were excluded. STUDY SELECTION: Over 4,000 articles met the search criteria. After eliminating single-case reports, pediatric cases, reports in pregnant patients, and duplicates, 87 articles underwent screening. Forty-two articles were included in this review. RESULTS: The literature is rich with cases of NMS associated with the use of neuroleptics and various medications with neuroleptic-like effects. Questions remain with regard to pathophysiology and optimal treatment. NMS is a rare but potentially lethal consequence of the use of antipsychotic medications that requires familiarity with the condition in order to rapidly recognize its onset and appropriately intervene. CONCLUSIONS: NMS mortality rates have declined over the past 30 years, most likely due to early recognition of the syndrome and appropriate intervention. Nonetheless, clinicians, especially primary care clinicians who are using this class of drugs more often for adjunctive treatments, must be cognizant of this syndrome and the implications of their use.â.
Asunto(s)
Síndrome Neuroléptico Maligno/diagnóstico , Síndrome Neuroléptico Maligno/terapia , Dopaminérgicos/toxicidad , Humanos , Síndrome Neuroléptico Maligno/mortalidad , Síndrome Neuroléptico Maligno/fisiopatologíaRESUMEN
BACKGROUND: Diffusion tensor imaging has received major interest to highlight markers of neurodegeneration in Parkinson's disease. Whether the alteration of diffusion parameters mostly depicts dopaminergic lesions or can also reveal serotonergic denervation remains a question. OBJECTIVES: The aim of this study was to determine the best diffusion tensor imaging markers of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylene-dioxy-methamphetamine (MDMA; also known as ecstasy) lesions in the nonhuman primate. METHODS: We acquired measures of mean diffusivity and fractional anisotropy longitudinally (before and after MPTP and MDMA) and correlated them with severity of parkinsonism, PET imaging, and postmortem fiber quantification. RESULTS: MPTP-induced lesions were associated with increases of mean diffusivity within both the caudate nucleus and the anterior cingulate cortex, whereas MDMA-induced lesions caused an increase of fractional anisotropy within the caudate nucleus. These variations of diffusion tensor imaging correlated with the motor score. CONCLUSION: Taken together, these results demonstrate that diffusion measures within specific brain regions can mark severity of dopaminergic and serotonergic induced lesions in a neurotoxic nonhuman primate model of Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.
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Encéfalo/metabolismo , Imagen de Difusión Tensora , Dopamina/metabolismo , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/metabolismo , Serotonina/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Dopaminérgicos/toxicidad , Macaca fascicularis , Masculino , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Serotoninérgicos/toxicidad , Estadísticas no Paramétricas , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Levo-dopa (L-DOPA) has shown significant and long-lasting efficacy in the treatment of motor features characteristic of Parkinson's disease (PD). However, the effects tend to wear off at a time typically when side-effects, such as L-DOPA induced dyskinesias (LIDs), start to emerge and for which the treatment options are very limited. In recent years, we have reported on the neuroprotective and neurorestorative properties of the compounds cystamine/cysteamine in ameliorating several aspects of PD. Building on these observations, we set out to further evaluate the benefits of cysteamine on LIDs. We thus treated mice displaying LIDs with single cysteamine challenges at various doses (20, 50 and 30mg/kg) or chronically for 2 weeks using cysteamine at a dose of 30mg/kg. None of the regimens nor doses ameliorated any LID-related behavioral impairments. Mice displaying LIDs did, however, respond to a single treatment of 60mg/kg of amantadine, a drug used to clinically manage LIDs. Taken together, our results suggest that cysteamine does not induce benefits on LIDs, at least at the doses and regimen tested in our study. However, the disease-modifying effects depicted by cystamine/cysteamine, which we have shown in several reports, would strongly encourage its continued evaluation in the clinical setting.
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Cisteamina/farmacología , Depletores de Cistina/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Dopaminérgicos/toxicidad , Levodopa/toxicidad , RatonesRESUMEN
The dopamine D3 receptor (D3R) belongs to the dopamine D2-like receptor family and is principally located in the ventral striatum. However, previous studies reported D3R overexpression in the dorsal striatum following l-DOPA treatment in parkinsonian animals. This fact has drawn attention in the importance of D3R in l-DOPA-induced dyskinesia (LID). Here, we used D3R knockout mice to assess the role of D3R in LID and rotational sensitization in the hemiparkinsonian model. Mice lacking D3R presented a reduction in dyskinesia without interfering with the antiparkinsonian l-DOPA effect and were accompanied by a reduction in the l-DOPA-induced rotations. Interestingly, deleting D3R attenuated important molecular markers in the D1R-neurons such as FosB, extracellular signal-regulated kinase, and histone-3 (H3)-activation. Colocalization studies in D1R-tomato and D2R-green fluorescent protein BAC-transgenic mice indicated that l-DOPA-induced D3R overexpression principally occurs in D1R-containing neurons although it is also present in the D2R-neurons. Moreover, D3R pharmacological blockade with PG01037 reduced dyskinesia and the molecular markers expressed in D1R-neurons. In addition, this antagonist further reduced dyskinetic symptoms in D1R heterozygous mice, indicating a direct interaction between D1R and D3R. Together, our results demonstrate that D3R modulates the development of dyskinesia by targeting D1R-mediated intracellular signaling and suggest that decreasing D3R activity may help to ameliorate LID.
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Cuerpo Estriado/metabolismo , Dopaminérgicos/toxicidad , Discinesia Inducida por Medicamentos/metabolismo , Levodopa/toxicidad , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D3/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Ratones , Ratones Noqueados , Trastornos Parkinsonianos/metabolismoRESUMEN
Glutamate chemical exchange saturation transfer (GluCEST) MRI was used to measure metabolic changes in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by mapping regional cerebral glutamate. The GluCEST contrast following MPTP treatment was correlated with 1 H-MR spectroscopy, motor function, and immunohistochemical measures. The GluCEST contrast was found to be significantly higher in the striatum and motor cortex of mice treated with MPTP than in controls (p < 0.001), which was confirmed by localized 1 H-MR spectroscopy. Elevated striatal GluCEST was positively associated with local astrogliosis measured by immunohistochemistry for glial fibrillary acidic protein. Additionally, a negative correlation was found between motor function, measured by the four-limb grip strength test, and GluCEST of the striatum (R = -0.705, p < 0.001) and the motor cortex (R = -0.617, p < 0.01), suggesting a role of elevated glutamate in the abnormal cerebral motor function regulation. The GluCEST contrast and glial fibrillary acidic protein immunostaining were unaltered in the thalamus indicating glutamate elevation was localized to the striatum and the motor cortex. These findings suggest that in addition to measuring spatial changes in glutamate, GluCEST may serve as an in vivo biomarker of metabolic and functional changes that may be applied to the assessment of a broad range of neuropathologies. Read the Editorial Highlight for this article on page 346.
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Dopamina/deficiencia , Ácido Glutámico/metabolismo , Intoxicación por MPTP/metabolismo , Imagen por Resonancia Magnética/métodos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Astrocitos/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Dopaminérgicos/toxicidad , Discinesia Inducida por Medicamentos/fisiopatología , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/patología , Fuerza de la Mano , Intoxicación por MPTP/diagnóstico por imagen , Intoxicación por MPTP/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
Rats given drugs of abuse such as amphetamine or morphine show longer-term effects, that is, signs of acute withdrawal, including hypoactivity, hypophagia, and blunted affect, sometime between 12 and 24h after treatment. This research explores the possibility that signs of acute withdrawal produced by different drugs of abuse are instigated by overlapping mechanisms. The specific objectives of the research were to see if amphetamine and morphine produced longer-term hypoactivity, and to see if any longer-term hypoactivity elicited by the drugs could be blocked by SCH23390, a dopamine D1 antagonist. Six groups of rats, with eight rats in each group, were exposed to a series of five-day tests. Near light onset of Test Day 1, each animal was given control administrations, consisting of a saline treatment (1.0ml/kg) followed 30m later by a saline posttreatment, and locomotor activity was monitored for the next 24h. On Test Day 3, each animal was given experimental administrations, and locomotor activity was again monitored for 24h. Each group received only one combination of experimental administrations across tests. Experimental administrations consisted of saline, amphetamine (2.0mg/kg), or morphine (5.0mg/kg), followed by saline or SCH23390 (0.05mg/kg). All administrations were subcutaneous. Amphetamine and morphine produced longer-term hypoactivity, having similar time courses and magnitudes. SCH23390 blocked the longer-term hypoactivity produced by both drugs. Saline and SCH23390 produced no changes in longer-term activity in their own right. The time course of amphetamine-elicited longer-term hypoactivity resembled that of amphetamine-elicited longer-term hypophagia observed in a prior study. Approximately 1/4 of the animals given amphetamine or morphine did not show longer-term hypoactivity ("low withdrawal" rats). Amphetamine and morphine may initiate the cascade of events resulting in signs of acute withdrawal by producing activation in a common pathway that uses dopamine as a neurotransmitter. Different signs of acute withdrawal (hypoactivity and hypophagia) may involve the short-term activation of the same common pathway. Low withdrawal rats may have a different vulnerability to amphetamine and may show differences in drug assessment outcomes relative to animals that manifest distinct signs of acute withdrawal.