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Identifying neurobiological mechanisms of aging-related parkinsonism, and lifestyle interventions that mitigate them, remain critical knowledge gaps. No aging study, from rodent to human, has reported loss of any dopamine (DA) signaling marker near the magnitude associated with onset of parkinsonian signs in Parkinson's disease (PD). However, in substantia nigra (SN), similar loss of DA signaling markers in PD or aging coincide with parkinsonian signs. Alleviation of these parkinsonian signs may be possible by interventions such as calorie restriction (CR), which augment DA signaling markers like tyrosine hydroxylase (TH) expression in the SN, but not striatum. Here, we interrogated respective contributions of nigral and striatal DA mechanisms to aging-related parkinsonian signs in aging (18 months old) rats in two studies: by the imposition of CR for 6 months, and inhibition of DA uptake within the SN or striatum by cannula-directed infusion of nomifensine. Parkinsonian signs were mitigated within 12 weeks after CR and maintained until 24 months old, commensurate with increased D1 receptor expression in the SN alone, and increased GDNF family receptor, GFR-α1, in the striatum, suggesting increased GDNF signaling. Nomifensine infusion into the SN or striatum selectively increased extracellular DA. However, only nigral infusion increased locomotor activity. These results indicate mechanisms that increase components of DA signaling in the SN alone mitigate parkinsonian signs in aging, and are modifiable by interventions, like CR, to offset parkinsonian signs, even at advanced age. Moreover, these results give evidence that changes in nigral DA signaling may modulate some parameters of locomotor activity autonomously from striatal DA signaling.
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Dopamina , Enfermedad de Parkinson , Humanos , Ratas , Animales , Dopamina/metabolismo , Ratas Endogámicas F344 , Restricción Calórica , Nomifensina/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/farmacología , Sustancia Negra/metabolismoRESUMEN
The presentation of virus-derived peptides by HLA class I molecules on the surface of an infected cell and the recognition of these HLA-peptide complexes by, and subsequent activation of, CD8+ cytotoxic T cells provides an important mechanism for immune protection against viruses. Recent advances in proteogenomics have allowed researchers to discover a growing number of unique HLA-restricted viral peptides, resulting in a rapidly expanding repertoire of targets for immunotherapeutics (i.e. bispecific antibodies, engineered T-cell receptors (TCRs), chimeric antigen receptor T-cells (CAR-Ts)) to infected tissues. However, genomic variability between viral strains, such as Hepatitis-B virus (HBV), in combination with differences in patient HLA alleles, make it difficult to develop therapeutics against these targets. To address this challenge, we developed a novel proteogenomics approach for generating patient-specific databases that enable the identification of viral peptides based on the viral transcriptomes sequenced from individual patient liver samples. We also utilized DNA sequencing of patient samples to identify HLA genotypes and assist in target selection. Liver samples from 48 HBV infected patients, primarily from Asia, were examined to reconstruct patient-specific HBV genomes, identify regions within the human chromosomes targeted by HBV integrations and obtain a comprehensive view of HBV peptide epitopes using our HLA class-I (HLA-I) immunopeptidomics discovery platform. Two previously reported HLA associated HBV-derived peptides, HLA-A02 binder FLLTRILTI (S194-202) from the large surface antigen and HLA-A11 binder STLPETTVVRR (C141-151) from the capsid protein were validated by our discovery platform, but both were detected at very low frequencies. In addition, we identified and validated, using heavy peptide analogues, novel strain-specific HBV-HLA associated peptides, such as GSLPQEHIVQK (P606-616) and variants. Overall, our novel approach can guide the development of bispecific antibody, TCR-T, or CAR-T based therapeutics for the treatment of HBV-related HCC and inform vaccine development.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteogenómica , Humanos , Virus de la Hepatitis B/genética , Carcinoma Hepatocelular/metabolismo , Linfocitos T CD8-positivos , Neoplasias Hepáticas/metabolismo , Péptidos , GenotipoRESUMEN
Monocytes are highly plastic immune cells that modulate antitumor immunity. Therefore, identifying factors that regulate tumor monocyte functions is critical for developing effective immunotherapies. Here, we determine that endogenous cancer cell-derived type I interferons (IFNs) control monocyte functional polarization. Guided by single-cell transcriptomic profiling of human and mouse tumors, we devise a strategy to distinguish and separate immunostimulatory from immunosuppressive tumor monocytes by surface CD88 and Sca-1 expression. Leveraging this approach, we show that cGAS-STING-regulated cancer cell-derived IFNs polarize immunostimulatory monocytes associated with anti-PD-1 immunotherapy response in mice. We also demonstrate that immunosuppressive monocytes convert into immunostimulatory monocytes upon cancer cell-intrinsic cGAS-STING activation. Consistently, we find that human cancer cells can produce type I IFNs that polarize monocytes, and our immunostimulatory monocyte gene signature is enriched in patient tumors that respond to anti-PD-1 immunotherapy. Our work exposes a role for cancer cell-derived IFNs in licensing monocyte functions that influence immunotherapy outcomes.
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Interferón Tipo I , Neoplasias , Humanos , Ratones , Animales , MonocitosRESUMEN
Amyotrophic lateral sclerosis is a fatal disease pathologically typified by motor and cortical neurodegeneration as well as microgliosis. The FUS P525L mutation is highly penetrant and causes ALS cases with earlier disease onset and more aggressive progression. To date, how P525L mutations may affect microglia during ALS pathogenesis had not been explored. In this study, we engineered isogenic control and P525L mutant FUS in independent human iPSC lines and differentiated them into microglia-like cells. We report that the P525L mutation causes FUS protein to mislocalize from the nucleus to cytoplasm. Homozygous P525L mutations perturb the transcriptome profile in which many differentially expressed genes are associated with microglial functions. Specifically, the dysregulation of several chemoreceptor genes leads to altered chemoreceptor-activated calcium signaling. However, other microglial functions such as phagocytosis and cytokine release are not significantly affected. Our study underscores the cell-autonomous effects of the ALS-linked FUS P525L mutation in a human microglia model.
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Esclerosis Amiotrófica Lateral , Células Madre Pluripotentes Inducidas , Proteína FUS de Unión a ARN , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Microglía/metabolismo , Mutación , Proteína FUS de Unión a ARN/genética , TranscriptomaRESUMEN
Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting.
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Anticuerpos Monoclonales/inmunología , COVID-19/inmunología , COVID-19/prevención & control , Mutación/genética , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Animales , COVID-19/virología , Chlorocebus aethiops , Cricetinae , Microscopía por Crioelectrón , Hospitalización , Humanos , Pulmón/patología , Pulmón/virología , Masculino , Pruebas de Neutralización , Células Vero , Carga ViralRESUMEN
Parkinson's Disease (PD) is characterized by primary and secondary plasticity that occurs in response to progressive degeneration and long-term L-DOPA treatment. Some of this plasticity contributes to the detrimental side effects associated with chronic L-DOPA treatment, namely L-DOPA-induced dyskinesia (LID). The dopamine D3 receptor (D3R) has emerged as a promising target in LID management as it is upregulated in LID. This upregulation occurs primarily in the D1-receptor-bearing (D1R) cells of the striatum, which have been repeatedly implicated in LID manifestation. D3R undergoes dynamic changes both in PD and in LID, making it difficult to delineate D3R's specific contributions, but recent genetic and pharmacologic tools have helped to clarify its role in LID. The following review will discuss these changes, recent advances to better clarify D3R in both PD and LID and potential steps for translating these findings.
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Pedunculopontine nucleus (PPN) cholinergic neurons are implicated in freezing of gait in Parkinson's disease (PD) and motor stereotypy in normal animals, but the causal role of these neurons on specific gait parameters and treatment-induced dyskinesia remains speculative. Therefore, we examined whether selective cholinergic lesion of the rostral PPN affects PD motor and gait deficits, L-DOPA-induced dyskinesia and motor improvement, and DA-agonist-induced dyskinesia. Sprague-Dawley rats were assigned to one unilaterally lesioned group: Sham lesion, PPN cholinergic lesion with diphtheria urotensin II fusion toxin, medial forebrain bundle dopamine lesion with 6-hydroxydopamine, or dual acetylcholine and dopamine lesion. We used gait analysis and forepaw adjusting steps to examine PD gait and motor deficits. Forepaw adjusting steps were also used to assess motor improvement with L-DOPA treatment. The abnormal involuntary movements scale measured L-DOPA and dopamine D1- and D2-receptor agonist-induced dyskinesia. Lesions, verified via tyrosine hydroxylase and choline acetyltransferase immunohistochemistry reduced an average of 95% of nigral dopamine neurons and 80% of PPN cholinergic neurons, respectively. Rats receiving acetylcholine and dual lesion demonstrated enhanced freezing, and acetylcholine lesioned rats exhibited increased print area and stand index. Dopamine and dual lesion produced similar forepaw adjusting steps task on and off L-DOPA. Relative to DA lesioned rats, dual lesioned rats displayed reduced L-DOPA and DA agonist-induced dyskinesia at specific time points. Our results indicate that PPN cholinergic neurons affect gait parameters related to postural stability. Therefore, therapeutically targeting PPN cholinergic neurons could reduce intractable postural instability in PD without affecting motor benefits or side effects of L-DOPA treatment.
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Discinesias , Trastornos Neurológicos de la Marcha , Enfermedad de Parkinson , Animales , Colinérgicos , Modelos Animales de Enfermedad , Marcha , Levodopa , Oxidopamina/toxicidad , Ratas , Ratas Sprague-DawleyRESUMEN
Parkinson's Disease (PD) is symptomatically managed with L-DOPA but chronic use results in L-DOPA-induced dyskinesia (LID) characterized by abnormal involuntary movements (AIMs). In LID, dopamine D3 receptors (D3R) are upregulated on D1 receptor (D1R)-bearing medium spiny neurons where the can synergistically drive downstream signaling and motor behaviors. Despite evidence implying D1R-D3R cooperativity in LID, the dyskinesiogenic role of D3R has never been directly tested. To this end, we developed a specific cre-dependent microRNA (miRNA) to irreversibly prevent D3R upregulation in D1R striatal cells. D1-Cre rats received unilateral 6-hydroxydopamine lesions. Three weeks later, rats received an adeno-associated virus expressing either D3R miRNA or a scrambled (SCR) miRNA delivered into the striatum. After 4 weeks, rats received chronic L-DOPA (6 mg/kg) or vehicle. AIMs development and motor behaviors were assayed throughout treatment. At the conclusion of the experiment, efficacy and fidelity of the miRNA strategy was analyzed using in situ hybridization (ISH). ISH analyses demonstrated that D1R+/D3R+ cells were upregulated in LID and that the selective D3R miRNA reduced D1R+/D3R+ co-expression. Importantly, silencing of D3R also significantly attenuated LID development without impacting L-DOPA efficacy or other locomotion. These data highlight a dyskinesiogenic role of D3R within D1R cells in LID and highlight aberrant D1R-D3R interactions as targets of LID management.
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Dopaminérgicos/efectos adversos , Discinesia Inducida por Medicamentos/genética , Discinesia Inducida por Medicamentos/prevención & control , Levodopa/efectos adversos , Neostriado/patología , Receptores de Dopamina D1/genética , Receptores de Dopamina D3/genética , Animales , Conducta Animal , Discinesia Inducida por Medicamentos/psicología , Femenino , Terapia Genética , Hidroxidopaminas , Masculino , MicroARNs/genética , Neostriado/metabolismo , Desempeño Psicomotor , RatasRESUMEN
An urgent global quest for effective therapies to prevent and treat coronavirus disease 2019 (COVID-19) is ongoing. We previously described REGN-COV2, a cocktail of two potent neutralizing antibodies (REGN10987 and REGN10933) that targets nonoverlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In this report, we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques, which may model mild disease, and golden hamsters, which may model more severe disease. We demonstrate that REGN-COV-2 can greatly reduce virus load in the lower and upper airways and decrease virus-induced pathological sequelae when administered prophylactically or therapeutically in rhesus macaques. Similarly, administration in hamsters limits weight loss and decreases lung titers and evidence of pneumonia in the lungs. Our results provide evidence of the therapeutic potential of this antibody cocktail.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , COVID-19/terapia , Animales , COVID-19/prevención & control , Combinación de Medicamentos , Macaca mulatta , MesocricetusRESUMEN
Antibodies targeting the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present a promising approach to combat the coronavirus disease 2019 (COVID-19) pandemic; however, concerns remain that mutations can yield antibody resistance. We investigated the development of resistance against four antibodies to the spike protein that potently neutralize SARS-CoV-2, individually as well as when combined into cocktails. These antibodies remain effective against spike variants that have arisen in the human population. However, novel spike mutants rapidly appeared after in vitro passaging in the presence of individual antibodies, resulting in loss of neutralization; such escape also occurred with combinations of antibodies binding diverse but overlapping regions of the spike protein. Escape mutants were not generated after treatment with a noncompeting antibody cocktail.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Betacoronavirus/química , Betacoronavirus/genética , COVID-19 , Epítopos , Genoma Viral , Humanos , Proteínas Mutantes/química , Proteínas Mutantes/inmunología , Mutación , Pruebas de Neutralización , Pandemias , Dominios y Motivos de Interacción de Proteínas , SARS-CoV-2 , Selección Genética , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
The striatum undergoes significant neuroplasticity both in Parkinson's Disease (PD) and following dopamine (DA) replacement therapy with l-DOPA. Unfortunately, these changes also contribute to the emergence of l-DOPA-induced dyskinesia (LID). While convergent strategies have demonstrated independent roles for DA D1 -receptors (D1R) and D2-receptors (D2R) in LID, DA receptor cooperativity, either by cellular or circuit mechanisms, has also been implicated in the dyskinetic brain. How this cooperativity is substantiated is vitally important given that l-DOPA, once converted to DA, stimulates all DA receptors. The present experiments sought to characterize the effect of individual or collective stimulation of D1R and D2R-like receptors both systemically and intrastriatally. In experiment 1, hemiparkinsonian l-DOPA-primed rats received systemic doses of the D1R agonist SKF38393 and D2R-like agonist quinpirole. Dyskinesia and motor improvement were monitored using the abnormal involuntary movements scale (AIMs) and the forepaw adjustment steps test (FAS), respectively. In experiment 2, SKF38393 and quinpirole were administered intrastriatally via reverse-phase in vivo microdialysis while coincident changes in striatal glutamate and gamma-Aminobutyric acid (GABA) were monitored. SKF38393 and quinpirole dose-dependently increased AIMs. When threshold DA agonist doses were co-administered, AIMs and motor performance were synergistically enhanced. Like systemic experiments, striatal co-administration of threshold concentrations of DA agonists resulted in synergistic exacerbation of AIMs, and concurrent increases in GABA efflux. These data highlight the role of striatal DA receptor cooperativity in LID and suggest a central role for striatal GABA release in these effects.
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Cuerpo Estriado/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Actividad Motora/fisiología , Trastornos Parkinsonianos/metabolismo , Receptores Dopaminérgicos/metabolismo , Ácido gamma-Aminobutírico/metabolismo , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/toxicidad , Animales , Cuerpo Estriado/efectos de los fármacos , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/toxicidad , Masculino , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/inducido químicamente , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
In the majority of Parkinson's disease (PD) patients, long-term dopamine (DA) replacement therapy leads to dyskinesia characterized by abnormal involuntary movements (AIMs). There are various mechanisms of dyskinesia, such as the sensitization of striatal DA D1 receptors (D1R) and upregulation of DA D3 receptors (D3R). These receptors interact physically and functionally in D1R-bearing medium spiny neurons to synergistically drive dyskinesia. However, the cross-receptor-mediated effects due to D1R-D3R cooperativity are still poorly understood. In pursuit of this, we examined whether or not pharmacological D1R or D3R stimulation sensitizes the dyskinetic response to the appositional agonist, a process known as cross-sensitization. First, we established D1R-D3R behavioral synergy in a cohort of 6-OHDA-lesioned female adult Sprague-Dawley rats. Then, in a new cohort, we tested for cross-sensitization in a between-subject design. Five groups received a sub-chronic regimen of either saline, the D1R agonist SKF38393 (1.0 mg/kg), or the D3R agonist PD128907 (0.3 mg/kg). For the final injection, each group received an acute injection of the other agonist. AIMs were monitored following each injection. Sub-chronic administration of both SKF38393 and PD128907 induced the development of dyskinesia. More importantly, cross-agonism tests revealed reciprocal cross-sensitization; chronic treatment with either SKF38393 or PD128907 induced sensitization to a single administration of the other agonist. This reciprocity was not marked by changes to either D1R or D3R striatal mRNA expression. The current study provides key behavioral data demonstrating the role of D3R in dyskinesia and provides behavioral evidence of D1R and D3R functional interactions.
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Cuerpo Estriado/metabolismo , Agonistas de Dopamina/farmacología , Discinesia Inducida por Medicamentos/metabolismo , Enfermedad de Parkinson Secundaria/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D3/metabolismo , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Benzopiranos/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Femenino , Oxazinas/farmacología , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Ratas , Ratas Sprague-DawleyRESUMEN
Aging is a primary risk factor for the development of Parkinson's disease (PD), and aging differentially predicts the incidence of L-DOPA-induced dyskinesia (LID). The goal of this work was to establish whether late aging-associated exacerbation of LID would be related to neuroinflammation in the hemi-parkinsonian rat. Two studies were conducted in which adult (3 months) and aged (18 months) male Fischer 344 rats bearing unilateral 6-hydroxydopamine lesions of the medial forebrain bundle were injected acutely with vehicle or L-DOPA (6 mg/kg). LID was quantified, and neuroinflammation was assessed postmortem via gene expression markers in the striatum (experiment 1) or through concurrent large-molecule microdialysis (experiment 2). In addition to exacerbating LID despite similar levels of striatal dopamine loss, late aging was associated with persistently elevated IL-1ß gene expression ipsilateral to lesion, as well as a trend toward greater extracellular concentrations of IL-1ß in response to acute L-DOPA treatment. In contrast, aged sham-operated rats displayed greater extracellular IL-6. Taken together, these data demonstrate an age-related vulnerability to LID and highlight potential neuroinflammatory mediators associated with these effects.
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Envejecimiento , Discinesia Inducida por Medicamentos/etiología , Levodopa/efectos adversos , Enfermedad de Parkinson , Animales , Expresión Génica , Inflamación , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Ratas , Ratas Endogámicas F344 , Factores de RiesgoRESUMEN
Standard treatment for Parkinson's disease (PD) is L-DOPA, but with chronic administration the majority of patients develop L-DOPA-induced dyskinesia (LID). Emerging evidence implicates the cholinergic system in PD and LID. Muscarinic acetylcholine receptors (mAChR) are known to modulate movement and of late have been implicated as possible targets for LID. Therefore the current study investigated the role of M1 and M4 mAChRs in LID, on motor performance following L-DOPA treatment, and sought to identify brain sites through which these receptors were acting. We first administered M1R-preferring antagonist trihexyphenidyl (0, 0.1, and 1.0â¯mg/kg, i.p.) or the M4R-preferring antagonist tropicamide (0, 10, and 30â¯mg/kg, i.p.) before L-DOPA, after which LID and motor performance were evaluated. Both compounds worsened and extended the time course of LID, while M1R blockade improved motor performance. We then evaluated the effects of tropicamide and trihexyphenidyl on dyskinesia induced by D1R agonist SKF81297 or D2R agonist quinpirole. Surprisingly, both M1R and M4R antagonists reduced D1R agonist-induced dyskinesia but not D2R agonist-induced dyskinesia, suggesting that mAChR blockade differentially affects MSN firing in the absence of postsynaptic DA. Finally, we evaluated effects of striatum- or PPN-targeted tropicamide microinfusion on LID and motor performance. Despite prior evidence, M4R blockade in either site alone did not affect the severity of LID via local striatal or PPN infusions. Taken together, these data suggest M4R as a promising therapeutic target for reducing LID using more selective compounds.
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Discinesia Inducida por Medicamentos/tratamiento farmacológico , Antagonistas Muscarínicos/uso terapéutico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Receptor Muscarínico M1/antagonistas & inhibidores , Receptor Muscarínico M4/antagonistas & inhibidores , Animales , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Conducta Animal/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Levodopa/efectos adversos , Levodopa/uso terapéutico , Masculino , Antagonistas Muscarínicos/farmacología , Oxidopamina , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Trihexifenidilo/farmacología , Trihexifenidilo/uso terapéutico , Tropicamida/farmacología , Tropicamida/uso terapéuticoRESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder characterized by hypokinetic motor features; however, patients also display non-motor symptoms like sleep disorders. The standard treatment for PD is dopamine replacement with L-DOPA; however, symptoms including gait deficits and sleep disorders are unresponsive to L-DOPA. Notably, these symptoms have been linked to aberrant activity in the pedunculopontine nucleus (PPN). Of late, clinical trials involving PPN deep brain stimulation (DBS) have been employed to alleviate gait deficits. Although preclinical evidence implicating PPN cholinergic neurons in gait dysfunction was initially promising, DBS trials fell short of expected outcomes. One reason for the failure of DBS may be that the PPN is a heterogenous nucleus that consists of GABAergic, cholinergic, and glutamatergic neurons that project to a diverse array of brain structures. Second, DBS trials may have been unsuccessful because PPN neurons are susceptible to mitochondrial dysfunction, Lewy body pathology, and degeneration in PD. Therefore, pharmaceutical or gene-therapy strategies targeting specific PPN neuronal populations or projections could better alleviate intractable PD symptoms. Unfortunately, how PPN neuronal populations and their respective projections influence PD motor and non-motor symptoms remains enigmatic. Herein, we discuss normal cellular and neuroanatomical features of the PPN, the differential susceptibility of PPN neurons to PD-related insults, and we give an overview of literature suggesting a role for PPN neurons in motor and sleep deficits in PD. Finally, we identify future approaches directed towards the PPN for the treatment of PD motor and sleep symptoms.
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BACKGROUND: The serotonergic system is a well-established modulator of l-dopa-induced dyskinesia. To date, targeting serotonin transporters or serotonin receptor subtype 1A (5-HT1A ) reduces l-dopa-induced dyskinesia in animal models; however, these strategies have failed to translate clinically. Ideally, a compound acting at both known antidyskinetic sites could optimize serotonin-mediated approaches. Vilazodone is a selective serotonin reuptake inhibitor and a partial 5-HT1A agonist approved by the U.S. Food and Drug Administration, situating Vilazodone in a unique position to reduce l-dopa-induced dyskinesia without compromising l-dopa-mediated motor improvements. OBJECTIVES: The goal of the present study was to characterize Vilazodone's effects on l-dopa-induced behaviors, neurochemistry and gene expression in unilateral 6-hydroxydopamine-lesioned hemi-parkinsonian rats. METHODS: In experiments 1 and 2, l-dopa-naïve and l-dopa-primed animals were coadministered Vilazodone and l-dopa daily for 3 weeks to model subchronic use, and behavioral, neurochemical, and messenger RNA (mRNA) expression changes were measured. In experiment 3, dyskinetic behavior was assessed following 5-HT1A or serotonin receptor subtype 1B blockade prior to Vilazodone-l-dopa coadministration. RESULTS: Vilazodone significantly suppressed developing and established l-dopa-induced dyskinesia without compromising the promotor effects of l-dopa therapy. In the dopamine-depleted striatum, Vilazodone-l-dopa cotreatment increased dopamine content, suggesting a normalization of dopamine kinetics in dyskinetic brain, and reduced l-dopa-induced c-Fos and preprodynorphin mRNA overexpression, indicative of attenuated dopamine D1 receptor-mediated direct pathway overactivity. Only 5-HT1A antagonism partially attenuated Vilazodone's antidyskinetic efficacy, suggesting both serotonin transporter-dependent effects and 5-HT1A receptors in Vilazodone's actions. CONCLUSIONS: Our findings show Vilazodone has a serotonin-dependent effect on rodent l-dopa-induced dyskinesia and implicate the potential for repositioning Vilazodone against l-dopa-induced dyskinesia development and expression in Parkinson's disease patients. © 2018 International Parkinson and Movement Disorder Society.
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Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/etiología , Levodopa/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Clorhidrato de Vilazodona/uso terapéutico , Animales , Modelos Animales de Enfermedad , Dinorfinas/genética , Dinorfinas/metabolismo , Encefalinas/genética , Encefalinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Piperazinas/farmacología , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Piridinas/farmacología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Factores de TiempoRESUMEN
Individually, D1 and D3 dopamine receptors (D1R and D3R, respectively) have been implicated in L-DOPA-induced dyskinesia (LID). Of late, direct D1R-D3R interactions have been linked to LID yet remain enigmatic. Therefore, the current research sought to characterize consequences of putative D1R-D3R interactions in dyskinesia expression and in LID-associated downstream cellular signaling. To do so, adult male Sprague-Dawley hemi-parkinsonian rats were given daily L-DOPA (6â¯mg/kg; s.c.) for 2 weeks to establish stable LID, as measured via the abnormal voluntary movements (AIMs) scale. Thereafter, rats underwent dose-response AIMs testing for the D1R agonist SKF38393 (0, 0.3, 1.0, 3.0â¯mg/kg) and the D3R agonist, PD128907 (0, 0.1, 0.3, 1.0â¯mg/kg). Each agonist dose-dependently induced dyskinesia, implicating individual receptor involvement. More importantly, when threshold doses were co-administered, rats displayed synergistic exacerbation of dyskinesia. Interestingly, this observation was not mirrored in general locomotor behaviors, highlighting a potentially dyskinesia-specific effect. To illuminate the mechanisms by which D1R-D3R co-stimulation led to in vivo synergy, levels of striatal phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) were quantified after administration of SKF38393 and/or PD128907. Combined agonist treatment synergistically drove striatal pERK1/2 expression. Together, these results support the presence of a functional, synergistic interaction between D1R and D3R that manifests both behaviorally and biochemically to drive dyskinesia in hemi-parkinsonian rats.
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Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/metabolismo , Levodopa/efectos adversos , Trastornos Parkinsonianos/tratamiento farmacológico , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D3/metabolismo , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Antiparkinsonianos/farmacología , Benzopiranos/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Lateralidad Funcional , Levodopa/farmacología , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Oxazinas/farmacología , Oxidopamina , Trastornos Parkinsonianos/metabolismo , Ratas Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D3/agonistasRESUMEN
Dopamine (DA) replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) continues to be the gold-standard treatment for Parkinson's disease (PD). Despite clear symptomatic benefit, long-term L-DOPA use often results in the development of L-DOPA-induced dyskinesia (LID), significantly reducing quality of life and increasing costs for PD patients and their caregivers. Accumulated research has demonstrated that several pre- and post-synaptic mechanisms contribute to LID development and expression. In particular, raphe-striatal hyperinnervation and unregulated DA release from 5-HT terminals is postulated to play a central role in LID manifestation. As such, manipulation of the 5-HT system has garnered considerable attention. Both pre-clinical and clinical research has supported the potential of modulating the 5-HT system for LID prevention and treatment. This review discusses the rationale for continued investigation of several potential anti-dyskinetic strategies including 5-HT stimulation of 5-HT1A and 5-HT1B receptors and blockade of 5-HT2A receptors and SERT. We present the latest findings from experimental and clinical investigations evaluating these 5-HT targets with the goal of identifying those with translational promise and the challenges associated with each.
Asunto(s)
Discinesia Inducida por Medicamentos , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Serotonina/metabolismo , Animales , Antiparkinsonianos/efectos adversos , Humanos , Levodopa/efectos adversos , Receptores de Serotonina/efectos de los fármacos , Serotonina/farmacologíaRESUMEN
BACKGROUND: Local public health agencies play a central role in response to an influenza pandemic, and understanding the willingness of their employees to report to work is therefore a critically relevant concern for pandemic influenza planning efforts. Witte's Extended Parallel Process Model (EPPM) has been found useful for understanding adaptive behavior in the face of unknown risk, and thus offers a framework for examining scenario-specific willingness to respond among local public health workers. We thus aim to use the EPPM as a lens for examining the influences of perceived threat and efficacy on local public health workers' response willingness to pandemic influenza. METHODOLOGY/PRINCIPAL FINDINGS: We administered an online, EPPM-based survey about attitudes/beliefs toward emergency response (Johns Hopkins approximately Public Health Infrastructure Response Survey Tool), to local public health employees in three states between November 2006-December 2007. A total of 1835 responses were collected for an overall response rate of 83%. With some regional variation, overall 16% of the workers in 2006-7 were not willing to "respond to a pandemic flu emergency regardless of its severity". Local health department employees with a perception of high threat and high efficacy--i.e., those fitting a 'concerned and confident' profile in the EPPM analysis--had the highest declared rates of willingness to respond to an influenza pandemic if required by their agency, which was 31.7 times higher than those fitting a 'low threat/low efficacy' EPPM profile. CONCLUSIONS/SIGNIFICANCE: In the context of pandemic influenza planning, the EPPM provides a useful framework to inform nuanced understanding of baseline levels of--and gaps in--local public health workers' response willingness. Within local health departments, 'concerned and confident' employees are most likely to be willing to respond. This finding may allow public health agencies to design, implement, and evaluate training programs focused on emergency response attitudes in health departments.
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Actitud del Personal de Salud , Gripe Humana/epidemiología , Práctica de Salud Pública , Humanos , Estados Unidos/epidemiologíaRESUMEN
Indoor air quality in restaurants was studied in two cities in northwest Ohio after clean indoor air ordinances had been enacted. Carbon dioxide and ultrafine particles were measured in two restaurants in Toledo and two restaurants in Bowling Green. One restaurant in each city was smoke free, and one restaurant in each city contained a dedicated smoking room. A smoke free office space was also assessed as a reference site. Measurements were collected with datalogging instrumentation simultaneously in both the designated smoking room, if present, and in the nonsmoking section. For smoke free establishments, datalogging instrumentation was also used. Carbon dioxide levels were elevated in all four restaurants, with only 32% of the measurements meeting the American Society of Heating, Refrigerating, and Air-Conditioning Engineers (ASHRAE) criterion level of 1000 ppm. Ultrafine particles currently do not have any formal standard or guideline. Statistically significant differences were evident between all four restaurants and the reference site. The largest differences were found between the two designated smoking rooms and the reference site (p < 0.001), with the mean levels in the smoking rooms up to 43 times higher than in the reference site. The results from this study indicate inadequate fresh air supply in all four restaurants, particularly in the designated smoking rooms, and the possibility that the designated smoking rooms were not containing the environment tobacco smoke, based on the ultrafine particle concentrations measured in the nonsmoking areas of the smoking restaurants.