Does the Use of Immunosuppressive Drugs Impact on SARS-CoV-2 Infection Outcome? Data From A National Cohort of Patients With Immune-Mediated Inflammatory Diseases (SAR-COVID Registry).

BACKGROUND/OBJECTIVE: This study describes the impact of immunomodulatory and/or immunosuppressive (IM/IS) drugs in the outcomes of COVID-19 infection in a cohort of patients with immune-mediated inflammatory diseases (IMIDs). METHODS: Adult patients with IMIDs with a confirmed SARS-CoV-2 infection were included. Data were reported by the treating physician between August 13, 2020 and July 31, 2021. Sociodemographic data, comorbidities, and DMARDs, as well as clinical characteristics, complications, and treatment of the SARS-CoV-2 infection, were recorded. Descriptive analysis and multivariable logistic regression models were carried out. RESULTS: A total of 1672 patients with IMIDs were included, of whom 1402 were treated with IM/IS drugs. The most frequent diseases were rheumatoid arthritis (47.7%) and systemic lupus erythematosus (18.4%). COVID-19 symptoms were present in 95.2% of the patients. A total of 461 (27.6%) patients were hospitalized, 8.2% were admitted to the intensive care unit, and 4.4% died due to COVID-19.Patients without IM/IS treatment used glucocorticoids less frequently but at higher doses, had higher levels of disease activity, were significantly older, were more frequently hospitalized, admitted to the intensive care unit, and died due to COVID-19. After adjusting for these factors, treatment with IM/IS drugs was not associated with a worse COVID-19 outcome (World Health Organization-Ordinal Scale ≥5) (odds ratio, 1.24; 95% confidence interval, 0.73-2.06). CONCLUSIONS: SAR-COVID is the first multicenter Argentine registry collecting data from patients with rheumatic diseases and SARS-CoV-2 infection. After adjusting for relevant covariates, treatment with IM/IS drugs was not associated with severe COVID-19 in patients with IMIDs. STUDY REGISTRATION: This study has been registered in ClinicalTrials.gov under the number NCT04568421.

Características clínicas y evolución de la infección por SARS-CoV-2 en pacientes con lupus eritematoso sistémico en Argentina: datos del registro nacional SAR-COVID / Clinical characteristics and course of SARS-CoV-2 infection in patients with systemic lupus erythematosus in Argentina: data from the SAR-COVID national registry

Introducción: el lupus eritematoso sistémico (LES) es una enfermedad sistémica que se ha asociado a mayor severidad con la infección por SARS-CoV-2. Particularmente la alta actividad de la enfermedad y algunos inmunosupresores se han vinculado a peores desenlaces. Objetivos: describir las características por SARS-CoV-2 en pacientes con LES en Argentina del registro SAR-COVID y establecer los factores asociados a peor desenlace de la misma. Materiales y métodos: estudio observacional. Se incluyeron pacientes con diagnóstico de LES con infección confirmada por SARS-CoV-2 (RT-PCR y/o serología positiva) del registro SAR-COVID. Los datos se recolectaron desde agosto de 2020 hasta marzo de 2022. El desenlace de la infección se midió mediante la escala ordinal de la Organización Mundial de la Salud (EO-OMS). Se definió COVID-19 severo con un valor EO-OMS ≥5. Análisis descriptivo, test T de Student, test de Mann Whitney U, ANOVA, chi2 y Fisher. Regresión logística múltiple. Resultados: se incluyeron 399 pacientes, el 93% de sexo femenino, con una edad media de 40,9 años (DE 12,2). El 39,6% tenía al menos una comorbilidad. Al momento de la infección, el 54,9% recibía glucocorticoides, el 30,8% inmunosupresores y el 3,3% agentes biológicos. La infección por SARS-CoV-2 fue leve en la mayoría de los casos, mientras que un 4,6% tuvo curso severo y/o falleció. Estos últimos presentaban comorbilidades, usaban glucocorticoides y tenían síndrome antifosfolipídico (SAF) con mayor frecuencia y mayor actividad de la enfermedad al momento de la infección. En el análisis multivariado, la hipertensión arterial, el diagnóstico de SAF y el uso de glucocorticoides se asociaron a hospitalización severa y/o muerte por COVID-19 (EO-OMS ≥5). Conclusiones: en esta cohorte de pacientes con LES con infección por SARS-CoV-2 confirmada, la mayoría cursó de manera sintomática, un 22,1% fue hospitalizado y un 5% requirió ventilación mecánica. La mortalidad fue cercana al 3%. El diagnóstico de SAF, tener hipertensión arterial y el uso de glucocorticoides se asociaron significativamente con COVID-19 severo.

Introduction: systemic lupus erythematosus (SLE) is a systemic disease that has been associated with greater severity with SARS-CoV-2 infection. Particularly high disease activity and some immunosuppressants have been linked to worse outcomes. Objectives: to describe the characteristics due to SARS-CoV-2 in patients with SLE in Argentina from the SAR-COVID registry and to establish the factors associated with a worse outcome of the same. Materials and methods: observational study. Patients diagnosed with SLE with confirmed SARS-CoV-2 infection (RT-PCR and/or positive serology) from the SAR-COVID registry were included. Data was collected from August 2020 to March 2022. The outcome of the infection was measured using the World Health Organization - ordinal scale (WHO-OS). Severe COVID-19 was defined as an WHO-OS value ≥5. Descriptive analysis, Student's T test, Mann Whitney U, ANOVA, chi2 and Fisher. Multiple logistic regression. Results: a total of 399 patients were included, 93% female, with a mean age of 40.9 years (SD 12.2), 39.6% had at least one comorbidity. At the time of infection, 54.9% were receiving glucocorticoids, 30.8% immunosuppressants, and 3.3% biological agents. SARS-CoV-2 infection was mild in most cases, while 4.6% had a severe course and/or died. The latter had comorbidities, used glucocorticoids and had antiphospholipid syndrome (APS) more frequently and higher disease activity at the time of infection. In the multivariate analysis, high blood pressure, the diagnosis of APS, and the use of glucocorticoids were associated with severe hospitalization and/or death from COVID-19 (WHO-EO ≥5). Conclusions: in this cohort of SLE patients with confirmed SARS-CoV-2 infection, most had a symptomatic course, 22.1% were hospitalized, and 5% required mechanical ventilation. Mortality was close to 3%. The diagnosis of APS, having high blood pressure, and the use of glucocorticoids were significantly associated with severe COVID-19.

Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study.

BACKGROUND: Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. METHODS: In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behçet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. FINDINGS: Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behçet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31-1·57]), were male compared with female (1·38 [1·05-1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23-1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50-3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49-3·02]). Risk factors varied among different disease subtypes. INTERPRETATION: Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. FUNDING: American College of Rheumatology and the European Alliance of Associations for Rheumatology.

Clinical and molecular characterization of mitochondrial DNA disorders in a group of Argentinian pediatric patients.

OBJECTIVE: To describe the clinical and molecular features of a group of Argentinian pediatric patients with mitochondrial DNA (mtDNA) disorders, and to evaluate the results of the implementation of a classical approach for the molecular diagnosis of mitochondrial diseases. METHODS: Clinical data from 27 patients with confirmed mtDNA pathogenic variants were obtained from a database of 89 patients with suspected mitochondrial disease, registered from 2014 to 2020. Clinical data, biochemical analysis, neuroimaging findings, muscle biopsy and molecular studies were analyzed. RESULTS: Patients were 18 females and 9 males, with ages at onset ranging from 1 week to 14 years (median = 4 years). The clinical phenotypes were: mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome (n = 11), Leigh syndrome (n = 5), Kearns-Sayre syndrome (n = 3), Chronic Progressive External Ophthalmoplegia (n = 2), Leber hereditary optic neuropathy (n = 2), myoclonic epilepsy associated with ragged-red fibers (n = 1) and reversible infantile myopathy with cytochrome-C oxidase deficiency (n = 3). Most of the patients harbored pathogenic single nucleotide variants, mainly involving mt-tRNA genes, such as MT-TL1, MT-TE and MT-TK. Other point variants were found in complex I subunits, like MT-ND6, MT-ND4, MT-ND5; or in MT-ATP6. The m.13513G > A variant in MT-ND5 and the m.9185 T > C variant in MT-ATP6 were apparently de novo. The rest of the patients presented large scale-rearrangements, either the "common" deletion or a larger deletion. CONCLUSIONS: This study highlights the clinical and genetic heterogeneity of pediatric mtDNA disorders. All the cases presented with classical phenotypes, being MELAS the most frequent. Applying classical molecular methods, it was possible to achieve a genetic diagnosis in 30% of the cases, suggesting that this is an effective first approach, especially for those centers from low-middle income countries, leaving NGS studies for those patients with inconclusive results.

Características epidemiológicas y desenlaces de la infección por SARS-CoV-2 en pacientes con patologías reumáticas: Primer reporte del registro argentino SAR-COVID / Epidemiological characteristics and outcomes of SARS-CoV-2 infection in patients with rheumatic diseases: First report from the Argentine SAR-COVID registry

Con el fin de evaluar el impacto de la infección por SARS-CoV-2 en pacientes con enfermedades reumáticas, la Sociedad Argentina de Reumatología desarrolló el Registro Nacional de Pacientes con Enfermedades Reumáticas y COVID-19 (SAR-COVID). El objetivo del presente trabajo fue evaluar las características sociodemográficas y clínicas de los pacientes con enfermedades reumáticas e infección por SARS-CoV-2 incluidos en el registro SAR-COVID y describir las complicaciones y desenlaces de la COVID-19 en esta población. Material y métodos: SAR-COVID es un registro nacional, multicéntrico y observacional, en el cual se incluyen de manera consecutiva pacientes ≥18 años de edad, con diagnóstico de alguna enfermedad reumática que hayan cursado infección por SARS-CoV-2. Se consignan datos sociodemográficos, comorbilidades, enfermedad reumática y su tratamiento, características clínicas, laboratorio, complicaciones y tratamientos de la infección por SARS-CoV-2. Resultados: Se incluyeron 525 pacientes, con una edad media de 51.3 años (DE 15.2). Las enfermedades reumatológicas más frecuentes fueron artritis reumatoidea (40.4%), lupus eritematoso sistémico (14.9%) y espondiloartritis (8.2%). El 72.9% recibía tratamiento inmunosupresor o inmunomodulador al momento del inicio de la infección y 36.9% glucocorticoides. En la mayoría de los casos, el diagnóstico de infección por SARS-CoV-2 se llevó a cabo mediante RT-PCR (95%), 39.4% en la consulta externa, 32.2% en el departamento de urgencias, y 14.7% durante la hospitalización. La mayoría de los pacientes presentaron síntomas, siendo los más frecuentes fiebre (56.2%), tos (46.7%) y cefalea (39.2%). Durante la infección, 35.1% requirieron hospitalización y 11.6% en unidad de cuidados intensivos. El 75.1% se recuperó completamente, 8.4% presentó secuelas y 6.9% murieron a causa de COVID-19. Conclusión: En este primer reporte del registro SAR-COVID encontramos una amplia distribución de enfermedades reumáticas. La mayoría de los pacientes tuvieron una buena evolución de la infección, sin embargo un 7% falleció como consecuencia de la misma, datos comparables a los reportados por otros registros latinoamericanos con poblaciones similares.

In order to assess the impact of SARS-CoV-2 infection in patients with rheumatic diseases, the Argentine Society of Rheumatology has developed the National Registry of Patients with Rheumatic Diseases and COVID-19 (SAR-COVID). The aim of this study was to evaluate the sociodemographic and clinical characteristics of patients with rheumatic diseases and SARS-CoV-2 infection included in the SAR-COVID registry and to describe the complications and outcomes of COVID-19 in this population. Methods: SAR-COVID is a national, multicenter and observational registry, in which patients ≥18 years of age, with a diagnosis of a rheumatic disease who had SARS-CoV-2 infection are consecutively included. Sociodemographic data, comorbidities, underlying rheumatic disease and treatment, clinical characteristics, complications, laboratory and treatment of the SARS-CoV-2 infection were recorded. Results: A total of 525 patients were included, with a mean age of 51.3 years (SD 15.2). The most frequent rheumatic diseases were rheumatoid arthritis (40.4%), systemic lupus erythematous (14.9%) and spondyloarthritis (8.2%). At the time of the infection, 72.9% were receiving immunosuppressive or immunomodulatory treatment and 36.9% glucocorticoids. Most of the patients were diagnosed using RT-PCR (95%), at outpatient consultation (39.4%), at the emergency room (32.2%) or during hospitalization (14.7%). Symptoms were present in 96% of the patients, the most frequent being fever (56.2%), cough (46.7%) and headache (39.2%). During infection, 35.1% were hospitalized, 11.6% were admitted to the ICU and 6.9% died due to COVID-19. Most of them (75.1%) recovered completely. Conclusions: In this first report of the SAR-COVID registry we found a wide distribution of rheumatic diseases. Most of the patients had a good evolution of the infection, however 7% died as a result of it, comparable to other Latin American registries with similar populations.

Molecular diagnosis of epileptic encephalopathy of the first year of life applying a customized gene panel in a group of Argentinean patients.

OBJECTIVE: The aim of this study was to perform a molecular characterization of 17 Argentinean pediatric patients with diagnosis of having epileptic encephalopathies (EEs) of the first year of life without known etiology, applying next-generation sequencing (NGS). METHODS: We included 17 patients with EE with age of onset under 12 months without known etiology after ruling out structural abnormalities, metabolic disorders, and large chromosomal abnormalities. They presented with the following clinical phenotypes: Dravet syndrome (DS; n: 7), epilepsy of infancy with migrating focal seizures (EIMFS; n: 3), West syndrome (WS; n: 2), and undetermined epileptic encephalopathy (UEE; n: 5). Neurologic examinations, seizure semiology, brain magnetic resonance imaging, and standard electroencephalography (EEG) or video-EEG studies were performed in all cases. Using a custom amplicon strategy, we designed an NGS panel to study 47 genes associated with EEs. RESULTS: Pathogenic variants were detected in 8 cases (47%), including seven novel pathogenic variants and one previously reported as being pathogenic. The pathogenic variants were identified in 6 patients with DS (SCN1A gene), one with EIMFS (SCN2A gene), and one with UEE (SLC2A1 gene). Nonrelevant variants were identified in the patients with WS. CONCLUSION: We demonstrated the feasibility of an NGS-gene panel approach for the analysis of patients with EE in our setting. A genetic diagnosis was achieved in nearly 50% of patients, 87% of them presenting with nonpreviously reported variants. The early identification of the underlying causative genetic alteration will be a valuable tool for providing prognostic information and genetic counselling and also to improve therapeutic decisions in Argentinean patients.

Construction and reconstruction of brain circuits: normal and pathological axon guidance.

Perception of our environment entirely depends on the close interaction between the central and peripheral nervous system. In order to communicate each other, both systems must develop in parallel and in coordination. During development, axonal projections from the CNS as well as the PNS must extend over large distances to reach their appropriate target cells. To do so, they read and follow a series of axon guidance molecules. Interestingly, while these molecules play critical roles in guiding developing axons, they have also been shown to be critical in other major neurodevelopmental processes, such as the migration of cortical progenitors. Currently, a major hurdle for brain repair after injury or neurodegeneration is the absence of axonal regeneration in the mammalian CNS. By contrasts, PNS axons can regenerate. Many hypotheses have been put forward to explain this paradox but recent studies suggest that hacking neurodevelopmental mechanisms may be the key to promote CNS regeneration. Here we provide a seminar report written by trainees attending the second Flagship school held in Alpbach, Austria in September 2018 organized by the International Society for Neurochemistry (ISN) together with the Journal of Neurochemistry (JCN). This advanced school has brought together leaders in the fields of neurodevelopment and regeneration in order to discuss major keystones and future challenges in these respective fields.

Acute acetaminophen intoxication induces direct neurotoxicity in rats manifested as astrogliosis and decreased dopaminergic markers in brain areas associated with locomotor regulation.

Acetaminophen (APAP) administration at therapeutic doses is safe, however overdosing produces hepatocellular injury via a multifactorial mechanism(s) that involves generation of reactive oxygen species (ROS), being the most common cause of acute liver failure (ALF) in the northern hemisphere. Brain alterations induced by APAP intoxication are usually considered secondary to hepatic encephalopathy development due to ALF. Although APAP is primarily metabolized in the liver, it is also distributed and metabolized homogeneously in the brain, affecting brain redox status. Nevertheless, comprehensive studies on the potential of APAP intoxication to produce brain toxicity are scarce. The aim of this study was to characterize the direct toxic effects of APAP in different regions of the brain and on behavior in rats where the magnitude of hepatotoxicity produced is not associated with ALF. The present work demonstrates that APAP intoxication producing hepatotoxicity, but not ALF in rats, is associated with marked hypolocomotion. Our studies also suggest that selective downregulation in dopamine levels in brain areas that regulate motor activity may be responsible, in part, for the decreased locomotion observed with APAP treatment. Furthermore, we observed that the brain histoarchitecture is conserved and that edema is not present. However, an increase in oxidative stress, reactive astrogliosis and a decrease in neuron processes are the main features observed in APAP-intoxicated animals. These effects might be partly due to direct toxic effects of APAP in brain, since the same reactive astrogliosis observed in rats was also observed in rat primary astrocyte cultures exposed to APAP.

Lupus eritematoso sistémico y parvovirus. ¿Relación causal?: Reporte de un caso / Systemic lupus erythematosus and parvovirus. Causal relationship?: Case report

El lupus eritematoso sistémico (LES) es una enfermedad autoinmune de etiología aún desconocida, afecta a individuos genéticamente predispuestos. Es desencadenado por factores hormonales, estrogénicos, ambientales y virales como hepatitis B/C, citomegalovirus (CMV), herpes o parvovirus B19 (PVB19). El PVB19 puede afectar diferentes órganos y presentar manifestaciones clínicas e inmunológicas, similares a las que se observan en pacientes con LES. Se han descripto alteraciones inmunológicas hasta en 79% de los pacientes con infección asociada por PVB19, principalmente positivización de anticuerpos antinucleares (ANA).

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology that affects genetically predisposed individuals. It is triggered by hormonal, estrogenic, environmental and viral factors such as hepatitis B/C, cytomegalovirus (CMV), herpes or parvovirus B19 (PVB19). PVB19 can affect different organs and present clinical and immunological diseases, as well as those observed in patients with SLE. Immunological alterations have been described in up to 79% of patients with infection associated with PVB19, mainly positivization of antinuclear antibodies (ANA).

The Kinase Fyn As a Novel Intermediate in L-DOPA-Induced Dyskinesia in Parkinson's Disease.

Dopamine replacement therapy with L-DOPA is the treatment of choice for Parkinson's disease; however, its long-term use is frequently associated with L-DOPA-induced dyskinesia (LID). Many molecules have been implicated in the development of LID, and several of these have been proposed as potential therapeutic targets. However, to date, none of these molecules have demonstrated full clinical efficacy, either because they lie downstream of dopaminergic signaling, or due to adverse side effects. Therefore, discovering new strategies to reduce LID in Parkinson's disease remains a major challenge. Here, we have explored the tyrosine kinase Fyn, as a novel intermediate molecule in the development of LID. Fyn, a member of the Src kinase family, is located in the postsynaptic density, where it regulates phosphorylation of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in response to dopamine D1 receptor stimulation. We have used Fyn knockout and wild-type mice, lesioned with 6-hydroxydopamine and chronically treated with L-DOPA, to investigate the role of Fyn in the induction of LID. We found that mice lacking Fyn displayed reduced LID, ΔFosB accumulation and NR2B phosphorylation compared to wild-type control mice. Pre-administration of saracatinib (AZD0530), an inhibitor of Fyn activity, also significantly reduced LID in dyskinetic wild-type mice. These results support that Fyn has a critical role in the molecular pathways affected during the development of LID and identify Fyn as a novel potential therapeutic target for the management of dyskinesia in Parkinson's disease.

Regulation of Pleiotrophin and Fyn in the striatum of rats undergoing L-DOPA-induced dyskinesia.

L-DOPA is the gold standard pharmacological therapy for symptomatic treatment of Parkinson's disease (PD), however, its long-term use is associated with the emergence of L-DOPA-induced dyskinesia (LID). Understanding the underlying molecular mechanisms of LID is crucial for the development of newer and more effective therapeutic approaches. In previous publications, we have shown that Pleiotrophin (PTN), a developmentally regulated trophic factor, is up-regulated by L-DOPA in the striatum of dopamine denervated rats. We have also shown that both mRNA and protein levels of RPTPζ/ß, a PTN receptor, were upregulated in the same experimental condition and expressed in striatal medium spiny neurons. The PTN-RPTPζ/ß intracellular pathway has not been fully explored and it might be implicated in the striatal plastic changes triggered by L-DOPA treatment. RPTPζ/ß is part of the postsynaptic density zone and modulates Fyn, a Src tyrosine kinase that regulates the NR2A and NR2B subunits of the NMDA receptor and has been singled out as a key molecule in the development of LID. In this study, we evaluated the changes in PTN and Fyn protein levels and Fyn phosphorylation status in the 6-OHDA rat model of PD rendered dyskinetic with L-DOPA. We found an increase in the number of PTN immunoreactive neurons, no changes in the amount of total Fyn but a significant increase in Fyn phosphorylation in the dorsolateral striatum of dyskinetic rats. Our results support the idea that both PTN and Fyn may be involved in the development of LID, further contributing to the understanding of its molecular mechanisms.

Combined Effects of Simultaneous Exposure to Caffeine and Cocaine in the Mouse Striatum.

Caffeine is the world's most popular psychoactive drug and is also an active adulterant found in many drugs of abuse, including seized cocaine samples. Despite several studies which examine the effects of caffeine or cocaine administered as single agents, little data are available for these agents when given in combination. The purpose of the present study was to determine if combined intake of both psychostimulants can lead to maladaptive changes in striatal function. Mice were injected with a binge regimen (intermittent treatment for 13 days) of caffeine (3 × 5 mg/kg), cocaine (3 × 10 mg/kg), or combined administration. We found that chronic caffeine potentiated locomotion induced by cocaine and that both caffeine-treated groups showed sensitization. Striatal tissue was obtained 24 h and 7 days after last injection (withdrawal) for immunohistochemistry and mRNA expression. Our results show that combined intake of both psychostimulants can increase GFAP immunoreactivity in the striatum at both times post treatment. Gene expression analysis, targeted at dopamine, adenosine, and glutamate receptor subunit genes, revealed significant transcript down-regulation in the dorsal striatum of AMPA, NMDA, D1 and D2 receptor subunit mRNA expression in the group that received combined treatment, but not after individual administration. At withdrawal, we found increased D1 receptor mRNA expression along with increased A1, AMPA, NMDA, and metabotropic subunit expression. A2A mRNA showed decreased expression after both times in all experimental groups. Our study provides evidence that there are striatal alterations mediated by combined caffeine and cocaine administration, and highlights negative outcomes of chronic intake of both psychostimulants.

Contrasting gene expression patterns induced by levodopa and pramipexole treatments in the rat model of Parkinson's disease.

Whether the treatment of Parkinson's disease has to be initiated with levodopa or a D2 agonist like pramipexole remains debatable. Levodopa is more potent against symptoms than D2 agonists, but D2 agonists are less prone to induce motor complications and may have neuroprotective effects. Although regulation of plastic changes in striatal circuits may be the key to their different therapeutic potential, the gene expression patterns induced by de novo treatments with levodopa or D2 agonists are currently unknown. By studying the whole striatal transcriptome in a rodent model of early stage Parkinson's disease, we have identified the gene expression patterns underlying therapeutically comparable chronic treatments with levodopa or pramipexole. Despite the overall relatively small size of mRNA expression changes at the level of individual transcripts, our data show a robust and complete segregation of the transcript expression patterns induced by both treatments. Moreover, transcripts related to oxidative metabolism and mitochondrial function were enriched in levodopa-treated compared to vehicle-treated and pramipexole-treated animals, whereas transcripts related to olfactory transduction pathways were enriched in both treatment groups compared to vehicle-treated animals. Thus, our data reveal the plasticity of genetic striatal networks possibly contributing to the therapeutic effects of the most common initial treatments for Parkinson's disease, suggesting a role for oxidative stress in the long term complications induced by levodopa and identifying previously overlooked signaling cascades as potentially new therapeutic targets.