The Degenerating Substantia Nigra as a Susceptible Region for Gene Transfer-Mediated Inflammation

Parkinson's disease (PD) is characterized by the progressive degeneration of neurons in the substantia nigra pars compacta (SN). The naïve SN is highly susceptible to inflammation. In addition, microglial activation in the degenerating SN displays distinct characteristics that increase the reactivity of the region towards inflammatory stimuli. On the other hand, gene therapy for PD has recently move forward into clinical settings, with PD being the neurodegenerative disorder with the highest number of Phase I/II gene therapy clinical trials approved and completed. These clinical trials are not targeting the SN, but this region is a certain candidate for future gene therapy interventions. Here, the unique immune-related properties of the degenerating SN in the context of a putative gene therapy intervention are reviewed. Several variables affecting the host response to gene delivery such as vector type and dosage, age and stage of disease of patients, and method of gene delivery and transgene used are discussed. Finally, approaches to diminish the risk of immune-mediated toxicity by gene transfer in the SN are presented

Differential vulnerability of adult neurogenesis by adult and prenatal inflammation: role of TGF-β1

Peripheral inflammation, both during the prenatal period and in adulthood, impairs adult neurogenesis. We hypothesized that, similar to other programming effects of prenatal treatments, only prenatal inflammation causes long-term consequences in adult neurogenesis and its neurogenic niche. To test this, pregnant Wistar rats were subcutaneously injected with lipopolysaccharide (LPS; 0.5 mg/kg) or saline solution every other day from gestational/embryonic day (GD) 14-20. In addition adult animals were injected with a single intraperitoneal saline or LPS injection (1 mg/kg) and the effects on neurogenesis were assessed 7 days later. Alternatively, to evaluate long-term consequences of adult LPS injections, LPS (1 mg/kg) was administered peripherally to adult rats four times every other day, and the effects on neurogenesis were assessed 60 days later. Prenatal and adult LPS treatments reduced adult neurogenesis and provoked specific microglial (but not astroglial) activation in the dentate gyrus (DG). However, only prenatal inflammation-mediated effects were long-lasting (at least 60 days). Moreover, these effects were specific to the DG since the Subventricular Zone (SVZ) and the Rostral Migratory Stream (RMS) were not affected. In addition, these stimuli caused differential effects on the molecular components of the neurogenic niche; only prenatal LPS treatment reduced the local levels of TGF-β1 mRNA in the DG. Finally, TGF-β1 exerted its pro-neurogenic effects via the Smad 2/3 pathway in a neural stem cell culture. Taken together, these data add evidence to the duration, regional specificity and dramatic consequences of prenatal immune programming on CNS physiology, compared with the limited response observed in the adult brain.Fil: Graciarena, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Roca, Valeria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Mathieu, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Depino, Amaicha Mara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Pitossi, Fernando Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Distal Tumors Elicit Distinctive Gene Expression Changes in Mouse Brain, Different from Those Induced by Arthritis

Background: Tumor progression is characterized by high mutation rates, each mutation potentially generating an “alarm” signal. The brain is the main integrator of signals arising in the periphery from changes in homeostasis. We hypothesized that tumors growing at a distant site might be a stimulus strong enough to be molecularly sensed and integrated by the brain. Results: Transcriptome analysis of the mouse hypothalamus, midbrain, and pre-fontal cortex at different time points following administration at a distant site of mammary, lung and colon cancer cells evidenced cancer-type and brain-region specific changes in gene expression. On the contrary, no significant gene expression changes were detected in the liver. The hypothalamus was the region with the largest number of differentially expressed genes. On the array and off the array analysis of hypothalamic samples using real time PCR confirmed changes in genes associated with synaptic activity and sickness response, respectively. Gene clustering allowed the discrimination between each cancer model and between the cancer models and arthritis. Conclusions: The present data provides evidence of changes in gene expression in the brain during progression of distal tumors and arthritis highlighting a potential link between distal pathological processes and the brain.Fil: Alvarez, Mariano J.. Gentron Research Unit; ArgentinaFil: Salibe, Mariano C.. Gentron Research Unit; ArgentinaFil: Stolovitzky, Gustavo. Ibm Research. Thomas J. Watson Research Center; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Pitossi, Fernando Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson‘s disease

Parkinson's disease is a neurodegenerative disorder with uncertain aetiology and ill-defined pathophysiology. Activated microglial cells in the substantia nigra (SN) are found in all animal models of Parkinson's disease and patients with the illness. Microglia may, however, have detrimental and protective functions in this disease. In this study, we tested the hypothesis that a sub-toxic dose of an inflammogen (lipopolysaccharide) can shift microglia to a pro-inflammatory state and exacerbate disease progression in an animal model of Parkinson's disease. Central lipopolysaccharide injection in a degenerating SN exacerbated neurodegeneration, accelerated and increased motor signs and shifted microglial activation towards a pro-inflammatory phenotype with increased interleukin-1β (IL-1β) secretion. Glucocorticoid treatment and specific IL-1 inhibition reversed these effects. Importantly, chronic systemic expression of IL-1 also exacerbated neurodegeneration and microglial activation in the SN. In vitro, IL-1 directly exacerbated 6-OHDA-triggered dopaminergic toxicity. In vivo, we found that nitric oxide was a downstream molecule of IL-1 action and partially responsible for the exacerbation of neurodegeneration observed. Thus, IL-1 exerts its exacerbating effect on degenerating dopaminergic neurons by direct and indirect mechanisms. This work demonstrates an unequivocal association between IL-1 overproduction and increased disease progression, pointing to inflammation as a risk factor for Parkinson's disease and suggesting that inflammation should be efficiently handled in patients to slow disease progression.Fil: Pott Godoy, María Clara. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Físico Matemática. Cátedra de Matemáticas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Tarelli, Rodolfo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Físico Matemática. Cátedra de Matemáticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Ferrari, Carina Cintia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Físico Matemática. Cátedra de Matemáticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Sarchi, María Inés. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Físico Matemática. Cátedra de Matemáticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Pitossi, Fernando Juan. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Físico Matemática. Cátedra de Matemáticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentin

Environmental enrichment improves cognitive symptoms and pathological features in a focal model of cortical damage of multiple sclerosis

Multiple Sclerosis (MS) is a neuroinflammatory disease affecting white and grey matter, it is characterized by demyelination, axonal degeneration along with loss of motor, sensitive and cognitive functions. MS is a heterogeneous disease that displays different clinical courses: relapsing/remitting MS (RRMS), and MS progressive forms: primary progressive (PPMS) and secondary progressive (SPMS). Cortical damage in the progressive MS forms has considerable clinical relevance due to its association with cognitive impairment and disability progression in patients. One treatment is available for the progressive forms of the disease, but none are specific for cognitive deficits. We developed an animal model that reflects most of the characteristics of the cortical damage, such as cortical neuroinflammation, demyelination, neurodegeneration and meningeal inflammation, which was associated with cognitive impairment. Cognitive rehabilitation, exercise and social support have begun to be evaluated in patients and animal models of neurodegenerative diseases. Environmental enrichment (EE) provides exercise as well as cognitive and social stimulation. EE has been demonstrated to exert positive effects on cognitive domains, such as learning and memory, and improving anxiety-like symptoms. We proposed to study the effect of EE on peripherally stimulated cortical lesion induced by the long term expression of interleukin IL-1β (IL-1β) in adult rats. Here, we demonstrated that EE: 1) reduces the peripheral inflammatory response to the stimulus, 2) ameliorates cognitive deficits and anxiety-like symptoms, 3) modulates neurodegeneration, demyelination and glial activation, 4) regulates neuroinflammation by reducing the expression of pro-inflammatory cytokines and enhancing the expression of anti-inflammatory ones. Our findings correlate with the fact that EE housing could be considered an effective non- pharmacological therapeutic agent that can synergistically aid in the rehabilitation of the disease.Fil: Silva, Berenice Anabel. Instituto Universidad Escuela de Medicina del Hospital Italiano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Leal, Maria Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Farias, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Erhardt, Brenda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Pitossi, Fernando Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ferrari, Carina Cintia. Instituto Universidad Escuela de Medicina del Hospital Italiano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

CNS response to a second pro-inflammatory event depends on whether the primary demyelinating lesion is active or resolved

Interleukin-1β (IL-1β) is considered to be one of the most important mediators in the pathogenesis of inflammatory diseases, particularly in neurodegenerative diseases such as multiple sclerosis (MS). MS is a chronic inflammatory disease characterized by demyelination and remyelination events, with unpredictable relapsing and remitting episodes that seldom worsen MS lesions. We proposed to study the effect of a unique component of the inflammatory process, IL-1β, and evaluate its effect in repeated episodes, similar to the relapsing-remitting MS pathology. Using adenoviral vectors, we developed a model of focal demyelination/remyelination triggered by the chronic expression of IL-1β. The long-term expression of IL-1β in the striatum produced blood-brain barrier (BBB) breakdown, demyelination, microglial/macrophage activation, and neutrophil infiltration but no overt neuronal degeneration. This demyelinating process was followed by complete remyelination of the area. This simple model allows us to study demyelination and remyelination independently of the autoimmune and adaptive immune components. Re-exposure to this cytokine when the first inflammatory response was still unresolved generated a lesion with decreased neuroinflammation, demyelination, axonal injury and glial response. However, a second long-term expression of IL-1β when the first lesion was resolved could not be differentiated from the first event. In this study, we demonstrated that the response to a second inflammatory stimulus varies depending on whether the initial lesion is still active or has been resolved. Considering that anti-inflammatory treatments have shown little improvement in MS patients, studies about the behavior of specific components of the inflammatory process should be taken into account to develop new therapeutic tools.Fil: Murta, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Pitossi, Fernando Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ferrari, Carina Cintia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Chronic expression of transforming growth factor-beta enhances adult neurogenesis

Neural stem cells reside in two neurogenic regions of the adult brain: the dentate gyrus of the hippocampus (DG) and the subventricular zone (SVZ). Their proliferation, differentiation, migration and survival are modulated by intrinsic and extrinsic signals, forming a neurogenic niche. Brain cytokines have only been recently regarded as possible components of this neurogenic niche. In particular, we have demonstrated that transforming growth factor-beta (TGF-beta) has a pro-neurogenic effect in the DG in a model of increased neurogenesis by adrenalectomy. We wanted to test whether TGF-beta has a similar effect in another neurogenic region, namely the SVZ. To test this possibility, adult rats were injected with adenoviral vectors expressing TGF-beta (Ad-TGF) or beta-galactosidase (Ad-bgal) in the SVZ and neurogenesis was evaluated 3 weeks later. We have observed that chronic TGF-beta expression increased neurogenesis in the ipsilateral hemisphere of Ad-TGF but not in Ad-bgal-treated rats compared to their contralateral side. In addition, an unspecific effect of the adenoviral vector per se could not be totally discarded. We conclude, under our experimental conditions, that TGF-beta could enhance adult neurogenesis in the SVZ. This data increase the growing evidence supporting a pro-neurogenic role of anti-inflammatory cytokines in the adult brain.Fil: Mathieu, Patricia Andrea. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Piantanida, Ana Paula. Fundación Instituto Leloir; . Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: Pitossi, Fernando Juan. Fundación Instituto Leloir; . Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentin