PPARs and Their Neuroprotective Effects in Parkinson’s Disease: A Novel Therapeutic Approach in α-Synucleinopathy?

Parkinson’s disease (PD) is the most common α-synucleinopathy worldwide. The pathognomonic hallmark of PD is the misfolding and propagation of the α-synuclein (α-syn) protein, observed in post-mortem histopathology. It has been hypothesized that α-synucleinopathy triggers oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction, leading to neurodegeneration. To this date, there are no disease-modifying drugs that generate neuroprotection against these neuropathological events and especially against α-synucleinopathy. Growing evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists confer neuroprotective effects in PD, however, whether they also confer an anti-α-synucleinopathy effect is unknown. Here we analyze the reported therapeutic effects of PPARs, specifically the gamma isoform (PPARγ), in preclinical PD animal models and clinical trials for PD, and we suggest possible anti-α-synucleinopathy mechanisms acting downstream from these receptors. Elucidating the neuroprotective mechanisms of PPARs through preclinical models that mimic PD as closely as possible will facilitate the execution of better clinical trials for disease-modifying drugs in PD

PPARs and Their Neuroprotective Effects in Parkinson’s Disease: A Novel Therapeutic Approach in α-Synucleinopathy?

Parkinson’s disease (PD) is the most common α-synucleinopathy worldwide. The pathognomonic hallmark of PD is the misfolding and propagation of the α-synuclein (α-syn) protein, observed in post-mortem histopathology. It has been hypothesized that α-synucleinopathy triggers oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction, leading to neurodegeneration. To this date, there are no disease-modifying drugs that generate neuroprotection against these neuropathological events and especially against α-synucleinopathy. Growing evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists confer neuroprotective effects in PD, however, whether they also confer an anti-α-synucleinopathy effect is unknown. Here we analyze the reported therapeutic effects of PPARs, specifically the gamma isoform (PPARγ), in preclinical PD animal models and clinical trials for PD, and we suggest possible anti-α-synucleinopathy mechanisms acting downstream from these receptors. Elucidating the neuroprotective mechanisms of PPARs through preclinical models that mimic PD as closely as possible will facilitate the execution of better clinical trials for disease-modifying drugs in PD

Acute Neuroinflammatory Response in the Substantia Nigra Pars Compacta of Rats after a Local Injection of Lipopolysaccharide

Models of Parkinson’s disease with neurotoxins have shown that microglial activation does not evoke a typical inflammatory response in the substantia nigra, questioning whether neuroinflammation leads to neurodegeneration. To address this issue, the archetypal inflammatory stimulus, lipopolysaccharide (LPS), was injected into the rat substantia nigra. LPS induced fever, sickness behavior, and microglial activation (OX42 immunoreactivity), followed by astrocyte activation and leukocyte infiltration (GFAP and CD45 immunoreactivities). During the acute phase of neuroinflammation, pro- and anti-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-4, and IL-10) responded differentially at mRNA and protein level. Increased NO production and lipid peroxidation occurred at 168 h after LPS injection. At this time, evidence of neurodegeneration could be seen, entailing decreased tyrosine hydroxylase (TH) immunoreactivity, irregular body contour, and prolongation discontinuity of TH+ cells, as well as apparent phagocytosis of TH+ cells by OX42+ cells. Altogether, these results show that LPS evokes a typical inflammatory response in the substantia nigra that is followed by dopaminergic neurodegeneration

Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats with α-synucleinopathy

[INLINE:1] Parkinsonism by unilateral, intranigral β-sitosterol β-D-glucoside administration in rats is distinguished in that the α-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time, thus replicating several clinical features of Parkinson's disease, a typical α-synucleinopathy. As Nurr1 represses α-synuclein, we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateral β-sitosterol β-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection. This study found that rNurr1-V5 expression but not that of the green fluorescent protein (the negative control) reduced β-sitosterol β-D-glucoside-induced neuropathology. Accordingly, a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum. In addition, tyrosine hydroxylase-positive cells displayed less senescence marker β-galactosidase and more neuron-cytoskeleton marker βIII-tubulin and brain-derived neurotrophic factor. A significant decrease in activated microglia (positive to ionized calcium-binding adaptor molecule 1) and neurotoxic astrocytes (positive to glial fibrillary acidic protein and complement component 3) and increased neurotrophic astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10) also occurred in the substantia nigra. These effects followed the bilateral reduction in α-synuclein aggregates in the nigrostriatal system, improving sensorimotor behavior. Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration (senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells), neuroinflammation (activated microglia, neurotoxic astrocytes), α-synuclein aggregation, and sensorimotor deficits. Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect, supporting its potential clinical use in the treatment of Parkinson's disease

Intranigral Administration of β-Sitosterol-β-D-Glucoside Elicits Neurotoxic A1 Astrocyte Reactivity and Chronic Neuroinflammation in the Rat Substantia Nigra

Chronic consumption of β-sitosterol-β-D-glucoside (BSSG), a neurotoxin contained in cycad seeds, leads to Parkinson’s disease in humans and rodents. Here, we explored whether a single intranigral administration of BSSG triggers neuroinflammation and neurotoxic A1 reactive astrocytes besides dopaminergic neurodegeneration. We injected 6 μg BSSG/1 μL DMSO or vehicle into the left substantia nigra and immunostained with antibodies against tyrosine hydroxylase (TH) together with markers of microglia (OX42), astrocytes (GFAP, S100β, C3), and leukocytes (CD45). We also measured nitric oxide (NO), lipid peroxidation (LPX), and proinflammatory cytokines (TNF-α, IL-1β, IL-6). The Evans blue assay was used to explore the blood-brain barrier (BBB) permeability. We found that BSSG activates NO production on days 15 and 30 and LPX on day 120. Throughout the study, high levels of TNF-α were present in BSSG-treated animals, whereas IL-1β was induced until day 60 and IL-6 until day 30. Immunoreactivity of activated microglia (899.0±80.20%) and reactive astrocytes (651.50±11.28%) progressively increased until day 30 and then decreased to remain 251.2±48.8% (microglia) and 91.02±39.8 (astrocytes) higher over controls on day 120. C3(+) cells were also GFAP and S100β immunoreactive, showing they were neurotoxic A1 reactive astrocytes. BBB remained permeable until day 15 when immune cell infiltration was maximum. TH immunoreactivity progressively declined, reaching 83.6±1.8% reduction on day 120. Our data show that BSSG acute administration causes chronic neuroinflammation mediated by activated microglia, neurotoxic A1 reactive astrocytes, and infiltrated immune cells. The severe neuroinflammation might trigger Parkinson’s disease in BSSG intoxication

3er. Coloquio: Fortalecimiento de los Colectivos de Docencia

Las memorias del 3er. Coloquio de Fortalecimiento de Colectivos de Docencia deben ser entendidas como un esfuerzo colectivo de la comunidad de académicos de la División de Ciencias y Artes para el Diseño, en medio de la pandemia COVID-19, con el fin de: • Analizar y proponer acciones concretas que promuevan el mejoramiento de la calidad docente en la División. • Proponer acciones que permitan continuar fortaleciendo los cursos con modalidad a distancia (remotos). • Ante un escenario que probablemente demandará en el mediano plazo, transitar del modelo remoto a un modelo híbrido, proponer acciones a considerar para la transición de los cursos. • Planear y preparar cursos de nivelación de conocimientos, para cuando se transite a la impartición de la docencia de manera mixta o presencial, dirigidos a los alumnos que no hayan tenido oportunidad de desarrollar actividades relevantes para su formación, como prácticas de talleres y laboratorios, visitas, o alguna otra actividad relevante