Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions.</p> <p>Methods</p> <p>We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers) provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662.</p> <p>Results</p> <p>We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662.</p> <p>Conclusion</p> <p>The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation. However, the results in AT1-deficient mice show that blockage of AT1, unrelated to the pharmacological properties of AT1 blockers, also protects against dopaminergic cell death and neuroinflammation. Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.</p

Dramatic Response of Leptomeningeal Carcinomatosis to Nivolumab in PD-L1 Highly Expressive Non-small Cell Lung Cancer: A Case Report

In a patient who had been diagnosed of located squamous cell lung carcinoma, pneumonectomy, and adjuvant chemotherapy were performed. Brain recurrence and subsequent lung metastatic disease were uncontrolled by neurosurgery, holocranial radiotherapy, and first-line chemotherapy. In August 2015, appearance of leptomeningeal carcinomatosis triggered severe clinical deterioration and threatened the patient's life. Anti-PD1 immune checkpoint inhibitor Nivolumab was initiated in an attempt to stop tumor growth, achieving a spectacular brain and pulmonary complete response and clinical improvement, without serious adverse effects. High expression PD-L1 level (100%) was found in the pathological tissue sample. Nivolumab was maintained for more than 2 years and stopped in December 2017 after 28 months of treatment, with no disease evidence. More than 3 years after its onset, the patient maintains an outstanding PS with complete tumor response and no evidence of disease in last surveillance CT scan and brain MRI

Floral Assemblages and Patterns of Insect Herbivory during the Permian to Triassic of Northeastern Italy

To discern the effect of the end-Permian (P-Tr) ecological crisis on land, interactions between plants and their insect herbivores were examined for four time intervals containing ten major floras from the Dolomites of northeastern Italy during a Permian-Triassic interval. These floras are: (i) the Kungurian Tregiovo Flora;(ii) the Wuchiapingian Bletterbach Flora;(iii) three Anisian floras;and (iv) five Ladinian floras. Derived plant-insect interactional data is based on 4242 plant specimens (1995 Permian, 2247 Triassic) allocated to 86 fossil taxa (32 Permian, 56 Triassic), representing lycophytes, sphenophytes, pteridophytes, pterido-sperms, ginkgophytes, cycadophytes and coniferophytes from 37 million-year interval (23 m. yr. Permian, 14 m. yr. Triassic). Major Kungurian herbivorized plants were unaffiliated taxa and pteridosperms;later during the Wuchiapingian cycadophytes were predominantly consumed. For the Anisian, pteridosperms and cycadophytes were preferentially consumed, and subordinately pteridophytes, lycophytes and conifers. Ladinian herbivores overwhelming targeted pteridosperms and subordinately cycadophytes and conifers. Throughout the interval the percentage of insect-damaged leaves in bulk floras, as a proportion of total leaves examined, varied from 3.6% for the Kungurian (N = 464 leaves), 1.95% for the Wuchiapingian (N = 1531), 11.65% for the pooled Anisian (N = 1324), to 10.72% for the pooled Ladinian (N = 923), documenting an overall herbivory rise. The percentage of generalized consumption, equivalent to external foliage feeding, consistently exceeded the level of specialized consumption from internal feeding. Generalized damage ranged from 73.6% (Kungurian) of all feeding damage, to 79% (Wuchiapingian), 65.5% (pooled Anisian) and 73.2% (pooled Ladinian). Generalized-to-specialized ratios show minimal change through the interval, although herbivore component community structure (herbivore species feeding on a single plant-host species) increasingly was partitioned from Wuchiapingian to Ladinian. The Paleozoic plant with the richest herbivore component community, the coniferophyte Pseudovoltzia liebeana, harbored four damage types (DTs), whereas its Triassic parallel, the pteridosperm Scytophyllum bergeri housed 11 DTs, almost four times that of P. liebeana. Although generalized DTs of P. liebeana were similar to S. bergeri, there was expansion of Triassic specialized feeding types, including leaf mining. Permian-Triassic generalized herbivory remained relatively constant, but specialized herbivores more finely partitioned plant- host tissues via new feeding modes, especially in the Anisian. Insect-damaged leaf percentages for Dolomites Kungurian and Wuchiapingian floras were similar to those of lower Permian, north-central Texas, but only one-third that of southeastern Brazil. Global herbivore patterns for Early Triassic plant-insect interactions remain unknown

Mapa epidemiológico transversal de las ataxias y paraparesias espásticas hereditarias en España

Resume: Introducción: Las ataxias (AT) y paraparesias espásticas hereditarias (PEH) son síndromes neurodegenerativos raros. Nos proponemos conocer la prevalencia de las AT y PEH en España en 2019. Pacientes y métodos: Estudio transversal, multicéntrico, descriptivo y retrospectivo de los pacientes con AT y PEH, desde marzo de 2018 a diciembre de 2019 en toda España. Resultados: Se obtuvo información de 1933 pacientes procedentes de 11 Comunidades Autónomas, de 47 neurólogos o genetistas. Edad media: 53,64 años ± 20,51 desviación estándar (DE); 938 varones (48,5%), 995 mujeres (51,5%). En 920 pacientes (47,6%) no se conoce el defecto genético. Por patologías, 1.371 pacientes (70,9%) diagnosticados de AT, 562 diagnosticados de PEH (29,1%). La prevalencia estimada de AT es 5,48/100.000 habitantes, y la de PEH es 2,24 casos/100.000 habitantes. La AT dominante más frecuente es la SCA3. La AT recesiva más frecuente es la ataxia de Friedreich (FRDA). La PEH dominante más frecuente es la SPG4, y la PEH recesiva más frecuente es la SPG7. Conclusiones: La prevalencia estimada de AT y PEH en nuestra serie es de 7,73 casos/100.000 habitantes. Estas frecuencias son similares a las del resto del mundo. En el 47,6% no se ha conseguido un diagnóstico genético. A pesar de las limitaciones, este estudio puede contribuir a estimar los recursos, visibilizar estas enfermedades, detectar las mutaciones más frecuentes para hacer los screenings por comunidades, y favorecer los ensayos clínicos. Abstract: Introduction: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019. Patients and methods: We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. Results: We gathered data from a total of 1933 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 938 patients were men (48.5%) and 995 were women (51.5%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7. Conclusions: In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials

Mapa epidemiológico transversal de las ataxias y paraparesias espásticas hereditarias en España

Introduction: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019. Patients and methods: We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. Results: We gathered data from a total of 1933 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 938 patients were men (48.5%) and 995 were women (51.5%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7. Conclusions: In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials. (c) 2021 Sociedad Espanola de Neurologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/)