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Publicaciones del Departamento de Histología y Embriología
Preoptic Area Activation and Vasotocin Involvement in the Reproductive Behavior of a Weakly Pulse-Type Electric Fish, Brachyhypopomus gauderio
Front Integr Neurosci 2019 13:37
Paula Pouso 1 2 , Álvaro Cabana 3 , James L Goodson 4 , Ana Silva 1 5
1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 2 Unidad Bases Neurales de la Conducta, Departamento de Neurofisiología Celular y Molecular, IIBCE, Montevideo, Uruguay. 3 Centro de Investigación Básica en Psicología (CIBPsi) and Instituto de Fundamentos y Métodos, Facultad de Psicología, Universidad de la República, Montevideo, Uruguay. 4 Department of Biology, Indiana University, Bloomington, IN, United States. 5 Laboratorio de Neurociencias, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
DOI: 10.3389/fnint.2019.00037
PMID: 31456670
Pubmed: https://pubmed.ncbi.nlm.nih.gov/31456670
Texto completo: https://doi.org//10.3389/fnint.2019.00037
Abstract:
Social behavior exhibits a wide diversity among vertebrates though it is controlled by a conserved neural network, the social behavior network (SBN). The activity of the SBN is shaped by hypothalamic nonapeptides of the vasopressin-oxytocin family. The weakly electric fish Brachyhypopomus gauderio emits social electrical signals during courtship. Three types of vasotocin (AVT) cells occur in the preoptic area (POA), one of the SBN nodes. In this study, we aimed to test if POA neurons of the nucleus preopticus ventricularis anterior (PPa) and posterior (PPp), and in particular AVT+ cells, were activated by social stimuli using a 2-day behavioral protocol. During the first night, male-female dyads were recorded to identify courting males. During the second night, these males were divided in two experimental conditions: isolated and social (male with a female). Both AVT cells and the cellular activation of the POA neurons (measured by FOS) were identified. We found that the PPa of social males showed more FOS+ cells than the PPa of isolated males, and that the PPa had more AVT+ cells in social males than in isolated males. The double-immunolabeling for AVT and FOS indicated the activation of AVT+ neurons. No significant differences in the activation of AVT+ cells were found between conditions, but a clear association was observed between the number of AVT+ cells and certain behavioral traits. In addition, a different activation of AVT+ cell-types was observed for social vs. isolated males. We conclude that the POA of B. gauderio exhibits changes induced by social stimuli in reproductive context, involving an increase in AVT production and a different profile activation among AVT+ cell populations.
Distribution of sperm antigen 6 (SPAG6) and 16 (SPAG16) in mouse ciliated and non-ciliated tissues
J Mol Histol 2019 50(3):189-202
Jimena Alciaturi 1 , Gabriel Anesetti 1 , Florencia Irigoin 1 2 , Fernanda Skowronek 1 , Rossana Sapiro 3
1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo, Uruguay. 2 Laboratorio de Genética Molecular Humana, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, Uruguay. 3 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo, Uruguay. rsapiro@fmed.edu.uy.
DOI: 10.1007/s10735-019-09817-z
PMID: 30911868
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30911868
Texto completo: https://doi.org/10.1007/s10735-019-09817-z
Abstract:
The cilia and flagella of eukaryotic cells serve many functions, exhibiting remarkable conservation of both structure and molecular composition in widely divergent eukaryotic organisms. SPAG6 and SPAG16 are the homologous in the mice to Chlamydomonas reinhardtii PF16 and PF20. Both proteins are associated with the axonemal central apparatus and are essential for ciliary and flagellar motility in mammals. Recent data derived from high-throughput studies revealed expression of these genes in tissues that do not contain motile cilia. However, the distribution of SPAG6 and SPAG16 in ciliated and non-ciliated tissues is not completely understood. In this work, we performed a quantitative analysis of the expression of Spag6 and Spag16 genes in parallel with the immune-localization of the proteins in several tissues of adult mice. Expression of mRNA was higher in the testis and tissues bearing motile cilia than in the other analyzed tissues. Both proteins were present in ciliated and non-ciliated tissues. In the testis, SPAG6 was detected in spermatogonia, spermatocytes, and in the sperm flagella whereas SPAG16 was found in spermatocytes and in the sperm flagella. In addition, both proteins were detected in the cytoplasm of cells from the brain, spinal cord, and ovary. A small isoform of SPAG16 was localized in the nucleus of germ cells and some neurons. In a parallel set of experiments, we overexpressed EGFP-SPAG6 in cultured cells and observed that the protein co-localized with a subset of acetylated cytoplasmic microtubules. A role of these proteins stabilizing the cytoplasmic microtubules of eukaryotic cells is discussed.
Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth
BMC Med Genomics 2019 12(1):53
Silvana Pereyra 1 , Claudio Sosa 2 , Bernardo Bertoni 1 , Rossana Sapiro 3
1 Departamento de Genética, Facultad de Medicina, Universidad de la República, Av. General Flores 2125, C.P, 11800, Montevideo, Uruguay. 2 Clínica Ginecotologica "C", Centro Hospitalario Pereira Rossell, Facultad de Medicina, Universidad de la República, Bvar. General Artigas 1590, C:P.11600, Montevideo, Uruguay. 3 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Av. General Flores 2125, C.P, 11800, Montevideo, Uruguay. rsapiro@fmed.edu.uy.
DOI: 10.1186/s12920-019-0498-3
PMID: 30935390
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30935390
Texto completo: https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-019-0498-3
Abstract:
Background: Preterm birth (PTB), defined as infant delivery before 37 weeks of completed gestation, results from the interaction of both genetic and environmental components and constitutes a complex multifactorial syndrome. Transcriptome analysis of PTB has proven challenging because of the multiple causes of PTB and the numerous maternal and fetal gestational tissues that must interact to facilitate parturition. The transcriptome of the chorioamnion membranes at the site of rupture in PTB and term fetuses may reflect the molecular pathways of preterm labor.
Methods: In this work, chorioamnion membranes from severe preterm and term fetuses were analyzed using RNA sequencing. Functional annotations and pathway analysis of differentially expressed genes were performed with the GAGE and GOSeq packages. A subset of differentially expressed genes in PTB was validated in a larger cohort using qRT-PCR and by comparing our results with genes and pathways previously reported in the literature.
Results: A total of 270 genes were differentially expressed (DE): 252 were upregulated and 18 were down-regulated in severe preterm births relative to term births. Inflammatory and immunological pathways were upregulated in PTB. Both types of pathways were previously suggested to lead to PTB. Pathways that were not previously reported in PTB, such as the hemopoietic pathway, appeared upregulated in preterm membranes. A group of 18 downregulated genes discriminated between term and severe preterm cases. These genes potentially characterize a severe preterm transcriptome pattern and therefore are candidate genes for understanding the syndrome. Some of the downregulated genes are involved in the nervous system, morphogenesis (WNT1, DLX5, PAPPA2) and ion channel complexes (KCNJ16, KCNB1), making them good candidates as biomarkers of PTB.
Conclusions: The identification of this DE gene pattern will help with the development of a multi-gene disease classifier. These markers were generated in an admixed South American population in which PTB has a high incidence. Since the genetic background may differentially impact different populations, it is necessary to include populations such as those from South America and Africa, which are usually excluded from high-throughput approaches. These classifiers should be compared to those in other populations to obtain a global landscape of PTB.
Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits
Front Pharmacol 2019 10:193
Soledad Marton 1 , Bruno González 2 , Sebastián Rodríguez-Bottero 1 , Ernesto Miquel 1 , Laura Martínez-Palma 1 , Mariana Pazos 2 , José Pedro Prieto 3 , Paola Rodríguez 2 , Dalibor Sames 4 , Gustavo Seoane 2 , Cecilia Scorza 3 , Patricia Cassina 1 , Ignacio Carrera 2
1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 2 Laboratorio de Síntesis Orgánica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay. 3 Departamento de Neurofarmacología Experimental, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay. 4 Department of Chemistry, Columbia University, New York, NY, United States.
DOI: 10.3389/fphar.2019.00193
PMID: 30890941
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30890941
Texto completo: https://doi.org/10.3389/fphar.2019.00193
Abstract:
Ibogaine is an atypical psychedelic alkaloid, which has been subject of research due to its reported ability to attenuate drug-seeking behavior. Recent work has suggested that ibogaine effects on alcohol self-administration in rats are related to the release of Glial cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts the soma of dopaminergic neurons. Although previous reports have shown ibogaine's ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF and other neurotrophic factors (NFs) such as Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct brain regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Rats were i.p. treated with ibogaine 20 mg/kg (I20), 40 mg/kg (I40) or vehicle, and NFs expression was analyzed after 3 and 24 h. At 24 h an increase of the expression of the NFs transcripts was observed in a site and dose dependent manner. Only for I40, GDNF was selectively upregulated in the VTA and SN. Both doses elicited a large increase in the expression of BDNF transcripts in the NAcc, SN and PFC, while in the VTA a significant effect was found only for I40. Finally, NGF mRNA was upregulated in all regions after I40, while I20 showed a selective upregulation in PFC and VTA. Regarding protein levels, an increase of GDNF was observed in the VTA only for I40 but no significant increase for BDNF was found in all the studied areas. Interestingly, an increase of proBDNF was detected in the NAcc for both doses. These results show for the first time a selective increase of GDNF specifically in the VTA for I40 but not for I20 after 24 h of administration, which agrees with the effective dose found in previous self-administration studies in rodents. Further research is needed to understand the contribution of these changes to ibogaine's ability to attenuate drug-seeking behavior.
Experimental polycystic ovarian syndrome is associated with reduced expression and function of P2Y2 receptors in rat theca cells
Mol Reprod Dev 2019 86(3):308-318
Anaí Del Rocío Campos-Contreras 1 , Ana Patricia Juárez-Mercado 1 , Adriana González-Gallardo 2 , Rebeca Chávez-Genaro 3 , Edith Garay 1 , Dalia Luz De Ita-Pérez 1 , Mauricio Díaz-Muñoz 1 , Francisco Gabriel Vázquez-Cuevas 1
1 Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla Querétaro, México. 2 Unidad de Proteogenómica. Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla Querétaro, México. 3 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
DOI: 10.1002/mrd.23106
PMID: 30624816
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30624816
Texto completo: https://doi.org/10.1002/mrd.23106
Abstract:
Extracellular purines through specific receptors have been recognized as new regulators of ovarian function. It is known that P2Y2 receptor activity induces theca cell proliferation, we hypothesized that purinergic signaling controls the changes related to hyperthecosis in polycystic ovarian syndrome (PCOS). The aim of this study was to analyze the expression of UTP-sensitive P2Y receptors and their role in theca cells (TC) proliferation in experimentally-induced PCOS (EI-PCOS). In primary cultures of TC from intact rats, all the transcripts of P2Y receptors were detected by polymerase chain reaction; in these cells, UTP (10 μM) induced extracellular signal-regulated kinases (ERK) phosphorylation. Rats with EI-PCOS showed a reduced expression of P2Y2R in TC whereas P2Y4R did not change. By analyzing ERK phosphorylation, it was determined that P2Y2R is the most relevant receptor in TC. UTP promoted cell proliferation in TC from control but not from EI-PCOS rats. The in silico analysis of P2yr2 promoter indicated the presence of androgen response elements; the stimulation of TC primary cultures with testosterone promoted a significant reduction in the expression of the P2yr2 transcript. We concluded that P2Y2R participates in controlling the proliferative rate of TCs from healthy ovaries, but this regulation is lost during EI-PCOS.
Mitochondrial Modulation by Dichloroacetate Reduces Toxicity of Aberrant Glial Cells and Gliosis in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis
Neurotherapeutics 2019 16(1):203-215
Laura Martínez-Palma 1 2 , Ernesto Miquel 3 4 , Valentina Lagos-Rodríguez 3 4 , Luis Barbeito 5 , Adriana Cassina 4 6 , Patricia Cassina 7 8
1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Av. Gral Flores 2125, 11800, Montevideo, Uruguay. lmartinezpalma07@gmail.com. 2 Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Av. Gral Flores 2125, 11800, Montevideo, Uruguay. lmartinezpalma07@gmail.com. 3 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Av. Gral Flores 2125, 11800, Montevideo, Uruguay. 4 Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Av. Gral Flores 2125, 11800, Montevideo, Uruguay. 5 Institut Pasteur de Montevideo, Mataojo 2020, 11400, Montevideo, Uruguay. 6 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Av. Gral Flores 2125, 11800, Montevideo, Uruguay. 7 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Av. Gral Flores 2125, 11800, Montevideo, Uruguay. pcassina@fmed.edu.uy. 8 Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Av. Gral Flores 2125, 11800, Montevideo, Uruguay. pcassina@fmed.edu.uy.
DOI: 10.1007/s13311-018-0659-7
PMID: 30159850
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30159850
Texto completo: https://linkinghub.elsevier.com/retrieve/pii/S1878-7479(23)01010-3
Abstract:
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron (MN) degeneration and gliosis. Neonatal astrocytes obtained from the SOD1G93A rat model of ALS exhibit mitochondrial dysfunction and neurotoxicity that can be reduced by dichloroacetate (DCA), a metabolic modulator that has been used in humans, and shows beneficial effects on disease outcome in SOD1G93A mice. Aberrant glial cells (AbGC) isolated from the spinal cords of adult paralytic SOD1G93A rats exhibit highly proliferative and neurotoxic properties and may contribute to disease progression. Here we analyze the mitochondrial activity of AbGC and whether metabolic modulation would modify their phenotypic profile. Our studies revealed fragmented mitochondria and lower respiratory control ratio in AbGC compared to neonatal SOD1G93A and nontransgenic rat astrocytes. DCA (5 mM) exposure improved AbGC mitochondrial function, reduced their proliferative rate, and importantly, decreased their toxicity to MNs. Furthermore, oral DCA administration (100 mg/kg, 10 days) to symptomatic SOD1G93A rats reduced MN degeneration, gliosis, and the number of GFAP/S100β double-labeled hypertrophic glial cells in the spinal cord. DCA treatment of AbGC reduced extracellular lactate levels indicating that the main recognized DCA action, targeting the pyruvate dehydrogenase kinase/pyruvate dehydrogenase complex, may underlie our findings. Our results show that AbGC metabolic phenotype is related to their toxicity to MNs and indicate that its modulation can reduce glial mediated pathology in the spinal cord. Together with previous findings, these results further support glial metabolic modulation as a valid therapeutic strategy in ALS.
First ovarian response to gonadotrophin stimulation in rats exposed to neonatal androgen excess
J Mol Histol 2018 49(6):631-637
Rebeca Chávez-Genaro 1 , Gabriel Anesetti 2
1 Histology and Embryology Department, School of Medicine, UdelaR, General Flores 2125, CP 11800, Montevideo, Uruguay. rchavez@fmed.edu.uy. 2 Histology and Embryology Department, School of Medicine, UdelaR, General Flores 2125, CP 11800, Montevideo, Uruguay.
DOI: 10.1007/s10735-018-9800-5
PMID: 30302594
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30302594
Texto completo: https://doi.org/10.1007/s10735-018-9800-5
Abstract:
This study analyzes the effects of neonatal androgenization on follicular growth and first ovulation in response to gonadotrophins, using a model of exogenous stimulation or the use of subcutaneous ovary grafts in castrated animals to replace the hypothalamus-pituitary signal. Neonatal rats (days 1-5) were treated with testosterone, dihydrotestosterone or vehicle. At juvenile period, rats were stimulated with PMSG, hCG (alone or combined) or used as ovarian donors to be grafted on castrated adult female rats. Ovulation and ovarian histology were analyzed in both groups. Animals treated with vehicle or dihydrotestosterone stimulated with gonadotrophins (pharmacological or by using an ovary graft) ovulated, showing a normal histological morphology whereas rats exposed to testosterone and injected with the same doses of gonadotrophins did not it. In this group, ovulation was reached using a higher dose of hCG. Ovaries in the testosterone group were characterized by the presence of follicles with atretic appearance and a larger size than those observed in control or dihydrotestosterone groups. A similar appearance was observed in testosterone ovary grafts although luteinization and some corpora lutea were also identified. Our findings suggest that neonatal exposure to aromatizable androgens induces a more drastic signalling on the ovarian tissue that those driven by non-aromatizable androgens in response to gonadotrophins.
Impact of monomeric, oligomeric and fibrillar alpha-synuclein on astrocyte reactivity and toxicity to neurons
Biochem J 2018 475(19):3153-3169
Cecilia Chavarría 1 , Sebastián Rodríguez-Bottero 2 , Celia Quijano 1 , Patricia Cassina 2 , José M Souza 3
1 Departamento de Bioquímica, Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 2 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Av. Gral. Flores 2125, Montevideo 11400, Uruguay. 3 Departamento de Bioquímica, Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay jsouza@fmed.edu.uy.
DOI: 10.1042/BCJ20180297
PMID: 30185433
Pubmed: https://pubmed.ncbi.nlm.nih.gov/30185433
Texto completo: https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BCJ20180297
Abstract:
Synucleinopathies are a group of neurodegenerative disorders characterized by the presence of aggregated and fibrillar forms of alpha-synuclein (α-syn). Here, we analyze the effect of different species of α-syn, including monomeric, oligomeric and fibrillar forms of the protein, on rat astrocytes. Astrocytes treated with these distinct forms of α-syn showed an increase in long and thin processes and glial fibrillary acidic protein expression, indicating cell activation, high levels of intracellular oxidants and increased expression of cytokines. Moreover, astrocytes incubated with the different species induced hippocampal neuronal death in co-culture, and cytotoxicity was particularly enhanced by exposure to fibrillar α-syn. Further exploration of the mechanisms behind astrocyte activation and cytotoxicity revealed differences between the assessed α-syn species. Only oligomers induced mitochondrial dysfunction in astrocytes and significantly increased extracellular hydrogen peroxide production by these cells. Besides, TNF-α and IL-1β (interleukin 1β) expression presented different kinetics and levels depending on which species induced the response. Our data suggest that α-syn species (monomeric, oligomeric and fibrillar) induce astrocyte activation that can lead to neuronal death. Nevertheless, the tested α-syn species act through different preferential mechanisms and potency. All together these results help to understand the effect of α-syn species on astrocyte function and their potential impact on the pathogenesis of Parkinson's disease and related α-synucleinopathies.
CD200 modulates spinal cord injury neuroinflammation and outcome through CD200R1
Brain Behav Immun 2018 73:416-426
Natalia Lago 1 , Bruno Pannunzio 2 , Jesús Amo-Aparicio 3 , Rubèn López-Vales 3 , Hugo Peluffo 2
1 Neuroinflammation and Gene Therapy Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay. Electronic address: nlago@pasteur.edu.uy. 2 Neuroinflammation and Gene Therapy Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay; Department of Histology and Embryology, Faculty of Medicine, UDELAR, Montevideo, Uruguay. 3 Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Catalonia, Spain.
DOI: 10.1016/j.bbi.2018.06.002
PMID: 29870752
Pubmed: https://pubmed.ncbi.nlm.nih.gov/29870752
Texto completo: https://linkinghub.elsevier.com/retrieve/pii/S0889-1591(18)30218-6
Abstract:
The interaction between CD200 and its receptor CD200R1 is among the central regulators of microglia and macrophage phenotype. However, it remains to be established whether, in the context of a traumatic CNS injury, CD200R1 act as a negative regulator of these particular innate immune cells, and if the exogenous delivery of CD200 may ameliorate neurological deficits. In the present study, we first evaluated whether preventing the local interaction between the pair CD200-CD200R1, by using a selective blocking antibody against CD200R1, has a role on functional and inflammatory outcome after contusion-induced spinal cord injury (SCI) in mice. The injection of the αCD200R1, but not control IgG1, into the lesioned spinal cord immediately after the SCI worsened locomotor performance and exacerbated neuronal loss and demyelination. At the neuroimmunological level, we observed that microglial cells and macrophages showed increased levels of iNOS and Ly6C upon CD200R1 blockade, indicating that the disruption of CD200R1 drove these cells towards a more pro-inflammatory phenotype. Moreover, although CD200R1 blockade had no effect in the initial infiltration of neutrophils into the lesioned spinal cord, it significantly impaired their clearance, which is a key sign of excessive inflammation. Interestingly, intraparenchymal injection of recombinant CD200-His immediately after the injury induced neuroprotection and robust and long-lasting locomotor recovery. In conclusion, this study reveals that interaction of CD200-CD200R1 plays a crucial role in limiting inflammation and lesion progression after SCI, and that boosting the stimulation of this pathway may constitute a new therapeutic approach.
Profile of Arachidonic Acid-Derived Inflammatory Markers and Its Modulation by Nitro-Oleic Acid in an Inherited Model of Amyotrophic Lateral Sclerosis
Front Mol Neurosci 2018 11:131
Andrés Trostchansky 1 2 , Mauricio Mastrogiovanni 1 2 , Ernesto Miquel 2 3 , Sebastián Rodríguez-Bottero 2 3 , Laura Martínez-Palma 2 3 , Patricia Cassina 2 3 , Homero Rubbo 1 2
1 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 2 Center for Free Radical and Biomedical Research, Universidad de la República, Montevideo, Uruguay. 3 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
DOI: 10.3389/fnmol.2018.00131
PMID: 29760648
Pubmed: https://pubmed.ncbi.nlm.nih.gov/29760648
Texto completo: https://doi.org/10.3389/fnmol.2018.00131
Abstract:
The lack of current treatments for amyotrophic lateral sclerosis (ALS) highlights the need of a comprehensive understanding of the biological mechanisms of the disease. A consistent neuropathological feature of ALS is the extensive inflammation around motor neurons and axonal degeneration, evidenced by accumulation of reactive astrocytes and activated microglia. Final products of inflammatory processes may be detected as a screening tool to identify treatment response. Herein, we focus on (a) detection of arachidonic acid (AA) metabolization products by lipoxygenase (LOX) and prostaglandin endoperoxide H synthase in SOD1G93A mice and (b) evaluate its response to the electrophilic nitro-oleic acid (NO2-OA). Regarding LOX-derived products, a significant increase in 12-hydroxyeicosatetraenoic acid (12-HETE) levels was detected in SOD1G93A mice both in plasma and brain whereas no changes were observed in age-matched non-Tg mice at the onset of motor symptoms (90 days-old). In addition, 15-hydroxyeicosatetraenoic acid (15-HETE) levels were greater in SOD1G93A brains compared to non-Tg. Prostaglandin levels were also increased at day 90 in plasma from SOD1G93A compared to non-Tg being similar in both types of animals at later stages of the disease. Administration of NO2-OA 16 mg/kg, subcutaneously (s/c) three times a week to SOD1G93A female mice, lowered the observed increase in brain 12-HETE levels compared to the non-nitrated fatty acid condition, and modified many others inflammatory markers. In addition, NO2-OA significantly improved grip strength and rotarod performance compared to vehicle or OA treated animals. These beneficial effects were associated with increased hemeoxygenase 1 (HO-1) expression in the spinal cord of treated mice co-localized with reactive astrocytes. Furthermore, significant levels of NO2-OA were detected in brain and spinal cord from NO2-OA -treated mice indicating that nitro-fatty acids (NFA) cross brain-blood barrier and reach the central nervous system to induce neuroprotective actions. In summary, we demonstrate that LOX-derived oxidation products correlate with disease progression. Overall, we are proposing that key inflammatory mediators of AA-derived pathways may be useful as novel footprints of ALS onset and progression as well as NO2-OA as a promising therapeutic compound.