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1.
Behav Brain Res ; 471: 115114, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38878972

RESUMEN

Zika virus (ZIKV) is a neurotropic Orthoflavivirus that causes a myriad of neurological manifestations in newborns exposed in uterus. Despite the devastating consequences of ZIKV on the developing brain, strategies to prevent or treat the consequences of viral infection are not yet available. We previously showed that short-term treatment with the TNF-α neutralizing monoclonal antibody. Infliximab could prevent seizures at acute and chronic stages of ZIKV infection, but had no impact on long-term cognitive and motor dysfunction. Due to the central role of inflammation in ZIKV-neuropathology, we hypothesized that prolonged treatment with the anti-TNF-α monoclonal antibody Infliximab could provide complete rescue of long-term behavioral deficits associated with neonatal ZIKV infection in mice. Here, neonatal (post-natal day 3) Swiss mice were submitted to subcutaneous (s.c.) injection of 106 PFU of ZIKV or mock medium and were then treated with Infliximab (20 µg/day) or sterile saline intraperitoneally (i.p.), for 40 days starting on the day of infection, and behavioral assessment started at 60 days post-infection (dpi). Infliximab prevented ZIKV-induced cognitive and motor impairments in mice. In addition, microgliosis and cell death found in mice following ZIKV infection were partially reversed by TNF-α blockage. Altogether, these results suggest that TNF-α-mediated inflammation is central for late ZIKV-induced behavioral deficits and cell death and strategies targeting this cytokine may be promising approaches to treat subjects exposed to the virus during development.

2.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167097, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38408544

RESUMEN

Zika virus (ZIKV) infection was first associated with Central Nervous System (CNS) infections in Brazil in 2015, correlated with an increased number of newborns with microcephaly, which ended up characterizing the Congenital Zika Syndrome (CZS). Here, we investigated the impact of ZIKV infection on the functionality of iPSC-derived astrocytes. Besides, we extrapolated our findings to a Brazilian cohort of 136 CZS children and validated our results using a mouse model. Interestingly, ZIKV infection in neuroprogenitor cells compromises cell migration and causes apoptosis but does not interfere in astrocyte generation. Moreover, infected astrocytes lost their ability to uptake glutamate while expressing more glutamate transporters and secreted higher levels of IL-6. Besides, infected astrocytes secreted factors that impaired neuronal synaptogenesis. Since these biological endophenotypes were already related to Autism Spectrum Disorder (ASD), we extrapolated these results to a cohort of children, now 6-7 years old, and found seven children with ASD diagnosis (5.14 %). Additionally, mice infected by ZIKV revealed autistic-like behaviors, with a significant increase of IL-6 mRNA levels in the brain. Considering these evidence, we inferred that ZIKV infection during pregnancy might lead to synaptogenesis impairment and neuroinflammation, which could increase the risk for ASD.


Asunto(s)
Astrocitos , Trastorno del Espectro Autista , Enfermedades Neuroinflamatorias , Sinapsis , Infección por el Virus Zika , Virus Zika , Infección por el Virus Zika/patología , Infección por el Virus Zika/metabolismo , Infección por el Virus Zika/virología , Infección por el Virus Zika/complicaciones , Trastorno del Espectro Autista/virología , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/etiología , Trastorno del Espectro Autista/patología , Humanos , Animales , Ratones , Virus Zika/fisiología , Femenino , Niño , Sinapsis/metabolismo , Sinapsis/patología , Enfermedades Neuroinflamatorias/virología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/etiología , Astrocitos/virología , Astrocitos/metabolismo , Astrocitos/patología , Masculino , Interleucina-6/metabolismo , Interleucina-6/genética , Embarazo , Factores de Riesgo , Células Madre Pluripotentes Inducidas/virología , Células Madre Pluripotentes Inducidas/metabolismo , Brasil/epidemiología , Modelos Animales de Enfermedad , Neurogénesis
3.
Neuropharmacology ; 245: 109828, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38158014

RESUMEN

Oxaliplatin (OXA) is an antineoplastic agent used for the treatment of cisplatin-resistant tumours, presenting lower incidence of nephrotoxicity and myelotoxicity than other platinum-based drugs. However, OXA treatment is highly associated with painful peripheral neuropathy, a well-known and relevant side effect caused by mitochondrial dysfunction. The transfer of functional exogenous mitochondria (mitotherapy) is a promising therapeutic strategy for mitochondrial diseases. We investigated the effect of mitotherapy on oxaliplatin-induced painful peripheral neuropathy (OIPN) in male mice. OIPN was induced by i.p. injections of oxaliplatin (3 mg/kg) over 5 consecutive days. Mechanical (von Frey test) and cold (acetone drop test) allodynia were evaluated between 7 and 17 days after the first OXA treatment. Mitochondria was isolated from donor mouse livers and mitochondrial oxidative phosphorylation was assessed with high resolution respirometry. After confirming that the isolated mitochondria were functional, the organelles were administered at the dose of 0.5 mg/kg of mitochondrial protein on days 1, 3 and 5. Treatment with OXA caused both mechanical and cold allodynia in mice that were significant 7 days after the initial injection of OXA and persisted for up to 17 days. Mitotherapy significantly prevented the development of both sensory alterations, and attenuated body weight loss induced by OXA. Mitotherapy also prevented spinal cord ERK1/2 activation, microgliosis and the increase in TLR4 mRNA levels. Mitotherapy prevented OIPN by inhibiting neuroinflammation and the consequent cellular overactivity in the spinal cord, presenting a potential therapeutic strategy for pain management in oncologic patients undergoing OXA treatment.


Asunto(s)
Antineoplásicos , Dolor , Enfermedades del Sistema Nervioso Periférico , Humanos , Masculino , Ratones , Animales , Oxaliplatino/toxicidad , Hiperalgesia/inducido químicamente , Hiperalgesia/prevención & control , Hiperalgesia/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & control , Antineoplásicos/toxicidad
4.
Behav Brain Res ; 451: 114519, 2023 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-37263423

RESUMEN

Zika virus (ZIKV) infection causes severe neurological consequences in both gestationally-exposed infants and adults. Sensorial gating deficits strongly correlate to the motor, sensorial and cognitive impairments observed in ZIKV-infected patients. However, no startle response or prepulse inhibition (PPI) assessment has been made in patients or animal models. In this study, we identified different outcomes according to the age of infection and sex in mice: neonatally infected animals presented an increase in PPI and delayed startle latency. However, adult-infected male mice presented lower startle amplitude, while a PPI impairment was observed 14 days after infection in both sexes. Our data further the understanding of the functional impacts of ZIKV on the developing and mature nervous system, which could help explain other behavioral and cognitive alterations caused by the virus. With this study, we support the startle reflex testing in ZIKV-exposed patients, especially infants, allowing for early detection of functional neuromotor damage and early intervention.


Asunto(s)
Infección por el Virus Zika , Virus Zika , Femenino , Masculino , Animales , Ratones , Reflejo de Sobresalto/fisiología , Inhibición Prepulso , Infección por el Virus Zika/complicaciones , Estimulación Acústica
5.
Cell Rep ; 42(3): 112189, 2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-36857178

RESUMEN

Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.


Asunto(s)
COVID-19 , Disfunción Cognitiva , Humanos , Animales , Ratones , COVID-19/complicaciones , Glicoproteína de la Espiga del Coronavirus/genética , SARS-CoV-2/metabolismo , Receptor Toll-Like 4 , Síndrome Post Agudo de COVID-19
7.
Mater Today Bio ; 18: 100525, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36619201

RESUMEN

Several human pathogens can cause long-lasting neurological damage. Despite the increasing clinical knowledge about these conditions, most still lack efficient therapeutic interventions. Gene therapy (GT) approaches comprise strategies to modify or adjust the expression or function of a gene, thus providing therapy for human diseases. Since recombinant nucleic acids used in GT have physicochemical limitations and can fail to reach the desired tissue, viral and non-viral vectors are applied to mediate gene delivery. Although viral vectors are associated to high levels of transfection, non-viral vectors are safer and have been further explored. Different types of nanosystems consisting of lipids, polymeric and inorganic materials are applied as non-viral vectors. In this review, we discuss potential targets for GT intervention in order to prevent neurological damage associated to infectious diseases as well as the role of nanosized non-viral vectors as agents to help the selective delivery of these gene-modifying molecules. Application of non-viral vectors for delivery of GT effectors comprise a promising alternative to treat brain inflammation induced by viral infections.

8.
Int J Mol Sci ; 23(20)2022 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-36292931

RESUMEN

The Wnt/ß-catenin signaling pathway dictates cell proliferation and differentiation during embryonic development and tissue homeostasis. Its deregulation is associated with many pathological conditions, including neurodegenerative disease, frequently downregulated. The lack of efficient treatment for these diseases, including Alzheimer's disease (AD), makes Wnt signaling an attractive target for therapies. Interestingly, novel Wnt signaling activating compounds are less frequently described than inhibitors, turning the quest for novel positive modulators even more appealing. In that sense, natural compounds are an outstanding source of potential drug leads. Here, we combine different experimental models, cell-based approaches, neuronal culture assays, and rodent behavior tests with Xenopus laevis phenotypic analysis to characterize quercitrin, a natural compound, as a novel Wnt signaling potentiator. We find that quercitrin potentiates the signaling in a concentration-dependent manner and increases the occurrence of the Xenopus secondary axis phenotype mediated by Xwnt8 injection. Using a GSK3 biosensor, we describe that quercitrin impairs GSK3 activity and increases phosphorylated GSK3ß S9 levels. Treatment with XAV939, an inhibitor downstream of GSK3, impairs the quercitrin-mediated effect. Next, we show that quercitrin potentiates the Wnt3a-synaptogenic effect in hippocampal neurons in culture, which is blocked by XAV939. Quercitrin treatment also rescues the hippocampal synapse loss induced by intracerebroventricular injection of amyloid-ß oligomers (AßO) in mice. Finally, quercitrin rescues AßO-mediated memory impairment, which is prevented by XAV939. Thus, our study uncovers a novel function for quercitrin as a Wnt/ß-catenin signaling potentiator, describes its mechanism of action, and opens new avenues for AD treatments.


Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Ratones , Animales , Vía de Señalización Wnt , Péptidos beta-Amiloides/farmacología , beta Catenina/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Enfermedad de Alzheimer/patología , Quercetina/farmacología , Quercetina/uso terapéutico
9.
Int J Mol Sci ; 23(10)2022 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-35628394

RESUMEN

RoundUp® (RUp) is a comercial formulation containing glyphosate (N-(phosphono-methyl) glycine), and is the world's leading wide-spectrum herbicide used in agriculture. Supporters of the broad use of glyphosate-based herbicides (GBH) claim they are innocuous to humans, since the active compound acts on the inhibition of enzymes which are absent in human cells. However, the neurotoxic effects of GBH have already been shown in many animal models. Further, these formulations were shown to disrupt the microbiome of different species. Here, we investigated the effects of a lifelong exposure to low doses of the GBH-RUp on the gut environment, including morphological and microbiome changes. We also aimed to determine whether exposure to GBH-RUp could harm the developing brain and lead to behavioral changes in adult mice. To this end, animals were exposed to GBH-RUp in drinking water from pregnancy to adulthood. GBH-RUp-exposed mice had no changes in cognitive function, but developed impaired social behavior and increased repetitive behavior. GBH-Rup-exposed mice also showed an activation of phagocytic cells (Iba-1-positive) in the cortical brain tissue. GBH-RUp exposure caused increased mucus production and the infiltration of plama cells (CD138-positive), with a reduction in phagocytic cells. Long-term exposure to GBH-RUp also induced changes in intestinal integrity, as demonstrated by the altered expression of tight junction effector proteins (ZO-1 and ZO-2) and a change in the distribution of syndecan-1 proteoglycan. The herbicide also led to changes in the gut microbiome composition, which is also crucial for the establishment of the intestinal barrier. Altogether, our findings suggest that long-term GBH-RUp exposure leads to morphological and functional changes in the gut, which correlate with behavioral changes that are similar to those observed in patients with neurodevelopmental disorders.


Asunto(s)
Microbioma Gastrointestinal , Herbicidas , Adulto , Animales , Disbiosis/inducido químicamente , Femenino , Glicina/análogos & derivados , Glicina/toxicidad , Herbicidas/toxicidad , Humanos , Ratones , Embarazo , Glifosato
10.
Behav Brain Res ; 419: 113680, 2022 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-34822947

RESUMEN

Conversion of the cellular prion protein (PrPC) into the scrapie form (PrPSc) is the leading step to the development of transmissible spongiform encephalopathies (TSEs), still incurable neurodegenerative disorders. Interaction of PrPC with cellular and synthetic ligands that induce formation of scrapie-like conformations has been deeply investigated in vitro. Different nucleic acid (NA) sequences bind PrP and convert it to ß-sheet-rich or unfolded species; among such NAs, a 21-mer double-stranded DNA, D67, was shown to induce formation of PrP aggregates that were cytotoxic. However, in vivo effects of these PrP-DNA complexes were not explored. Herein, aggregates of recombinant full-length PrP (rPrP23-231) induced by interaction with the D67 aptamer were inoculated into the lateral ventricle of Swiss mice and acute effects were investigated. The aggregates had no influence on emotional, locomotor and motor behavior of mice. In contrast, mice developed cognitive impairment and hippocampal synapse loss, which was accompanied by intense activation of glial cells in this brain region. Our results suggest that the i.c.v. injection of rPrP:D67 aggregates is an interesting model to study the neurotoxicity of aggregated PrP in vivo, and that glial cell activation may be an important step for behavioral and cognitive dysfunction in prion diseases.


Asunto(s)
Aptámeros de Nucleótidos/farmacología , Conducta Animal/efectos de los fármacos , Disfunción Cognitiva/inducido químicamente , Hipocampo/efectos de los fármacos , Proteínas Priónicas/farmacología , Sinapsis/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Ventrículos Laterales/efectos de los fármacos , Masculino , Ratones
11.
PLoS Negl Trop Dis ; 15(11): e0009907, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34735450

RESUMEN

Zika virus (ZIKV) emerged as an important infectious disease agent in Brazil in 2016. Infection usually leads to mild symptoms, but severe congenital neurological disorders and Guillain-Barré syndrome have been reported following ZIKV exposure. Creating an effective vaccine against ZIKV is a public health priority. We describe the protective effect of an already licensed attenuated yellow fever vaccine (YFV, 17DD) in type-I interferon receptor knockout mice (A129) and immunocompetent BALB/c and SV-129 (A129 background) mice infected with ZIKV. YFV vaccination provided protection against ZIKV, with decreased mortality in A129 mice, a reduction in the cerebral viral load in all mice, and weight loss prevention in BALB/c mice. The A129 mice that were challenged two and three weeks after the first dose of the vaccine were fully protected, whereas partial protection was observed five weeks after vaccination. In all cases, the YFV vaccine provoked a substantial decrease in the cerebral viral load. YFV immunization also prevented hippocampal synapse loss and microgliosis in ZIKV-infected mice. Our vaccine model is T cell-dependent, with AG129 mice being unable to tolerate immunization (vaccination is lethal in this mouse model), indicating the importance of IFN-γ in immunogenicity. To confirm the role of T cells, we immunized nude mice that we demonstrated to be very susceptible to infection. Immunization with YFV and challenge 7 days after booster did not protect nude mice in terms of weight loss and showed partial protection in the survival curve. When we evaluated the humoral response, the vaccine elicited significant antibody titers against ZIKV; however, it showed no neutralizing activity in vitro and in vivo. The data indicate that a cell-mediated response promotes protection against cerebral infection, which is crucial to vaccine protection, and it appears to not necessarily require a humoral response. This protective effect can also be attributed to innate factors, but more studies are needed to strengthen this hypothesis. Our findings open the way to using an available and inexpensive vaccine for large-scale immunization in the event of a ZIKV outbreak.


Asunto(s)
Vacuna contra la Fiebre Amarilla/administración & dosificación , Infección por el Virus Zika/prevención & control , Virus Zika/fisiología , Animales , Anticuerpos Antivirales/inmunología , Chlorocebus aethiops , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunidad Celular , Interferón gamma/inmunología , Ratones , Ratones Endogámicos BALB C , Linfocitos T/inmunología , Vacunación , Células Vero , Fiebre Amarilla/virología , Virus de la Fiebre Amarilla/genética , Virus de la Fiebre Amarilla/inmunología , Virus Zika/genética , Virus Zika/inmunología , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/virología
12.
Neuropharmacology ; 201: 108841, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34666076

RESUMEN

A strong association between perinatal viral infections and neurodevelopmental disorders has been established. Both the direct contact of the virus with the developing brain and the strong maternal immune response originated by viral infections can impair proper neurodevelopment. Coronavirus disease 2019 (COVID-19), caused by the highly-infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a large global outbreak and is a major public health issue. While initial studies focused on the viral impact on the respiratory system, increasing evidence suggest that SARS-CoV-2 infects other organs and tissues including the mature brain. While studies continue to determine the neuropathology associated to COVID-19, the consequences of SARS-CoV-2 infection to the developing brain remain largely unexplored. The present review discusses evidence suggesting that SARS-CoV-2 infection may have persistent effects on the course of pregnancy and on brain development. Studies have shown that several proinflammatory mediators which are increased in the SARS-CoV-2-associated cytokine storm, are also modified in other viral infections known to increase the risk of neurodevelopmental disorders. In this sense, further studies should assess the genuine effects of SARS-CoV-2 infection during pregnancy and delivery along with an extended follow-up of the offspring, including neurocognitive, neuroimaging, and electrophysiological examination. It also remains to be determined whether and by which mechanisms SARS-CoV-2 intrauterine and early life infection could lead to an increased risk of developing neuropsychiatric disorders, such as autism (ASD) and schizophrenia (SZ), in the offspring.


Asunto(s)
Trastorno del Espectro Autista/epidemiología , COVID-19/epidemiología , Síndrome de Liberación de Citoquinas/epidemiología , Trastornos del Neurodesarrollo/epidemiología , Complicaciones Infecciosas del Embarazo/epidemiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Esquizofrenia/epidemiología , Trastorno del Espectro Autista/inmunología , Encéfalo/embriología , Encéfalo/inmunología , COVID-19/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Femenino , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Trastornos del Neurodesarrollo/inmunología , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Factores de Riesgo , SARS-CoV-2 , Esquizofrenia/inmunología
14.
Brain Behav Immun ; 95: 287-298, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33838250

RESUMEN

Sepsis survivors show long-term impairments, including alterations in memory and executive function. Evidence suggests that systemic inflammation contributes to the progression of Alzheimers disease (AD), but the mechanisms involved in this process are still unclear. Boosted (trained) and diminished (tolerant) innate immune memory has been described in peripheral immune cells after sepsis. However, the occurrence of long-term innate immune memory in the post-septic brain is fully unexplored. Here, we demonstrate that sepsis causes long-lasting trained innate immune memory in the mouse brain, leading to an increased susceptibility to Aß oligomers (AßO), central neurotoxins found in AD. Hippocampal microglia from sepsis-surviving mice shift to an amoeboid/phagocytic morphological profile when exposed to low amounts of AßO, and this event was accompanied by the upregulation of several pro-inflammatory proteins (IL-1ß, IL-6, INF-γ and P2X7 receptor) in the mouse hippocampus, suggesting that a trained innate immune memory occurs in the brain after sepsis. Brain exposure to low amounts of AßO increased microglial phagocytic ability against hippocampal synapses. Pharmacological blockage of brain phagocytic cells or microglial depletion, using minocycline and colony stimulating factor 1 receptor inhibitor (PLX3397), respectively, prevents cognitive dysfunction induced by AßO in sepsis-surviving mice. Altogether, our findings suggest that sepsis induces a long-lasting trained innate immune memory in the mouse brain, leading to an increased susceptibility to AßO-induced neurotoxicity and cognitive impairment.


Asunto(s)
Enfermedad de Alzheimer , Sepsis , Péptidos beta-Amiloides/metabolismo , Animales , Hipocampo/metabolismo , Memoria Inmunológica , Ratones , Microglía/metabolismo
15.
ACS Infect Dis ; 7(1): 47-63, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33291887

RESUMEN

Current chemotherapeutics for leishmaniasis have multiple deficiencies, and there is a need for new safe, efficacious, and affordable medicines. This study describes a successful drug repurposing approach that identifies the over-the-counter antihistamine, clemastine fumarate, as a potential antileishmanial drug candidate. The screening for inhibitors of the sphingolipid synthase (inositol phosphorylceramide synthase, IPCS) afforded, following secondary screening against Leishmania major (Lmj) promastigotes, 16 active compounds. Further refinement through the dose response against LmjIPCS and intramacrophage L. major amastigotes identified clemastine fumarate with good activity and selectivity with respect to the host macrophage. On target engagement was supported by diminished sensitivity in a sphingolipid-deficient L. major mutant (ΔLmjLCB2) and altered phospholipid and sphingolipid profiles upon treatment with clemastine fumarate. The drug also induced an enhanced host cell response to infection indicative of polypharmacology. The activity was sustained across a panel of Old and New World Leishmania species, displaying an in vivo activity equivalent to the currently used drug, glucantime, in a mouse model of L. amazonensis infection. Overall, these data validate IPCS as an antileishmanial drug target and indicate that clemastine fumarate is a candidate for repurposing for the treatment of leishmaniasis.


Asunto(s)
Antiprotozoarios , Leishmaniasis , Preparaciones Farmacéuticas , Animales , Antiprotozoarios/farmacología , Clemastina/uso terapéutico , Inositol , Leishmaniasis/tratamiento farmacológico , Ratones
16.
Neurochem Int ; 138: 104758, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32439533

RESUMEN

α-Synuclein protein (α-syn) is a central player in Parkinson's disease (PD) and in a spectrum of neurodegenerative diseases collectively known as synucleinopathies. These diseases are characterized by abnormal motor symptoms, such as tremor at rest, slowness of movement, rigidity of posture, and bradykinesia. Histopathological features of PD include preferential loss of dopaminergic neurons in the substantia nigra and formation of fibrillar intraneuronal inclusions called Lewy bodies and Lewy neurites, which are composed primarily of the α-syn protein. Currently, it is well accepted that α-syn oligomers (αSO) are the main toxic agent responsible for the etiology of PD. Glutamatergic excitotoxicity is associated with several neurological disorders, including PD. Excess glutamate in the synaptic cleft can be taken up by the astrocytic glutamate transporters GLAST and GLT-1. Although this event is the main defense against glutamatergic excitotoxicity, the molecular mechanisms that regulate this process have not yet been investigated in an early sporadic model of synucleinopathy. Here, using an early sporadic model of synucleinopathy, we demonstrated that the treatment of astrocytes with αSO increased glutamate uptake. This was associated with higher levels of GLAST and GLT-1 in astrocyte cultures and in a mouse model of synucleinopathy 24 h and 45 days after inoculation with αSO, respectively. Pharmacological inhibition of the TGF-ß1 (transforming growth factor beta 1) pathway in vivo reverted GLAST/GLT-1 enhancement induced by αSO injection. Therefore, our study describes a new neuroprotective role of astrocytes in an early sporadic model of synucleinopathy and sheds light on the mechanisms of glutamate transporter regulation for neuroprotection against glutamatergic excitotoxicity in synucleinopathy.


Asunto(s)
Sistema de Transporte de Aminoácidos X-AG/metabolismo , Astrocitos/metabolismo , Modelos Animales de Enfermedad , Sinucleinopatías/metabolismo , alfa-Sinucleína/toxicidad , Animales , Animales Recién Nacidos , Astrocitos/efectos de los fármacos , Astrocitos/patología , Células Cultivadas , Femenino , Ratones , Embarazo , Sinucleinopatías/inducido químicamente , Sinucleinopatías/patología , alfa-Sinucleína/química
17.
Sci Rep ; 10(1): 6763, 2020 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-32317689

RESUMEN

Modulation of brain activity is one of the main mechanisms capable of demonstrating the synchronization dynamics of neural oscillations. In epilepsy, modulation is a key concept since seizures essentially result from neural hypersynchronization and hyperexcitability. In this study, we have introduced a time-dependent index based on the Kullback-Leibler divergence to quantify the effects of phase and frequency modulations of neural oscillations in neonatal mice exhibiting epileptiform activity induced by Zika virus (ZIKV) infection. Through this index, we demonstrate that fast oscillations (gamma and beta 2) are the more susceptible modulated rhythms in terms of phase, during seizures, whereas slow waves (delta and theta) mainly undergo changes in frequency. The index also allowed detection of specific patterns associated with the interdependent modulation of phase and frequency in neural activity. Furthermore, by comparing ZIKV modulations with the general computational model Epileptors, we verify different signatures related to the brain rhythms modulation in phase and frequency. These findings instigate new studies on the effects of ZIKV infection on neuronal networks from electrophysiological activities, and how different mechanisms can trigger epilepsy.


Asunto(s)
Ondas Encefálicas/fisiología , Epilepsia/fisiopatología , Neuronas/fisiología , Infección por el Virus Zika/virología , Animales , Ritmo beta/fisiología , Encéfalo/patología , Encéfalo/virología , Modelos Animales de Enfermedad , Epilepsia/complicaciones , Epilepsia/virología , Ritmo Gamma/fisiología , Humanos , Ratones , Neuronas/virología , Virus Zika/patogenicidad , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/fisiopatología
18.
Cell Rep ; 30(7): 2180-2194.e8, 2020 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-32075735

RESUMEN

Obesity has been associated with cognitive decline, atrophy of brain regions related to learning and memory, and higher risk of developing dementia. However, the molecular mechanisms underlying these neurological alterations are still largely unknown. Here, we investigate the effects of palmitate, a saturated fatty acid present at high amounts in fat-rich diets, in the brain. Palmitate is increased in the cerebrospinal fluid (CSF) of overweight and obese patients with amnestic mild cognitive impairment. In mice, intracerebroventricular infusion of palmitate impairs synaptic plasticity and memory. Palmitate induces astroglial and microglial activation in the mouse hippocampus, and its deleterious impact is mediated by microglia-derived tumor necrosis factor alpha (TNF-α) signaling. Our results establish that obesity is associated with increases in CSF palmitate. By defining a pro-inflammatory mechanism by which abnormal levels of palmitate in the brain impair memory, the results further suggest that anti-inflammatory strategies may attenuate memory impairment in obesity.


Asunto(s)
Trastornos de la Memoria/etiología , Obesidad/líquido cefalorraquídeo , Palmitatos/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Humanos , Trastornos de la Memoria/patología , Ratones , Obesidad/patología
19.
Br J Cancer ; 122(2): 194-208, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31819176

RESUMEN

BACKGROUND: Although produced by several types of tumours, the role of serotonin on cancer biology is yet to be understood. METHODS: The effects of serotonin (5-HT) on human breast cancer cells proliferation, signalling pathways and metabolic profile were evaluated by cytometry, western blotting, qPCR, enzymology and confocal microscopy. RESULTS: Our results revealed that incubation of MCF-7 cells with 10 µM 5-HT increased cell growth rate by 28%, an effect that was prevented by the 5-HTR2A/C antagonist, ketanserin. Conversely, increasing concentrations of 5-HT promoted glucose consumption and lactate production by MCF-7 cells. We also showed that increased glucose metabolism is provoked by the upregulation of pyruvate kinase M2 (PKM2) isoform through 5-HTR2A/C-triggered activation of Jak1/STAT3 and ERK1/2 subcellular pathways. However, we noticed a decrease in the rate of produced lactate per consumed glucose as a function of the hormone concentration, suggesting a disruption of the Warburg effect. The latter effect is due to 5-HTR2A/C-dependent mitochondrial biogenesis and metabolism, which is triggered by adenylyl cyclase/PKA, enhancing the oxidation of lactate within these cells. CONCLUSIONS: We showed that serotonin, through 5-HTR2A/C, interferes with breast cancer cells proliferation and metabolism by triggering two distinct signalling pathways: Jak1/STAT3 that boosts glycolysis through upregulation of PKM2, and adenylyl cyclase/PKA that enhances mitochondrial biogenesis.


Asunto(s)
Neoplasias de la Mama/genética , Proliferación Celular/efectos de los fármacos , Janus Quinasa 1/genética , Factor de Transcripción STAT3/genética , Adenilil Ciclasas/genética , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteínas Portadoras/genética , Supervivencia Celular/efectos de los fármacos , Femenino , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Humanos , Ketanserina/farmacología , Sistema de Señalización de MAP Quinasas/genética , Células MCF-7 , Proteínas de la Membrana/genética , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Serotonina/farmacología , Hormonas Tiroideas/genética , Proteínas de Unión a Hormona Tiroide
20.
Nat Commun ; 10(1): 3890, 2019 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-31488835

RESUMEN

Neurological complications affecting the central nervous system have been reported in adult patients infected by Zika virus (ZIKV) but the underlying mechanisms remain unknown. Here, we report that ZIKV replicates in human and mouse adult brain tissue, targeting mature neurons. ZIKV preferentially targets memory-related brain regions, inhibits hippocampal long-term potentiation and induces memory impairment in adult mice. TNF-α upregulation, microgliosis and upregulation of complement system proteins, C1q and C3, are induced by ZIKV infection. Microglia are found to engulf hippocampal presynaptic terminals during acute infection. Neutralization of TNF-α signaling, blockage of microglial activation or of C1q/C3 prevent synapse and memory impairment in ZIKV-infected mice. Results suggest that ZIKV induces synapse and memory dysfunction via aberrant activation of TNF-α, microglia and complement. Our findings establish a mechanism by which ZIKV affects the adult brain, and point to the need of evaluating cognitive deficits as a potential comorbidity in ZIKV-infected adults.


Asunto(s)
Encéfalo/virología , Sinapsis/virología , Replicación Viral , Infección por el Virus Zika/virología , Virus Zika/fisiología , Animales , Conducta Animal , Encéfalo/metabolismo , Encéfalo/patología , Proteínas del Sistema Complemento/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Humanos , Inflamación , Aprendizaje , Masculino , Memoria , Trastornos de la Memoria , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , Microglía/patología , Neuronas/virología , Terminales Presinápticos/metabolismo , Receptores Tipo I de Interleucina-1/genética , Sinapsis/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
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