Perinatal hipoxic ischemic injury in the auditory pathway and the effect of several neuroprotective agents

192 p.Despite improvements in neonatology, perinatal hypoxic-ischemic (HI) encephalopathy remains one of the main causes of disabilities in term-born infants. This specific pathology underlies many neurological disorders such as learning difficulties, language and attention deficit, hyperactivity disorders and cerebral palsy. Moreover, it is also a notable risk factor for hearing impairments which affect neonates.Insult from hypoxia-ischemia causes immediate neuronal injury and exhaustion of cellular energy stores, as the main cause of HI brain injury is the deprivation of glucose and oxygen supply, which initiates a multi-faceted cascade of biochemical events. The combined effects of cellular energy failure, acidosis, glutamate release, intracellular calcium accumulation, lipid peroxidation, and nitric oxide neurotoxicity provoke, in many cases, the death of the cells, either by necrosis or apoptosis, a divergence that will depend on the severity of the insult, the maturational state of the cell or the brain region affected, among others. After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury, various neuroprotective therapies have been developed for alleviating brain injury.The aim of this work is to evaluate with morphofunctional, molecular and cellular methods the effect of a panel of antioxidants on HI-induced auditory deficits. To this end, we studied the effects of Nicotine, Melatonin, Resveratrol and DHA on the neonatal auditory system via measurement of auditory evoked potentials and characterization of the morphological, molecular and cellular integrity of the IC

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

Increase of deposits of amyloid beta peptides in the extracellular matrix is landmark during Alzheimer's Disease (AD) due to the imbalance in the production vs. clearance. This accumulation of amyloid beta deposits triggers microglial activation. Microglia plays a dual role in AD, a protective role by clearing the deposits of amyloid beta peptides increasing the phagocytic response (CD163, IGF-1 or BDNF) and a cytotoxic role, releasing free radicals (ROS or NO) and proinflammatory cytokines (TNF-alpha, IL-1beta) in response to reactive gliosis activated by the amyloid beta aggregates. Microglia activation correlated with an increase KV1.3 channels expression, protein levels and current density. Several studies highlight the importance of KV1.3 in the activation of inflammatory response and inhibition of neural progenitor cell proliferation and neuronal differentiation. However, little is known about the pathways of this activation in neural stem cells differentiation and proliferation and the role in amyloid beta accumulation. In recent studies using in vitro cells derived from mice models, it has been demonstrated that KV1.3 blockers inhibit microglia-mediated neurotoxicity in culture reducing the expression and production of the pro-inflammatory cytokines IL-1beta and TNF-alpha through the NF-kB and p38MAPK pathway. Overall, we conclude that KV1.3 blockers change the course of AD development, reducing microglial cytotoxic activation and increasing neural stem cell differentiation. However, further investigations are needed to establish the specific pathway and to validate the use of this blocker as therapeutic treatment in Alzheimer patients.This work was supported by a grant from the MICINN (PID2020-118814RB-I00), the Government of the Autonomous Community of the Basque Country (IT1165-19 and KK-2020/00110), and the Spanish Ministry of Science and Innovation (RTI2018-097839-B-100 to AV)

Zer dela-eta zahartzen gara?

Aging is a natural human process that produces functional impairment. Numerous hypotheses try to explain human aging, such as seeing aging as an effect of the exhaustion of stem cells. Stem cells have renewal and differentiation capacity and the number of these cells decreases with aging. Brain is one of the most affected organs during aging. The decrease of Neural Stem Cells (NSC) reduces neuronal regeneration, provoking cognitive decline. Neurogenesis occurs in specific niches of the brain: the subventricular zone and the dentate gyrus of the hippocampus. Recent studies have demonstrated that this neurogenesis occurs not only in the childhood but also as the individual ages. It is therefore extremely important to investigate how to maintain neural stem cell function during aging in order to reduce cognitive decline.; Zahartzea bizidun guztietan gertatzen den prozesu natural bat da, denbora igarotzea-ren ondoriozko gainbehera funtzional gisa defini daitekeena. Gaur egun, hainbat hipotesi proposatu dira zahartzearen zergatia azaltzeko, eta horien artean aurkitzen da zelula amak agortzearen ikerketa-lerroa. Zelula amak, berritze-gaitasuna izateaz gain, ondoren zelula diferentziatuak sortzeko gai dira, baina kopuru aldetik murriztuz doaz zahartzaroarekin. Zehazki, garuna da zahartzaroak fisiologikoki gehien kaltetzen duen organoa. Adinak eragindako garuneko zelula amen agortze honek neuronen berritzea zailtzen du eta, ondorioz, indibiduo helduetan ikus dezakegun gainbehera kognitiboa eragiten du. Neurogenesia garuneko eremu espezifikoetan gertatzen da, bentrikulu azpiko eremuan eta hipokanpoko granulu azpiko eremuan, eta azken ikerketen arabera, haurtzaroan zein zahartzaroan gertatzen den prozesu bat da. Beraz, oso garrantzitsua da zahartzaroan zehar zelula ama hauen funtzioa nola mantendu daitekeen ikertzea, alderdi kognitiboan gertatzen diren galerak ekiditeko

In vitro P38MAPK inhibition in aged astrocytes decreases reactive astrocytes, inflammation and increases nutritive capacity after oxygen-glucose deprivation

Envelliment; Astròcits; P38MAPKEnvejecimiento; Astrocitos; P38MAPKAgeing; Atrocytes; P38MAPKProper astroglial functioning is essential for the development and survival of neurons and oligodendroglia under physiologic and pathological circumstances. Indeed, malfunctioning of astrocytes represents an important factor contributing to brain injury. However, the molecular pathways of this astroglial dysfunction are poorly defined. In this work we show that aging itself can drastically perturb astrocyte viability with an increase of inflammation, cell death and astrogliosis. Moreover, we demonstrate that oxygen glucose deprivation (OGD) has a higher impact on nutritive loss in aged astrocytes compared to young ones, whereas aged astrocytes have a higher activity of the anti-oxidant systems. P38MAPK signaling has been identified to be upregulated in neurons, astrocytes and microglia after ischemic stroke. By using a pharmacological p38α specific inhibitor (PH-797804), we show that p38MAPK pathway has an important role in aged astrocytes for inflammatory and oxidative stress responses with the subsequent cell death that occurs after OGD.Deutsche Forschungsgemeinschaft (SCHE 2078/2-1). Förderverein für frühgeborene Kinder an der Charité e.V. Basque Government Postdoc (2017_1_0095)

Pretreatment with Resveratrol Prevents Neuronal Injury and Cognitive Deficits Induced by Perinatal Hypoxia-Ischemia in Rats

Despite advances in neonatal care, hypoxic-ischemic brain injury is still a serious clinical problem, which is responsible for many cases of perinatal mortality, cerebral palsy, motor impairment and cognitive deficits. Resveratrol, a natural polyphenol with important anti-oxidant and anti-inflammatory properties, is present in grapevines, peanuts and pomegranates. The aim of the present work was to evaluate the possible neuroprotective effect of resveratrol when administered before or immediately after a hypoxic-ischemic brain event in neonatal rats by analyzing brain damage, the mitochondrial status and long-term cognitive impairment. Our results indicate that pretreatment with resveratrol protects against brain damage, reducing infarct volume, preserving myelination and minimizing the astroglial reactive response. Moreover its neuroprotective effect was found to be long lasting, as behavioral outcomes were significantly improved at adulthood. We speculate that one of the mechanisms for this neuroprotection may be related to the maintenance of the mitochondrial inner membrane integrity and potential, and to the reduction of reactive oxygen species. Curiously, none of these protective features was observed when resveratrol was administered immediately after hypoxia-ischemia.Funding was provided by Basque Government IT 773/13 and BFI-2011-129. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Role of Antioxidants in Neonatal Hypoxic–Ischemic Brain Injury: New Therapeutic Approaches

Hypoxic-ischemic brain damage is an alarming health and economic problem in spite of the advances in neonatal care. It can cause mortality or detrimental neurological disorders such as cerebral palsy, motor impairment and cognitive deficits in neonates. When hypoxia-ischemia occurs, a multi-faceted cascade of events starts out, which can eventually cause cell death. Lower levels of oxygen due to reduced blood supply increase the production of reactive oxygen species, which leads to oxidative stress, a higher concentration of free cytosolic calcium and impaired mitochondrial function, triggering the activation of apoptotic pathways, DNA fragmentation and cell death. The high incidence of this type of lesion in newborns can be partly attributed to the fact that the developing brain is particularly vulnerable to oxidative stress. Since antioxidants can safely interact with free radicals and terminate that chain reaction before vital molecules are damaged, exogenous antioxidant therapy may have the potential to diminish cellular damage caused by hypoxia-ischemia. In this review, we focus on the neuroprotective effects of antioxidant treatments against perinatal hypoxic-ischemic brain injury, in the light of the most recent advances

In Vitro P38MAPK Inhibition in Aged Astrocytes Decreases Reactive Astrocytes, Inflammation and Increases Nutritive Capacity After Oxygen-Glucose Deprivation

Proper astroglial functioning is essential for the development and survival of neurons and oligodendroglia under physiologic and pathological circumstances. Indeed, malfunctioning of astrocytes represents an important factor contributing to brain injury. However, the molecular pathways of this astroglial dysfunction are poorly defined. In this work we show that aging itself can drastically perturb astrocyte viability with an increase of inflammation, cell death and astrogliosis. Moreover, we demonstrate that oxygen glucose deprivation (OGD) has a higher impact on nutritive loss in aged astrocytes compared to young ones, whereas aged astrocytes have a higher activity of the anti-oxidant systems. P38MAPK signaling has been identified to be upregulated in neurons, astrocytes and microglia after ischemic stroke. By using a pharmacological p38 alpha specific inhibitor (PH-797804), we show that p38MAPK pathway has an important role in aged astrocytes for inflammatory and oxidative stress responses with the subsequent cell death that occurs after OGD.Deutsche Forschungsgemeinschaft (SCHE 2078/2-1). Forderverein fur fruhgeborene Kinder an der Charite e.V. Basque Government Postdoc (2017_1_0095

Neuronal p38α mediates age‐associated neural stem cell exhaustion and cognitive decline

[EN] Neuronal activity regulates cognition and neural stem cell (NSC) function. The molecular pathways limiting neuronal activity during aging remain largely unknown. In this work, we show that p38MAPK activity increases in neurons with age. By using mice expressing p38α-lox and CamkII-Cre alleles (p38α∆-N), we demonstrate that genetic deletion of p38α in neurons suffices to reduce age-associated elevation of p38MAPK activity, neuronal loss and cognitive decline. Moreover, aged p38α∆-N mice present elevated numbers of NSCs in the hippocampus and the subventricular zone. These results reveal novel roles for neuronal p38MAPK in age-associated NSC exhaustion and cognitive decline

Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma

The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials

Perinatal hipoxic ischemic injury in the auditory pathway and the effect of several neuroprotective agents

192 p.Despite improvements in neonatology, perinatal hypoxic-ischemic (HI) encephalopathy remains one of the main causes of disabilities in term-born infants. This specific pathology underlies many neurological disorders such as learning difficulties, language and attention deficit, hyperactivity disorders and cerebral palsy. Moreover, it is also a notable risk factor for hearing impairments which affect neonates.Insult from hypoxia-ischemia causes immediate neuronal injury and exhaustion of cellular energy stores, as the main cause of HI brain injury is the deprivation of glucose and oxygen supply, which initiates a multi-faceted cascade of biochemical events. The combined effects of cellular energy failure, acidosis, glutamate release, intracellular calcium accumulation, lipid peroxidation, and nitric oxide neurotoxicity provoke, in many cases, the death of the cells, either by necrosis or apoptosis, a divergence that will depend on the severity of the insult, the maturational state of the cell or the brain region affected, among others. After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury, various neuroprotective therapies have been developed for alleviating brain injury.The aim of this work is to evaluate with morphofunctional, molecular and cellular methods the effect of a panel of antioxidants on HI-induced auditory deficits. To this end, we studied the effects of Nicotine, Melatonin, Resveratrol and DHA on the neonatal auditory system via measurement of auditory evoked potentials and characterization of the morphological, molecular and cellular integrity of the IC