RESUMO
Since its detection in the brain, the cannabinoid receptor type 2 (CB2) has been considered a promising therapeutic target for various neurological and psychiatric disorders. However, precise brain mapping of its expression is still lacking. Using magnetic cell sorting, calibrated RT-qPCR and single-nucleus RNAseq, we show that CB2 is expressed at a low level in all brain regions studied, mainly by few microglial cells, and by neurons in an even lower proportion. Upon lipopolysaccharide stimulation, modeling neuroinflammation in non-sterile conditions, we demonstrate that the inflammatory response is associated with a transient reduction in CB2 mRNA levels in brain tissue, particularly in microglial cells. This result, confirmed in the BV2 microglial cell line, contrasts with the positive correlation observed between CB2 mRNA levels and the inflammatory response upon stimulation by interferon-gamma, modeling neuroinflammation in sterile condition. Discrete brain CB2 expression might thus be up- or down-regulated depending on the inflammatory context.
Assuntos
Encéfalo , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Microglia , Receptor CB2 de Canabinoide , Animais , Microglia/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/biossíntese , Camundongos , Encéfalo/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/patologia , Doenças Neuroinflamatórias/metabolismoRESUMO
Because of its involvement in breathing control and neuronal excitability, dysregulation of the serotonin (5-HT) 2C receptor (5-HT2C) might play a key role in sudden unexpected death in epilepsy. Seizure-induced respiratory arrest is thus prevented by a 5-HT2B/C agonist in different seizure model. However, the specific contribution of 5-HT2C in chronic epilepsy-related respiratory dysfunction remains unknown. In a rat model of temporal lobe epilepsy (EPI rats), in which we previously reported interictal respiratory dysfunctions and a reduction of brainstem 5-HT tone, quantitative reverse transcriptase polymerase chain reaction showed overexpression of TPH2 (5-HT synthesis enzyme), SERT (5-HT reuptake transporter), and 5-HT2C transcript levels in the brainstem of EPI rats, and of RNA-specific adenosine deaminase (ADAR1, ADAR2) involved in the production of 5-HT2C isoforms. Interictal ventilation was assessed with whole-body plethysmography before and 2 h after administration of SB242084 (2 mg/kg), a specific antagonist of 5-HT2C. As expected, SB242084 administration induced a progressive decrease in ventilatory parameters and an alteration of breathing stability in both control and EPI rats. However, the size of the SB242084 effect was lower in EPI rats than in controls. Increased 5-HT2C gene expression in the brainstem of EPI rats could be part of a compensatory mechanism against epilepsy-related low 5-HT tone and expression of 5-HT2C isoforms for which 5-HT affinity might be lower.
Assuntos
Tronco Encefálico , Modelos Animais de Doenças , Epilepsia do Lobo Temporal , Receptor 5-HT2C de Serotonina , Animais , Receptor 5-HT2C de Serotonina/genética , Receptor 5-HT2C de Serotonina/metabolismo , Ratos , Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/metabolismo , Tronco Encefálico/metabolismo , Tronco Encefálico/efeitos dos fármacos , Masculino , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Indóis/farmacologia , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Aminopiridinas , TiofenosRESUMO
Genomic imprinting is a process that causes genes to be expressed from one allele only according to parental origin, the other allele being silent. Diseases can arise when the normally active alleles are not expressed. In this context, low level of expression of the normally silent alleles has been considered as genetic noise although such expression has never been further studied. Prader-Willi Syndrome (PWS) is a neurodevelopmental disease involving imprinted genes, including NDN, which are only expressed from the paternally inherited allele, with the maternally inherited allele silent. We present the first in-depth study of the low expression of a normally silent imprinted allele, in pathological context. Using a variety of qualitative and quantitative approaches and comparing wild-type, heterozygous and homozygous mice deleted for Ndn, we show that, in absence of the paternal Ndn allele, the maternal Ndn allele is expressed at an extremely low level with a high degree of non-genetic heterogeneity. The level of this expression is sex-dependent and shows transgenerational epigenetic inheritance. In about 50% of mutant mice, this expression reduces birth lethality and severity of the breathing deficiency, correlated with a reduction in the loss of serotonergic neurons. In wild-type brains, the maternal Ndn allele is never expressed. However, using several mouse models, we reveal a competition between non-imprinted Ndn promoters which results in monoallelic (paternal or maternal) Ndn expression, suggesting that Ndn allelic exclusion occurs in the absence of imprinting regulation. Importantly, specific expression of the maternal NDN allele is also detected in post-mortem brain samples of PWS individuals. Our data reveal an unexpected epigenetic flexibility of PWS imprinted genes that could be exploited to reactivate the functional but dormant maternal alleles in PWS. Overall our results reveal high non-genetic heterogeneity between genetically identical individuals that might underlie the variability of the phenotype.
Assuntos
Epigênese Genética/genética , Impressão Genômica , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Síndrome de Prader-Willi/genética , Alelos , Animais , Apneia/genética , Apneia/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Heterozigoto , Humanos , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Síndrome de Prader-Willi/patologia , Regiões Promotoras GenéticasRESUMO
Erythropoietin receptor (EpoR) binding mediates neuroprotection by endogenous Epo or by exogenous recombinant human (rh)Epo. The level of EpoR gene expression may determine tissue responsiveness to Epo. Thus, harnessing the neuroprotective power of Epo requires an understanding of the Epo-EpoR system and its regulation. We tested the hypothesis that neuronal expression of EpoR is required to achieve optimal neuroprotection by Epo. The ventral limbic region (VLR) in the rat brain was used because we determined that its neurons express minimal EpoR under basal conditions, and they are highly sensitive to excitotoxic damage, such as occurs with pilocarpine-induced status epilepticus (Pilo-SE). We report that (i) EpoR expression is significantly elevated in nearly all VLR neurons when rats are subjected to 3 moderate hypoxic exposures, with each separated by a 4-day interval; (ii) synergistic induction of EpoR expression is achieved in the dorsal hippocampus and neocortex by the combination of hypoxia and exposure to an enriched environment, with minimal increased expression by either treatment alone; and (iii) rhEpo administered after Pilo-SE cannot rescue neurons in the VLR, unless neuronal induction of EpoR is elicited by hypoxia before Pilo-SE. This study thus demonstrates using environmental manipulations in normal rodents, the strict requirement for induction of EpoR expression in brain neurons to achieve optimal neuroprotection. Our results indicate that regulation of EpoR gene expression may facilitate the neuroprotective potential of rhEpo.
Assuntos
Eritropoetina/farmacologia , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Receptores da Eritropoetina/metabolismo , Animais , Ensaio de Imunoadsorção Enzimática , Eritropoetina/metabolismo , Regulação da Expressão Gênica , Hipóxia/metabolismo , Masculino , Pilocarpina/farmacologia , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptores da Eritropoetina/genética , Receptores da Eritropoetina/fisiologia , Proteínas Recombinantes/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologiaRESUMO
Patients with drug-resistant epilepsy can experience respiratory alterations, notably during seizures. The mechanisms underlying long-term alterations in respiratory function remain unclear. As the brainstem 5-HT system is a prominent modulator of respiratory function, this study aimed at determining whether epilepsy is associated with alterations in both the respiratory function and brainstem serotonin (5-HT) system in rats. Epilepsy was triggered by pilocarpine-induced status epilepticus in rats. Our results showed that 30-50% of epileptic (EPI) rats exhibited a sharp decrease in oxygen consumption (SDOC), low metabolic rate of oxygen, and slow regular ventilation (EPI/SDOC + rats). These alterations were detected only in rats with chronic epilepsy, independent of behavioral seizures, were persistent over time, and not associated with death. In these rats, 5-HT fiber density in the nucleus tractus solitarius was lower than that in the control and EPI/SDOC- rats. Both EPI/SDOC + rats and DBA/2 mice that present with audiogenic-induced seizure followed by fatal respiratory arrest-a model of sudden and expected death in epilepsy-had increased transcript levels of tryptophan hydroxylase 2 and 5-HT presynaptic transporter. Thus, our data support that 5-HT alterations are associated with chronic and acute epilepsy-related respiratory dysfunction.
Assuntos
Epilepsia Reflexa , Transtornos Respiratórios , Animais , Tronco Encefálico/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos DBA , Ratos , Roedores/metabolismo , Convulsões , Serotonina/metabolismoRESUMO
Heparanase is an endo-beta-d-glucuronidase which specifically cleaves extracellular and cell surface heparan sulphates at intra-chain sites. Its enzymatic activity is strongly implicated in cell dissemination associated with tumor metastasis and inflammation. Indeed, heparanase gene is expressed in various tumors and its over-expression is correlated with increased tumor vascularity and metastatic potential of tumor cells. However, heparanase expression in non-invasive and non-immune tissue, including brain, has received less attention. Using RT-qPCR, western blot and histological analysis, we demonstrate in the adult rat that heparanase transcript is differentially expressed according to brain area, and that heparanase protein is mainly detected in neurons. Furthermore, we provide evidence that heparanase transcript and protein reach their greatest levels at early postnatal stages, in particular within the neocortex characterized by intensive structural plasticity. Using the in vitro model of PC12-induced neuronal differentiation, we suggest that developmental regulation of heparanase may coincide with axonal and dendritic pathfinding. At adulthood, we demonstrate that the increased heparanase transcript level correlates in the hippocampus with enhanced angiogenesis following repeated hypoxia exposures. Taken together, our results emphasize the potential importance of heparanase in brain homeostasis, both during development and adaptative responses to severe environmental challenges.
Assuntos
Encéfalo/enzimologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Glucuronidase/metabolismo , Hipóxia/complicações , Neovascularização Patológica/etiologia , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Antígenos CD34/metabolismo , Encéfalo/crescimento & desenvolvimento , Bromodesoxiuridina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Meio Ambiente , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Glucuronidase/genética , Precondicionamento Isquêmico/métodos , Masculino , Neovascularização Patológica/patologia , Fator de Crescimento Neural/farmacologia , Células PC12 , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Extracellular ATP regulates cell proliferation, muscle contraction and myoblast differentiation. ATP present in the muscle interstitium can be released from contracting skeletal muscle cells. L-Carnitine is a key element in muscle cell metabolism, as it serves as a carrier for fatty acid through mitochondrial membranes, controlling oxidation and energy production. Treatment of C2C12 cells with 1 mmol/l of ATP induced a marked increase in L-carnitine uptake that was associated with an increase in L-carnitine content in these cells. These effects were found to be dependent on the density of the cultured cells and on the dose of ATP. The use of specific inhibitors of P2X and P2Y receptors abolished the effect of ATP on L-carnitine metabolism. As ATP can be released from stressed or exercising cells, it can be hypothesized that ATP acts as a messenger in the muscle. ATP will be released to recruit the next cells and increase their metabolism.
Assuntos
Trifosfato de Adenosina/metabolismo , Carnitina/metabolismo , Receptores Purinérgicos P2/metabolismo , Complexo Vitamínico B/metabolismo , Trifosfato de Adenosina/administração & dosagem , Animais , Transporte Biológico , Linhagem Celular , Relação Dose-Resposta a Droga , Camundongos , Mioblastos/metabolismo , Antagonistas do Receptor Purinérgico P2RESUMO
Traumatic brain injury (TBI) is common in both military and civilian populations, and often results in neurobehavioral sequelae that impair quality of life in both patients and their families. Although individuals who are chronically exposed to stress are more likely to experience TBI, it is still unknown whether pre-injury stress influences the outcome after TBI. The present study tested whether behavioral and cognitive long-term outcome after TBI in rats is affected by prior exposure to an innate stress stimulus. Young adult male Sprague-Dawley rats were exposed to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) or to water (WAT); exposure was repeated eight times at irregular intervals over a 2-week period. Rats were subsequently subjected to either mild-to-moderate bilateral brain injury (lateral fluid percussion [LFP]) or sham surgery (Sham). Four experimental groups were studied: Sham-WAT, Sham-TMT, LFP-WAT and LFP-TMT. Compared with Sham-WAT rats, LFP-WAT rats exhibited transient locomotor hyperactivity without signs of anxiety, minor spatial learning acquisition and hippocampal long-term potentiation deficits, and lower baseline activity of the hypothalamic-pituitary-adrenal axis with slightly stronger reactivity to restraint stress. Exposure to TMT had only negligible effects on Sham rats, whereas it exacerbated all deficits in LFP rats except for locomotor hyperactivity. Early brain inflammatory response (8 h post-trauma) was aggravated in rats pre-exposed to TMT, suggesting that increased brain inflammation may sustain functional deficits in these rats. Hence, these data suggest that pre-exposure to stressful conditions can aggravate long-term deficits induced by TBI, leading to severe stress response deficits, possibly due to dysregulated inflammatory response.
Assuntos
Comportamento Animal , Lesões Encefálicas Traumáticas/complicações , Disfunção Cognitiva/etiologia , Inflamação/etiologia , Estresse Psicológico/complicações , Animais , Comportamento Animal/fisiologia , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/fisiopatologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Aprendizagem em Labirinto , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
Orexin-A (OX-A) and -B (OX-B) peptides present in the hippocampus are considered to be exclusively contained in fibers arising from hypothalamus neurons, which were established as the only source of orexins (OXs). Because OX-A is known to exert excitatory actions in the hippocampus, we hypothesized that the level of OXs targeted toward the hippocampus may be increased following status-epilepticus (SE)-induced epileptogenesis in the rat pilocarpine model of temporal lobe epilepsy. We found that tissue concentration of prepro-OX mRNA, which encodes for both peptides, rapidly decreased in the hypothalamus of rats having experienced pilocarpine-induced SE (Pilo-SE) followed by a reduced density of OX-A and OX-B immunopositive fibers arising from these neurons. By contrast, it was unexpected to detect within the hippocampus the presence of prepro-OX mRNA in basal conditions and to evidence its up-regulation during the 1- to 3-day period following Pilo-SE. The number of prepro-OX mRNA copies determined by real-time RT-PCR was approximately 50-fold lower in the hippocampus than that in the hypothalamus, precluding the use of in situ hybridization to localize the cells which synthesize the transcript within the hippocampus. The increase in prepro-OX mRNA level within the hippocampus was accompanied by the detection of OX-B-like immunoreactivity 2-3 days post-SE, not only in pyramidal neurons, granule cells and cell bodies resembling interneurons, but also in some astrocytes scattered throughout the hippocampus. The present data suggest that the gene encoding OXs can be activated in the hippocampus, which may play a role in the pathogenesis of epilepsy.
Assuntos
Epilepsia/metabolismo , Regulação da Expressão Gênica/fisiologia , Hipocampo/metabolismo , Neuropeptídeos/metabolismo , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Contagem de Células/métodos , Modelos Animais de Doenças , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Epilepsia/induzido quimicamente , Epilepsia/patologia , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Agonistas Muscarínicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuropeptídeos/genética , Orexinas , Pilocarpina , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de TempoRESUMO
L-Carnitine is a key molecule in the transfer of fatty acid across mitochondrial membranes. Bioavailable L-carnitine is either provided by an endogeneous biosynthesis or after intestinal absorption of dietary items containing L-carnitine. After intestinal absorption or hepatic biosynthesis, L-carnitine is transferred to organs whose metabolism is dependent upon fatty acid oxidation, such as skeletal muscle. To cross the muscle plasma membrane, there are several transporters involved. Among those transporters, OCTN2 is actually the only one to have been clearly characterized. Zidovudine is a commonly used inhibitor of human immunodeficiency virus (HIV) replication. Zidovudine has many side effects, including induction of myopathy characterized by a metabolic mitochondria dysfunction and a diminution of the muscle L-carnitine content. In this study, we described the characteristics of L-carnitine transport in C2C12 cells. We also demonstrated that zidovudine inhibited the L-carnitine transporter. This inhibition led to a significant reduction of the muscle cell growth. In C2C12 cells, the supplementation of L-carnitine prevented the effects of zidovudine and restored the normal cell growth.
Assuntos
Antimetabólitos/farmacologia , Carnitina/metabolismo , Mioblastos/efeitos dos fármacos , Zidovudina/farmacologia , Animais , Antimetabólitos/efeitos adversos , Transporte Biológico , Divisão Celular/efeitos dos fármacos , Interações Medicamentosas , Cinética , Camundongos , Especificidade por Substrato , Zidovudina/efeitos adversosRESUMO
Environmental enrichment of laboratory animals influences brain plasticity, stimulates neurogenesis, increases neurotrophic factor expression, and protects against the effects of brain insult. However, these positive effects are not constantly observed, probably because standardized procedures of environmental enrichment are lacking. Therefore, we engineered an enriched cage (the Marlau™ cage), which offers: (1) minimally stressful social interactions; (2) increased voluntary exercise; (3) multiple entertaining activities; (4) cognitive stimulation (maze exploration), and (5) novelty (maze configuration changed three times a week). The maze, which separates food pellet and water bottle compartments, guarantees cognitive stimulation for all animals. Compared to rats raised in groups in conventional cages, rats housed in Marlau™ cages exhibited increased cortical thickness, hippocampal neurogenesis and hippocampal levels of transcripts encoding various genes involved in tissue plasticity and remodeling. In addition, rats housed in Marlau™ cages exhibited better performances in learning and memory, decreased anxiety-associated behaviors, and better recovery of basal plasma corticosterone level after acute restraint stress. Marlau™ cages also insure inter-experiment reproducibility in spatial learning and brain gene expression assays. Finally, housing rats in Marlau™ cages after severe status epilepticus at weaning prevents the cognitive impairment observed in rats subjected to the same insult and then housed in conventional cages. By providing a standardized enriched environment for rodents during housing, the Marlau™ cage should facilitate the uniformity of environmental enrichment across laboratories.
Assuntos
Encéfalo/fisiologia , Encéfalo/fisiopatologia , Cognição , Abrigo para Animais/normas , Plasticidade Neuronal , Estado Epiléptico/patologia , Estado Epiléptico/fisiopatologia , Adaptação Psicológica/fisiologia , Animais , Ansiedade/complicações , Peso Corporal , Encéfalo/citologia , Encéfalo/patologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/fisiologia , Região CA1 Hipocampal/fisiopatologia , Ingestão de Alimentos , Comportamento Exploratório/fisiologia , Saúde , Metabolismo dos Lipídeos , Masculino , Neurogênese/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Padrões de Referência , Reprodutibilidade dos Testes , Restrição Física/psicologia , Estado Epiléptico/psicologia , Estresse Psicológico/complicações , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia , Sinapses/patologiaRESUMO
Brain effects of erythropoietin (Epo) are proposed to involve a heteromeric receptor comprising the classical Epo receptor (Epo-R) and the common beta chain (betac). However, data documenting the pattern of betac gene expression in the healthy brain, in comparison with that of the Epo-R gene, are still lacking. The present study is the first to investigate at the same time betac, Epo-R, and Epo gene expression within different rat brain areas throughout the life span, from neonatal to elderly stages, using quantitative RT-PCR for transcripts. Corresponding proteins were localized by using immunohistochemistry. We demonstrate that the betac transcript level does not correlate with that of Epo-R or Epo, whereas the Epo-R transcript level strongly correlates with that of Epo throughout the life span in all brain structures analyzed. Both Epo and Epo-R were detected primarily in neurons. In the hippocampus, the greatest Epo-R mRNA levels were measured during the early postnatal period and in middle-aged rats, associated with an intense neuronal immunolabeling. Conversely, betac protein was barely detectable in the brain at all ages, even in neurons expressing high levels of Epo-R. Finally, betac transcript could not be detected in PC12 cells, even after nerve growth factor-induced neuritogenesis, which is a condition that dramatically enhances Epo-R transcript level. Altogether, our data suggest that most neurons are likely to express high levels of Epo-R but low, if not null, levels of betac. Given that Epo protects extended populations of neurons after injury, a yet-to-be-identified receptor heterocomplex including Epo-R may exist in the large population of brain neurons that does not express betac.
Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Eritropoetina/metabolismo , Receptores da Eritropoetina/metabolismo , Envelhecimento/metabolismo , Análise de Variância , Animais , Astrócitos/metabolismo , Expressão Gênica , Imuno-Histoquímica , Masculino , Microglia/metabolismo , Neuritos/metabolismo , Neurônios/metabolismo , Células PC12 , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
L-Carnitine plays an important role in skeletal muscle bioenergetics, and its bioavailability and thus its import may be crucial for muscle function. We studied the effect of thyroid hormone, insulin, and iron overload, hormones and nutrients known to alter muscle metabolism, on L-carnitine import into C2C12 cells. We report here L-carnitine uptake is increased by thyroid hormones and decreased by iron. Insulin was found to be ineffective in altering the L-carnitine uptake.
Assuntos
Carnitina/metabolismo , Hormônios/fisiologia , Músculo Esquelético/metabolismo , Fenômenos Fisiológicos da Nutrição/fisiologia , Northern Blotting , Linhagem Celular , Humanos , Insulina/farmacologia , Compostos de Ferro/farmacologia , Sobrecarga de Ferro/metabolismo , Músculo Esquelético/citologia , Proteínas de Transporte de Cátions Orgânicos/biossíntese , Proteínas de Transporte de Cátions Orgânicos/genética , RNA Mensageiro/biossíntese , Membro 5 da Família 22 de Carreadores de Soluto , Tri-Iodotironina/farmacologiaRESUMO
Neuroprotective functions of erythropoietin (Epo) are thought to involve a heteroreceptor composed of both Epo receptor (Epo-R) and common beta chain (betac). Here, we measured the response of hippocampal Epo system components (Epo, Epo-R and betac) during neurodegenerative processes following pilocarpine-induced status epilepticus (SE), and examined whether recombinant human Epo (rHuEpo) could support neuronal survival. We evidence that Epo is induced in astroglia following SE, in particular within areas displaying delayed neuronal death. In addition, we demonstrate for the first time that rHuEpo reduces considerably hippocampal neurodegeneration following SE. rHuEpo may thus supplement astroglial induction of Epo to promote enhanced hippocampal neuronal survival following SE. We also show that Epo-R is expressed by neurons and astrocytes mainly, while betac is barely detectable in basal conditions and induced in reactive microglia exclusively following SE. Altogether, our results suggest that Epo/rHuEpo exerts neuroprotection, through Epo-R signaling and independently of betac, and, therefore, may be anti-epileptogenic.