Neuroprotective effect of ACTH on collagenase-induced peri-intraventricular hemorrhage in newborn male rats

Martins, Camila Aparecida da Silva; Neves, Laura Tartari; Oliveira, Marina M. B. P. de; Bagatini, Pamela Brambilla; Barboza, Rafaela; Mestriner, Régis Gemerasca; Xavier, Léder Leal; Rasia‐Filho, Alberto A.

doi:10.1038/s41598-020-74712-7

Cited by 7 publications

(3 citation statements)

References 55 publications

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“…Thus, these treatments are only palliative and can only prevent some PHH-associated damage. Treatments are also being sought to prevent the development of GMH, although the molecular causes of its development are not well understood 35,36 . Attempts to develop (which was not certified by peer review) is the author/funder.…”

Section: Germinalmentioning

confidence: 99%

Design of a stem cell-based therapy for ependymal repair in hydrocephalus associated with germinal matrix hemorrhages

Rodríguez-Pérez

Ojeda-Pérez

García-Bonilla

et al. 2023

Preprint

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Germinal matrix hemorrhages (GMH) and the consequent posthemorrhagic hydrocephalus (PHH) are among the most common and severe neurological complications of preterm birth that require lifelong complex neurosurgical care. GMH and PHH provoke disruption of neuroepithelium/ependyma development, a key structure implicated in brain development and homeostasis. Neuroepithelial/ependymal damage causes lifelong cognitive and motor deficits; however, no therapy is directed to recover the damaged ependyma. This study is aimed to test the possibilities of ependymal repair in GMH/PHH using neural stem cells (NSCs) or ependymal progenitors (EpPs). Thus, it sets the basis for a therapeutic approach to treating ependymal damage and preventing brain developmental deficits. GMH/PHH was induced in 4-day-old mice using different experimental procedures involving collagenase, blood, or blood serum injections. PHH severity was characterized using magnetic resonance, immunofluorescence, and protein expression quantification with mass spectrometry. Additionally, a newexvivoapproach using ventricular walls from mice developing moderate and severe GMH/PHH was generated to study ependymal restoration and wall regeneration after stem cell treatments. NSCs or EpPs obtained from newborn mice were transplanted in the explants, and pretreatment with mesenchymal stem cells (MSCs) was tested. Ependymal differentiation and the effect of MSC-conditioned microenvironment were investigated in both explants and primary cultures. In the animals, PHH severity was correlated with the extension of GMH, ependymal disruption, astroglial/microglial reactions, and ventriculomegaly. In the explants, the severity and extension of GMH hindered the survival rates of the transplanted NSCs/EpPs. In the explants affected with GMH, new multiciliated ependymal cells could be generated from transplanted NSCs and, more efficiently, from EpPs. Blood and TNFα negatively affected ciliogenesis in cells expressing Foxj1. Pretreatment with mesenchymal stem cells (MSC) improved the survival rates of EpPs and ependymal differentiation while reducing the edematous and inflammatory conditions in the explants. In conclusion, in GMH/PHH, the ependyma can be restored from either NSC or EpP transplantation, being EpPs in an MSC-conditioned microenvironment more efficient for this purpose. Modifying the neuroinflammatory microenvironment by MSC pretreatment positively influenced the success of the ependymal restoration.

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Section: Germinalmentioning

confidence: 99%

Design of a stem cell-based therapy for ependymal repair in hydrocephalus associated with germinal matrix hemorrhages

Rodríguez-Pérez

Ojeda-Pérez

García-Bonilla

et al. 2023

Preprint

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“…ACTH has been found to promote oligodendrocyte protection ( 103 ) and neuron protection from inflammatory, excitotoxic, and apoptotic damages ( 104 , 105 ). Dated research showed that rat embryo neurons respond to ACTH displaying a denser neuritic network ( 106 ) and displayed neuroprotective effects after hemorrhage insult by activating anti-inflammatory pathways ( 107 , 108 ). Melanocortins have been proposed as therapy for brain injuries and several chronic neurodegenerative disorders ( 102 ).…”

Section: Extra-adrenal Effects Of Acthmentioning

confidence: 99%

Non-Canonical Effects of ACTH: Insights Into Adrenal Insufficiency

et al. 2021

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IntroductionAdrenocorticotropic hormone (ACTH) is produced from proopiomelanocortin, which is predominantly synthetized in the corticotroph and melanotroph cells of the anterior and intermediate lobes of the pituitary gland and the arcuate nucleus of the hypothalamus. Although ACTH clearly has an effect on adrenal homeostasis and maintenance of steroid hormone production, it also has extra-adrenal effects that require further elucidation.MethodsWe comprehensively reviewed English language articles, regardless of whether they reported the presence or absence of adrenal and extra-adrenal ACTH effects.ResultsIn the present review, we provide an overview on the current knowledge on adrenal and extra-adrenal effects of ACTH. In the section on adrenal ACTH effects, we focused on corticosteroid rhythmicity and effects on steroidogenesis, mineralocorticoids and adrenal growth. In the section on extra-adrenal effects, we have analyzed the effects of ACTH on the osteoarticular and reproductive systems, adipocytes, immune system, brain and skin. Finally, we focused on adrenal insufficiency.ConclusionsThe role of ACTH in maintaining the function of the hypothalamic–pituitary–adrenal axis is well known. Conversely, if we broaden our vision and analyze its role as a potential treatment strategy in other conditions, it will be evident in the literature that researchers seem to have abandoned this aspect in studies conducted several years ago. We believe it is worth re-evaluating the role of ACTH considering its noncanonical effects on the adrenal gland itself and on extra-adrenal organs and tissues; however, this would not have been possible without the recent advances in the pertinent technologies.

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“…Studies showed that ACTH promotes the differentiation of oligodendroglial progenitor cells to oligodendrocytes accompanied by increased myelination and protects the progenitor cells from excitotoxic and inflammation-related damage ( 32 ). In a rat model of intraventricular hemorrhage, ACTH showed neuroprotective effects in newborn rats ( 33 ).…”

Section: Introductionmentioning

confidence: 99%

Hyperoxia Leads to Transient Endocrine Alterations in the Neonatal Rat During Postnatal Development

et al. 2021

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Introduction: High oxygen concentrations have been identified as one factor contributing to the pathogenesis of the retinopathia of prematurity, chronic lung disease of the preterm infant and preterm brain injury. Preterm infants also show short- and long-term alterations of the endocrine system. If hyperoxia is one pathogenetic factor has not been investigated yet. With regard to the high prevalence of neurodevelopmental impairments in preterm infants, the hypothalamus-pituitary-thyroid (HPT) axis, the hypothalamus-pituitary-adrenal (HPA) axis and the hypothalamus-pituitary-somatotropic (HPS) axis are of special interest due to their important role in neurodevelopment.Objective: The aim of this study was to investigate the effect of hyperoxia on the endocrine system in the neonatal rat by analyzing the activities of the HPT, HPA and HPS axes, respectively.Methods: Three-days old Wistar rats were exposed to hyperoxia (oxygen 80%, 48 h). On postnatal day 5 (P5) and P11, transcript levels of thyroid-stimulating hormone (TSH), proopiomelanocortin and growth hormone (GH) were analyzed in pituitary sections by in situ hybridization. Serologic quantification of TSH and thyroxine (T4), adrenocorticotropic hormone and GH were performed by Multiplex analysis and Enzyme-linked Immunosorbent Assay.Results: At P5, significantly lower GH levels were observed in pituitaries (mRNA) and in sera of rats exposed to hyperoxia. Serum TSH was significantly elevated without changes in T4.Conclusion: This is the first study demonstrating transient endocrine alterations following hyperoxia in the neonatal rat making oxygen a possible contributor to the pathogenesis of endocrine alterations seen in preterm infants. Considering the detrimental multi-organ effects of hyperoxia on the immature organism, a rational use of therapeutic oxygen in the treatrnent of preterm infants is of utmost importance.

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Neuroprotective effect of ACTH on collagenase-induced peri-intraventricular hemorrhage in newborn male rats

Cited by 7 publications

References 55 publications

Design of a stem cell-based therapy for ependymal repair in hydrocephalus associated with germinal matrix hemorrhages

Design of a stem cell-based therapy for ependymal repair in hydrocephalus associated with germinal matrix hemorrhages

Non-Canonical Effects of ACTH: Insights Into Adrenal Insufficiency

Hyperoxia Leads to Transient Endocrine Alterations in the Neonatal Rat During Postnatal Development

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