Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1862, Issue 9, Pages 1852-1861Publisher
ELSEVIER
DOI: 10.1016/j.bbagen.2018.05.017
Keywords
Alpha 1-antitrypsin; Neuronal cultures; Astrocytes; Oligodendrocytes; Interleukins; Nuclear factor-kappaB
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Funding
- Grifols Worldwide Operations Limited [023/13]
- University of Girona [MPCUdG2016/036]
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF-2014-57160R]
- Fundacio Marato TV3
- Generalitat de Catalunya [2014SGR-968]
- Instituto Carlos III: Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)
- Red de Terapia Celular (RETICS) [RD06/0010/0006]
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Background: Death due to cerebral stroke afflicts a large number of neuronal populations, including glial cells depending on the brain region affected. Drugs with a wide cellular range of protection are needed to develop effective therapies for stroke. Human alpha 1-antitrypsin (hAAT) is a serine proteinase inhibitor with potent anti-inflammatory, anti-apoptotic and immunoregulatory activities. This study aimed to test whether hAAT can protect different kind of neurons and glial cells after the oxygen and glucose deprivation (OGD). Methods: Addition of hAAT to mouse neuronal cortical, hippocampal and striatal cultures, as well as glial cultures, was performed 30 min after OGD induction and cell viability was assessed 24 h later. The expression of different apoptotic markers and several inflammatory parameters were assessed by immunoblotting and RT-PCR. Results: hAAT had a concentration-dependent survival effect in all neuronal cultures exposed to OGD, with a maximal effect at 1-2 mg/mL. The addition of hAAT at 1 mg/mL reduced the OGD-mediated necrotic and apoptotic death in all neuronal cultures. This neuroprotective activity of hAAT was associated with a decrease of cleaved caspase-3 and an increase of MAP2 levels. It was also associated with a reduction of pro-inflammatory cytokines protein levels and expression, increase of IL-10 protein levels and decrease of nuclear localization of nuclear factor-kappaB. Similar to neurons, addition of hAAT protected astrocytes and oligodendrocytes against OGD-induced cell death. Conclusions: Human AAT protects neuronal and glial cells against OGD through interaction with cytokines. General significance: Human AAT could be a good therapeutic neuroprotective candidate to treat ischemic stroke.
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