Abstract
Anoxia is one of the most prevalent causes of neonatal morbidity and mortality, especially in preterm neonates, constituting an important public health problem due to permanent neurological sequelae observed in patients. Oxygen deprivation triggers a series of simultaneous cascades, culminating in cell death mainly located in more vulnerable metabolic brain regions, such as the hippocampus. In the process of cell death by oxygen deprivation, cytosolic calcium plays crucial roles. Intracellular inositol 1,4,5-trisphosphate receptors (IP3Rs) are important regulators of cytosolic calcium levels, although the role of these receptors in neonatal anoxia is completely unknown. This study focused on the functional role of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) in rat hippocampus after neonatal anoxia. Quantitative real-time PCR revealed a decrease of IP3R1 gene expression 24 hours after neonatal anoxia. We detected that IP3R1 accumulates specially in CA1, and this spatial pattern did not change after neonatal anoxia. Interestingly, we observed that anoxia triggers translocation of IP3R1 to nucleus in hippocampal cells. We were able to observe that anoxia changes distribution of IP3R1 immunofluorescence signals, as revealed by cluster size analysis. We next examined the role of IP3R1 in the neuronal cell loss triggered by neonatal anoxia. Intrahippocampal injection of non-specific IP3R1 blocker 2-APB clearly reduced the number of Fluoro-Jade C and Tunel positive cells, revealing that activation of IP3R1 increases cell death after neonatal anoxia. Finally, we aimed to disclose mechanistics of IP3R1 in cell death. We were able to determine that blockade of IP3R1 did not reduced the distribution and pixel density of activated caspase 3-positive cells, indicating that the participation of IP3R1 in neuronal cell loss is not related to classical caspase-mediated apoptosis. In summary, this study may contribute to new perspectives in the investigation of neurodegenerative mechanisms triggered by oxygen deprivation.
Highlights
The brain is an organ with a high energetic consumption using 20% of total body oxygen and 25% of glucose, and it is highly sensitive to oxygen reduction [1]
To understand the participation of IP3R1 in neurodegeneration caused by anoxic insult, we investigated the distribution, subcellular localisation and functional role of IP3R1 in hippocampal cell death triggered by neonatal anoxia
Since we observed that anoxia decreased IP3R1 gene expression, we examined whether distribution of IP3R1 changes after this neurodegenerative insult
Summary
The brain is an organ with a high energetic consumption using 20% of total body oxygen and 25% of glucose, and it is highly sensitive to oxygen reduction [1]. One of the brain regions more sensitive to oxygen deprivation is the hippocampus, a very well-studied structure related to spatial memory and learning [3]. Takada et al demonstrated that neonatal anoxia induced alterations in rat hippocampal cells, such as different types of cell death, including apoptosis, necrosis, excitotoxicity, and maybe as a consequence, these rats present spatial memory deficits [4]. A study using NMDA-induced neuronal excitotoxicity demonstrated evidence that endoplasmic reticulum (ER)-Ca2+ release through ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) contributes to cell death. The inhibition of these receptors during the excitotoxicity insult suggests that calcium release by IP3R1 promotes mitochondrial dysfunction and ER-specific cell death pathway in neuronal excitotoxicity [6]
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