Abstract
Development of the olfactory system begins early in embryogenesis and is important for the survival of new-borns in postnatal life. Olfactory malfunction in early life disrupts development of behavioural patterns while with ageing manifests development of neurodegenerative disorders. Previously, we have shown that prenatal hypoxia in rats leads to impaired olfaction in the offspring and correlates with reduced expression of a neuropeptidase neprilysin (NEP) in the brain structures involved in processing of the olfactory stimuli. Prenatal hypoxia also resulted in an increased activity of caspases in rat brain and its inhibition restored NEP content in the brain tissue and improved rat memory. In this study, we have analysed effects of intraventricular administration of a caspase inhibitor Ac-DEVD-CHO on NEP mRNA expression, the number of dendritic spines and olfactory function of rats subjected to prenatal hypoxia on E14. The data obtained demonstrated that a single injection of the inhibitor on P20 restored NEP mRNA levels and number of dendritic spines in the entorhinal and parietal cortices, hippocampus and rescued rat olfactory function in food search and odour preference tests. The data obtained suggest that caspase activation caused by prenatal hypoxia contributes to the olfactory dysfunction in developing animals and that caspase inhibition restores the olfactory deficit via upregulating NEP expression and neuronal networking. Because NEP is a major amyloid-degrading enzyme, any decrease in its expression and activity not only impairs brain functions but also predisposes to accumulation of the amyloid-β peptide and development of neurodegeneration characteristic of Alzheimer’s disease.
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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
Authors express their deep gratitude to Dr Olga S Alekseeva (IEPhB RAS) for assistance in performing prenatal hypoxia experiments. All molecular biology experiments were carried out using the facilities of the Communal Research Resource Centre for physiological, biochemical and molecular-biological research of IEPhB RAS.
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The work was supported by the Russian Foundation for Basic Research, grant 19–015-00232, and Russian Federation state budget (assignment AAAA-A18-118012290373–7).
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All authors have been participating in design of the study and discussion of the results. Dr DS Vasilev performed tissue extraction, rt-PCR and statistical analysis of the data, and Dr NM Dubrovskaya performed animal and behavioural experiments and statistical analysis of the data. Dr NL Tumanova performed microscopy studies. Dr NN Nalivaeva has built the concept of the study and written the manuscript.
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This paper is a part of a special issue dedicated to the 1st ESN Virtual Conference “FUTURE PERSPECTIVES FOR EUROPEAN NEUROCHEMISTRY – A YOUNG SCIENTIST’S CONFERENCE”
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Vasilev, D., Dubrovskaya, N.M. & Nalivaeva, N.N. Caspase Inhibition Restores NEP Expression and Rescues Olfactory Deficit in Rats Caused by Prenatal Hypoxia. J Mol Neurosci 72, 1516–1526 (2022). https://doi.org/10.1007/s12031-022-01986-z
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DOI: https://doi.org/10.1007/s12031-022-01986-z