Network activity in primary hippocampal cultures upon HIF-prolyl hydroxylase inhibition

Abstract

Neural network functional activity study and estimation of activity changes in different pathological states (e.g. in hypoxia conditions) is an important scientific task. Hypoxia is one of key damaging factors of various brain pathologies such as stroke, traumatic brain injury, neurodegenerative disease etc. Hypoxia causes structural and functional destruction of neuron-glial networks. The protein calls hypoxia-inducible factor (HIF) is one of the main endogenous molecular regulators of the cell’s response to hypoxia. It’s functional activity is under the control of HIF-prolyl hydroxylase (protein of the prolyl hydroxylase domain, PHD). Recent studies have shown that we can influence HIF activity using PHD-inhibitors and thus increase the cells adaptability to hypoxia. The aim of this work was to determine the effect of PHD on network characteristics of the functional calcium activity in primary neuronal cultures in hypoxia model in vitro. Methods. We investigated Ca2+ signaling in hippocampal cultures using our recently developed method of processing calcium fluorescence imaging data. It includes signal decomposition into individual cells and network reconstruction of dynamical interactions. Results. Our data reveals that the blockade PHD by compound 4896-3212 (neuradapt) during hypoxia modeling preserves the connectivity of neuron-glial networks in the post-hypoxic period. Conclusion. Pharmacological inhibition of PHD which causes the accumulation of HIF, can be used as an effective approach for therapeutic correction of hypoxic damage.

Keywords

• hif-prolyl hydroxylases
• neuroprotection
• primary hippocampal cultures
• hypoxia modeling
• network activity