Khrestchatisky, M. | bioRxiv Science

bioRxiv2023

LDLR-mediated targeting and productive uptake of siRNA-peptide ligand conjugates in vitro and in vivo

siRNAs have become one of the most promising therapeutic agents because of their specificity and their potential to modulate the expression of gene-related diseases. Any gene of interest can be potentially up or down-regulated, making RNA-based technology the healthcare breakthrough of our era. However, the functional and specific delivery of siRNAs into tissues of interest and into the cytosol of target cells remains highly challenging, mainly due to the lack of efficient and selective delivery systems. Among the variety of carriers for siRNA delivery, peptides have become essential candidates because of their high selectivity, stability and conjugation versatility. Here, we describe the development of molecules encompassing siRNAs against SOD1, conjugated to peptides that target the LDLR, and their biological evaluation both in vitro and in vivo. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/526778v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@11146borg.highwire.dtl.DTLVardef@1537ee2org.highwire.dtl.DTLVardef@af67b5org.highwire.dtl.DTLVardef@1c1d7ec_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG

biochemistry↗

bioRxiv2020

Neurotensin receptor 2 is induced in astrocytes and brain endothelial cells in relation to status epilepticus and neuroinflammation following pilocarpine administration in rats

Neurotensin (NT) acts as a primary neurotransmitter and neuromodulator in the CNS and has been involved in a number of CNS pathologies including epilepsy. NT mediates its central and peripheral effects by interacting with the NTSR1, NTSR2 and NTSR3 receptor subtypes. To date, little is known about the precise expression of the NT receptors in brain neural cells and their regulation in pathology. In the present work, we studied expression of the NTSR2 protein in the rat hippocampus using a model of temporal lobe epilepsy induced by pilocarpine and questioned whether NTSR2 was modulated in conditions of neuro-inflammation. This model is characterized by a rapid and intense inflammatory reaction with a pattern of reactive gliosis in the hippocampus. We show that NTSR2 protein is expressed in hippocampal astrocytes and its expression increases together with astrocyte reactivity following induction of status epilepticus. NTSR2 immunoreactivity is also increased in perivascular astrocytes and their end-feet and is apparent in endothelial cells following induction of status epilepticus. Proinflammatory factors such as IL1{beta} and LPS induced NTSR2 in astrocytes, but also in microglia in vitro. Glial NTSR2 expression showed characteristic immediate early gene response under inflammatory conditions. Treating inflamed glial cells with a vectorized NT analogue decreased NTSR2 expression as well as astrocytic and microglial reactivity. Together, these results suggest that NTSR2 is implicated in astroglial and gliovascular inflammation and that targeting the NTSR2 receptor may open new avenues in the regulation of neuroinflammation in CNS diseases. TABLE OF CONTENTS IMAGE O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/166637v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@108f93corg.highwire.dtl.DTLVardef@2300d5org.highwire.dtl.DTLVardef@bb58forg.highwire.dtl.DTLVardef@bcf08c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗