Dibutyryl cyclic AMP downregulates tenascin-C in neurons and astrocytes and reduces AAV-mediated gene expression in DRG neurons

Stepankova, K.; Cimpean, A.; Smejkalova, B.; Holota, R.; Bachanova, L.; Cerny, J.; Sprincl, V.; Marekova, D.; van den Herik, J.; de Winter, F.; Jendelova, P.; Urdzikova, L. M.

doi:10.1101/2025.05.13.653846

bioRxiv · 10.1101/2025.05.13.653846

Dibutyryl cyclic AMP downregulates tenascin-C in neurons and astrocytes and reduces AAV-mediated gene expression in DRG neurons

Stepankova, K.·Cimpean, A.·Smejkalova, B.·Holota, R.·Bachanova, L.·Cerny, J.·Sprincl, V.·Marekova, D.·van den Herik, J.·de Winter, F.·Jendelova, P.·Urdzikova, L. M.

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Abstract

Functional recovery after spinal cord injury (SCI) is hindered by the limited ability of axons to regenerate in the adult mammalian central nervous system (CNS). Overcoming this barrier is critical for achieving effective recovery. Axonal regeneration depends on the activation of intracellular processes like transcription factor induction, protein and lipid trafficking, and cytoskeletal remodelling. Targeting these pathways offers a promising approach for promoting neuronal repair. This study examined the combined therapeutic effects of dibutyryl-cAMP (db-cAMP), which primes neurons for growth, and integrin 9 overexpression, which supports axonal extension. Using in vitro models with dorsal root ganglion (DRG) neurons and astrocytes, as well as an in vivo SCI model, we evaluated the potential of this approach. In vitro, the combination of db-cAMP and integrin 9 significantly enhanced neuronal growth. However, in vivo results were less consistent, with db-cAMP affecting AAV-mediated transcription and the expression of tenascin C (TnC) in neurons and astrocytes. These findings highlight the potential of modulating intracellular signalling and integrin activation but underscore the challenges posed by the complexity of the in vivo environment. Further studies are necessary to unravel these mechanisms and refine therapeutic strategies for effective SCI recovery. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/653846v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1473630org.highwire.dtl.DTLVardef@36a8beorg.highwire.dtl.DTLVardef@80593corg.highwire.dtl.DTLVardef@6285e3_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Stepankova, K., Cimpean, A., Smejkalova, B., Holota, R., Bachanova, L., Cerny, J., Sprincl, V., Marekova, D., van den Herik, J., de Winter, F., Jendelova, P., Urdzikova, L. M.. 2025-05-17. Dibutyryl cyclic AMP downregulates tenascin-C in neurons and astrocytes and reduces AAV-mediated gene expression in DRG neurons. https://doi.org/10.1101/2025.05.13.653846

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