Boldine modulates glial transcription and functional recovery in a murine model of contusion spinal cord injury

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dc.contributor.authorToro, Carlos A.
dc.contributor.authorJohnson, Kaitlin
dc.contributor.authorHansen, Jens
dc.contributor.authorSiddiq, Mustafa M.
dc.contributor.authorVasquez, Walter
dc.contributor.authorZhao, Wei
dc.contributor.authorGraham, Zachary A.
dc.contributor.authorSaez, Juan C.
dc.contributor.authorIyengar, Ravi
dc.contributor.authorCardozo, Christopher P.
dc.date.accessioned2025-01-20T20:09:21Z
dc.date.available2025-01-20T20:09:21Z
dc.date.issued2023
dc.description.abstractMembrane channels such as those formed by connexins (Cx) and P2X(7) receptors (P2X(7)R) are permeable to calcium ions and other small molecules such as adenosine triphosphate (ATP) and glutamate. Release of ATP and glutamate through these channels is a key mechanism driving tissue response to traumas such as spinal cord injury (SCI). Boldine, an alkaloid isolated from the Chilean boldo tree, blocks both Cx and Panx1 hemichannels (HCs). To test if boldine could improve function after SCI, boldine or vehicle was administered to treat mice with a moderate severity contusion-induced SCI. Boldine led to greater spared white matter and increased locomotor function as determined by the Basso Mouse Scale and horizontal ladder rung walk tests. Boldine treatment reduced immunostaining for markers of activated microglia (Iba1) and astrocytic (GFAP) markers while increasing that for axon growth and neuroplasticity (GAP-43). Cell culture studies demonstrated that boldine blocked glial HC, specifically Cx26 and Cx30, in cultured astrocytes and blocked calcium entry through activated P2X(7)R. RT-qPCR studies showed that boldine treatment reduced expression of the chemokine Ccl2, cytokine IL-6 and microglial gene CD68, while increasing expression of the neurotransmission genes Snap25 and Grin2b, and Gap-43. Bulk RNA sequencing revealed that boldine modulated a large number of genes involved in neurotransmission in spinal cord tissue just caudal from the lesion epicenter at 14 days after SCI. Numbers of genes regulated by boldine was much lower at 28 days after injury. These results indicate that boldine treatment ameliorates injury and spares tissue to increase locomotor function.
dc.fuente.origenWOS
dc.identifier.doi10.3389/fncel.2023.1163436
dc.identifier.eissn1662-5102
dc.identifier.urihttps://doi.org/10.3389/fncel.2023.1163436
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/91989
dc.identifier.wosidWOS:001019989600001
dc.language.isoen
dc.revistaFrontiers in cellular neuroscience
dc.rightsacceso restringido
dc.subjectboldine
dc.subjectcontusion SCI
dc.subjectfunctional recovery
dc.subjecthemichannel blockade
dc.subjectspared white matter
dc.subjectglial response
dc.subjectconnexins
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleBoldine modulates glial transcription and functional recovery in a murine model of contusion spinal cord injury
dc.typeartículo
dc.volumen17
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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