Inhibition of glial hemichannels by boldine treatment reduces neuronal suffering in a murine model of Alzheimer's disease

Abstract

The contribution of reactive gliosis to the pathological phenotype of Alzheimer's disease (AD) opened the way for therapeutic strategies targeting glial cells instead of neurons. In such context, connexin hemichannels were proposed recently as potential targets since neuronal suffering is alleviated when connexin expression is genetically suppressed in astrocytes of a murine model of AD. Here, we show that boldine, an alkaloid from the boldo tree, inhibited hemichannel activity in astrocytes and microglia without affecting gap junctional communication in culture and acute hippocampal slices. Long-term oral administration of boldine in AD mice prevented the increase in glial hemichannel activity, astrocytic Ca signal, ATP and glutamate release and alleviated hippocampal neuronal suffering. These findings highlight the important pathological role of hemichannels in AD mice. The neuroprotective effect of boldine treatment might provide the basis for future pharmacological strategies that target glial hemichannels to reduce neuronal damage in neurodegenerative diseases.

Connexin 43 deletion in astrocytes promotes CNS remyelination by modulating local inflammation

“…Enhanced astrocytic Cx43 hemichannel activity has been observed under inflammatory conditions, while intercellular communication via Cx43 gap junction channels either decreases or does not change (Abudara et al, ; Retamal et al, ). To determine whether the above observed phenomena can be mainly attributed to the loss of Cx43 hemichannel function, we made use of a natural alkaloid (i.e., boldine), which blocks Cx hemichannels without altering gap junctional communication (Yi et al, ). Similarly, local demyelination was induced with lysolecithin in the corpus callosum of 8‐w‐old mice.…”

“…Similarly, local demyelination was induced with lysolecithin in the corpus callosum of 8‐w‐old mice. On the day of injection, boldine, which has no secondary toxic effects and can cross the blood‐brain barrier to reach the brain (Yi et al, ), was administered via drinking water (Figure a). The degree of remyelination was detected at 14 dpi, and boldine treatment dramatically reduced the non‐remyelination volume in the corpus callosum in the Cx43 cKO mice (Figure b,c).…”

“…Finally, this finding was strengthened by chronic administration of boldine, a natural alkaloid, which prevented Cx hemichannel activity from increasing without impacting gap junction communication in astrocytes. This compound mimics the effects of Cx43 cKO, although only hemichannel activity is inhibited in glia (Yi et al, ).…”

“…Boldine is an alkaloid extracted from a Chilean tree called boldo (Yi et al, ). It was administered in vivo via drinking water (100 mg/ml) begin from the day of lysolecithin injection.…”

“…Interestingly, the persistent activation of astrocytes and microglial cells was down‐regulated during remyelination in Cx43 cKO mice. In addition, a two‐week treatment with the natural alkaloid boldine, a hemichannel blocker that does not affect gap junctional communication (Hernandez‐Salinas et al, ; Yi et al, ), promoted remyelination in the lysolecithin model of demyelination. Altogether, these results provide direct evidence that Cx43 hemichannel activity in astrocytes is crucial for regulating the inflammatory environment, thus contributing to the remyelination process.…”