Grant: Travel Awards - Institute Community Support

The connexin family comprises 21 proteins in humans representing the structural units of intercellular gap junction channels. Compelling evidence implicates connexin-mediated cell-cell communication in the control of neural progenitor cell proliferation, survival, and migration. Moreover, the dysregulation of connexin function and expression that results from such central nervous system insults as spinal cord injury, cerebral ischemia, and neurodegeneration has been shown to further contribute to the secondary expansion of lesions days and weeks after the initial insult. While these data suggest that connexins represent a novel therapeutic target with potential to both 1) reduce the extent of neural injury and 2) promote neural repair and regeneration, we currently lack the necessary repertoire of therapeutically useful connexin-specific modulators to test these hypotheses. We present here the results of a series of functional and expression screens exploring a rare collection of phenolics, alkaloids, terpenes, ethnobotanical extracts, and natural products purified from medicinal plants from Central America, Indonesian Borneo, and West Africa for compounds that differentially alter connexin expression, metabolic gap junction coupling and/or hemichannel function. High-content cell imaging analysis of NT2/D1 human neural-stem cell like cell line or the Oli-neu immortalized murine oligodendrocyte precursor cell line was carried out using the calcein-based parachute assay to assess gap junction intercellular communication and Lucifer yellow dye uptake to assess hemichannel function. Real-time quantitative reverse transcription PCR (qRT-PCR) was performed to assess connexin expression. Together, these screens have identified a number of novel connexin-altering compounds that exhibit minimal to no toxicity in vitro at effective concentrations.