A 512-compound screen in patient-derived motor neurons identified resveratrol tetramers with neuroprotective activity. Follow-up work covered 14 iPSC lines and linked protection to changes in neuronal excitability.
A university-led team screened 512 natural products in spinal motor neurons generated from sporadic and familial amyotrophic lateral sclerosis (ALS) donor induced pluripotent stem cells (iPSCs). Live-cell imaging, whole-cell patch clamp and proteomics assessed degeneration, neurite damage and intrinsic hyperexcitability. The library included compounds from fungal, plant and marine-invertebrate sources.
Two resveratrol tetramers, vaticanol B and (−)-hopeaphenol, protected neurons and neurites across the tested genetic backgrounds. Both were more potent than resveratrol in these assays, with (−)-hopeaphenol producing the strongest effects.
In an expanded cohort of 14 iPSC lines spanning sporadic ALS and TARDBP, SOD1 or C9ORF72 backgrounds, (−)-hopeaphenol showed broad cellular protection. It also countered abnormal sodium currents and changes in repetitive firing.
The SIRT1 activator SRT2104 protected neurites, improved ALS-related hyperexcitability and increased neuroprotective pathway activity at one-third of the concentration used for (−)-hopeaphenol. The authors selected it in part for previously described brain permeability and human tolerability; those properties were not new clinical ALS outcomes from this study.
The findings provide preclinical support for a convergent SIRT1-related strategy across the studied genotypes. They combine morphological and electrical measures in patient-derived cells while leaving clinical benefit and disease progression untested.
A four-platform comparison combined lipid imaging, liver-function measurements, expression profiling and CYP assays. Lipid accumulation did not uniformly reduce drug metabolism, and differences depended on the model and donor.
A study links sensory-neuron clock state to sodium-channel function. Synchronized human iPSC-derived nociceptors showed clock-state-dependent changes in excitability, and cryptochrome stabilization reduced hyperexcitability.
