Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate.

SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine (NSDP) as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.

[Mixed amanita phalloides poisoning with rhabdomyolysis: analysis of 4 cases].

We report the clinical characteristics, treatments and outcomes of 4 rare cases of mixed amanita fuliginea and amanita rimosa poisoning with rhabdomyolysis, and review the research progress in the intoxication mechanism and treatment. The latent time of amanita poisoning, defined as the period from the ingestion of poisonous mushroom to the onset of gastrointestinal symptoms, was about 8 days, and the severity of poisoning was associated with the amount of mushroom ingested. All the 4 patients developed multiple organ dysfunctions within 3 to 4 days after mushroom ingestion, predominantly in the liver, kidney and central nervous system accompanied with acute gastrointestinal injury and rhabdomyolysis. The treatment measures included persistent hemofiltration and intermittent hemoperfusion once daily for 5-7 days, and plasma exchange was administered in 2 cases for 1 or 2 times. High-dose vitamin C, glucose and corticosteroid were also given to the patients. After the treatments, two patients were cured and the other two died due to an excess intake of poisonous mushroom and lack of early preemptive therapies. Early emetic, gastric lavage, catharsis, fluid infusion and diuresis are critical to interrupt the enterohepatic circulation of amanita phalloides toxins and prevent the development of multiple organ dysfunction. Enhanced hemofiltration and sequential plasma therapy might effectively eliminate toxin from the blood to protect against further organ damages.