GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain.

Ca2+/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα) is a key neuronal signaling protein and an emerging drug target. The central hub domain regulates the activity of CaMKIIα by organizing the holoenzyme complex into functional oligomers, yet pharmacological modulation of the hub domain has never been demonstrated. Here, using a combination of photoaffinity labeling and chemical proteomics, we show that compounds related to the natural substance γ-hydroxybutyrate (GHB) bind selectively to CaMKIIα. By means of a 2.2-Å x-ray crystal structure of ligand-bound CaMKIIα hub, we reveal the molecular details of the binding site deep within the hub. Furthermore, we show that binding of GHB and related analogs to this site promotes concentration-dependent increases in hub thermal stability believed to alter holoenzyme functionality. Selectively under states of pathological CaMKIIα activation, hub ligands provide a significant and sustained neuroprotection, which is both time and dose dependent. This is demonstrated in neurons exposed to excitotoxicity and in a mouse model of cerebral ischemia with the selective GHB analog, HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid). Together, our results indicate a hitherto unknown mechanism for neuroprotection by a highly specific and unforeseen interaction between the CaMKIIα hub domain and small molecule brain-penetrant GHB analogs. This establishes GHB analogs as powerful tools for investigating CaMKII neuropharmacology in general and as potential therapeutic compounds for cerebral ischemia in particular.

Calciphylaxis and sodium thiosulphate: a glimmer of hope in desperate situation.

BACKGROUND: Calciphylaxis is an uncommon and often under diagnosed condition affecting patients undergoing chronic dialysis. Its pathogenesis is poorly understood. The abnormalities of calcium, phosphate and parathyroid hormone homeostasis leading to vascular calcification and ischaemic skin necrosis are thought to be the central problem. Meticulous wound care and aggressive metabolic control remain the cornerstone of the treatment; however, the overall benefit of these treatment options remains low and mortality and morbidity remain very high. Sodium thiosulphate is an inorganic salt, which is used for treating acute cyanide poisoning, recurrent calcium urolithiasis and nephrocalcinosis. Recently, it has also been reported to be useful in treating severe cases of calciphylaxis with promising results. METHODS: A resistant case of calciphylaxis in a patient on long-term haemodialysis was treated with sodium thiosulphate (50 ml solution with 50% sodium thiosulphate) three times a week during the end of each dialysis session. RESULTS: The skin lesions started to heal after two weeks and completely resolved after five months of treatment. CONCLUSIONS: Sodium thiosulphate can be a safe and effective treatment option for resistant and severe cases of calciphylaxis.