Thapsigargin induces apoptosis in SH-SY5Y neuroblastoma cells and cerebrocortical cultures.

Thapsigargin, a specific inhibitor of the endoplasmic reticular Ca(2+)-ATPase, has been used previously to mobilize calcium release from intracellular calcium stores. We now show that thapsigargin (1-10 microM) induces apoptosis in a neuroblastoma cell line (SH-SY5Y) and in fetal rat cerebrocortical cultures. Cell death measured by lactate dehydrogenase release was observed 24-48 hours after treatment with thapsigargin.

Neuronal nitric oxide synthase and calmodulin-dependent protein kinase IIalpha undergo neurotoxin-induced proteolysis.

Calpain (calcium-activated neutral protease) has been implicated as playing a role of neuronal injury in cerebral ischemia and excitotoxicity. Here we report that, in addition to extreme excitotoxic conditions [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate challenges], other neurotoxins such as maitotoxin, A23187, and okadaic acid also induce calpain activation, as detected by m-calpain autolytic fragmentation and nonerythroid alpha-spectrin breakdown. Under the same conditions, calmodulin-dependent protein kinase II-alpha (CaMPK-IIalpha) and neuronal nitric oxide synthase (nNOS) are both proteolytically cleaved by calpain.

Non-erythroid alpha-spectrin breakdown by calpain and interleukin 1 beta-converting-enzyme-like protease(s) in apoptotic cells: contributory roles of both protease families in neuronal apoptosis.

The cytoskeletal protein non-erythroid alpha-spectrin is well documented as an endogenous calpain substrate, especially under pathophysiological conditions. In cell necrosis (e.g.

Maitotoxin induces calpain activation in SH-SY5Y neuroblastoma cells and cerebrocortical cultures.

Maitotoxin (MTX) is a highly potent marine toxin that activates both voltage-sensitive and receptor-operated calcium channels in the plasma membrane. This results in calcium overload that rapidly leads to cell death. We now report that maitotoxin (0.

An alpha-mercaptoacrylic acid derivative is a selective nonpeptide cell-permeable calpain inhibitor and is neuroprotective.

Overactivation of calcium-activated neutral protease (calpain) has been implicated in the pathophysiology of several degenerative conditions, including stroke, myocardial ischemia, neuromuscular degeneration, and cataract formation. Alpha-mercaptoacrylate derivatives (exemplified by PD150606), with potent and selective inhibitory actions against calpain, have been identified. PD150606 exhibits the following characteristics: (i) Ki values for mu- and m-calpains of 0.