Deans' stroke musings: Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury

Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

Monday, February 18, 2013

Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury

I have no idea on this one, that's what your genius doctor is for.
http://www.nature.com/nchembio/journal/v9/n3/full/nchembio0313-192a.html
In this Article¹, we described a small-molecule inhibitor of necroptosis, termed Necrostatin-1 (Nec-1). Since the original publication, additional data regarding the properties of Nec-1 have been reported, including off-target activity and metabolic stability in mice, that are important in designing in vitro and, especially, in vivo experiments with Nec-1.
Teng et al.² reported an optimized derivative of Nec-1, termed 7-Cl-O-Nec-1 (66 in ref. 2), that was used in ref. 1 to demonstrate the protection in an ischemic brain injury model. This molecule showed higher activity in inhibiting necroptosis in Jurkat cells than Nec-1 (EC₅₀ = 210 nM versus EC₅₀ = 490 nM), no nonspecific cytotoxicity at high concentrations (~100 mM) and reasonable pharmacokinetic characteristics following intravenous administration in mice. Degterev et al.³ subsequently reported that Nec-1 shows limited metabolic stability, which is substantially improved with 7-Cl-O-Nec-1. Takahashi et al.⁴ also reported that Nec-1 showed paradoxical toxicity at lower, but not higher, doses in a mouse model of systemic inflammatory stress syndrome (SIRS). No such toxicity was observed with 7-Cl-O-Nec-1. Thus, for in-cell and in vivo experiments, we recommend the use of 7-Cl-O-Nec-1.
Muller et al.⁵ reported that Nec-1, also known by its chemical name of methylthiohydantoin-tryptophan, is a micromolar inhibitor of indolamine 2,3-deoxygenase (IDO) with EC₅₀ = 11.4 mM in a cell-based assay. Thus, given the ~20-fold higher activity of Nec-1 in a necroptotic assay, the use of lower concentrations of this molecule could be helpful in distinguishing between inhibition of necroptosis and IDO-related processes. Another known inhibitor of IDO, 1-methyl-DL-tryptophan, lacks activity against necroptosis as reported by both Degterev et al.³ and Takahashi et al.⁴ Notably, both reports show that optimized 7-Cl-O-Nec-1 lacks activity against IDO. Overall, potential nonspecific toxicity, inhibition of IDO and limited stability of Nec-1 should be taken into account when the molecule is used in vivo, whereas 7-Cl-O-Nec-1 lacks these liabilities and thus represents a superior choice for in vivo studies.