Molecular Dissection of Cyclosporin A’s Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury

Once more ebselen is shown to be useful in the hyperacute stage. Who the hell is going to translate this into a stroke protocol?

Molecular Dissection of Cyclosporin A's Neuroprotective Effect Reveals Potential Therapeutics for Ischemic Brain Injury

treatment within 48 h of stroke onset were enrolled in one study. The improvement
was significant in patients who started ebselen within 24 h of stroke onset but not in
those who started treatment after 24 h. A phase III trial exploring 

Minoru Kawakami
Aquatic Animal Health Division, National Research Institute of Aquaculture, Fisheries Research
Agency, Tamaki, Mie 519-0423, Japan; E-Mail: minkawa@gmail.com; Tel./Fax: +81-96-372-8602
Received: 23 June 2013; in revised form: 30 July 2013 / Accepted: 14 August 2013 /
Published: 5 September 2013
Abstract: After the onset of brain ischemia, a series of events leads ultimately to the death of neurons. Many molecules can be pharmacologically targeted to protect neurons during
these events, which include glutamate release, glutamate receptor activation, excitotoxicity, Ca2+ influx into cells, mitochondrial dysfunction, activation of intracellular enzymes, free radical production, nitric oxide production, and inflammation. There have been a number of attempts to develop neuroprotectants for brain ischemia, but many of these attempts
have failed. It was reported that cyclosporin A (CsA) dramatically ameliorates neuronal cell damage during ischemia. Some researchers consider ischemic cell death as a unique process that is distinct from both apoptosis and necrosis, and suggested that mitochondrial dysfunction and Δψ collapse are key steps for ischemic cell death. It was also suggested
that CsA has a unique neuroprotective effect that is related to mitochondrial dysfunction.  Here, I will exhibit examples of neuroprotectants that are now being developed or in clinical trials, and will discuss previous researches about the mechanism underlying the unique CsA action. I will then introduce the results of our cDNA subtraction experiment with or without CsA administration in the rat brain, along with our hypothesis about the
mechanism underlying CsA’s effect on transcriptional regulation.

Exposure of Cyclosporin A in Whole Blood, Cerebral Spinal Fluid and Brain Extracellular Fluid Dialysate in Adults with Traumatic Brain Injury

Your doctor and researcher should look into this for strokes.
http://online.liebertpub.com/doi/abs/10.1089/neu.2012.2524

ABSTRACT

Cyclosporin A (CsA), an immunosuppressive medication traditionally used in the prevention of post-transplant rejection, is a promising neuroprotective agent for traumatic brain injury (TBI). Preliminary studies in animals and humans describe the efficacy and safety of CsA when administered following neurotrauma. The objective of this study is to describe CsA exposure in adults with severe traumatic brain injury by assessing concentrations in whole blood, cerebrospinal fluid (CSF), and brain extracellular fluid (ECF) dialysate as measured by brain microdialysis. Severe TBI patients were enrolled into a randomized controlled trial following the written informed consent of their legal guardians. Patients received either CsA 5mg/kg as a continuous infusion over 24 hours, or matching placebo. Noncompartmental exposure analyses were performed using CsA concentrations in whole blood, CSF and ECF dialysate. There were 37 patients randomized to the CsA arm of the trial and included in this exposure analysis. CsA was detected in the ECF dialysate and CSF at a fraction of the whole blood concentration. Mean CsA maximum concentrations were achieved at 24 and 30 hours from the start of the 24 hour infusion, in the CSF and ECF dialysate, respectively. A correlation was found between ECF dialysate and CSF concentrations. CsA was detected in the blood, CSF and brain ECF dialysate. CsA exposure characteristics differences exist for whole blood, CSF and ECF dialysate in severe TBI patients when administered as a continuous intravenous infusion. These exposure characteristics should be used for safer CsA dose optimization to achieve target CsA concentrations for neuroprotection in future TBI studies.