You may find our recent paper in PLoS ONE of interest: combination therapy of hypothermia and MSCs...

Neuroprotectants effective in animals have a history of failing in human trials. Reason may be that humans have a uniquely high level of antioxidants such as uric acid, which does not leave a lot of therapeutic room for similar ectopic agents to work.

Arguably, this is related to human longevity. Two agents have shown arguable efficacy in humans-- uric acid itself, and (by inference) methylnitrosopropane (MNP), the breakdown product of NXY-059. See: http://stroke.ahajournals.org/content/39/5/e88.full.pdf+html and http://stroke.ahajournals.org/content/38/10/e109

SOD-mimetic agents such as TEMPOL are also worth a shot, as is plain old acetylcysteine

Selenium may a agent with protective effect after CPR.

Does early administration of selenium improve neurological outcome after cardiac arrest? Johann Reisinger et.al

American Journal of Emergency Medicine - February 2009 (Vol. 27, Issue 2, Pages 176-181)

Because it is cheap and has nor serious adverse effects we use it routinely in MTH-patients

Currently, the County of Los Angeles, has a clinical trial which will complete recruitment in January, 2013 called MagFast to see if IV magnesium helps to stabilize the brain during ischemic stroke in patients to limit central molecular events in the ischemic cascade include accumulation of intracellular calcium, release of excitatory amino acid neurotransmitters, generation of oxygen-free radicals, nitric oxide formation, and the release of cytokines by infiltrating polymorphonuclear leukocytes. These and additional events afford numerous targets for pharmacologic blockade. A multitude of neuroprotective drugs interfering with various pathways of ischemic injury reduce infarct volume substantially in focal stroke animal models when administered 10-120 minutes after ischemia onset, including excitatory amino acid antagonists, oxygen free radical scavengers, and voltage sensitive calcium channel blockers.

The ideal neuroprotective agent for stroke would be inexpensive, readily available, easy to administer and have no significant adverse side effects. An agent demonstrated to be safe and potentially beneficial in both ischemic and hemorrhagic stroke would have the added benefit of potentially earlier administration prior to obtaining a head CT scan. Intravenous magnesium sulfate offers promise as just such an agent.

Stroke is the third leading cause of death and the leading cause of adult disability in the United States. Each year in the US, over 750,000 Americans suffer a symptomatic stroke. More than 4 out of 5 strokes are due to ischemic infarction. Unfortunately, current therapies for acute ischemic stroke are of extremely limited effectiveness. To date, the only FDA approved treatment for acute ischemic stroke is intravenous tissue plasminogen activator (tPA), a thrombolytic agent which must be administered within 3 hours of symptom onset, and only after neuroimaging has ruled out intracerebral hemorrhage. Current estimates are that only 1-3% of acute ischemic stroke patients in the US receive TPA. The only other agent of proven utility in acute ischemic stroke is aspirin, which confers only minimal benefit, helping only one of every 110 patients treated. New, effective, widely applicable treatments for acute ischemic stroke are desperately needed.

The FAST-MAG Study will address this urgent need in two critical ways: 1) the study will constitute a definitive phase 3 trial of magnesium sulfate, a highly promising neuroprotective agent; and 2) the study will pioneer the prehospital initiation of neuroprotective agents in pivotal clinical trials of neuroprotective agents, permitting more patients to be treated in the first critical minutes after onset, and solving a major design defect of prior trials of neuroprotective stroke therapy.

One combination that meets all the requirements listed above-- caffeinol, a combination of caffeine plus ethanol. From Grotta's group at UT Houston. See:

http://stroke.ahajournals.org/content/34/5/1246.short

http://stroke.ahajournals.org/content/34/5/1242.short

Google/pubmed.gov "caffeinol" for more. The literature is fairly extensive.

Mechanism? Lots of conjecture. E.g., caffeine is converted to tetramethyuric acid. Uric acid is one of the neuroprotectants that does seem to work in huans. Or perhaps it is some effect of adenosine receptors. Anyway, the level required of ethanol and caffeine are the equivalent of a few Irish coffees.

Another neuroprotective step is using hypothermia for decreasing metabolic demand in ischemic or brains injured by trauma. Mild hypothermia is known to be neuroprotective and to reduce damage caused by the return of blood flow to an area of the brain starved of oxygen by a clot. Researchers from the University of Erlangen, led by Dr Rainer Kollmar, tested whether mild hyperthermia could also prevent damage to the brain due to tPA treatment in rats. After 24 hours they found that, while hypothermia reduced the amount of swelling and damaged tissue in the brain after a stroke, tPA (administered 90 minutes after the onset of stroke) increased it. However, they also discovered that hypothermia therapy was able to offset the damage due to tPA.

Looks like Progesterone may have significant benefit...at least pre-clinically. There are two, large Phase III trials using it for traumatic brain injury that you can find on ClinicalTrials.gov There is a growing literature on this neurosteroid as a neuroprotective agent and thus far, no known side effects. It seems to work better when combined with vitamin D hormone. About 230 publications on the topic on PubMEd. See what you think.

http://www.ncbi.nlm.nih.gov/pubmed?term=progesterone%20brain%20injury

Thanks, Don! Have you combined it with Vitamin D hormone in your models? Any other ideas for agents that might work synergistically?

Since many years and in spite of huge amount of money spent on research no effective brain protection drug has been introduced to the clinic. However, no current restorative treatment is available on the clinics, we should encourage industry to understand that restorative drugs target completely different mechanisms from neuroprotection but still they can offer an extended therapeutic effect, which potentially would offer some help to stroke patients’ recovery.

I invite you to read: Francisco J. Ortega, Jukka Jolkkonen; Restorative therapies to enhance sensorimotor recovery following cerebral ischemia. Acta Neurobiologiae experimentalis 2013.

That will be soon avaiable in pubmed.

This is my very mosdest opinion: Neuroprotection and neurorestoration are relatively new concepts that some new and not so new drugs tried to achieve in recent trials like ICTUS Trial with citicoline. From Dávalos I learned that we have different time windows for each action. Neuroptotection needs a very early acute intervention. Neurorestoration needs a prolongued time to be achieved. At first i founded citicoline very interesting for both, but again, the ICTUS trial showed no difference in neuroprotection over placebo. Neurorestoration was not assessed in this trial. I belive that we don´t have the tools to evaluate well the efficacy of any intervention on neuro protection/restoration. If we continue to use the Modified Rankin Score as the main end point the chances to loose is too high. We need to recognize that even we neurologist have a poor agreement when we perform the modified Rankin score in our patients. We need a better selections of patients, not all patients with very different prognosis by the time of randomization, and we need a better tool to assess the efficacy. The COBRIT trial used a very interesting pannel of multiple cognitive and sensorymotor tests to evaluate efficacy. Again the trial was not positive and we are continuing learning, I think. Maybe we are thinking better, maybe we´ll do better in the future. Combined therapies are the future, but right now I think to test neuroprotection in Stroke with reperfusion strategies not a good idea.We need to prove that any drug or intervention for neuroptotection have efficacy and then combine with treatment. Maybe we need a better animal model, after all we still are a little different from rats

The issue appears to centre around being able to predict who is at risk for stroke, The studies which I have gone through with regards to Stroke from a Psychological perspective indicate that this approach is not currently feasible. When I consider how long it can take for an MRI to be conducted, the time required to administer some neuroprotectant agents is past before the MRI is performed. Though I am not an expert in the area of Neuroprotectants, I have seen articles referring to the possible use of anti-epilectic drugs for instance " Anti-epileptic drugs as possible neuroprotectants in cerebral ischemia" (Leker, R & Neufeld, M, 2003). The evidence does not seem to indicate one way or the other if they are successful. Would it be possible to consider, or has the neurogenesis properties of estrogen been considered in a neuroprotectant light?

I invite you to read: Restorative therapies to enhance sensorimotor recovery following cerebral ischemia. http://www.ncbi.nlm.nih.gov/pubmed/23595284

This may actually be pretty simple. We have suggested (http://stroke.ahajournals.org/content/39/8/e126.full) that promising antiexcitotoxic agents in animals fail human trials because humans are endowed with extraordinarily high levels of their own powerful endogenous antioxidant and antiexcitotoxic agent, uric acid. Urate levels in humans are 5-10x that in (say) rats. This does not leave much room for similar ectopic agents to work.

For example, it is easy to demonstrate that NXY-059 would not have worked in stroke. Just on the basis of target levels (125 mcm) it would not have contributed much to blood antioxidant capacity compared to urate (200-400 mcm), whose antioxidant ability on a molar basis exceeds that of NXY-059. This does not even factor in urates antiexcitotoxic properties.

Not coincidentally, raising serum uric acid is currently in clinical trials for Parkinson's, MS, and stroke. BTW, we have suggested the use of birds, who also combine longevity with high UA levels, to screen neuroprotectants. (Birds as Potential Models in Ischemic Injury, Experimental & Translational Stroke Medicine 2009, 1:7 doi:10.1186/2040-7378-1-7)

Links to clinical trials with urate for neuroprotection in Stroke (http://clinicaltrials.gov/ct2/show/NCT00860366?term=uric+acid&rank=3 ),

Parkinsons (http://www.clinicaltrials.gov/ct2/show/NCT00833690?term=SURE&rank=1 ) , and MS ( http://www.clinicaltrials.gov/ct2/show/NCT00067327?term=uric+acid+sclerosis&rank=1 ). Read the cited papers for the rationale.

Note: So many human neuroprotection trials have failed in the face of successful animal ones that it can't be defective clinical trials. Ergo, there is some fundamental physiological/biochemical difference between humans and the experimental animals. The one difference that really stands out is higher primate's several-fold higher urate levels, likely related to our extreme longevity for sie.

Comments: In the face of all that urate, regular antoxidants don't work in people. So what does ?

First, The first wing of the SAINT trial with NXY-059 probably did work. Hard to explain a near halving of incidence of tpa-induced hemorrhagic stroke otherwise The active agent was likely the breakdown product MNP (methylnitrosopropane), well-known to account for the activity of such PBN derivatives.

Second, catalytic antioxidants such as superoxide dismutase (SOD) and SOD-mimetics do work in humans. Before people got worried about prion disease, bovine SOD even had regulatory approval in Europe for (e.g.) Peyronies.

Similarly for TEMPOL. (Disclosure: I own some patents here-- stuff makes breast cysts flatly melt away). Lots of work reported-- Search "TEMPOL" on pubmed.gov for the papers. Significant work on neuroprotection. Just sayin'.

Ischemia is mainly occur due to occlusion of BCA mainly responsible for blood supply to the brain. Due to free radical various enzymes like SOD, catalase, thiols etc level is reduced. All this enzyme has protective effects on the brain. It is more critical situation and it is the emerging field of research now a days. So use of some free radical scavenging compound or antioxidant compound like vitamin c, vitamin e and some herbal compound are also beneficial without any side effect.

In my opinion Nilvadipine - calcium channel blocker with the highest antioxidant activity together with neuroprotection due to cross blood-brain barrier.