1) As we all known, in clinical trials,the NMDAR antagonists show prominent neuroprotective effect. However, all of them failed in clinical trials.
2) Why should t-PA should be used within 4.5h?
3) Cortical neurons can be more resistant to hypoxic injury than microglia in a relatively short period according to our own observation.
I am thinking that should a neuron-glia protective strategy should be more reasonable in stroke since that more and more functions exerted by glial cells have been found.
The clinical trials failed because of randomized population, using sex and age matched population would have given better outcomes.
Time window arises from the clinical trials NINDS-2 and subgroup results from IST-3.
Acute damage seems to affect more prominently cells with high metabolic turnover, so it is still safe to assume that neurons would bethe first affected in ischemic stroke. One can be similarly sure that glia plays a role at later stages. However, there have been trials aimed at inflammation, all of them resulting in no improvement.
About the failure of nmdar antagonists: partly it is because intervention is started too late; my view of the problem is that nmdar role has been overrated and the whole excitotoxicity concept should be a bit reworked.
This is addressed to Francesco Roselli. I don't agree with your first point. It is for sure that that saving neurons is the priority, but we have known that glial cells' role are not just restricted to inflammation with more and more physiological functions being uncovered. For example, now we know that microglia are active sensors in the CNS rather than being rest. So if there occurs disturbance, I think maybe it's microglia that respond in a faster fashion than neurons. So i think glia cells' role in stroke may need further explored.
Hello colleagues
Very interesting questions indeed. I'm totally agree with Dr. Lee's statement about glial cell's role and functions in a more dynamic way, not only limited to a structural or inflammatory pathways. It's a very interesting point of view, to extend our saving strategies (not limited to reperfusion) to glial cells. Some of the studies with NMDAR antagonists as Dr. Roselli points, are started too late and possibly in non-structured models to assess cellular improvement, and many other mediators should be assessed. An interesting lecture regarding glial role in reperfusion strategies in stroke could be found on: Glia. 2014 Jan;62(1):1-16. doi: 10.1002/glia.22585. Epub 2013 Nov 4.
Dear Lee, The clinical trial on NMDAR antagonists show failed it may be due to the randomized mixed population and moreover, I don't think the stroke can be prevented by single target. Always should go for computational therapy. As we all know there are so many drugs and reports showing protection by inhibition of different molecule through different reagent or compound in ischemia. Then how could be possible prevents ischemia by one target like NMDA receptor.
Secondly t-PA with acute ischemic stroke, why it is three-hour window because after three hours of ischemic condition goes to more damage of brain becuase it is not now the acute ischemic stroke, Its a severe and cause intra-cranial bleed and more intravenous thrombolysis.
Third, in case of sensitivity of neurons towards ischemic damage is less because glial cells initially protects the neurons in pathological condition.
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