Pathophysiologic cascades in ischemic stroke

It took me years to come up with my interpretation of the 5 causes of the neuronal cascade of death in the first week. Your doctor can compare that with this review and come up with a potential strategy of what the RFP to researchers should look like to solve for these issues.  Your doctor and hospital can't shirk from this responsibility, but I bet they have been incompetent for 5 years already since this came out.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985770/ July 2012

Changhong Xing,¹ Ken Arai,¹ Eng H. Lo,¹ and Marc Hommel^2,*

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The publisher's final edited version of this article is available at Int J Stroke

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Abstract

Many advances have been achieved in terms of understanding the molecular and cellular mechanisms of ischemic stroke. But thus far, clinically effective neuroprotectants remain elusive. In this minireview, we summarize the basics of ischemic cascades after stroke, covering neuronal death mechanisms, white matter pathophysiology, and inflammation with an emphasis on microglia. Translating promising mechanistic knowledge into clinically meaningful stroke drugs is very challenging. An integrative approach that encompasses the multimodal and multicell signaling phenomenon of stroke will be required to move forward.

Keywords: microglia, neurovascular unit, penumbra, reperfusion, white matter

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Introduction

Stroke and cerebrovascular disease is a major cause of mortality and disability worldwide (1,2). Ischemic stroke is caused by a reduction in blood flow to the brain. Hence, the decrease in cerebral blood flow (CBF) has received an effective answer: accelerated reperfusion via thrombolysis using recombinant tissue plasminogen activator (rt-PA) is associated with an improved clinical outcome. This achievement is now routinely transferred to practice.(NO it is not, maybe 5-10% get it) This ease of translation is due to the fact that the underlying conceptual model is simple: an arterial occlusion decreases CBF. So an effective treatment should increase CBF.

The best way to do this currently might be with rt-PA. However, due to the moderate recanalization rate, the limited time window, and the number of contraindications for thrombolysis, only minority of patients receive tPA so other treatments with potential additive effects are still urgently needed. Furthermore, even in patients who receive tPA, those with more severe initial strokes often do not significantly improve. In part, this might be related to some aspect of reperfusion injury. Overall, additive treatments that combine with rt-PA should be worth pursuing.

In terms of the blood flow distribution, cerebral ischemic strokes are often focal. In the central core regions of the insult, there is almost total CBF arrest. This area evolves rapidly toward death within minutes. Surrounding this core, CBF levels may fall below functional thresholds yet transiently lie above the threshold of cell death – this zone has been called the penumbra. The penumbra, a metastable zone, permits only cell survival for a certain period of time. Thus, this potentially salvageable tissue is the target for neuroprotective therapy. Over the past two decades, tremendous progress has been achieved in terms of understanding the intricate cellular and molecular mechanisms of stroke pathophysiology (3,4). However, to date, we still do not have a clinically effective neuroprotectant. In this minireview, we briefly survey the fundamentals of the ischemic cascade. Many excellent and more detailed reviews on this topic have been published (5–7). Our more limited scope here is focused on an attempt to discuss translational hurdles and identify promising targets.

Much more at link with 115 references. I bet your doctor has not read a single one of those references.