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2.3.5 Pyroptosis
Pyroptosis is an inflammasome-dependent programmed cell death. Inflammasomes activate Caspase-1 by the Caspase recruitment domain (CARD) or pyrin domain (PYD)-containing inflammasome, including nod-like receptor (NLRP1, 3, 6, 7, 12, NLRC4), absent in melanoma 2 (AIM2), or pyrin [76, 77]. And then Caspase-1 induces the activation and secretion of pro-IL-1b and pro-IL-18 [77]. It is the pri- mary cause of anthrax-lethal- toxin-induced lung injury that pyroptosis induced by the NLRP1B inflammasome or a gain-of-function mutation in Nlrp1a [78]. The newly research indicated that interdomain cleavage of gasdermin D (GSDMD) by caspase-1/4/5/11 determines pyroptosis [79]. AIM2 contains a HIN200 domain and is specific for cytosolic DNA [80–83]. In 2014, the research firstly reported embry- onic cortical neurons express a functional AIM2 inflammasome and identify pyrop- tosis as a cell death mechanism in neurons. It demonstrated pannexin1 as a cell death effector channel in pyroptosis and inhibition of pannexin1 by probenecid attenuates pyroptosis in neurons, which suggested that active Caspase-1 cleaves inflammatory cytokines, opens the pannexin1 pore, and induces cell death [84]. It is unclear of the pyroptosis mechanism in ischemic stroke. What is the role of pyrop- tosis and the relationship with apoptosis and autophagy? It is worthy to explore the role of pyroptosis deeply in the ischemic stroke models.
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patients eligible for intravenous rt-PA should receive intravenous rt-PA even if endo- vascular treatments are being considered (Class I; Level of Evidence A) [89]. In recent years, some studies focus on trials to evaluate the ischemic stroke patients with small cores and substantial salvageable penumbra, as identified by CT or MR perfusion, whether could be benefit from rt-PA and endovascular thrombectomy beyond 6 h [90]. With regard to the antiplatelet therapy, the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial indi- cates Clopidogrel-Aspirin therapy (loading dose of 300 mg of Clopidogrel on day 1, followed by 75 mg of Clopidogrel per day for 90 days, plus 75 mg of Aspirin per day for the first 21 days) or to the Aspirin-alone group (75 mg/day for 90 days) within 24 h after onset of minor stroke or high-risk TIA, which could reduce the risk of subsequent stroke persisted for the duration of 1-year of follow-up [91].
3.2 Endovascular Treatment for Acute Ischemic Stroke
Endovascular therapies include clot disruption or mechanical retrieval. The intra- arterial (IA) application of fibrinolytic agents was initially motivated by consider- ations of benefit ratio and extending the time window. The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) implemented the patients with acute (0–6 h) M1 and M2 occlusions to either IA Urokinase or placebo.
Although the primary endpoint did not show the statistical significance, the second- ary analyses suggested that IA treatment has the potential to increase the possibility of positive functional outcome. Later, IA treatment was commonly administered as an off-label therapy for stroke within 6 h of onset in the anterior circulation and up to 12–24 h after onset in the posterior circulation [92]. However the newest AHA/
ASA guidelines suggest endovascular therapy with stent retrievers is recommended over intra-arterial fibrinolysis as the first-line therapy (Class I; Level of Evidence E). Intra-arterial fibrinolysis initiated within 6 h of stroke onset in carefully selected patients who have contraindications to the use of intravenous rt-PA might be consid- ered, but the consequences are unknown (Class IIb; Level of Evidence C).
So far rt-PA does not have FDA approval for intra-arterial use [89]. More and more prospective, randomized, open-label, blinded-end-point (PROBE) researches evaluate efficacy of recanalization after ischemic stroke. Intra-arterial Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS Expansion) aimed to compare the intravenous rt-PA and endovascular therapy. And the score of mRS, symptomatic intracerebral hemorrhage (sICH), NIHSS were used to evaluate between the subgroups. While the result shows there are no significant differences in out- comes in subgroups [93]. The Interventional Management of Stroke Trial III (IMS III) allocated ischemic stroke patients (NIHSS score ≥10, within 3 h onset) to two groups, the one group receive the standard-dose intravenous rt-PA (0.9 mg/kg), the another group was treated with rt-PA (0.6 mg/kg). After therapy, if the arteries were still occlusion, a device and/or intra-arterial rt-PA were used follow-up. Recanalization
Q. Dai et al.
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occurred 325 ± 52 min after stroke onset. Finally, there was no significant difference in mRS scores between the two groups [94]. The EPITHET study tests rt-PA given 3–6 h after stroke onset and PWI and DWI were done before and 3–5 days after therapy. It is the prospective, randomized, double blind, placebo- controlled and phase II trial research. The result shows that it could increase reperfusion beyond 3 h treat- ment, but it could not lower infarct growth. It is said reperfusion is associated with improved clinical outcomes [95]. The AHA/ASA guidelines suggest patients should receive endovascular therapy with a stent retriever if they meet all the following cri- teria (Class I; Level of Evidence A). (1) Prestroke mRS score 0–1. (2) Acute ischemic stroke receiving intravenous r-tPA within 4.5 h of onset according to guidelines from professional medical societies. (3) Causative occlusion of the ICA or proximal MCA (M1). (4) Age ≥18 years. (5) NIHSS score of ≥6. (6) ASPECTS of ≥6. (7) Treatment can be initiated (groin puncture) within 6 h of symptom onset [89] (Fig. 2.4).
3.3 Antioxidant and Other Treatment
The neuronal metabolism depends upon the lactate and activated glycolysis [96]. It has been shown that neurons synthesize energy mainly rely on the oxidative metab- olism of glucose. Nevertheless, if the glucose and lactate are present at the same time, neurons can efficiently utilize lactate [97]. The superoxide anions, hydrogen peroxide, hydroxyl radicals, and peroxynitrite or nitrogen dioxide express in infil- trating phagocytes, vascular cells, and glial in the area of penumbra [98, 99].
Because of the high consumption of oxygen and its relatively low endogenous anti- oxidant capacity in the ischemic brain tissue, neutralisation of oxidative stresses is a potential and positive therapeutic way [100]. The research shows for the first time that mitochondrial metabolic oscillations happened in the vivo with the rapid time (10–15 s), while cellular reactive oxygen species (ROS) plays a role in promoting
Fig. 2.4 Mechanical retrieval performed on the patient with cardiac source of emboli. A 50-year- old female with rheumatic heart disease, atrial flutter presented with right hemiparesis, aphasia and conscious disturbance. (a) Angiogram shows the left internal carotid artery occlusion as the arrow indicates. (b) There isn’t any compensatory action from right internal carotid artery occlusion as the arrow indicates. (c) and (d) Recanalization of left internal carotid artery after receiving the endovascular therapy with a stent retriever. Anterior cerebral artery (A3), indicating by the arrow, is still occlusive
2 Characters of Ischemic Stroke and Recanalization Arteries
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the NADH oscillations [101]. ROS is mainly produce by mitochondria, which could impair endothelium dependent vasodilator mechanisms, direct damage to biomole- cules that result in necrosis, necroptosis and apoptosis. It could be said the mito- chondria is very essential in pathogenesis of ischemic stroke [102, 103]. It seems a major cause of enhancing mitochondrial ROS production in stroke by impairing the function of respiratory chain complexes and ATP synthase [104].
In the penumbra region of ischemic stroke, ATP decreases obviously. Some of the ADP is further metabolised to AMP and ATP [105]. After hypoxic/ischemic injury, with the ROS is produced, antioxidant capacities are reduced. Because of the mito- chondrial lipid peroxidation, Ca2+ overload so that mitochondrial membrane depolar- ization, which promote cytochrome c to be released and result in cell apoptosis [106–108]. As an antioxidant drug, Edaravone could scavenge hydroxyl, peroxyl and superoxide radicals. It was approved for use in patients with acute stroke in Japan in 2001 and the compound is widely used in China [109]. According to the research with cell culture and animal model, it has shown Edaravone inhibits microglia- induced neurotoxicity, chronic inflammation, lipo-oxygenase, oxidation of low-den- sity lipoproteins, and altered expression of endothelial and neuronal proteins [110].
Some studies also focus on the non-pharmaceutical therapy for recanalization.
Brain is extremely sensitive to hypoxia or ischemia, while ischemic/hypoxic con- ditioning is a neuroprotective strategy for stroke. The study shows according the pathway of PI3 kinase (phosphatidylinositol 3-kinase)/Akt and the inhibitor-of- apoptosis proteins, hypoxic preconditioning (HPC) could inhibit apoptotic cell death in brain microvascular endothelial cells [111]. Another research indicates HPC could protect the BBB integrity in the wild-type mice, but the HPC-induced BBB protec- tion would be damage in SphK (Sphingosine kinase)-knockout mice [112].
As the neuroprotective approach, hypothermia could decrease utilization of oxy- gen and glucose, keep the level of ATP and pH in ischemic tissues, reduce the down- stream consequences of lactate overload and alleviate acidosis [113]. It is beneficial to mitochondrial function. Hypothermia could inhibit of cPKCδ translocation to the mitochondria, further hinder the process of reactive oxygen species and initiation of apoptosis [114]. On the other hand hypothermia could protect the BBB integrity according to decreasing MMP proteolytic activity and degrading the components of the extracellular matrix comprising the BBB [115]. But the efficacy, safety of hypo- thermia in clinical still requires further investigation.