During the acute period after cerebral ischemia, uncontrolled inflammation is a major mediator of cerebrovascular injury and brain damage [21]. Compared to healthy con- trols, inflammation and oxidative stress significantly increased in DM patients. Recent clinical studies revealed that the expression of proinflammatory proteins such as TNF- α, interleukin-1 (IL-1), IL-6 and monocyte chemoattractant protein-1 (MCP-1) are much higher in diabetic patient plasma. A recent experimental study also demon- strated that at 12 h of reperfusion following 45 min transient middle cerebral artery
Fig. 10.1 Hyperglycemia enhances cerebral ischemia-induced brain injury. (a) Representative images for TTC stained ischemic brain infarctions. Bar = 1 mm. (b) Ischemic infarct volumes were quantified at 24 h after stroke. (c) Neurological score on day 1 after stroke. Data are mean±SEM.
*P < 0.05, DM = Diabetes mellitus
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occlusion (MCAO), several inflammatory cytokines expression at the cortex are sig- nificantly increased in db/db mice when compared to db/+ mice (IL-1β, 164%; IL-6, 84%; MCP-1, 65%; MIP-1α, 135%) [22]. TNF-α, IL-1 and IL-6 play critical roles in ischemia- induced cerebral vascular injury have been demonstrated by numerous stud- ies showing that reduced expression of IL-6 is accompanied by a better neurological outcome [23]. Moerover, both in vivo and in vitro experiments have identified the important function of MCP-1 on (MCAO)/reperfusion-induced (BBB) breakdown [24, 25]. A recent study by El-Sahar AE et al. showed that, in the diabetic condition, acute oxidative stress is increased in rat brain following cerebral ischemic reperfusion injury, and this alteration is associated with the exacerbation of ischemia-induced infract size [26]. More recently, our group demonstrated that methylglyoxal (MGO), a reactive dicarbonyl accumulated in diabetic patients, significantly increases 4 h oxy- gen-glucose deprivation (OGD)/20 h reperfusion-induced primary human brain microvascular endothelial cells cytotoxicity by down-regulating glutathione (GSH) production and up-regulating reactive oxygen species (ROS) release [27].
Including the upregulated proinflammatory cytokines, increased infiltration of inflammatory cells, such as leukocytes, and white blood cells, into ischemic brain tis- sue has also been demonstrated in several diabetic ischemia-reperfusion animal mod- els [28]. Cerebral vascular endothelial cells are activated in the setting of cerebral ischemia, leading to production of adhesion molecules, which enables inflammatory cells to attach to endothelial cells and then migrate to the ischemic tissue to further release proinflammatory cytokines and activate local microglial [29, 30]. Using immu- nohistochemistry and Western blot methods, Ding CN et al. showed that the number of intercellular cell adhesion molecule-1 (ICAM-1) expressed in microvascular of cortex is obviously increased at 3 days of reperfusion in diabetic rats compared to non-dia- betic rats [31]. Protein kinase C (PKC) is known to mediate the expression of ICAM-1.
Previously published literature also demonstrated that hyperglycemia and diabetes can activate PKC, which promotes cerebral endothelial dysfunction with increased inflam- matory-endothelium interactions [32, 33]. In addition to ICAM-1, db/db mice also exhibit significantly higher increases at cortex under reperfusion period after 45 min or 2 h/MCAO of other adhesion molecules, such as P-selectin and E-selectin [22].
The expression of pro-inflammatory cytokines and inflammatory mediators, such as IL-1β, IL-6, TNF-α, MCP-1, CCL-2, iNOS and ICAM-1, in the cerebral vascular is regulated by the induction of transcription factors during ischemic reperfusion inflam- mation [34, 35]. Thus, the transcription factor NFκB becomes a key regulator in cere- bral ischemic reperfusion associated with regulating cell death and inflammation [36].
At 3 h reperfusion after MCAO, translocation of NFκB from cytoplasm to nucleus is detected in the cortex tissue of rats. Interestingly, the translocation of NFκB is signifi- cantly enhanced in diabetic rat cortex compared to non-diabetic rat cortex. This trend can be observed even at 24 h reperfusion after MCAO. The nuclear translocation of NFκB will further affect the mRNA expression of COX-2, iNOS, and ICAM-1 [37].
Matrix metalloproteinases (MMPs), as proteolytic enzymes, could degrade all components of the extracellular matrix (ECM) around the blood vessels [38].
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MMPs-induced (BBB) leakage during cerebral ischemia may aggravate ischemic brain tissue to bleeding during reperfusion [39]. Using a model of 1 h MACO/23 h reperfusion, Kamada H et al. found that hyperglycemia induced by streptozoto- cin could enhance the level of MMP-9 activity compared to normal control rats [40]. In another diabetic animal model, the Goto-Kakizaki (GK) rat model, Elgebaly MM et al. also demonstrated that hyperglycemic augments 3 h MCAO/21 h reperfusion-induced stimulation of MMP-9 activity in isolated cere- bral vessels [41].
Taken together, diabetes and its associated hypoglycemia are linked to cere- bral ischemia-induced mortality and poor functional recovery. A number of stud- ies showed that diabetes enhances inflammation, oxidative stress, and MMPs activity, which are associated with exacerbated cerebral vascular damage after ischemia/reperfusion injury (Fig. 10.2). In addition, a few literature published recently reported that autophagy and hyperglycemia-induced advanced glycation end products (AGEs) and its receptor (RAGE) also contribute to diabetes- enhanced cerebral ischemia/reperfusion injury [42–44]. However, the precise mechanisms in diabetic- exacerbated cerebral ischemia injury remain unknown.
Thus, a better understanding of cerebral vascular injury in diabetic ischemia may provide novel therapeutic approaches for the treatment and prevention of diabe- tes-associated stroke damage.
Fig. 10.2 Mechanisms of cerebral vascular injury in diabetic ischemia and reperfusion. Schematic representation of mechanisms involved in aggravating brain damage following cerebral ischemia under diabetic condition
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W. Jiang et al. (eds.), Cerebral Ischemic Reperfusion Injuries (CIRI), Springer Series in Translational Stroke Research, https://doi.org/10.1007/978-3-319-90194-7_11