Prolonged CBF decrease after stroke irreversibly damages neurons, hence the re- establishment of CBF and increasing functional microvasculature in the ischemic penumbra are essential to maintain neural function, and create a hospitable micro- environment for neuronal plasticity and functional recovery. The major adverse effects of I/R injury in diabetic stroke include exacerbated BBB disruption, exten- sive vascular damage, aggravated inflammatory responses, increased susceptibility to spontaneous intracerebral hemorrhage and formation of cerebral edema. These pathophysiological events and their underlying mechanisms are discussed in the following sections, and summarized in Fig. 11.1.
3.1 Neurovascular Uncoupling After I/R Injury in Diabetic Stroke
The neurovascular unit is a functional unit encompassing the anatomical and metabolic interactions between the neurons, astrocytes and vascular components of the BBB [30].
The BBB serves as a dynamic semi-permeable barrier separating the peripheral circu- lation and the central nervous system [31, 32]. While allowing influx of hydrophobic molecules and metabolic products by passive diffusion, the BBB prevents the entry of microscopic substances, hydrophilic molecules, and potential neurotoxins [31, 32].
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Neurovascular uncoupling and BBB disruption are among the initial steps of the pathophysiological cascade in DM and stroke [33]. In the minutes to hours follow- ing ischemia, endothelial swelling and pericyte damage and death lead to irrevers- ible constriction of capillaries and BBB disruption [34, 35]. Stroke in DM patients aggravates BBB disruption; and BBB permeability that usually increases within 7 days post stroke in non-DM conditions has been shown to be extended to 14 days or longer in DM stroke animals [36–38]. A ruptured BBB facilitates the entry of large molecules and the invasion of inflammatory factors, neurotoxins and patho- gens into the brain [32], and in a vicious cycle, these inflammatory factors in turn promote BBB disruption and lead to hemorrhagic transformation in diabetic stroke animals [37, 39, 40].
DM induces endothelial dysfunction including impaired blood vessel tone, plate- let activation, leukocyte adhesion, thrombogenesis, and inflammation [41]. DM increases vasoconstriction via increasing expression of vasoconstrictor endothelin-1 and decreasing expression of vasodilator Nitric Oxide (NO), leading to vasoconstriction of blood vessels and prolonged CBF decrease [41]. Prolonged attenuation of vasodilation can trigger endothelial dysfunction and aggravate ath- erosclerosis [42]. DM also creates an environment of high oxidative stress and inflammatory factors, which are conducive to atherosclerosis [43]. DM induced mitochondrial oxidative stress leads to endothelial cell damage, pericyte depletion and BBB leakage [44].
The interactions between the glial and vascular component of the neurovascular unit, i.e. astrocytes and endothelial cell interactions, are needed to regulate brain water content and electrolyte balance both under normal and disease states [30, 45].
In the setting of ischemic brain injury, activation of astrocytes can be both construc-
Fig. 11.1 Summary of key pathophysiological changes and mechanisms of reperfusion damage in diabetic stroke
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tive and destructive [46, 47]. In the acute phase of stroke, reactive astrocytes secrete proinflammatory cytokines, inhibit axonal regeneration, and aid in infarct expan- sion [47]. During the chronic phase after stroke, reactive astrocytes aid in neurite sprouting, synapse formation, rebuilding the BBB and secrete neurotrophic factors that aid in brain repair mechanims [46, 47]. Under the hyperglycemic conditions of DM, post stroke astrocyte activation is suppressed, and there is greater cell death of astrocytes as demonstrated in a rodent model of forebrain ischemia [48, 49]. On the whole, neurovascular uncoupling is a gateway leading to mitochondrial dysfunction and oxidative stress, neuronal death and brain tissue atrophy [50, 51].
3.2 Edema in Diabetic Stroke
The interaction between the astrocytes, the water channel protein Aquaporin-4 and endothelial cells is critical to brain water content regulation as well as post stroke edema resolution [45, 52]. Immediately following ischemic injury, cytotoxic cere- bral edema may ensue. In cytotoxic edema, impaired cellular metabolism and dys- function of sodium and potassium ion pumps lead to accumulation of sodium and increased water uptake, resulting in swelling of brain cells [53]. Cytotoxic edema may give way and/or occur together with vasogenic edema. Vasogenic cerebral edema is a pathological condition in which the intracranial pressure is increased by increasing brain water content in the interstitial space; and can last for several days after stroke [45, 52]. Edema resolution involves cerebral vasculature and cerebro- spinal fluid pathways mediated transport of water from the brain parenchyma to the vascular, intra ventricular and subarachnoid compartments via bulk flow [45, 52].
In the evolution of cytotoxic edema, Aquaporin-4 has been implicated in water uptake into the brain tissue, while in vasogenic edema; Aquaporin-4 plays a key role in water reabsorption and clearance [45, 54, 55]. Compared to control wild type mice, Aquaporin-4 deficient mice subjected to stroke exhibit ~30% decrease in cerebral cytotoxic edema; suggesting that during the early phase of ischemia, Aquaporin-4 inhibition could attenuate cytotoxic edema formation [45, 55].
However, Aquaporin-4 deficient mice subjected to a freeze-injury model of vaso- genic brain edema, exhibit worse neurological function, increased intracranial pres- sure and greater brain water content compared to control mice; indicating an essential role of Aquaporin-4 in fluid clearance and reabsorption of vasogenic edema [52]. Hence, altered Aquaporin-4 expression can have adverse effect in edema formation and resolution in diabetic stroke [56]. Middle aged rats induced with DM exhibit a significant decrease of paravascular Aquaporin-4 expression in the hippocampus [57]. Stroke in DM rodents damages the astrocytic end-foot lining around cerebral vessels, and damaged astrocytes exhibit increased withdrawal of the astrocyte end-foot from the cerebral vessel wall [48, 49]. Several studies have reported increased edema formation after diabetic stroke compared to non diabetic stroke, and I/R injury may exacerbate edema after stroke in diabetes [56]. Impaired
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water channel function and Aquaporin-4 expression may play a key role in edema formation and poor edema resolution in diabetic stroke.
3.3 Hemorrhagic Transformation in Diabetic Stroke
Hemorrhagic transformation (HT) is a commonly encountered critical effect of reperfusion therapy in ischemic stroke [58]. Particularly in DM stroke patients, tPA increases the risk of symptomatic intracerebral hemorrhage [58, 59]. HT may lead to hemorrhagic infarction or hematoma formation. The main predictors of HT after I/R injury include massive infarction volume, edema formation, gray matter injury with greater collateral CBF and hyperglycemia. HT formation is directly related to infarct volume, and DM patients (clinical studies) and DM rats (experimental stud- ies) exhibit greater infarct volume, worse neurological functional outcome, and decreased efficacy of thrombolysis with tPA following stroke compared to non DM stroke subjects [60, 61]. I/R injury in hyperglycemic cats induced a fivefold increase in HT incidence and a 25-fold increase in the extent of hemorrhagic infarction com- pared to non-DM cats [27]. HT after I/R injury in DM animals has been associated with metabolic alterations and a significant decrease in tissue energy, free radical production, inflammatory responses, and increase in lactate acidosis which damages the cerebral vasculature and facilitates entry of edema fluid and red blood cells extravasation [27, 62, 63]. Compared to non-DM rats, DM rats exhibit a greater CBF reduction and HT when subject to transient stroke with reperfusion injury, but not when subject to permanent ischemic stroke without reperfusion [60, 64]. This indi- cates that HT formation in DM stroke is largely an adverse effect of reperfusion.