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Advanced Neurology Inflammation in diabetic stroke: Pathogenesis

1. Introduction endothelial injury. Lipoprotein-driven inflammation
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plays an important role in the development of atheroma
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Stroke is the leading cause of disability and the second (Figure 1). The accumulation of low-density lipoprotein
leading cause of death worldwide. Diabetes mellitus (LDL) in the vessel wall can be modified by oxidation. The
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is a significant independent cardiovascular risk factor oxidized lipid induces endothelial cells and smooth muscle
in patients, irrespective of age, smoking habit, and cells (SMC) to activate nuclear factor kappa B (NF-κB), a
hypertension. Approximately one-third of first-time universal transcription factor regulating genes involved
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ischemic stroke patients have diabetes. The incidence 12
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of diabetes, especially type 2 diabetes which accounts in the immune and inflammatory responses. Under
for approximately 95% of all diabetic cases, is rising normal condition, NF-κB remains in an inactive form in
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significantly, and it has been predicted that diabetes will the cytoplasm. When activated, NF-κB translocates to the
affect 642 million people worldwide by 2040. 5 nucleus, upregulating the expression of adhesion molecules
(e.g., vascular cell adhesion molecule-1 [VCAM-1])
Stroke can be classified as ischemic (~80%) and, less and chemoattractants (e.g., monocyte chemoattractant
commonly, hemorrhagic. Ischemic stroke occurs when protein 1), which recruit inflammatory cells, including
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blood flow to the brain is severely interrupted by a clot. monocytes and lymphocytes into the endothelium. These
This triggers a cascade of complex peripheral and more inflammatory cells secrete cytokines including interleukin
importantly central pathophysiological events that evolve (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-α). 11,13
temporally and spatially in the brain. Inflammation Monocytes recruited to the vessel wall mature into
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and maladaptive immune mechanisms are among the macrophages and take up cholesterol particles to form
most important pathological mechanisms in atheroma foam cells. The cytokines promote proliferation of SMCs,
formation, and in the damage cascades of the acute, which can migrate to the intima, also take up lipid and
subacute and chronic phases after stroke. Individuals with express foam cell markers. 11,13 Apoptosis/ferroptosis and
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type 2 diabetes are twice as likely to experience a stroke secondary necrosis of foam cells promote the development
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than those without diabetes. Diabetes is often present for of a necrotic core. Plaque rupture activates a coagulation
a long time before stroke takes place, causing low-grade cascade and thrombus formation, which may lead to
inflammation, and disrupting the proper functioning of ischemic stroke. 11,13,14
the neurovascular units (NVUs). These proinflammatory
processes are further accelerated after cerebral ischemia 3. Inflammation accelerates atherosclerosis
and worsen the stroke outcome in diabetic patients. in patients with type 2 diabetes
Current clinical treatments for ischemic stroke are
focused on restoring cerebral blood flow (reperfusion) in Diabetes contributes to accelerated atherosclerotic
processes and hampers regression through multiple
the acute phase, including thrombolysis and mechanical mechanisms (Figure 1). Chronic hyperglycemia, a
thrombectomy. However, many patients that fall outside hallmark of diabetes, generates high levels of advanced
of the treatment window and/or without large-vessel
occlusion are, therefore, not eligible for acute reperfusion glycation end products (AGEs) that accumulate in blood
treatment and becoming subject to the development and tissues, including blood vessels. Although AGEs can
of ischemic brain injury. Although inflammation after be absorbed from food, especially from highly processed
ischemic stroke is a well-described phenomenon and is food, AGEs are predominantly synthesized endogenously
hypothesized to play a key role in secondary injury, the by nonenzymatic glycation of heterogeneous substances
underlying mechanisms are not fully understood, and via Maillard reaction. The levels of AGEs are significantly
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there are no approved treatments targeting cellular injury higher in diabetic patients with chronic hyperglycemia.
caused by inflammation. There are even fewer data on Glycation of the protein component of LDL in the vessel
anti-inflammation treatments in diabetic stroke. This wall renders LDL unrecognizable to LDL receptors;
review focuses on the complex temporospatial aspects of therefore, they are absorbed by macrophages, hastening
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inflammation in ischemic stroke pathophysiology as well the formation of foam cells. Meanwhile, glycation of
as the potential therapeutic targets for inflammation in high-density lipoprotein (HDL) inhibits its function of
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stroke patients with type 2 diabetes. transporting cholesterol and preventing LDL oxidation.
AGEs can also cause the dysfunction of extracellular
2. Inflammation in atheroma development matrix, leading to crosslinking and impaired endothelial
cell function, thereby resulting in vessel stiffness. 18
Atherosclerosis is a major cause of ischemic stroke. The
formation of atherosclerosis is multifactorial. It is a chronic There are different types of AGE receptors (RAGEs),
inflammatory disorder of the arterial wall triggered by among which the full-length transmembrane RAGEs are

Volume 3 Issue 2 (2024) 2 doi: 10.36922/an.1683