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Advanced Neurology Inflammation in diabetic stroke: Treatment target

1. Introduction sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and
metformin, however, showed that they have unexpected
Stroke is the leading cause of disability and the second benefits in cardiovascular disease risk reduction.
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leading cause of death worldwide. Individuals with type 2
diabetes are twice as likely to experience a stroke than those GLP-1 is an endogenous hormone secreted by the
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without diabetes. In part I of this review, we summarize the intestine and brainstem on food consumption to lower
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pathophysiological evidence of inflammation in ischemic glucose and promotes satiety. It lowers glucose through
stroke and discuss the increased risk of ischemic stroke a glucose-dependent insulin secretion mechanism, thus
in patients with type 2 diabetes due to chronic low-grade having low risk of causing hypoglycemia. Endogenous
inflammations caused by hyperglycemia. The imbalance GLP-1 has a short half-life of around 1 -2 minutes, primarily
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of pro- and anti-inflammatory responses worsens their degraded by DPP-4. Hence, GLP-1 RAs are recommended
ischemic brain damage and increases their risks of post- as glucose-lowering agents. Since its clinical use, it was
stroke infection, resulting in poor clinical outcome after found that GLP-1 RAs reduces the risk of stroke, as
ischemic stroke. confirmed in clinical trials. Meta-analyses have shown that
GLP-1 RAs reduce the risk of major adverse cardiovascular
At present, the primary prevention of stroke focuses events (MACE) by 14% and non-fatal stroke by 16%, but
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on controlling the risk factors of stroke, including the glucose control is not the only contributor to such risk
control of hyperglycemia in diabetes. In the event of acute reduction. Animal studies showed that GLP-1 receptors
ischemic stroke, reperfusion treatments, thrombolysis are widely distributed in brain, especially in macrophages,
and/or thrombectomy, are routine practice. Although astrocytes, neurons, and endothelial cells. Both GLP-1 and
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there is significant preclinical evidence for inflammation GLP-1 RAs readily across the blood-brain barrier (BBB).
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in ischemic brain damage, there are few successful clinical There is evidence that GLP-1 RAs reduce inflammation
trials on treatments targeting inflammation in stroke, and by decreasing proinflammatory cytokines (e.g., nuclear
even fewer in diabetic stroke. In the second part of the factor kappa B [NF-κB]), oxidative stress, and apoptosis.
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review, we attempt to summarize the evidence on potential Clinical studies showed that GLP-1 RA treatment reduces
treatments that target inflammation in diabetic ischemic occurrence of carotid atherosclerosis in individuals with
stroke and hope to shed light on future research. type 2 diabetes independent of glucose and cholesterol
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2. Treatment targets in stroke primary control. However, some GLP-1 RAs may be associated
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prevention with a higher risk of diabetic retinopathy. DPP-4
degrades GLP-1, and DPP-4 inhibitors would increase
2.1. New glucose-lowering agents the availability of GLP-1. Although DPP-4 inhibitors
In diabetic setting, chronic hyperglycemia leads to elevated may improve glycemic control, a meta-analysis did not
level of advanced glycation end-products (AGEs). Glycation demonstrate a significant benefit of DPP-4 inhibitors in the
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of protein components of low-density lipoprotein (LDL) risk reduction of MACE. Clinical observations noted that
interferes its metabolism, promoting atheroma formation. GLP-1 RA treatment is associated with weight reduction,
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High levels of AGE induce the expression of its receptors which is not seen in treatment with DPP4 inhibitors. Of
(receptor for AGEs [RAGE]). The interaction between note, DPP4 inhibitors may increase the risk of heart failure,
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AGE and RAGE accelerates atherosclerosis progression which further negates their benefit.
and hampers plaque regression by increasing oxidative SGLT-2 inhibitors lower glucose levels by preventing
stress, the expression of proinflammatory cytokines, renal glucose resorption. SGLT-2 is solely located in
chemoattractants, and vessel adhesion molecules. Hence, the renal proximal tubule. However, data from clinical
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glycemic control has been a primary stroke prevention trials confirmed the benefit of SGLT-2 inhibitors in
target. However, epidemiologic data have shown that cardiovascular disease, especially in heart failure.
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improved glycemic control is associated with reduced Although the mechanism of action is not known, preclinical
cardiovascular diseases in type 1 diabetes, but not in studies suggested that SGLT-2 inhibitors may exert anti-
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type 2 diabetes. These results suggest that there are factors inflammatory effects through other glucose transporters
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other than hyperglycemia associated with cardiovascular to improve mitochondrial functions, reduce oxidative
risk in individuals with type 2 diabetes. Furthermore, stress, promote macrophage M2 anti-inflammatory phase
intensive glycemic control in type 2 diabetes is linked to an polarization, and regulate autophagy. However, the clinical
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increased risk of severe hypoglycemia and congestive heart use of SGLT-2 inhibitors continues to pose challenges due
failure. Studies on some newer classes of glucose-lowering to their side effects, such as increased risk of ketoacidosis
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agents, such as glucagon-like peoptide-1 (GLP-1) receptor and fracture. There is clinical evidence that supports the
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agonist (GLP-1 RA), dipeptidyl peptidase-4 inhibitors, combination use of GLP-1 RAs and SGLT-2 inhibitors in

Volume 3 Issue 2 (2024) 2 doi: 10.36922/an.1694