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Advanced Neurology Inflammation in diabetic stroke: Treatment target

is important for signal transduction stimulated by AGE- cells, anti-inflammation, immunomodulation, attenuation
RAGE. Further, preclinical studies showed the expression of oxidative stress, and remote preconditioning.
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of DIAPH1 in mouse atherosclerotic lesions. Although
the mechanisms of its action are not fully understood, 3.1. Inhibition of CNS infiltration by peripheral
RAGE may modulate inflammation through a DIAPH1- inflammatory cells
dependent pathway. DIAPH1 may also be a novel target for After an ischemic insult, microglia are activated within
atherosclerotic treatment in diabetes. 47 minutes leading to the production of cytokines and
chemokines, resulting in CNS infiltration of leukocytes.
2.4. Others Results of clinical trials targeting cell adhesion molecules
Diabetic patients tend to have other stroke risk factors and leukocyte infiltration have been disappointing.
contributing to atherogenesis, such as hyperlipidemia, Enlimomab, an antibody against intercellular adhesion
especially high LDL, and hypertension. Statins are the molecule 1 (ICAM-1), is associated with worse functional
primary treatment for reducing cholesterol and lowering outcomes at 90 days, primarily due to infection and
the risk of cardiovascular disease. Recent studies have fever, because it interferes with the endogenous immune
shown that statins also have an anti-inflammatory effect defences. In non-human primates, HuEP5C7, an antibody
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as evidenced by a significant reduction in hsCRP. 48,49 against E- or P-selectin, led to smaller infarct volume and
Studies have shown that proprotein convertase subtilisin/ improved functional outcome. However, clinical trials on
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kexin type 9 inhibitors are safe in diabetic patients and can E-selectin were terminated early. In the ACTION II trial,
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further reduce LDL by 50%, as compared to statins alone. 17 natalizumab – an antibody that blocks antigen-4 integrin,
which is a key player in cell adhesion – did not improve
Diabetes impairs atherosclerosis plaque regression 54
even after aggressive cholesterol lowering. MicroRNAs patient outcome. Recombinant neutrophil inhibitory
factor (UK-279,276) that blocks neutrophil adhesion to
(miRNAs) are a class of short non-coding RNA that vascular endothelial cells failed to show an improved
regulates macrophage, endothelial, and smooth muscle functional outcomes at 90 days (ASTIN trial). These
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cells dysfunction. They can serve as markers and studies suggest that CNS infiltration by leukocytes may
therapeutic targets for improving atherosclerosis and not necessarily be the malevolent player but may also have
preventing stroke. Studies have shown that anti-miR33 some beneficial effects.
antisense oligonucleotides decrease macrophage content
in atherosclerotic plaque and inflammation in diabetic Fingolimod is a sphingosine-1-phosphage receptor
mice. Several clinical trials are ongoing, using miRNA agonist that prevents the egress of lymphocytes from
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to monitor carotid atherosclerosis (NCT05680935, lymph nodes, hence limiting the CNS infiltration of
NCT03855891). lymphocytes. Many preclinical studies have shown that
it reduces infarct volume and function deficit. A pilot
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In summary, a variety of treatment strategies targeting clinical trial showed that patients without thrombolysis
chronic inflammation in patients with type 2 diabetes treated with oral fingolimod within 72 h of stroke onset
have been studied. These include unexpected anti- had milder neurological deficit and reduced secondary
inflammatory effects of new glucose-lowering agents, and infarct enlargement at day 7. At present, several
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new insights into adipose-derived hormones and direct clinical trials test Fingolimod in stroke patients receiving
anti-inflammatory agents. Many of these strategies have reperfusion treatment. Although both are targeting
shown promise in preclinical studies, but require further reducing inflammation cells CNS infiltration, the difference
validation in clinical trials, especially those on patients results between natalizumab and fingolimod are not fully
with diabetes. understood. 58
3. Treatment targets in acute ischemic 3.2. Anti-inflammatory drugs
stroke Medicines with non-selective anti-inflammatory effects
The complex post-ischemic inflammatory cascade occurs have been studied in individuals with acute ischemia.
minutes after vessel occlusion. Numerous preclinical Colchicine has been used in secondary prevention for
and clinical trials that target the neuroinflammation and cardiovascular diseases. In a pilot study, colchicine reduced
immune-mediated neuronal damage in acute ischemia hsCRP, but it did not improve clinical outcomes at 90 days
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have been published. In this section, we summarize the when given within 24 h of transient ischemic attack (TIA)
major studies conducted on mechanism of inflammation or minor-to-moderate ischemic stroke. Chloroquine is
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and immunomodulation: inhibition of central nervous an anti-malarial drug which also has anti-inflammatory
system (CNS) infiltration by peripheral inflammatory effect. Pretreated with chloroquine, ob/ob mice (a type 2

Volume 3 Issue 2 (2024) 4 doi: 10.36922/an.1694