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Advanced Neurology Inflammation in diabetic stroke: Treatment target

diabetes model) showed reduced ischemic brain damage ischemic brain, resulting in dampened inflammation and
and inflammatory cytokines. Metformin is widely used in reduced neurological deficit. 68
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patients with type 2 diabetes as a glucose-lowering agent. Sustained activation of the NLRP3 inflammasome is
Preclinical studies have shown that metformin given 24 h a crucial player in diabetic cerebral ischemia. Several
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after ischemia reduces ischemic volume by inhibiting potential therapies targeting the NLRPS inflammasome
neuronal apoptosis and microglial inflammation. have been studied in diabetic animal stroke models.
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Minocycline is a tetracycline derivative. In preclinical Pretreating diabetic mice with MCC950, a specific NLRP3
studies, minocycline has demonstrated anti-inflammatory inflammasome inhibitor, before transient ischemia resulted
properties, resulting in a reduction of tumor necrosis in reduced IL-1β and infarct volume, and improved
factor alpha (TNF-α) and improved motor performance survival. When treating diabetic rats 1 h or 3 h after
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after acute ischemia. 56,63 However, it did not show any reperfusion, MCC950 ameliorated deficits in hippocampal-
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clinical benefits in clinical trials (NeuMAST trial). At dependent memory after stroke, with reduced IL-1β and
present, there is an ongoing trial on the use of minocycline improved BBB integrity. Tripartite motif containing
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in patients undergoing thrombectomy (NCT05487417). 9 (TRIM9) is a brain-specific ubiquitin ligase, a potent
IL-1β, IL-6, IL-18, and TNF-α are important inhibitor of the NF-κB signaling pathway. Studies have
proinflammatory cytokines. Preclinical studies have shown that systemic administration of a recombinant
consistently showcased the benefits of anakinra (an IL-1β TRIM9 adeno-associated virus that drives brain-wide
antagonist) in acute ischemia. A pilot clinical trial showed TRIM9 expression effectively reduced neuroinflammation
that subcutaneous IL-1β antagonist can significantly and alleviated neuronal death, especially in aged mice. 72,73
reduce IL-6 levels, but did not improved clinical outcome None of the ongoing clinical studies are investigating these
(SCIL-STROKE trial). A phase III trial using Hu23F2G, two anti-inflammatory agents.
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an antibody against neutrophil β2 integrin CD18, was
stopped early due to futility. TNF-α antagonists, such 3.3. Modulation of inflammation
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as infliximab and adalimumab, are commonly used Post-stroke inflammatory processes are inherently
for inflammatory diseases (such as Crohn’s disease). complex. Depending on their environment, microglia/
However, no clinical trials have been conducted to test macrophages may transition from a proinflammatory
the effect of TNF-α antagonists on ischemic stroke. M1 phenotype to an anti-inflammatory M2 phase, which
Studies on IL-6 antagonists have reported conflicting exerts neuroprotection and tissue repair, depending on
results on cardiovascular disease prevention, and there its inflammation environment status. These continuous
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are currently no data on their efficacy in treating acute biphasic responses of the immune system make targeting
ischemia. inflammation for overall improvement of stroke outcome
Directly inhibiting proinflammatory cytokines may cause a considerable challenge. Recent research has shifted from
unwanted off-target effects, such as toxicity and infection, modulation of proinflammatory mechanisms to promotion
given their broad spectrum of effects in both the brain of protective M2 phenotypes to facilitate healing and
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and periphery. Purified polyclonal immunoglobulin G, repair.
intravenous immunoglobulin (IVIg) can bind to pathogens PPAR-γ is a hypoglycemic agent and a ligand-activated
and regulate inflammation. IVIg has been used for treating transcription factor belonging to the nuclear receptor
various inflammatory and autoimmune diseases. Toll-like superfamily. Preclinical studies have demonstrated that
receptor 4 (TLR-4) on microglia is one of the primary acutely administered PPAR-γ promotes M2 microglia/
receptors that recognize damage-associated molecular macrophage, resulting in increased protein expression of
patterns (DAMPs), which lead to NF-κB activation brain-derived neurotrophic factor (BDNF), insulin-like
on binding. Preclinical studies have shown that IVIg growth factor (IGF-1), and vascular endothelial growth
can dampen post-ischemic inflammation by blocking factor (VEGF). 75,76 In addition, it has been shown that
TLR-4 activation by DAMPs, resulting in reduced levels a single dose of azithromycin after ischemia may shift
of NLRP inflammasome, proinflammatory cytokines infiltrating leukocytes to the M2 phenotype, which is
(IL-1β and IL-18), and neutrophil infiltration. Aiming associated with reduced infarct volume and improved
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to control the thrombophilia side effects from high- neurological deficit. Following the preclinical evidence of
dose IVIg treatment, a preclinical study has shown that decreased TLR4 activity could promote M2 polarization in
early infusion of a low dose of IVIg encapsulated in microglia, ApTOLL a TLR4 antagonist has been tested. 77,78
nanocarriers labeled with a choline and acetylcholine A phase 1b/2a randomized clinical trial showed that
analogue can achieve high IVIg accumulation in the ApTOLL given within 6 h of stroke onset was safe and may

Volume 3 Issue 2 (2024) 5 doi: 10.36922/an.1694