INTRODUCTION:

Stroke remains a leading global cause of mortality and long-term disability, with ischemic stroke (IS) comprising approximately 87% of all stroke cases¹. The pathophysiology of IS involves a complex interplay of neuronal injury, excitotoxicity, oxidative stress, and inflammation, which collectively contribute to tissue damage and functional impairment^1,2. Over the past few years, inflammation has emerged as a pivotal mechanism in both the acute and chronic phases of stroke, driving secondary injury while also facilitating repair and recovery³. The inflammatory cascade, triggered by cerebral ischemia, involves the activation of resident brain cells (e.g., microglia, astrocytes, endothelial cells) and the infiltration of peripheral immune cells (e.g., neutrophils, monocytes, lymphocytes)^4,5. These cells release a plethora of inflammatory mediators, including cytokines, chemokines, adhesion molecules, and damage-associated molecular patterns (DAMPs), which exacerbate neuronal damage, disrupt the blood-brain barrier (BBB), and contribute to reperfusion injury following recanalization therapies like mechanical thrombectomy (MT) or thrombolysis⁶.

The identification of reliable, blood-based inflammatory biomarkers has been a major focus of stroke research, driven by the need to improve diagnostic accuracy, stratify risk, predict outcomes, and guide therapeutic interventions^7,8. Biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and intercellular adhesion molecule-1 (ICAM-1) have been extensively studied for their roles in stroke severity, post-stroke complications (e.g., infections, cognitive impairment), and long-term prognosis⁹. Additionally, novel markers, such as the systemic immune-inflammation index (SII), have gained attention for their ability to reflect systemic inflammatory states¹⁰. Advances in high-sensitivity detection technologies, such as single-molecule array (Simoa), and the integration of machine learning have further enhanced the potential of these biomarkers¹¹. Despite these advancements, challenges remain, including the lack of specificity, variability in biomarker kinetics, and difficulties in standardizing assays across diverse stroke populations^11,12. This review aims to provide a comprehensive synthesis of the latest evidence on inflammatory biomarkers in IS, focusing on their diagnostic and prognostic utility, therapeutic implications, and emerging research directions. By consolidating recent findings, we seek to highlight the potential of these biomarkers to transform stroke management while identifying gaps that warrant further investigation¹³.

METHODS:

We have conducted a comprehensive literature search on PubMed, MEDLINE, and Web of Science, covering studies published from January 2016 to July 2025. Search terms included “ischemic stroke,” “inflammatory biomarkers,” “cytokines,” “adhesion molecules,” “acute-phase proteins,” and “stroke prognosis.¹⁴” Only peer-reviewed, full-text articles in English were included. We have prioritized studies investigating blood-based inflammatory biomarkers, their association with stroke severity, etiology, and outcomes, and their potential as therapeutic targets⁷. Data were synthesized into thematic sections, with tables and figures to summarize key findings.

Inflammatory Pathways in Ischemic Stroke:

Inflammation in IS has been characterized as a double-edged sword, with both detrimental and neuroprotective effects¹⁵. The sudden cessation of blood flow triggers tissue hypoxia, leading to neuronal excitotoxicity, oxidative stress, and blood-brain barrier (BBB) disruption¹⁶. Resident cells (microglia, astrocytes, endothelial cells) and infiltrating immune cells (neutrophils, monocytes, lymphocytes) release inflammatory mediators, including cytokines, chemokines, and adhesion molecules^16,17. These processes exacerbate tissue injury during the acute phase (1–7 days) and contribute to reperfusion injury following blood flow restoration. Conversely, inflammation promotes tissue repair and neuroregeneration in the subacute and chronic phases^18,19.

Key Inflammatory Biomarkers:

Cytokines:

Cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10), have been extensively studied for their roles in stroke pathophysiology²⁰.

· IL-6: IL-6, a pro-inflammatory cytokine, has been consistently associated with stroke severity and poor outcomes^20,21. Studies have shown elevated IL-6 levels within 24 hours of stroke onset, correlating with larger infarct volumes and higher National Institutes of Health Stroke Scale (NIHSS) scores^22,23. A 2023 study reported that IL-6 levels at admission predict stroke-associated infections (SAIs), particularly lower respiratory tract infections (LRTIs), with an area under the curve (AUC) of 0.685 in receiver operating characteristic (ROC) analysis²⁴. IL-6 has also been linked to post-stroke cognitive impairment (PSCI), with higher baseline levels associated with lower Montreal Cognitive Assessment (MoCA) scores at 3–36 months²⁵.

· TNF-α: TNF-α, another pro-inflammatory cytokine, has been implicated in neuronal damage and muscle catabolism post-stroke^25,26. Research from 2021 demonstrated elevated TNF-α levels within 24 hours of stroke, correlating with stroke severity and infarct size²¹. However, its prognostic utility remains controversial due to variability in study designs^21,27.

· IL-10: IL-10, an anti-inflammatory cytokine, has been investigated for its neuroprotective properties²⁸. Studies have reported that higher IL-10 levels correlate with smaller infarct sizes and better functional outcomes, suggesting a role in mitigating stroke-induced immunodepression²⁹.

Adhesion Molecules:

Adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), facilitate leukocyte infiltration into the ischemic brain, exacerbating neuroinflammation^5,30.

· ICAM-1: ICAM-1 levels have been found to be significantly elevated within 8 hours of stroke onset, with a sensitivity of 74% and specificity of 76% for diagnosing acute ischemic stroke (AIS)³¹. Elevated ICAM-1 has been associated with worse neurological outcomes and BBB disruption³².

· VCAM-1: VCAM-1 has been similarly implicated in stroke pathogenesis, with increased levels detected in the blood and infarct regions. However, its prognostic value remains less clear due to inconsistent findings across studies³⁰.

· Selectins: E-selectin and P-selectin have been studied for their roles in leukocyte rolling and adhesion³³. While some studies report elevated E-selectin levels in the acute phase, others have found no significant differences compared to healthy controls. P-selectin has been associated with a prothrombotic state, particularly in older patients^34-35.

Acute-Phase Proteins:

Acute-phase proteins, such as C-reactive protein (CRP) and serum amyloid A (SAA), have been widely investigated as markers of systemic inflammation³⁴.

· CRP: High-sensitivity CRP (hsCRP) has been identified as a predictor of poor stroke outcomes, including increased mortality and disability³⁶. A 2023 study found that post-mechanical thrombectomy (MT) CRP levels predict mortality with an AUC of 0.737. However, CRP’s lack of specificity limits its diagnostic utility^37-38.

· SAA: SAA has been associated with stroke etiology, with higher levels observed in cardioembolic and arteriopathic strokes compared to idiopathic cases³⁹. In pediatric stroke, elevated SAA levels have been linked to a higher risk of recurrence in arteriopathic cases⁴⁰.

Novel Biomarkers:

Recent studies have explored novel inflammatory biomarkers, such as the systemic immune-inflammation index (SII), which integrates neutrophil, lymphocyte, and platelet counts⁴¹. A 2025 study using NHANES data (2015–2020) reported a significant association between SII and stroke prevalence, with an odds ratio of 1.02. Other emerging biomarkers include myeloperoxidase (MPO) and lipopolysaccharide-binding protein (LBP), which have shown promise in predicting SAIs and stroke severity^38,42.

Diagnostic and Prognostic Applications:

The diagnostic accuracy of brain imaging, such as computed tomography (CT), has been reported at approximately 85%, underscoring the need for complementary blood-based biomarkers⁴⁹. An ideal stroke biomarker should be sensitive to early ischemia, specific to brain tissue, and capable of distinguishing stroke etiologies (e.g., cardioembolic, large-vessel, small-vessel) while ruling out mimics like hypoglycemia or seizures⁵⁰.

Diagnostic Potential:

· IL-6 and CRP: These biomarkers have shown promise in early stroke detection. IL-6 levels within 24hours have been associated with stroke severity and SAIs, though their specificity is limited. CRP has been less useful for diagnosis due to its elevation in various inflammatory conditions⁴².

· ICAM-1: Studies have demonstrated that ICAM-1 is a sensitive marker for AIS, with elevated levels detectable within 8 hours of onset³¹.

· S100B and NSE: While neuronal biomarkers like S100B and neuron-specific enolase (NSE) have been investigated, their diagnostic utility is hampered by low sensitivity and variable kinetics⁵¹.

Prognostic Value:

· Stroke Severity and Outcomes: Biomarkers like IL-6, CRP, and SII have been consistently associated with stroke severity (NIHSS) and functional outcomes (modified Rankin Scale, mRS). For instance, post-MT CRP levels predict mortality, while SII is linked to stroke prevalence⁵².

· Post-Stroke Complications: IL-6 and LBP have been identified as predictors of SAIs, particularly pneumonia, which is a major cause of post-stroke mortality. Elevated NSE levels post-MT have been associated with symptomatic intracranial hemorrhage⁴².

· Cognitive Impairment: The Nor-COAST study (2015–2017) found that baseline inflammatory biomarkers, including IL-6 and the terminal C5b-9 complement complex (TCC), predict PSCI at 3–36 months⁵³.

Figure 1: Temporal Dynamics of Inflammatory Biomarkers in Stroke

Caption: This figure illustrates the temporal profile of key inflammatory biomarkers (IL-6, TNF-α, IL-10, CRP, ICAM-1) in the acute (1–7 days), subacute (7 days–3 months), and chronic (>6 months) phases of ischemic stroke. IL-6 and CRP peak early, while IL-10 shows sustained elevation in the subacute phase.

Therapeutic Implications:

The dual role of inflammation in stroke has prompted investigations into anti-inflammatory and immunomodulatory therapies. Statins, such as simvastatin and atorvastatin, have been widely studied for their anti-inflammatory properties beyond cholesterol reduction⁵⁴.

· Statins: Studies have confirmed that statins reduce stroke incidence by 16–30% in high-risk populations, partly through modulation of inflammatory pathways(55). However, their impact on specific biomarkers (e.g., IL-6, CRP) has been inconsistent, and recent trials have shown no significant improvement in neurological outcomes when combined with tissue plasminogen activator (tPA)⁵⁶.

· Monoclonal Antibodies: Therapies targeting pro-inflammatory cytokines (e.g., anti-IL-6 or anti-TNF-α antibodies) have shown promise in preclinical models but have yet to translate into clinical practice⁵⁷.

· Cell-Based Therapies: Emerging research has explored cell-based approaches, such as mesenchymal stem cells, to modulate inflammation and promote neuroregeneration. These therapies remain in early-stage trials⁵⁸.

Challenges in Clinical Translation:

Despite extensive research, no single inflammatory biomarker has been validated for routine clinical use.

Key challenges include:

· Specificity and Sensitivity: Biomarkers like CRP and IL-6 are elevated in various inflammatory conditions, reducing their specificity for stroke⁵⁹.

· BBB Penetration: Biomarkers of central nervous tissue face challenges in crossing the BBB, complicating their detection in peripheral blood⁶⁰.

· Heterogeneity: Stroke’s etiological diversity (e.g., cardioembolic vs. large-vessel) affects biomarker profiles, necessitating subtype-specific markers⁶¹.

· Standardization: Variability in study designs, timing of sample collection, and assay methods has hindered biomarker standardization⁶².

Emerging Technologies and Future Directions:

Recent advancements in biosensing technologies, such as single-molecule array (Simoa), have improved the detection of low-abundance biomarkers like neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP)⁶³. Simoa-based multiplex platforms have enabled simultaneous measurement of multiple inflammatory and neuronal markers, enhancing diagnostic accuracy. Machine learning approaches have also been applied to integrate biomarker profiles with clinical data, improving prediction of stroke outcomes and recurrence risk⁶⁴.

Table 2: Emerging Technologies for Biomarker Detection

Technology	Description	Application in Stroke	Reference
Simoa	Single-molecule array for ultra-sensitive detection	Simultaneous detection of IL-6, NfL, GFAP	(11)
Multiplex Assays	Measures multiple biomarkers in a single sample	Identifies inflammatory and neuronal injury markers	(69)
Machine Learning	Integrates biomarker and clinical data	Predicts stroke outcomes and recurrence	(70)

Future research should focus on:

· Multimarker Panels: Combining inflammatory biomarkers (e.g., IL-6, CRP, ICAM-1) with neuronal markers (e.g., GFAP, NfL) to improve diagnostic and prognostic accuracy⁶⁵.

· Personalized Medicine: Identifying subtype-specific biomarkers to guide targeted therapies based on stroke etiology⁶⁶.

· Longitudinal Studies: Investigating the temporal dynamics of biomarkers across all stroke phases to better understand their prognostic utility⁶⁷.

Therapeutic Trials: Conducting large-scale clinical trials to evaluate anti-inflammatory therapies, such as monoclonal antibodies and cell-based treatments⁶⁸.

CONCLUSION:

The exploration of inflammatory biomarkers in ischemic stroke has significantly advanced our understanding of the complex interplay between inflammation and stroke pathophysiology. Key biomarkers, including cytokines (IL-6, TNF-α, IL-10), adhesion molecules (ICAM-1, VCAM-1), acute-phase proteins (CRP, SAA), and novel indices like the systemic immune-inflammation index (SII), have been extensively investigated for their diagnostic, prognostic, and therapeutic potential. These biomarkers have demonstrated associations with stroke severity, post-stroke complications (e.g., infections, cognitive impairment), and long-term functional outcomes, offering insights into the acute, subacute, and chronic phases of stroke. However, challenges such as limited specificity, variability in biomarker kinetics, and lack of standardization have prevented their routine integration into clinical practice.

Emerging technologies, such as single-molecule array (Simoa) and machine learning, have opened new avenues for detecting low-abundance biomarkers and integrating complex datasets to improve diagnostic and prognostic accuracy. The development of multimarker panels combining inflammatory and neuronal markers holds promise for overcoming current limitations and enabling personalized stroke management. Moreover, ongoing research into anti-inflammatory therapies, including statins, monoclonal antibodies, and cell-based approaches, has highlighted the potential to modulate inflammation for improved outcomes, though clinical translation remains a significant hurdle. Future studies should prioritize longitudinal analyses to capture the dynamic nature of inflammatory biomarkers, validate subtype-specific markers to account for stroke heterogeneity, and conduct large-scale clinical trials to evaluate novel therapeutic strategies. By addressing these challenges, inflammatory biomarkers have the potential to revolutionize stroke care, enabling earlier diagnosis, tailored interventions, and improved patient outcomes in the coming years.

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Received on 18.08.2025 Revised on 10.09.2025

Accepted on 30.09.2025 Published on 08.10.2025

Available online from October 17, 2025

Asian J. Pharm. Tech. 2025; 15(4):370-376.

DOI: 10.52711/2231-5713.2025.00054

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Biomarker	Type	Role in Stroke	Clinical Utility	Key Findings	Reference
IL-6	Cytokine	Pro-inflammatory	Predicts severity, SAIs, PSCI	Elevated within 24h, AUC 0.685 for LRTIs	43
TNF-α	Cytokine	Pro-inflammatory	Associated with infarct size	Elevated in acute phase, variable prognostic value	44
IL-10	Cytokine	Anti-inflammatory	Neuroprotective, predicts outcomes	Higher levels linked to smaller infarcts	45
ICAM-1	Adhesion Molecule	Mediates leukocyte infiltration	Diagnostic, prognostic	Sensitivity 74%, specificity 76% for AIS	46
VCAM-1	Adhesion Molecule	Mediates leukocyte infiltration	Prognostic	Elevated in infarct regions, inconsistent findings	30
CRP	Acute-Phase Protein	Systemic inflammation marker	Predicts mortality, disability	Post-MT AUC 0.737 for mortality	47
SAA	Acute-Phase Protein	Systemic inflammation marker	Predicts recurrence in pediatric stroke	Higher in cardioembolic/arteriopathic strokes	39
SII	Composite Index	Reflects systemic inflammation	Predicts stroke prevalence	OR 1.02 in NHANES 2015–2020	48