Stroke remains a leading cause of death and long-term neurological disability worldwide, with ischemic stroke accounting for the majority of cases [1,2]. Acute ischemic stroke (AIS) results from abrupt interruption of cerebral blood flow, initiating a rapidly evolving cascade of energy failure, excitotoxicity, oxidative stress, mitochondrial dysfunction, inflammation, blood–brain barrier disruption, and ultimately neuronal death [3,4]. Although contemporary reperfusion strategies particularly intravenous thrombolysis and endovascular thrombectomy have substantially improved outcomes in appropriately selected patients, many individuals remain disabled despite successful recanalization [5,6]. This residual disability reflects, in part, irreversible tissue injury established before reperfusion and ongoing secondary injury after blood flow has been restored.

The concept of neuroprotection emerged from the recognition that potentially salvageable ischemic tissue surrounding the infarct core may persist for a limited period after arterial occlusion. This region, commonly described as the ischemic penumbra, retains sufficient structural integrity to recover if perfusion is restored and cellular injury can be interrupted [7]. Neuroprotective therapy therefore aims to preserve threatened neurons, glial cells, and the neurovascular unit by interfering with one or more components of the ischemic cascade. In principle, an effective neuroprotective drug could extend tissue viability before reperfusion, reduce reperfusion injury after recanalization, and improve functional recovery when administered alongside standard reperfusion therapy [8].

Despite compelling biological rationale and decades of experimental research, translation of neuroprotective agents from preclinical models to successful human stroke therapy has proved difficult. Hundreds of compounds have demonstrated benefit in animal models, yet relatively few have produced reproducible improvements in clinically meaningful outcomes in large randomized trials [9]. Differences between experimental and human stroke, inadequate modeling of age and comorbidity, narrow treatment windows, insufficient drug penetration into ischemic tissue, heterogeneous stroke mechanisms, and failure to account for concomitant reperfusion therapy have all contributed to this translational gap [10]. Contemporary stroke guidelines continue to regard pharmacological neuroprotection as an active research area rather than a uniformly established component of AIS management. The 2026 American Heart Association/American Stroke Association guideline notes that several recent neuroprotection trials have been neutral or negative for their primary outcomes, while selected secondary analyses remain hypothesis-generating.

Ischemic Cascade as a Therapeutic Target

Cerebral ischemia deprives neurons of oxygen and glucose, rapidly impairing oxidative phosphorylation and adenosine triphosphate production [11]. Failure of energy-dependent ion pumps leads to membrane depolarization, excessive release of excitatory neurotransmitters—particularly glutamate and activation of N-methyl-D-aspartate and other excitatory receptors. The resulting influx of calcium and sodium activates proteases, phospholipases, endonucleases, and other destructive pathways that contribute to cellular injury [12].

Mitochondrial dysfunction further aggravates energy failure and promotes production of reactive oxygen species. Oxidative stress damages cellular membranes, proteins, nucleic acids, and mitochondrial structures while amplifying inflammatory signaling [13]. Reperfusion, although essential for tissue survival, can paradoxically increase oxidative stress and inflammatory activity in previously ischemic tissue. Neuroprotective strategies targeting free-radical generation and oxidative injury therefore remain biologically attractive.

Inflammatory responses develop alongside excitotoxic and oxidative injury. Activated microglia, circulating leukocytes, endothelial cells, and inflammatory mediators contribute to disruption of the blood–brain barrier, vasogenic edema, and secondary tissue injury [14]. At the same time, inflammatory responses are heterogeneous and may participate in later repair, complicating therapeutic attempts to suppress inflammation indiscriminately.

The complexity of this cascade explains why single-target neuroprotective drugs have often failed. Multiple overlapping pathways operate simultaneously and at different stages after stroke onset. Agents with pleiotropic actions or those administered in combination with rapid reperfusion may therefore have greater therapeutic potential than treatments targeting one isolated biochemical pathway.

Neuroprotection in the Reperfusion Era

Earlier neuroprotection trials were often conducted before modern thrombectomy and widespread organized stroke systems. The contemporary therapeutic environment is fundamentally different. Rapid reperfusion can restore drug delivery to threatened tissue while simultaneously generating ischemia-reperfusion injury that may itself represent a neuroprotective target [15]. Consequently, modern neuroprotection increasingly focuses on adjunctive therapy, rather than replacing thrombolysis or thrombectomy.

This concept is particularly important in large-vessel occlusion. Endovascular thrombectomy can achieve high rates of arterial recanalization, but angiographic success does not guarantee neurological recovery. Infarct progression before reperfusion, microvascular dysfunction, distal embolization, edema, and reperfusion-associated cellular injury may all limit benefit [16]. A neuroprotective drug administered before or during thrombectomy could theoretically preserve penumbral tissue while reperfusion is being achieved.

However, interactions between neuroprotective agents and reperfusion therapies can complicate efficacy. The development of nerinetide illustrates this problem. In ESCAPE-NA1, nerinetide did not significantly improve 90-day functional outcome in the overall thrombectomy population, although exploratory analyses suggested treatment interaction with alteplase exposure. A subsequent phase 3 study, ESCAPE-NEXT, specifically evaluated patients undergoing thrombectomy without preceding thrombolysis but again failed to demonstrate improvement in the primary 90-day functional outcome. These findings underscore the importance of evaluating neuroprotective therapies within the exact reperfusion context in which they are intended to be used.

Major Pharmacological Neuroprotective Strategies

Several pharmacological agents have reached clinical evaluation in AIS. Their mechanisms differ substantially, making “neuroprotective drugs” a heterogeneous therapeutic category rather than a single class.

Edaravone is a free-radical scavenger intended to reduce oxidative injury and lipid peroxidation [17]. It has been used clinically in some Asian countries and has been evaluated alone and in combination formulations. Edaravone dexborneol combines edaravone with dexborneol in an attempt to target oxidative and inflammatory pathways simultaneously. Recent comparative analyses suggest potential benefit for selected early neurological outcomes, although the degree to which these findings translate into consistent long-term functional independence requires careful evaluation. A 2025 network meta-analysis of 42 randomized trials reported that edaravone ranked favorably for some early neurological and Barthel Index outcomes, but treatment rankings varied according to outcome and assessment time.

N-butylphthalide (NBP) has been investigated for effects on microcirculation, mitochondrial function, oxidative stress, and neurovascular recovery [18]. A large randomized clinical trial published in 2023 found favorable functional outcomes with butylphthalide in patients with AIS receiving reperfusion or standard therapy, contributing to renewed interest in this agent. In the 2025 network meta-analysis, NBP ranked highest for several 90-day outcomes, although indirect treatment comparisons and geographic concentration of evidence warrant caution.

Citicoline, an intermediate in phosphatidylcholine synthesis, has been proposed to stabilize neuronal membranes and support cellular repair [19]. Early trials and pooled analyses suggested potential benefit, but the large ICTUS randomized trial failed to confirm significant improvement in global recovery after moderate-to-severe AIS. Citicoline therefore represents an important example of the difficulty translating mechanistic plausibility and early positive findings into definitive clinical benefit.

Cerebrolysin, a peptide-based preparation with proposed neurotrophic and neurorestorative properties, has also been studied extensively [20]. Earlier meta-analyses did not demonstrate clear improvement in 90-day functional recovery despite an apparently acceptable safety profile. More recent synthesis has suggested improvement in early neurological recovery measured by NIHSS without convincing evidence of improved functional independence, reinforcing the distinction between changes in neurological scores and patient-centered outcomes such as 90-day modified Rankin Scale status.

Other investigated agents include minocycline, human urinary kallidinogenase, vinpocetine, magnesium, uric acid, NA-1/nerinetide derivatives, and various anti-inflammatory, antioxidant, anti-excitotoxic, and mitochondrial-targeted compounds [21]. Many remain supported by limited, heterogeneous, or geographically concentrated clinical evidence.

Outcome Selection in Neuroprotection Trials

Interpretation of neuroprotection studies depends heavily on the outcome selected. Early changes in the National Institutes of Health Stroke Scale (NIHSS) can indicate neurological improvement, but they are not equivalent to long-term functional independence [22]. The modified Rankin Scale (mRS), particularly the proportion achieving mRS 0–2 or ordinal shift analysis at approximately 90 days, is generally more clinically meaningful because it reflects disability and independence.

Similarly, improvement in the Barthel Index or reduction in infarct volume may support biological activity without establishing a meaningful effect on overall disability, quality of life, or survival. Trials may therefore appear positive on secondary neurological measures while remaining neutral for their primary functional endpoint.

This distinction is particularly relevant to current neuroprotective evidence. For example, some comparative analyses report favorable NIHSS rankings for particular agents, whereas large definitive trials of specific drugs have failed to demonstrate significant improvement in 90-day functional outcomes. A rigorous systematic review should therefore avoid treating all neurological and functional endpoints as interchangeable.

Safety and Treatment Timing

The therapeutic window for neuroprotection is another critical issue. Neuroprotective agents are theoretically most effective before irreversible cellular injury has developed, making rapid administration important [23]. Yet treatment too early may precede diagnostic certainty, while delayed treatment may occur after salvageable tissue has been lost.

The optimal strategy may involve administration in the prehospital setting, immediately after imaging, or during preparation for reperfusion therapy. Such approaches require drugs with favorable safety profiles, limited interaction with thrombolysis or thrombectomy, and minimal risk if administered to patients later found to have alternative diagnoses.

Safety outcomes must also be evaluated independently of efficacy. A biologically active agent may increase hemorrhage, infection, renal dysfunction, hypotension, or other complications even if neurological outcomes appear favorable. Conversely, demonstration of safety without functional benefit is insufficient to justify routine clinical use.

Translational Failure and Emerging Directions

The history of stroke neuroprotection has generated substantial debate regarding preclinical study design and clinical trial methodology. Experimental models often involve young animals, tightly controlled infarcts, rapid treatment, and limited comorbidity, whereas human patients are older, heterogeneous, and frequently have hypertension, diabetes, atrial fibrillation, renal disease, or prior cerebrovascular injury [24]. Stroke location, collateral circulation, reperfusion timing, and baseline functional status also vary considerably.

Modern neuroprotection research increasingly emphasizes better patient selection, imaging-based identification of salvageable tissue, interaction with reperfusion therapy, and combination approaches addressing multiple mechanisms simultaneously. The 2026 AHA/ASA guideline similarly emphasizes that experience from recent neutral or negative trials should inform more biologically precise selection of targets and patients rather than being interpreted as evidence that neuroprotection is inherently impossible.

Rationale and Objective of the Review

Despite decades of investigation, uncertainty persists regarding which pharmacological neuroprotective agents provide clinically meaningful benefit in AIS. Recent randomized trials, newer combination agents, modern thrombectomy-era studies, and updated comparative analyses justify reassessment of the evidence.

Accordingly, this systematic review aims to evaluate the efficacy and safety of pharmacological neuroprotective therapies in adults with acute ischemic stroke, with particular emphasis on edaravone, edaravone dexborneol, N-butylphthalide, citicoline, cerebrolysin, minocycline, nerinetide, and other clinically investigated agents. The review will distinguish early neurological improvement

Study Design This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [25]. PRISMA 2020 provides standardized guidance for reporting literature searches, eligibility assessment, study selection, and synthesis of systematic reviews. Eligibility Criteria Randomized controlled trials involving adults aged ≥18 years with acute ischemic stroke were eligible. Studies were required to evaluate a pharmacological neuroprotective agent and report at least one neurological, functional, mortality, or safety outcome. Eligible interventions included edaravone, edaravone dexborneol, N-butylphthalide, citicoline, cerebrolysin, minocycline, nerinetide, human urinary kallidinogenase, vinpocetine, and other pharmacological agents investigated for neuroprotection. Studies involving hemorrhagic stroke, pediatric populations, animal or in-vitro experiments, non-pharmacological interventions, case reports, reviews, editorials, protocols, and conference abstracts without adequate clinical data were excluded. Information Sources and Search Strategy PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. The search combined terms related to: “acute ischemic stroke,” “ischemic stroke,” “neuroprotection,” “neuroprotective drug,” “edaravone,” “edaravone dexborneol,” “N-butylphthalide,” “citicoline,” “cerebrolysin,” “minocycline,” “nerinetide,” “kallidinogenase,” and “randomized controlled trial.” Study Selection After removal of duplicate records, titles and abstracts were screened for relevance. Potentially eligible articles underwent full-text assessment according to the predefined eligibility criteria. Reasons for full-text exclusion were documented. The study-selection process was summarized using a PRISMA 2020 flow diagram [25]. Data Extraction Data extracted from eligible trials included author, publication year, country, sample size, intervention and comparator, drug dose, treatment duration, time from stroke onset to treatment, reperfusion therapy, follow-up duration, and reported efficacy and safety outcomes. The principal outcomes included modified Rankin Scale (mRS), National Institutes of Health Stroke Scale (NIHSS), Barthel Index, mortality, symptomatic intracranial hemorrhage, and adverse events. Outcomes The primary outcome was functional recovery at approximately 90 days, preferably assessed using the modified Rankin Scale. Secondary outcomes included: • neurological improvement measured by NIHSS; • Barthel Index; • mortality; • symptomatic intracranial hemorrhage; • infarct-related outcomes; and • serious or treatment-emergent adverse events. Early neurological improvement was analyzed separately from long-term functional independence. Risk-of-Bias Assessment Risk of bias in randomized trials was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool [26]. The assessment considered the randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selective reporting. Data Synthesis Because substantial heterogeneity was anticipated in neuroprotective agents, treatment windows, doses, stroke severity, reperfusion strategies, and outcome measures, findings were primarily synthesized qualitatively. Results were organized according to individual neuroprotective agents and compared in terms of functional recovery, neurological improvement, mortality, and safety. Certainty of Evidence Where sufficient evidence was available, the certainty of evidence for major outcomes was assessed using the GRADE approach [27], considering risk of bias, inconsistency, indirectness, imprecision, and publication bias.

Table 1. Major Clinically Investigated Neuroprotective Agents in Acute Ischemic Stroke

PRISMA 2020 Study-Selection Flow

Overview of Included Evidence

The eligible randomized trials evaluated a heterogeneous group of pharmacological neuroprotective agents, including N-butylphthalide (NBP), edaravone, edaravone dexborneol, citicoline, cerebrolysin, minocycline, nerinetide, human urinary kallidinogenase, and vinpocetine. Considerable variation was observed across studies with respect to sample size, baseline stroke severity, treatment window, reperfusion strategy, dosing regimen, and outcome assessment. This heterogeneity limits direct comparison between agents and is one of the major reasons why the results are better interpreted drug by drug rather than as a single therapeutic class.

A recent network meta-analysis of 42 randomized controlled trials involving 12,210 participants provides a broad comparative context for these interventions, although the certainty of evidence differed substantially by drug and outcome [28].

N-Butylphthalide

Among the reviewed agents, NBP demonstrated one of the clearest signals of clinically meaningful benefit. In the BAST randomized trial, 1,216 patients with acute ischemic stroke who had received intravenous thrombolysis, endovascular therapy, or both were randomized to NBP or placebo. Favorable functional outcome at 90 days occurred in 56.7% of patients receiving NBP compared with 44.0% of those receiving placebo, corresponding to an odds ratio of 1.70 (95% CI 1.35–2.14; P<0.001) [29].

The benefit of NBP was therefore demonstrated on a clinically meaningful functional endpoint rather than on neurological scores alone. Earlier pooled evidence also suggested improvement in disability, dependency, and activities of daily living, although many earlier studies were relatively small and predominantly conducted in China [30].

Despite these favorable findings, the external generalizability of NBP remains an important consideration. Large multinational trials outside East Asian populations are still limited, and differences in background stroke care may influence the observed effect size.

Edaravone

Edaravone has been investigated primarily for its antioxidant and free-radical-scavenging effects. Across randomized studies and comparative analyses, edaravone has shown a relatively consistent signal for early neurological improvement, particularly improvement in NIHSS scores.

However, the evidence for long-term functional recovery is less consistent than the evidence for short-term neurological improvement. This distinction is important because a reduction in NIHSS during hospitalization does not necessarily translate into greater functional independence at 90 days.

In the 2025 network meta-analysis, edaravone ranked favorably for some early neurological outcomes, but its relative position differed depending on the endpoint and follow-up period [28].

Edaravone Dexborneol

Edaravone dexborneol combines antioxidant activity with additional anti-inflammatory and cytoprotective mechanisms. Randomized trials have reported improvement in neurological and functional outcomes compared with edaravone alone, suggesting that its multimodal mechanism may provide broader protection against ischemic injury.

More recent studies have also examined edaravone dexborneol in patients undergoing endovascular thrombectomy, making it particularly relevant to modern reperfusion-based stroke care [31]. The available findings are encouraging, but they should be interpreted cautiously because trial populations, comparators, and outcome definitions differ across studies.

Citicoline

Citicoline has been studied extensively because of its proposed effects on neuronal membrane stabilization and phospholipid synthesis. Earlier trials suggested possible benefit, particularly in neurological recovery, but results from larger trials were less convincing. The large ICTUS trial failed to demonstrate a significant improvement in global functional recovery at 90 days. This substantially weakened the argument for routine citicoline use in unselected AIS populations.

Thus, although citicoline remains biologically plausible and generally well tolerated, the available evidence does not support a consistent clinically important functional benefit.

Cerebrolysin

Cerebrolysin has shown a more favorable signal for early neurological recovery than for long-term disability reduction. Several trials have reported improvements in NIHSS scores, and pooled analyses suggest possible short-term neurological benefit.

However, evidence for improvement in 90-day modified Rankin Scale outcomes remains less certain. Variability in dose, treatment duration, concomitant therapy, sample size, and stroke severity contributes to inconsistent findings.

This agent therefore illustrates a recurring pattern in the neuroprotection literature: improvement in neurological impairment does not necessarily translate into improved functional independence.

Minocycline

Minocycline has attracted interest because of its anti-inflammatory, anti-apoptotic, and microglial-modulating effects. Clinical trials have generally been smaller than those evaluating NBP, citicoline, or nerinetide. Some studies have reported neurological improvement, but the overall evidence remains inconsistent. Comparative work has suggested that minocycline may be less effective than some other neuroprotective agents in terms of NIHSS improvement [32].

At present, the evidence is insufficient to support a strong conclusion regarding its effect on long-term functional independence.

Nerinetide

Nerinetide represents a mechanistically targeted neuroprotective strategy designed to reduce excitotoxic neuronal injury by disrupting PSD-95-associated signaling.

The ESCAPE-NA1 trial did not demonstrate a significant improvement in overall 90-day functional outcome. However, subgroup analyses raised the possibility that concomitant alteplase exposure may modify the treatment effect, prompting further investigation.

More recent pooled analyses have suggested a possible benefit when nerinetide is administered early, particularly within 3 hours in selected reperfusion-treated patients. One patient-level analysis reported an adjusted odds ratio of 1.48 (95% CI 1.07–2.06) for favorable outcome in an early-treated subgroup [33]. Conversely, meta-analytic evidence focusing on patients treated with thrombectomy without intravenous thrombolysis has not shown a clear improvement in functional outcomes [34].

Therefore, nerinetide remains a promising but unconfirmed therapy whose efficacy may depend heavily on treatment timing and interaction with reperfusion therapy.

Other Neuroprotective Agents

Human urinary kallidinogenase and vinpocetine have also been evaluated in randomized studies. Some trials have reported favorable neurological or functional outcomes, but the evidence base is smaller and more geographically concentrated than that for NBP, edaravone, or citicoline.

Differences in trial quality, sample size, treatment protocols, and outcome definitions limit the certainty of conclusions for these agents. At present, their role remains investigational rather than established.

Functional Versus Neurological Outcomes

A consistent pattern across the reviewed literature was the difference between early neurological improvement and long-term functional recovery. Several agents, particularly edaravone and cerebrolysin, showed favorable effects on NIHSS scores. However, long-term improvement in modified Rankin Scale outcomes was less consistently demonstrated. NBP was notable because its strongest contemporary evidence involved a clinically meaningful 90-day functional endpoint rather than only short-term neurological change [34]. This distinction is important because a neuroprotective therapy should ideally improve not only neurological scores but also independence, disability, and quality of life.

Safety Outcomes

Most neuroprotective agents were generally well tolerated. In the BAST trial, serious adverse events occurred in 10.1% of patients receiving NBP and 12.0% receiving placebo, suggesting no major excess safety signal [35]. Nerinetide has also not demonstrated major treatment-related safety concerns in large randomized trials, although uncertainty regarding efficacy remains greater than concern regarding toxicity. For the remaining agents, adverse-event profiles were generally acceptable, but differences in reporting standards and follow-up duration limited direct comparison.

Overall Pattern of Evidence

Overall, the most convincing contemporary evidence favors N-butylphthalide, particularly for 90-day functional recovery. Edaravone and edaravone dexborneol show encouraging evidence for neurological improvement, with edaravone dexborneol increasingly relevant in the thrombectomy era. Evidence for citicoline, cerebrolysin, minocycline, nerinetide, kallidinogenase, and vinpocetine remains inconsistent, context-dependent, or limited by trial quality and generalizability.

No neuroprotective agent can presently be regarded as universally effective across all patients with acute ischemic stroke. Treatment timing, reperfusion therapy, stroke severity, and the choice of outcome measure appear to substantially influence the observed treatment effect.

Table 2. Summary of Major Neuroprotective Agents

This systematic review indicates that pharmacological neuroprotection in acute ischemic stroke remains a promising but clinically unsettled field. Across the available randomized evidence, the magnitude and consistency of benefit differed substantially among agents, treatment windows, reperfusion strategies, and outcome measures. N-butylphthalide showed the clearest contemporary signal for improvement in 90-day functional recovery, whereas edaravone and edaravone dexborneol demonstrated more consistent effects on neurological improvement. Evidence for citicoline, cerebrolysin, minocycline, nerinetide, human urinary kallidinogenase, and vinpocetine was less consistent or limited by heterogeneity and trial quality [28–34]. A recent network meta-analysis of 42 RCTs involving 12,210 participants likewise found substantial differences between agents and outcomes rather than a uniform class effect. (PubMed) N-Butylphthalide and Functional Recovery NBP emerged as one of the most promising agents because its strongest evidence involves a clinically meaningful 90-day functional outcome. In the BAST trial, favorable functional outcome occurred in 56.7% of patients receiving NBP compared with 44.0% receiving placebo, corresponding to an odds ratio of 1.70 [29]. Importantly, these patients had received intravenous thrombolysis, endovascular therapy, or both, indicating that NBP was investigated as an adjunct to contemporary reperfusion rather than as an alternative to it. The potential mechanisms of NBP are multimodal and include improvement of microcirculation, attenuation of oxidative stress, preservation of mitochondrial function, and reduction of inflammatory injury. Such pleiotropic activity may theoretically be advantageous in stroke, where multiple components of the ischemic cascade operate simultaneously. Nevertheless, much of the clinical evidence for NBP originates from China, and independent multinational validation is needed before its effects can be generalized across broader stroke populations. Edaravone and Edaravone Dexborneol Edaravone appears particularly effective for early neurological improvement. Its free-radical-scavenging activity targets oxidative stress, an important component of ischemia-reperfusion injury. Comparative analyses suggest favorable effects on short-term NIHSS outcomes, although evidence for durable long-term functional independence is less consistent [36]. Edaravone dexborneol may provide additional benefit by combining antioxidant and anti-inflammatory actions. This multimodal strategy is mechanistically attractive because isolated inhibition of a single component of the ischemic cascade has frequently failed in previous neuroprotection trials. However, superiority on short-term neurological measures should not automatically be interpreted as proof of improved long-term disability outcomes. Larger externally validated trials incorporating 90-day mRS outcomes remain important. Why Citicoline and Cerebrolysin Have Produced Mixed Results Citicoline illustrates the difficulty of translating biological plausibility into reproducible clinical benefit. Despite proposed effects on membrane stabilization, phospholipid synthesis, and cellular repair, the large ICTUS trial failed to demonstrate significant improvement in overall functional recovery. The discrepancy between earlier positive studies and later large trials may reflect differences in sample size, stroke severity, treatment timing, concomitant care, or publication bias. Cerebrolysin has similarly demonstrated encouraging effects on early neurological outcomes but less convincing evidence for long-term functional independence. These findings emphasize that surrogate or intermediate neurological improvements should not be considered equivalent to reductions in disability. Nerinetide and the Importance of Reperfusion Context Nerinetide provides one of the clearest examples of how interaction with reperfusion therapy can influence apparent neuroprotective efficacy. In ESCAPE-NA1, 1,105 patients undergoing thrombectomy were randomized to nerinetide or placebo. The proportion achieving mRS 0–2 at 90 days did not differ significantly in the overall population, although a possible interaction with alteplase generated considerable interest [37-38]. (PubMed) The subsequent ESCAPE-NEXT trial specifically tested nerinetide in thrombectomy-treated patients without previous thrombolysis. In that study, 45% of patients receiving nerinetide and 46% receiving placebo achieved mRS 0–2 at 90 days, providing no confirmation of a clinically meaningful overall treatment effect [34]. These findings suggest that neuroprotection cannot be evaluated independently of reperfusion strategy. Drug delivery, recanalization timing, thrombolytic interactions, and the persistence of salvageable penumbral tissue may all modify treatment response. Neurological Improvement Versus Functional Independence One of the most important findings of this review is the distinction between early neurological improvement and long-term functional recovery. Many neuroprotective trials report favorable changes in NIHSS scores, while fewer demonstrate consistent improvement in 90-day modified Rankin Scale outcomes. This distinction has direct clinical relevance. NIHSS improvement may indicate biological activity, but the ultimate goal of acute stroke treatment is reduction in disability and dependence. Future trials should therefore prioritize ordinal mRS analysis, functional independence, survival, and quality-of-life outcomes rather than relying predominantly on early neurological scores. The Translational Problem in Stroke Neuroprotection The limited clinical success of neuroprotective therapy contrasts sharply with the large number of compounds that have shown benefit in experimental stroke models. Several factors may explain this translational failure. Experimental animals are often young, have few comorbidities, experience controlled vascular occlusion, and receive treatment rapidly. Human stroke populations are substantially more heterogeneous with respect to age, vascular risk factors, collateral circulation, infarct location, treatment delay, and reperfusion status. Earlier clinical trials also frequently evaluated neuroprotective agents without ensuring successful recanalization. In the modern thrombectomy era, this paradigm has changed. Rapid reperfusion may restore delivery of neuroprotective agents to ischemic tissue and create an opportunity to attenuate reperfusion injury. Consequently, future neuroprotective therapies may be most effective as adjuncts to reperfusion, rather than as stand-alone treatments. Safety The reviewed agents were generally associated with acceptable safety profiles. In the BAST trial, serious adverse events occurred in 10.1% of the NBP group compared with 12.0% of the placebo group [29]. Nerinetide similarly showed no clear excess in serious adverse events despite its lack of demonstrated efficacy in the major phase III trials. (PubMed) This is important because neuroprotective agents intended for rapid use alongside thrombolysis or thrombectomy must have a wide safety margin and minimal interaction with established reperfusion therapies. Clinical Implications Current evidence is not sufficient to support routine use of pharmacological neuroprotection as a general treatment strategy for all patients with AIS. The 2026 AHA/ASA guideline gives pharmacological and non-pharmacological neuroprotective treatments a Class 3: No Benefit recommendation for improving functional outcome, while acknowledging that secondary and hypothesis-generating findings justify continued investigation. (AHA Journals) Therefore, even though NBP and several other agents show encouraging signals, the results of individual trials should not be interpreted as establishing neuroprotection as standard care. Reperfusion therapy remains the cornerstone of eligible AIS treatment. Strengths and Limitations A major strength of this review is its emphasis on clinically meaningful functional outcomes and its separation of long-term disability from early neurological improvement. The review also considers interactions between neuroprotective treatment and modern reperfusion strategies. However, several limitations affect the available evidence. Trials differed substantially in intervention type, dose, treatment window, baseline stroke severity, comparator, reperfusion therapy, and outcome definition. Many studies were geographically concentrated, and some agents were supported by relatively small trials. Direct head-to-head comparisons were uncommon, making indirect comparisons less certain. These factors limit definitive ranking of neuroprotective treatments. Future Research Future neuroprotection trials should prioritize rapid treatment, biologically informed patient selection, and integration with thrombolysis and thrombectomy. Imaging biomarkers capable of identifying salvageable tissue may help select patients most likely to benefit. Trials should also standardize 90-day functional outcomes and investigate whether treatment effects vary according to stroke mechanism, reperfusion success, collateral status, or time from onset. Combination approaches targeting several components of the ischemic cascade may ultimately prove more effective than single-target drugs. However, these strategies require large multicenter randomized trials with appropriate safety monitoring and clinically meaningful endpoints. Overall Interpretation The available evidence suggests that neuroprotection remains biologically compelling but clinically unproven as a universal strategy in acute ischemic stroke. N-butylphthalide currently provides one of the strongest signals for functional benefit, while edaravone and edaravone dexborneol show promising neurological effects. Conversely, large trials of citicoline and nerinetide demonstrate how promising mechanistic approaches may fail to produce meaningful functional improvement. The future of neuroprotection is therefore likely to depend less on identifying a single universally effective drug and more on matching the appropriate agent to the right patient, treatment window, and reperfusion context.

Pharmacological neuroprotection in acute ischemic stroke remains promising but not yet established as a universally effective treatment. Among the agents reviewed, N-butylphthalide showed one of the strongest signals for improvement in 90-day functional outcomes, while edaravone and edaravone dexborneol demonstrated encouraging effects on neurological recovery. Evidence for citicoline, cerebrolysin, minocycline, nerinetide, human urinary kallidinogenase, and vinpocetine was less consistent or context-dependent. Overall, neuroprotective therapy should currently be viewed as an adjunctive strategy rather than a replacement for established reperfusion treatments. Future large, multicenter randomized trials should focus on early administration, appropriate patient selection, interaction with thrombolysis and thrombectomy, and clinically meaningful long-term functional outcomes.

Pharmacological neuroprotection in acute ischemic stroke remains promising but not yet established as a universally effective treatment. Among the agents reviewed, N-butylphthalide showed one of the strongest signals for improvement in 90-day functional outcomes, while edaravone and edaravone dexborneol demonstrated encouraging effects on neurological recovery. Evidence for citicoline, cerebrolysin, minocycline, nerinetide, human urinary kallidinogenase, and vinpocetine was less consistent or context-dependent. Overall, neuroprotective therapy should currently be viewed as an adjunctive strategy rather than a replacement for established reperfusion treatments. Future large, multicenter randomized trials should focus on early administration, appropriate patient selection, interaction with thrombolysis and thrombectomy, and clinically meaningful long-term functional outcomes.