Нейрозащитный и терапевтический потенциал ресвератрола для травм спинного мозга: систематический обзор.

Introduction

Overview of the traumatic spinal cord injuries

Traumatic spinal cord injuries (tSCIs) are considered one of the most complex neurologic injuries, severely impacting the quality of life of individuals causing long-term dependency and possible mortality. Traumatic incidences, such as traffic accidents, sports’ falls or other falls, typically cause severe lesions in the spinal cord tissue causing substantial damage. According to the World Health Organization (WHO), in 2024, over 15 million people were living with SCI globally [ 55 ].

Traumatic spinal cord injuries can be classified into primary injuries that occur at the initial moment of incident which encompass hemorrhage and edema or secondary injuries that occur just after the primary injury and these include: ischemia, infarction, cell death, neuroinflammation, oxidative stress, lipid peroxidation and glial activation, all of which intensify the damage further [ 2 ].

The pathophysiology of tSCIs has been elucidated to run over a temporal frame beginning with the primary injury that signals a cascade of secondary damage represented by necrosis, neurons’ apoptosis, demyelination and glial scar formation while creating a microenvironment flooded with debris, oxygen reactive species and released inhibitors that prohibit attempts of neural regeneration [ 1 ].

Implication of the gut-spinal cord axis and effect of social determinants of health

Recovery following SCI is influenced by a variety of biological and social factors beyond traditional molecular mechanisms. Emerging evidence suggests that the gut microbiome plays a significant role in shaping systemic inflammation and neuroimmune responses through bidirectional communication between the gut and the central nervous system, a relationship known as the gut-spinal cord axis. Dysbiosis, or an imbalance in the gut microbiome, after SCI has been linked to increased inflammation and impaired recovery processes [ 15 ].

Furthermore, social determinants of health (SDOH), including socioeconomic status, geographic location (rural versus urban), and access to healthcare resources, have a substantial impact on neurological and functional outcomes after SCI. Research shows that structural inequities are associated with higher mortality rates and more severe neurological deficits across diverse populations [ 8 ].

Understanding these external influences, alongside cellular and molecular pathways, offers a more comprehensive framework for explaining variability in recovery outcomes. This perspective emphasizes the need for integrative therapeutic strategies that address biological, environmental, and social aspects of recovery from SCI.

Structure of resveratol

Resveratrol (3,5,4′-Trihydroxystilbene) is a natural polyphenol belonging to the family of stilbenes. Its molecular structure presents two polyphenolic rings connected by a double styrene bond either in cis or trans position (Fig. 1 ), with the latter isomer being more stable in nature. Resveratrol is considered as a phytoalexin, meaning it’s produced by plants in response to stress to avoid viral and parasitic infections.

Reactivity of resveratrol

The primary source of resveratrol is the grape fruit in addition to other sources including black berries, blue berries and peanuts [ 21 ]. However, resveratrol possesses bioavailability challenges including low water solubility, low chemical stability by being prone to rapid degradation if exposed to high temperatures, UV radiations, and severe pH alterations in addition to its rapid metabolism. Current research is working to tackle these limitations by considering combination therapies which involve the co-administration of resveratrol with another drug that may increase resveratrol’s stability. Other methods subject resveratrol to modification reactions such as hydroxylation or glycosylation to increase its water solubility. Moreover, encapsulating resveratrol with nanoparticles such as polymer or metal nanoparticles shows promise in protecting resveratrol from degradation and rapid metabolism in addition to ensuring efficient and precise delivery [ 48 ].

Clinical research evidence on resveratrol

Culminating research evidence shows resveratrol’s efficiency in combatting several chronic diseases including cardiovascular diseases (CVDs), esophageal cancer, breast cancer, hepatic fibrosis, diabetes, obesity, in addition to serious neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD) [ 38 ]. Furthermore, research unravels the potential of resveratrol as an anti-aging molecule given extensive evidence about its role in stabilizing oxidation and inflammation biomarkers by reducing ROS and pro-inflammatory cytokines [ 32 ].

Different neuroprotective effects of resveratrol

A growing body of evidence demonstrates the plethora of neuroprotective effects offered by resveratrol via alleviating oxidative stress and inflammation and promoting neurons’ preservation and axons’ regeneration in neurological diseases such as stroke, multiple sclerosis, Huntington, Alzheimer and Parkinson’s Disease [ 9 ]. The exact mechanisms through which resveratrol offers neuroprotection rely on downstream molecular pathways such as activating the famous Silent Information Regulator 2 homolog 1 (SIRT1) pathway and AMP-activated protein kinase/mechanistic target of rapamycin signaling pathway (AMPK/mTOR pathway) [ 54 ].

As resveratrol has shown promising results in alleviating neuroinflammation, oxidative stress, and apoptosis in numerous neurodegenerative diseases like Alzheimer’s disease and in traumatic injuries including traumatic brain injury (TBI) [ 23 , 65 ]. This may suggest a neuroprotection potential of resveratrol for treating tSCI.

Current clinical settings of SCI

In clinical settings, acute SCI management remains supportive, focusing on hemodynamic stabilization, early surgical decompression within 24 h, and prevention of secondary complications like infections and Deep Vein Thrombosis (DVT), while rehabilitation emphasizes physical therapy and assistive devices rather than neuroprotection or regeneration [ 17 , 18 , 51 ].

Current pharmacological treatments of tSCIs include the administration of steroid drugs, namely methylprednisolone (MP), which possesses minimal effectiveness, requiring early administration and high dosage, and drastic health repercussions including respiratory tract infections and gastrointestinal hemorrhage [ 34 , 35 ].

Emerging research on potential therapies

Emerging clinical research for SCI therapy includes Phase I-III trials that focus on neuroprotection and regeneration. Some notable therapies being studied are Riluzole, which helps reduce excitotoxicity; mesenchymal stem cells, such as those used in the Neuro-Cells Phase IIb trial for thoracic lesions; induced pluripotent stem cells (iPSCs)-derived neural progenitors based on the Keio University protocol; NVG-291, a Rho-associated coiled-coil containing protein kinase II (ROCK-II) inhibitor that promotes axon growth; and epidural electrical stimulation aimed at chronic motor recovery [ 42 ]. Despite these advancements, no therapies have received the approval of Food and Drug Administration (FDA) beyond supportive care, and the effect sizes for these treatments remain modest, with improvements typically around 5–10 points on the American Spinal Injury Association (ASIA) Impairment Scale (AIS). This underscores the ongoing challenges of translating findings from preclinical models to effective clinical therapies [ 26 , 49 ].

Promising effect of Resveratrol on traumatic spinal cord injury

Emerging studies have investigated the effect of resveratrol on tSCI murine models with promising evidence which suggests primary efficacy [ 39 ]. Yet, no definitive conclusions have been made regarding the true potential of resveratrol for neuroprotection after traumatic spinal cord injuries given the multitude of studies done but the absence of a clear systematic evaluation of the findings and evidence generated.

Rationale and objectives

Despite an increasing number of experimental studies highlighting the neuroprotective potential of resveratrol in tSCI, its application in clinical practice remains limited. Notably, there is a lack of clinical studies assessing its effectiveness for tSCI, which creates a significant gap between promising preclinical findings and real-world application. Furthermore, existing preclinical evidence is highly heterogeneous regarding animal models, dosing strategies, timing of administration, and outcome measures. This variability makes it challenging to draw consistent conclusions or to establish optimal therapeutic approaches. While various studies suggest that resveratrol influences key mechanisms such as apoptosis, autophagy, oxidative stress, and inflammation, these findings have not been systematically compiled in the context of tSCI.

This systematic review aims to evaluate the neuroprotective effects of resveratrol in experimental models of traumatic spinal cord injury, with a focus on functional recovery, neuronal preservation, and the underlying molecular mechanisms. Additionally, it seeks to identify gaps that may inform future clinical translation.

Methods

This study addresses this research question.

Does resveratrol administration exert neuroprotection in animal models of traumatic spinal cord injury compared to control or other treatments?

The above research question is formulated using the PICOS approach:

Population (P): Murine models of tSCI.

Intervention (I): Resveratrol.

Control(C): SCI group (or SHAM group in absence of SCI group).

Outcome (O): neuroprotection assessed in terms of autophagy, apoptosis, inflammation, survival and motor function recovery.

Study design

This study is a systematic review exploring the neuroprotection manifested by resveratrol in murine models of tSCI, offering insights about the potential of resveratrol as an effective treatment for tSCI. It adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-2020) guideline, which consists of a 27-item checklist and a four-phase flow diagram [ 44 ].

Due to the specific focus of this preclinical systematic review and its exploratory nature, we did not pursue prospective protocol registration (such as with PROSPERO or INPLASY), as there were no planned deviations from the published search strategy. All methods, including the PICO criteria, search terms, and risk-of-bias assessments, were finalized before data extraction. We fully report these details to ensure transparency and reproducibility.

Eligibility criteria

Included articles in this study satisfied the following conditions of inclusion:

- Preclinical experimental studies on animals, namely murine, that have experienced tSCI.

- The intervention should be only resveratrol, regardless of the route of administration.

- The control group is SCI group, and it could be the sham group when the SCI group is absent from the study groups.

- Studies investigating the neuroprotective effects of resveratrol.

- Articles must be original studies published no later than January 2025 and written in English.

On the other hand, articles were excluded if they met the following exclusion criteria:

- Human studies or in-vitro experiments.

- Interventions that don’t include resveratrol or include resveratrol in combination with other drugs.

- Studies not exploring neuroprotection as the main outcome.

- Manuscripts that are not original studies: reviews, letters, books, conference papers and pre-prints.

Databases and search strategys

On March 16, 2025, we conducted a comprehensive literature search in an attempt to gather the relevant studies published no later than January 2025. Databases included were PUBMED, SCOPUS, WEB OF SCIENCE and EMBASE. No research restrictions were made except for language. Keywords used were: resveratrol, traumatic spinal cord injury (s), and neuroprotection and their corresponding MeSH terms using the necessary Boolean operators (see supplementary file 1).

The research strategy was adjusted for each database. All retrieved articles were imported into EndNote, where all duplicates were removed.

Selection process

The screening process adhered to the PRISMA-2020 guidelines to identify the appropriate studies [ 44 ]. Two independent reviewers (SA and AM) manually screened the record to identify potential included articles by evaluating the relevance of their titles and abstracts to the established research question. Any conflicts were settled through the discussion with a third reviewer (MM). After primary screening, secondary full-text screening was performed by each of the three reviewers. No automated screening tools were utilized at this stage.

Data extraction process

Two independent reviewers performed data extraction about (1) Article description: title, first author, publication year, and country of origin; (2) Utilized murine models: strain, sex, age, weight and housing conditions; (3) SCI model and injury location; (4) Intervention explored: name, dose, route of administration, timing and duration of treatment; (5) Outcomes studied: neuroprotection in terms of autophagy, apoptosis, neuroinflammation, oxidative stress, survival and motor function recovery; (6) molecular mechanisms and pathways mediating the explored outcome.

Quality assessment

Because this review assesses preclinical experimental studies, the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool was utilized to investigate the quality of the selected studies [ 24 ]. This step is essential to identify potential biases in the finally included studies. This tool performs assessment based on ten items that address different types of bias including selection performance, detection, attrition, reporting and other bias. The evaluation of bias risk for each category/item is described by: high, low, or unclear.

Two independent reviewers critically appraised the quality of the articles included. Any disagreements were resolved through the discussion with a third reviewer .

Results

Search results from databases

Four databases were searched to obtain the relevant studies: PUBMED, SCOPUS, EMBASE, and WEB OF SCIENCE (WOS). The search yielded 456 articles where 66 duplicates were removed after search results were imported to Endnote. 390 articles were screened by title and abstract. The primary screening excluded 377 articles that did not adhere to the mentioned inclusion criteria, thus retrieving 13 articles. After a thorough review of the full texts, additional five articles were excluded for various reasons, including being irrelevant to the research question and investigated outcome. This detailed selection process resulted in a final selection of eight studies to be included in this systematic review as presented in the PRISMA flow chart (Fig. 2 ).

Characteristics of the included studies

This systematic review investigates the studies on the topic from 2015 to 2025. From the eight included articles, seven studies utilized Sprague Dawley rats while one used C57BL/6 mice strain as appropriate animal models to carry out the experiments investigating the neuroprotective potential of resveratrol for SCI. The majority of these studies used Allen’s contusion method to replicate tSCI in the animal models, whereas only two others used Rivlin-Tator compression model and Dolan’s aneurysm clip compression method. All of the articles investigated neuroprotection as a primary outcome while encompassing variability in the timing and dosage of the administered resveratrol. The study's baseline characteristics and general description are summarized in Table 1 .

Quality assessment

While domains such as baseline characteristics (D3), and selective outcome reporting (D9) were rated as low risk for all of the included studies, other domains such as sequence generation (D1), allocation concealment (D2), random housing (D4), blinding of caregivers (D5), random outcome assessment (D6), incomplete outcome data (D8) were consistently rated as “unclear” for all studies because they lacked the proper information necessary for evaluation. As for blinding of outcome assessors (D7), only half of the eight studies adhered to this condition while lacking enough information for evaluating (D7) in the rest of the articles. No domain was rated as “high” risk across all the included eight studies.

Supporting these results, Fig. 2 shows the traffic-light plot summarizing the risk of bias assessment for the included studies, and Fig. 3 shows an unweighted bar chart summarizing the risk of bias across all included studies (Fig. 4 ).

Overview of articles’ outcomes

Table 2 provides a precise overview of the eight included studies, outlining their study groups, type of SCI model, intervention’s (resveratrol) timing, dosage, and route of administration in addition to the primary outcomes related to neuroprotection (motor function recovery, survival of motor neurons, inflammation and oxidative stress, apoptosis and autophagy).

Survival and regeneration

Five studies examined motor neuron survival and tissue regeneration. All five reported consistent results: resveratrol treatment yielded significantly more surviving motor neurons compared to SCI controls, especially above (rostral) and below (caudal) the injury site. For example, two studies noted that the lesion area was dramatically smaller (roughly half the size in treated vs. control animals) with correspondingly higher neuron counts. Post-treatment, the lesion was about a 2:1 ratio favouring the resveratrol group. In two studies, resveratrol-treated spinal cords showed visibly healthier tissue: less bleeding and markedly reduced necrosis and chromatolysis compared to injured controls [ 6 , 43 ].

Moreover, other reports found evidence of new fibre growth and repair in treated animals. Histology revealed regenerated axons and better myelin integrity after resveratrol treatment [ 34 , 62 ]. These studies also detected higher levels of regeneration markers (e.g. NF421) in resveratrol groups. Consistently, Ni et al. [ 43 ] found far fewer Fluoro-Jade C (FJC) positive cells (indicating degenerating neurons) in the treated group. Together, these findings indicate that resveratrol promotes motor neuron survival and spinal tissue regeneration.

Motor function recovery

Most studies (6 of 8) assessed locomotor recovery and found significant improvements with resveratrol. Treated rats consistently had higher Basso, Beattie, and Bresnahan score (BBB) or Basso Mouse Scale (BMS) scores and steeper inclined-plane angles than SCI-only controls. (The BBB/BMS tests score hindlimb function on scales of 0—21 or 0—9, respectively; the inclined-plane test measures the maximal slope a rat can hold.)

In two studies, functional gains appeared as early as 7 days post-injury. By day 7, resveratrol-treated rats scored 5 versus 4 in controls [ 37 , 61 ]. Scores then climbed steadily: Meng et al. reported that by day 21, the treated group reached a BBB of 15 (1.5 × higher than SCI), while Wang et al. observed the score doubled from 5 to 10 by day 21, surpassing the SCI group’s 6. In both cases, the inclined plane angles increased in parallel, reflecting better strength and balance each week [ 37 , 61 ].

Other studies confirmed this trend, though the timing varied. Zhao et al. [ 67 ] saw significantly higher BBB only by day 14,Xiang et al. [ 62 ] by day 28, Liu et al. [ 34 ] by day 35. For example, at 28 days, the resveratrol group’s BBB scores were nearly double those of SCI rats in Zhao and Xiang’s work. In Liu et al., scores only became significant at day 35, when treated rats reached nearly 19 (indicating almost full recovery), compared to much lower SCI scores. One notable study [ 43 ] used the BMS test and likewise found dramatic gains: resveratrol-treated rats improved from a score of 3 at day 14 to 6 by day 35, with markedly better gait and coordination, whereas the SCI group remained low and unchanged.

Apoptosis

To understand neuron preservation, most papers measured apoptosis markers (caspase-3, Bax, Bcl-2, TUNEL, etc.). Generally, resveratrol had an anti-apoptotic effect. In treated animals, levels of pro-apoptotic proteins (caspase-3, Bax) were lower, while the anti-apoptotic Bcl-2 was higher, yielding a reduced Bax/Bcl-2 ratio [ 67 ], 51, 52. These shifts indicate that resveratrol dampened the cell-death pathways compared to SCI rats.

However, Liu et al. [ 34 ] reported an initial spike in apoptosis markers immediately post-injury: Bax and caspase-3 rose and Bcl-2 fell, before reversing after day 14. This suggests resveratrol did not prevent the very first wave of apoptosis. In support of anti-apoptotic action, Senturk et al. [ 50 ] and Xiang et al. [ 62 ] both found dramatically fewer TUNEL-positive cells (dead neurons) in resveratrol-treated animals. In fact, the resveratrol groups had nearly no TUNEL-positive cells, levels comparable to control-operated rats. These results reinforce that resveratrol ultimately suppresses apoptosis in injured spinal cords.

(*Caspase 3: Cysteine-aspartic acid protease 3; *Bax: Bcl-2-associated X protein; *Bcl-2: B-cell lymphoma 2).

Autophagy

Several studies investigated autophagy as part of resveratrol’s mechanism. Resveratrol enhanced autophagy compared to SCI alone. Zhao et al. [ 67 ] reported higher expression of autophagy markers (SIRT1, phosphorylated AMPK (p-AMPK), Beclin-1, LC3-II/LC3-I) in treated rats. Similarly, Wang et al. [ 61 ] reported an increased Microtubule-associated protein 1 light chain 3 (LC3) LC3-II/LC3-I ratio along with a decrease in p62 levels following treatment with Resveratrol, indicating enhanced autophagic activity. In contrast, Meng et al. [ 37 ] demonstrated activation of autophagy primarily through an increase in the LC3-II/LC3-I ratio, without reporting p62 expression. Notably, these autophagy-related changes were associated with improved neuronal survival and better locomotor function outcomes in both studies.

Conversely, blocking autophagy reduced resveratrol’s benefits. Meng et al. and Wang et al. both showed that applying the autophagy inhibitor 3-Methyladenine (3-MA) partly cancelled the improvements: treated rats no longer showed the same functional gains, and apoptosis markers increased again. In other words, when autophagy was inhibited, resveratrol could not exert full neuroprotection. This inverse link suggests autophagy activation is crucial for resveratrol’s effects [ 37 , 61 ].

Neuroinflammation and oxidative stress

Four studies measured inflammatory cytokines. Consistently, resveratrol suppressed inflammation. Tumor Necrosis Factor alpha (TNF-α) and Interleukin 1 beta (IL-1β) levels were much lower in treated rats than SCI controls [ 37 , 50 , 62 , 67 ]. For instance, Xiang et al. found TNF-α/IL-1β roughly halved by resveratrol, and Senturk et al. saw levels drop to near-control values. Meng et al. additionally reported a 1.5 × increase in IL-10 with resveratrol. Ciftci et al. [ 6 ] noted almost no visible inflammation in treated cords: minimal swelling, neutrophil or microglia infiltration, and overall normal appearance. They also found higher antioxidant markers (total antioxidant status and Paraoxonase 1, PON1) in serum/tissue of resveratrol rats.

Ni et al. [ 43 ] looked further at oxidative stress. Resveratrol normalized mitochondria (no shrinkage) and reduced ferroptosis. Treated rats had significantly lower Fe 2 ⁺ levels and higher Glutathione (GSH) than SCI rats, indicating less oxidative injury. Resveratrol also boosted iron-export/storage proteins, including ferroportin (FPN) and ferritin heavy chain 1 (FTH1), reflecting healthier iron metabolism. Together, these data show resveratrol effectively counters SCI-induced oxidative damage and ferroptosis.

Overview of the mechanisms governing resveratrol’s neuroprotection

Five studies probed how resveratrol works at the molecular level, implicating distinct but related pathways:

SIRT1/AMPK pathway [ 67 ]: Resveratrol upregulated SIRT1 and p-AMPK along with autophagy markers (Beclin-1, LC3B). Blocking SIRT1/AMPK (with EX527/Compound C) reversed these effects and increased apoptosis (more TUNEL-positive cells). Thus, SIRT1/AMPK activation mediates resveratrol’s autophagy and neuroprotection.

AMPK/mTOR pathway [ 37 ]: Treated rats showed higher p-AMPK and lower p-mTOR at days 3 and 21, coinciding with better function and tissue repair. Blocking autophagy (with 3-MA) removed these gains, indicating resveratrol enhances autophagy via AMPK/mTOR signaling after SCI.

(*p-: phosphorylated form)

LKB1/AMPK/mTOR/p70S6K pathway [ 61 ]: Resveratrol markedly increased Liver Kinase B1 (LKB1) and p-AMPK, while decreasing p-mTOR and p-p70S6K, suggesting this cascade also drives autophagy-related protection.

Wnt/β-catenin pathway [ 62 ]: Resveratrol elevated Wnt3a and β-catenin and lowered GSK3β, changes that correlated with axon regeneration. Inhibiting Wnt/β-catenin (with XAV939) blocked these effects and worsened apoptosis, showing resveratrol’s benefits depend partly on this pathway.

Nrf2/GPX4 pathway [ 43 ]: Resveratrol upregulated Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), which in turn increased antioxidants xCT and Glutathione Peroxidase 4, GPX4 (downregulated by SCI). Inhibiting Nrf2 (with ML385) reversed these, leading to uncontrolled ferroptosis. This indicates resveratrol activates Nrf2/GPX4 signaling to prevent oxidative cell death.

(*Xct: Cystine/Glutamate Antiporter, SLC7A11; *GSK3β: Glycogen Synthase Kinase 3 Beta)

Each pathway appears to contribute to resveratrol’s overall neuroprotective effect by boosting autophagy or antioxidant defences and suppressing apoptosis/inflammation. These findings highlight multiple, interconnected mechanisms by which resveratrol aids SCI recovery.

Discussion

Summary of results

To our knowledge, in this first-of-its-kind systematic review, we explored the neuroprotective effects of resveratrol for traumatic spinal cord injury in murine models, highlighting treatment outcomes and the regulating mechanisms of recovery in pre-clinical studies.

To begin with, in the studies investigating motor function recovery, the consistent finding of improved motor function [ 34 , 37 , 43 , 61 , 62 , 67 ], can be justified by the increased survival and regeneration of spinal motor neurons observed [ 6 , 34 , 43 , 61 , 67 ], as a result of the regulation of apoptosis and autophagy [ 37 , 50 , 61 , 67 ], and the reduction of neuroinflammation [ 6 , 37 , 50 , 62 ], oxidative stress [ 6 ] and ferroptosis [ 43 ].

All eight studies administered resveratrol intraperitoneally (IP) at doses ranging from 10 mg/kg (acute single-dose protocols) to 200 mg/kg (high-dose chronic regimens), with most using 20–100 mg/kg daily. Dosing regimens varied from single post-injury injections [ 6 ],acute neuroprotection focus) to repeated administration over 7–35 days [ 67 ]: 50 mg/kg daily × 21 days, [ 37 ]: 100 mg/kg daily × 21 days, [ 43 ]: 30 mg/kg × 35 days), typically initiated 30–60 min post-SCI to target secondary injury cascades. Chronic dosing (≥ 14 days) correlated with sustained BBB improvements and histological preservation across studies, while acute dosing emphasized early antioxidant effects.

Molecular induction of the secondary SCI

Following primary tSCI demonstrated by fractures and bleeding, the secondary injury manifests at the molecular level by glutamate excitotoxicity, lipid peroxidation, oxidative stress and neuroinflammation which altogether stimulate an exaggerated apoptosis and necrosis [ 66 ]. If the secondary injury persists for a longer time, the microenvironment flooded with inflammatory cytokines, free radicals, and pro-apoptotic proteins makes it impossible for the motor neurons to survive, branch and reconnect resulting in the death of a high number of neurons [ 56 ] which explains the deterioration of motor function and motor skills.

Switching from autophagy to apoptosis

During the phase of secondary SCI injury, the process of autophagy is gradually blocked evidenced by the building up of autophagy substrate protein p62, accumulation of LC3-II positive autophagosomes, and the drop down of lysosomal proteases such as cathepsin D indicating lysosomal dis-function [ 33 ]. As a consequence of blocking autophagy, apoptosis of injured motor neurons takes over in an exaggerated manner due to the activation of mitochondria molecular pathways that lead to the release of cytochrome c and the activation of the pro-apoptotic proteins such as caspase 9 [ 68 ].

What causes this shift from autophagy to apoptosis at the molecular level is the cleavage of beclin1, an autophagy starter, by caspase 3 into a fragment that targets the mitochondria to signal the release of cytochrome c which amplifies apoptosis to an unwanted extent [ 53 ].

Molecular mechanisms of resveratrol’s neuroprotection

The neuroprotective role of resveratrol lies in the modulation of the autophagy-apoptosis crosstalk shifting the balance towards autophagy rather than apoptosis by multiple signaling pathways, including stabilizing Beclin1 and downregulating caspase 3 [ 25 ]. Additionally, other molecular pathways are involved in shifting the balance toward autophagy.

SIRT1/AMPK pathway

The SIRT1/AMPK pathway is crucial for mediating the neuroprotective effects of resveratrol [ 67 ] (Fig. 5 ). Research indicates that resveratrol activates AMPK, which serves as a key intracellular energy sensor, resulting in increased levels of NAD⁺. This rise in NAD⁺ then activates SIRT1 by allowing it to bind with NAD⁺ as a cofactor [ 4 ]. Once SIRT1 is activated, it deacetylates downstream targets, such as Beclin-1, which facilitates the conversion of LC3-I to LC3-II. This conversion is vital for the formation of autophagosomes and plays a significant role in activating autophagy (Zhiya [ 13 ].

AMPK/mTOR pathway

Two included studies have demonstrated that the AMPK/mTOR pathway also plays a role in mediating the neuroprotective effects of resveratrol [ 37 , 61 ] (Fig. 6 ). Supporting evidence indicates that resveratrol activates AMPK [ 29 ]. When activated, AMPK inhibits mTORC1, a known suppressor of autophagy, leading to the activation of ULK1, a serine/threonine kinase essential for the initiation of autophagy [ 12 ].

Based on our findings and other related studies, this process begins with the activation of LKB1, which subsequently activates AMPK. AMPK then inhibits mTORC1, resulting in the activation of ULK1 and downregulation of p70S6K, a protein involved in cell growth and protein synthesis. Overall, this signalling cascade shifts the cellular response from growth-related processes to autophagy, thereby contributing to the neuroprotective effects observed with resveratrol [ 10 , 37 , 46 , 61 ].

(*mTORC1: Mechanistic Target of Rapamycin Complex 1; *ULK1: Unc-51 Like Autophagy Activating Kinase 1).

Wnt/B-catenin pathway

The administration of resveratrol enhances the expression of Wnt3a, a ligand that activates the Wnt signaling pathway. This signaling pathway inhibits GSK3β, a kinase responsible for degrading β-catenin. By preventing the phosphorylation of β-catenin, a transcriptional co-activator, resveratrol allows β-catenin to remain stable and active [ 62 ] (Fig. 7 ).

As a result, non-phosphorylated β-catenin avoids ubiquitination and proteasomal degradation, leading to its accumulation in the cytoplasm. It then translocates into the nucleus, where it binds to transcription factors such as TCF/LEF. This binding activates the expression of target genes, including Bcl-2, an anti-apoptotic protein leading to cell survival [ 3 , 30 ].

(*TCF: T-cell Factor; *LEF: Lymphoid Enhancer Factor).

Role of Ferroptosis

One study highlighted the potential of resveratrol in reducing ferroptosis and providing neuroprotection [ 43 ] (Fig. 8 ). Consistent with other research on non-traumatic SCI, the findings indicate that resveratrol activates Nrf2, a master regulator of antioxidant responses. This activation promotes the expression of GPX4, an enzyme that protects against lipid peroxidation, subsequently inhibiting ferroptosis [ 43 , 45 ].

Mechanistically, resveratrol facilitates the release of Nrf2 from Keap1, a cytoplasmic protein that inhibits Nrf2 and targets it for degradation. Once Nrf2 is released, it translocates to the nucleus, where it acts as a transcription factor to upregulate several antioxidant genes, including GPX4 and GSH, which is a major intracellular antioxidant and cofactor [ 64 ]. When both GPX4 and GSH are upregulated, GPX4 uses GSH as a cofactor to convert toxic lipid peroxides into non-toxic lipid alcohols, thereby suppressing ferroptosis [ 64 ].

(*Keap1: Kelch-like ECH-associated protein 1).

Additionally, Nrf2 has been shown to regulate iron metabolism by increasing the expression of FPN1, an iron exporter that helps reduce intracellular iron levels, and modulating FTH1, an iron storage protein. These actions further contribute to the inhibition of ferroptosis and promote the survival of motor neurons [ 64 ].

Comparative analysis of findings with other studies

Our findings confirm that resveratrol has strong neuroprotective effects by reducing neuroinflammation and oxidative stress. It lowers inflammatory cytokines (IL-1, IL-6, and TNFα) and reactive oxygen species through the activation of the Sirt1 pathway, creating an environment that supports the survival and regeneration of motor neurons [ 14 , 56 ]. Additionally, the regulation of apoptosis and autophagy helps preserve motor neuron populations and maintain motor function.

Autophagy is a critical cellular process that removes damaged organelles and cellular debris, protecting against neurodegenerative damage [ 31 ]. On the other hand, apoptosis eliminates cells that are damaged, unnecessary, or potentially harmful [ 69 ]. These mechanisms are supported by preclinical studies using SCI models, which show that resveratrol enhances autophagy and Sirt1 signaling, improving motor neuron survival and functional recovery [ 59 ]. Studies involving SCI cell lines and BV2 microglia have reported reductions in inflammation and oxidative stress [ 34 , 62 , 67 ], as well as in VSC4.1 motor neurons [ 58 ].

Beyond spinal cord injuries, resveratrol consistently reduces neuronal damage in cases of traumatic brain injury [ 33 ]. It also modulates apoptosis and autophagy through the PI3K/Akt/mTOR signaling pathway [ 20 ] and improves outcomes in Alzheimer's and Parkinson's diseases by decreasing neuroinflammation and preserving motor function [ 40 , 47 ]. Its effectiveness is further enhanced in demyelinating conditions like multiple sclerosis when delivered via nanoparticle systems [ 52 ]. Emerging clinical evidence, including trials for AD, shows reductions in amyloid-β levels, reinforcing the rationale for evaluating resveratrol in spinal cord injuries [ 22 ].

(*PI3K: Phosphoinositide 3-Kinase; *Akt: Protein Kinase B).

Addressing clinical trials challenges and research needs

Clinical trials challenges

Current clinical trials for SCI are exploring various treatments, including Riluzole (currently in Phase III for neuroprotection) [ 19 ], mesenchymal stem cells (Phase IIb for regeneration) [ 11 ], NVG-291 (Phase Ib/IIa for ROCK-II inhibition) [ 36 ], and epidural stimulation [ 5 ]. However, these trials have not produced transformative results, largely due to several factors:

Injury heterogeneity (differences in injury level and completeness).

Inadequate sample sizes, often with fewer than 100 participants.

Inconsistent timing of treatment (whether applied in acute or chronic phases).

Overreliance on suboptimal outcomes, such as ASIA scores alone.

Insufficient preclinical rigor, typically limited to studies involving young rodents without comorbidities.

Historical cases, such as the National Acute Spinal Cord Injury Studies (NASCIS) MP trials, highlight these issues by demonstrating only marginal gains (approximately 5–10 ASIA points), which were overshadowed by adverse events like sepsis. This underscores the risks of proceeding with treatments without comprehensive evidence synthesis [ 16 – 18 ].

To achieve future success, it is crucial to improve the alignment between bench research and clinical practice. This involves emphasising preclinical systematic reviews, such as ours, to refine dosing, elucidate mechanisms, and improve patient selection for the 15 million individuals worldwide living with SCI [ 63 ].

Research needs

Based on our comprehensive research study, preclinical studies should utilize standardized, clinically relevant models. This includes large-animal contusion injuries at thoracic levels that reflect human demographics, such as older age and incomplete lesions. It is crucial to incorporate multi-site validation and human-relevant biomarkers, like serum Glial Fibrillary Acidic Protein (GFAP) and neurofilament light, to ensure robust proof of concept before moving to Phase I trials [ 57 ].

Clinical studies must emphasize large-scale, stratified randomized controlled trials with more than 200 participants, focusing on harmonized outcomes, such as the ASIA motor score combined with the Walking Index for Spinal Cord Injury. Early intervention should be prioritized, ideally within 24 h, and combination therapies, such as stem cells paired with neuromodulation, should be leveraged. Additionally, employing AI-driven patient matching can help address heterogeneity and potentially raise success rates from less than 10% to levels that are clinically viable [ 28 , 60 ].

This rigorous standardization is essential for bridging the current translational gap, allowing agents like resveratrol, which has consistently improved blood–brain barrier scores by 3–8 points in rodent models through the SIRT1/AMPK and Nrf2 pathways, to move toward human testing with greater confidence (Scheuren & Kramer [ 49 ].

Emerging Modifiers in SCI Outcomes

As previously mentioned in the introduction, emerging evidence underscores the significant role of the gut microbiome in SCI pathophysiology through the gut-spinal cord axis. Injury-induced dysbiosis, characterized by a reduction in butyrate-producing bacteria, such as Firmicutes and Clostridiales, exacerbates neuroinflammation, impairs recovery, and intensifies pain due to vagal-immune-metabolic dysregulation [ 27 ]. The use of antibiotics post-SCI and bowel dysfunction further complicate matters by delaying the restoration of a healthy microbiome, which correlates with poorer functional outcomes. Microbiome-targeted interventions, including probiotics, prebiotics, and fecal transplants, show promise in preclinical studies for modulating short-chain fatty acid (SCFA) production, microglial polarization, and maintaining barrier integrity [ 15 ]. These approaches warrant clinical exploration to enhance therapies like resveratrol.

Limitations of the included studies

The quality assessment of the included studies revealed several methodological limitations that may affect the robustness of the findings. None of the studies clearly described the random allocation of animals to experimental groups, and there was no report on whether caregivers were blinded, which introduces potential bias. Only half of the studies ensured that outcome assessors were blinded, raising concerns about the reliability of the results.

Additionally, none of the studies examined the effects of resveratrol in a dose-dependent manner, which would have clarified its optimal therapeutic dosage. Moreover, long-term consequences of resveratrol administration were not investigated. The issue of resveratrol's low bioavailability was also not addressed; however, all studies circumvented this issue by using intraperitoneal administration instead of oral administration. Notably, loading resveratrol into exosomes has been shown to prolong its half-life and enhance neuroprotection by restoring mitochondrial function in rat models of SCI [ 7 ].

Lastly, one of the included studies [ 37 ], DOI:/10.3892/mmr.2025.13679) is currently under an Expression of Concern due to potential data integrity and methodological issues. While this study provided valuable insights into autophagy, inflammation (TNF-α, IL-1β, IL-10), and motor recovery, its findings should be interpreted with caution. Sensitivity analyses that excluded this study, however, demonstrated consistent trends across the remaining trials.

Strengths and limitations of the current study

This systematic review is the first of its kind to explore the neuroprotective potential of resveratrol for traumatic spinal cord injury. It highlights several critical outcomes, including motor function recovery, and provides a comprehensive overview of the mechanisms underlying resveratrol's effects. By presenting positive evidence for resveratrol, this study paves the way for future research on its dosing parameters in both preclinical settings and large-scale controlled clinical trials.

The study fully adhered to the PRISMA (2020) guidelines throughout its execution, which enhances its credibility and authenticity. While this review focuses on preclinical studies whose findings cannot be directly applied to human patients, its results can inform future research aimed at harnessing the potential of resveratrol in the treatment of tSCI.

It's also worth noting that a meta-analysis was not feasible due to the heterogeneity of methodologies and outcome measures across the included studies. As a result, a qualitative analysis of the outcomes was chosen for this review.

Conclusion

Our current study provides insightful evidence about the compelling role of resveratrol in providing neuroprotection after traumatic spinal cord injuries. The findings showed that resveratrol improves motor function recovery, preserves motor neurons and promotes regeneration by regulating the significant crosstalk between autophagy and apoptosis, shifting the balance towards autophagy, in addition to reducing neuroinflammation and oxidative stress. Although the findings are promising but they are still limited and cannot be translated to patients. It is therefore recommended to have better transparency in allocation, blinding and randomization in addition to adjusting preclinical studies that assess resveratrol’s efficacy and safety in a dose–response methodology to transition afterwards into early phase clinical trials that could eventually yield fruitful translational findings.

Supplementary Information

Supplementary Material 1.

Supplementary Material 2.

Supplementary Material 3.

Supplementary Material 4.

Supplementary Material 5.

Authors’ contributions

Mariam Moselmani: Conceptualization, Screening, Data Extraction, Quality Assessment, Writing, Figure Formation. Dana Khayat: Reviewing and correcting the all the comments of the reviewers. Sara Ajami: Literature Search, Screening, Data-Extraction, Quality Assessment Aya Mansour: Screening, Data-Extraction, Quality Assessment Ghina Rammal: Critical Review and Language editing Nada Alaaeddine: Conceptualization, Critical Evaluation and Supervision (Main Corresponding Author).

Funding

Not applicable.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

Declarations

Ethics approval and consent to participate

Not Applicable.

Consent for publication

Approved by all authors.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Supplementary Materials

Supplementary Material 1.

Supplementary Material 2.

Supplementary Material 3.

Supplementary Material 4.

Supplementary Material 5.

Data Availability Statement

All data generated or analysed during this study are included in this published article and its supplementary information files.