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Review

Resveratrol and Neuroinflammation: Total-Scale Analysis of the Scientific Literature

by
Michele Goulart dos Santos
1,
Diele Bopsin da Luz
1,
Fernanda Barros de Miranda
2,
Rafael Felipe de Aguiar
1,
Anna Maria Siebel
2,3,
Bruno Dutra Arbo
4 and
Mariana Appel Hort
1,2,5,*
1
Programa de Pós-Graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande 96209-900, RS, Brazil
2
Programa de Pós-Graduação em Ciências da Saúde, Faculdade de Medicina, Universidade Federal do Rio Grande, Rio Grande 96209-900, RS, Brazil
3
Departamento de Farmacologia, Setor de Ciências Biológicas, Universidade Federal do Paraná, Curitiba 81531-980, PR, Brazil
4
Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, RS, Brazil
5
Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande 96209-900, RS, Brazil
*
Author to whom correspondence should be addressed.
Nutraceuticals 2024, 4(2), 165-180; https://doi.org/10.3390/nutraceuticals4020011
Submission received: 28 December 2023 / Revised: 23 February 2024 / Accepted: 1 March 2024 / Published: 22 March 2024
(This article belongs to the Special Issue The Role of Nutraceuticals in Central Nervous System Disorders)
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Versions Notes

Abstract

:
Neuroinflammation plays a crucial role in the development of various neurological diseases, including neurodegenerative disorders, leading to significant neuronal dysfunction. Current treatments involve the use of non-steroidal anti-inflammatory drugs and steroids; however, they are associated with serious adverse effects, limiting their efficacy. Exploring natural products with anti-inflammatory properties appears promising, with resveratrol, a polyphenol found in various plants, standing out for its potential benefits. Studies on resveratrol and its anti-inflammatory properties have been increasing in recent years, and analyzing the profile of this knowledge area can bring benefits to the scientific community. Therefore, this study conducted bibliometric analyses, using “resveratrol AND neuroinflammation” as search terms in the Web of Science Core Collection database. The analysis, performed with VOSviewer software version 1.6.18, encompasses 323 publications. Key terms in the studies include “resveratrol”, “neuroinflammation”, and “oxidative stress”, with China leading in the number of publications. The Federal University of Rio Grande do Sul in Brazil emerges as the institution with the highest contribution, and a phase 2 clinical study on resveratrol was the most cited. These results provide an overview of the global research landscape related to resveratrol and neuroinflammation, aiding decision making for future publications and advancing scientific understanding in this field.

Graphical Abstract

1. Introduction

Numerous studies have aimed to comprehend the inflammatory processes occurring in the central nervous system (CNS) and their roles in brain pathologies. This phenomenon is termed neuroinflammation and represents a response of the innate immune system to aseptic or non-aseptic injuries [1]. Neuroinflammation is a complex process involving various cell types in the CNS, including glial cells, such as microglia and astrocytes [2], peripheral immune cells such as macrophages and mast cells, as well as oligodendrocytes and neurons [3,4,5].
Although inflammation’s initial role is protective, its chronic effects can lead to neural damage [6]. Neuroinflammation is closely linked to the onset and progression of neurodegenerative diseases [7]. There is substantial evidence demonstrating that the activation of microglia and astrocytes increases the progression of neurodegenerative diseases, suggesting that neuroinflammation contributes to neuronal dysfunction and death [8]. It is present in diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), among others [9].
Currently, therapeutic approaches for inflammatory conditions comprise the use of non-steroidal anti-inflammatory drugs (NSAIDs) and steroidal drugs [2]. The most recognized effect of NSAIDs is the inhibition of cyclooxygenase (COX), which leads to a reduction in the levels of prostaglandins, prostacyclin, and thromboxane. COX comprises two functionally relevant isozymes, namely COX-1 and COX-2. Regarding the CNS, several studies have demonstrated that NSAIDs exhibit anti-inflammatory and anti-amyloidogenic effects both in vitro and in vivo, thereby enhancing cognitive function in preclinical models of AD [10,11]. However, clinical studies with NSAIDs in individuals predisposed to Alzheimer’s have given unimpressive results. Researchers assessed the effects of two NSAIDs, celecoxib and naproxen, in 2.528 patients aged over 70 with a family history of AD. The outcomes revealed that neither naproxen nor celecoxib improved cognitive function, leading to treatment discontinuation due to an observed increased cardiovascular risk with celecoxib in another prevention trial [12]. In addition to the lack of efficacy, these approaches have demonstrated adverse effects, including intestinal toxicity, ulcers, and cardiovascular problems [13]. The prolonged use of anti-inflammatory drugs can lead to resistance or tolerance, reducing their effectiveness over time [14]. This may require higher doses or frequent drug changes, increasing the risk of side effects. Despite clinical studies not being favorable, the importance of neuroinflammation in neurodegenerative diseases is well-documented, and the exploration of other molecules with inflammatory properties, such as those of natural origin, continues to be a promising strategy.
Several studies suggest the use of molecules derived from natural products as potential anti-inflammatory agents [15,16,17,18]. Numerous natural products are capable of exerting anti-inflammatory activity through multiple mechanisms of action and various signaling pathways. These natural products have demonstrated mechanisms that involve inhibiting microglia activation, reducing the release of pro-inflammatory cytokines, inhibiting Nuclear Factor Kappa-B (NF-κB) activation, and other pathways such as p38 MAPK [19]. Moreover, many of these natural molecules can activate Nrf2, a mechanism that has been shown to contribute, at least in part, to their anti-neuroinflammatory activity. It is due to these multifaceted actions of natural compounds that they have been proposed for the treatment of neurodegenerative diseases.
In particular, resveratrol, a polyphenol found in a wide variety of plants, including red grapes and walnuts, presents effectiveness as an anti-neuroinflammatory agent [20,21]. Among its molecular mechanisms in neuroinflammation, notable aspects include the inhibition of COX-2 activity [22], modulation of NF-κB signaling [23], reduction in the production of pro-inflammatory cytokines and chemokines [24], and attenuation of microglia and astrocyte activation [25], in addition to playing a significant role in inhibiting Aβ aggregation through binding to Aβ species. It has been demonstrated that resveratrol not only prevents the stacking of lower-molecular-weight oligomers into higher-molecular-weight oligomers [26], but also disrupts pre-formed Aβ aggregates [27]. Therefore, given the increasing number of studies conducted in this area, it is necessary to objectively document the growth of research on the topic.
Despite its numerous beneficial effects, resveratrol has low water solubility and rapid metabolization, which limits its absorption and distribution in the body. However, there are several approaches to increase its bioavailability, such as nanoformulations [28] coadministration with other molecules [29,30], slow-release formulations [31] and structural modifications [32].
Bibliometrics is a statistical method used to analyze publications within an important scientific subject that has been utilized for measuring the output of individuals, institutions, and countries over the years [33]. The impact of research can be explored, along with trends over time within the topic, as well as the main contributions to topics in a particular field of study through the analysis of keywords and citations [34,35].
Therefore, the aim of this study was to conduct a bibliometric review of the published literature on resveratrol and neuroinflammation in order to gain a quantitative and statistical understanding of this research area. This information is valuable for offering a quick overview of production in the field, identifying trends and assessing the impact of the most influential research and researchers, as well as recognizing the most productive institutions and the impact of the journals and countries that publish the most on the subject.

2. Materials and Methods

2.1. Data Source and Search Strategy

This bibliometric study analyzed articles on resveratrol and neuroinflammation from the first publication (2007) on the subject until September 2023. The multidisciplinary database Web of Science (WoS) was used with the following search terms (ALL = (resveratrol)) AND (ALL = (neuroinflammation)) to find publications containing these terms in the title, abstract and keywords. No filters, such as language, type of document and year, were applied in the search.
The publications identified from the search were evaluated for (1) publication year; (2) publication type (WoS category); (3) keywords; (3) most-cited bibliography; (4) the main journals; (5) countries and (6) organization. The full records and cited references of these identified publications were extracted and analyzed by the VOSviewer software for bibliometrics [36]. The VOSviewer software was also applied to analyze the semantic contents of titles, abstracts, and keywords of publications in order to relate them to the citation data count and synthesize a bubble map to visualize the results. VOSviewer is a free tool for bibliometric analysis work, as it enables advanced and interactive visualization of bibliometric networks, such as co-authorship networks, citation networks, and co-occurrence networks of key terms within the topic. This facilitates the understanding of patterns and trends within large sets of bibliographic data, as well as identifying emerging themes and areas of research related to the topic at hand [37].

2.2. Data Analysis and Presentation

The data found were imported into VOSviewer version 1.6.18 for bibliometric analysis. The following program commands were selected to create the bubble map of keywords: “Create a map based on bibliographic data”, “read data from bibliographic database files”, (1) type of analysis: “co-occurrence”, “unit of analysis: all keywords” using the “counting method: full counting”. The full count shows that a term with numerous occurrences in a single document is considered as one; each bubble represents a word, and its size reflects the frequency at which these words appear. The distance between the terms is determined by the frequency of their co-occurrence in the documents. In addition, a limit of at least 5 times for these words to appear in publications was established. To build the tables, the following commands were used: (2) type of analysis: “citation”, “unit of analysis: documents, sources, countries, organization”, and the data were exported for analysis in Excel 2019. A choropleth map of the countries that have published the most on the subject was built using Excel 2019. This thematic map is used to represent statistical data using the symbology technique of color mapping.

3. Results

3.1. Annual Publication Profile

The search of published literature found 323 publications, all in English, with the first article published in 2007. There was an increase in publications from 2008. It stabilized for 3 years from 2013 to 2015. Finally, the number of publications increased considerably in the following years (except in 2018). Figure 1 shows the annual publication profile of articles dealing with resveratrol and neuroinflammation.
In this study, all types of documents were included in the analysis. The vast majority of the publications belong to the document types “original articles” (n = 242, 75%), “review” (n = 68, 21%), and “others” (n = 13, 4%), such as conference abstracts and retraction publications.

3.2. Keyword Analysis

The VOSviewer software was used to analyze and visualize the recurring terms in the titles and abstracts of the 323 publications on resveratrol and neuroinflammation. Only words that appeared at least 5 times in the publications were visualized and analyzed. In total, 123 terms appeared at least five times in the evaluated publications.
Figure 2 illustrates the frequency of appearance of the keywords (multiple appearances in a single manuscript count as one). The larger the word, the more frequently it appears”. Two words that are close and connected to each other indicate more frequent co-occurrence in the evaluated publications.
The colors of the bubbles represent the timeline of occurrence, blue bubbles represent older articles, from 2016 onwards, and yellow bubbles represent the most recent articles. Complementing Figure 2, Table 1 presents the number of occurrences of the terms, with the three most frequently cited terms being “resveratrol”, “neuroinflammation”, and “oxidative stress”. These are followed by other processes related to inflammation and signaling pathways, such as “NF-kappa-B” and “Sirt-1” (sirtuin 1). Among the cell types, “microglia” was the most prominently studied, and “Alzheimer’s disease” was the most extensively investigated pathology in the articles.

3.3. Most Cited Documents

Table 2 presents data on the top 10 most cited documents among the 323 articles included in the analysis. The article from Moussa et al. [38] had the highest number of citations; it is a phase 2 clinical study that assessed the effect of resveratrol on individuals with mild to moderate AD. The second most cited document was a review by Gonzalez-Reyes et al. [39], also from 2017, focusing on the role of astrocytes in AD and neuroinflammation. The third most cited was another review by Rahimifard Mahban et al. [40], with a focus on the TLR4 signaling pathway as a therapeutic target for polyphenols in neuroinflammation. In general, among the most cited documents, there are five literature reviews, four original articles, and one phase 2 clinical study, with four studies from the year 2017. In addition, the articles were published in different journals.

3.4. Journals, Organizations and Countries with the Most Publications in the Field

Considering the number of publications, Table 3 presents the top 10 countries, organizations, and journals. The organizations with the highest number of publications were the Federal University of Rio Grande do Sul, from Brazil, leading with 10 publications, followed by University Jiao Tong of Shanghai, from China, and a university in the United States, Case Western Reserve University. Next, we have an Iranian university, the Tehran University of Medical Sciences, followed by Nanjing Medical University (China) and the University of Bari (Italy). These numbers not only reflect the quantity but also the diversity of the institutions involved, indicating a broad knowledge base about the impacts of resveratrol on the inflammatory response of the CNS.
The journals with the highest number of publications were the Journal of Neuroinflammation, an open access journal with an impact factor of 9.3 (JCR 2022), followed by molecular biology journals such as the International Journal of Molecular Sciences, an open access journal with an impact factor of 5.6. Next in line was Molecular Neurobiology, with a hybrid publication model and an impact factor of 5.1 (JCR 2022), and Cellular and Molecular Neurobiology, also with a hybrid publication model until January 2024 and an impact factor of 4.0 (JCR 2022). Other journals in the field of biochemistry included the Journal of Nutritional Biochemistry and Neurochemistry International, the latter having a high number of citations per manuscript (58.5), as well as Oxidative Medicine and Cellular Longevity. In the area of immunology, the International Immunopharmacology Journal, which accepts hybrid publications and has an impact factor of 5.6 (JCR 2022), had a high number of citations per manuscript (39.6), but journals in other areas such as Nutrients and Antioxidants had the lowest number of citations per manuscript (7.6 and 1.5, respectively), and were the least sought after in this area.
The bibliometric analysis showed that China is the country with the highest number of publications on resveratrol and neuroinflammation (Figure 3), which complements what was observed for the main authors, since most of them were Chinese. In second position is the United States, but with a higher number of citations per manuscript than China, followed by India, Brazil and Italy. The countries mentioned, along with others, can be found in Table 3, with a minimum of nine publications on the subject, as well as the number of citations per manuscript, conducted using information on the total number of citations, divided by the number of manuscripts published.

4. Discussion

This bibliometric analysis provides a quantitative analysis of scientific production on resveratrol and neuroinflammation over the years in order to identify patterns, trends and gaps in knowledge. For this analysis, the Web of Science database was used, and 323 publications were found. It was possible to observe that there has been a significant increase in the number of publications since 2015, associated with an increase in the number of countries and institutions involved in the publications, as well as a greater diversity of topics found in the studies.
The increase in the participation of Asian countries in scientific publications, consistently observed in others bibliometric reviews [48,49], highlights China as a leader in this area. This growth can be partly attributed to a combination of factors such as population size, robust investments in science, abundant access to natural resources, the establishment of international collaborations and a continued emphasis on traditional medicine. In many Asian countries, ancient medicinal traditions incorporate the use of natural products to treat diseases [50]. This cultural heritage encourages scientific research to validate and understand the therapeutic effects of natural substances, as these are elements that converge to drive the ethnopharmacological science of natural products, solidifying the position of Asian countries as significant contributors to this field of study [51].
According to a previous bibliometric study, articles on resveratrol in the research fields of nutraceuticals, such as the role of the Mediterranean diet with polyphenols as preventive agents for neurodegenerative diseases, are more extensive in Asian countries [49]. Furthermore, this pattern of contributions from Asian countries within the subject was also observed by Chinese, Japanese, and Korean institutions, represented in Table 2. It is essential to emphasize that these Asian contributions started to emerge from 2010 onward.
In addition, there are significant contributions from the United States, including a higher number of citations per manuscript compared to China, followed by India and then Brazil (Table 3). This high number of citations can be attributed to the fact that 75% of articles in the United States are open access.
Taken as a whole, the articles about resveratrol and neuroinflammation focus predominantly on molecular mechanisms, especially in the most recent publications. In addition, there have been numerous studies with a biochemical and pharmacological focus. The initial publications concentrated on neurology, exploring the polyphenol-rich Mediterranean diet and its applications in various pathologies, primarily focusing on PD, with the current shift towards AD. Through this bibliometric analysis, it is clear that the majority of studies, both original articles and reviews, address microglial activation, a fundamental feature of neuroinflammation. This information highlights that inhibiting microglial activation seems to be a promising therapeutic approach for neurological diseases.
The first review on the effects of resveratrol focusing on the brain was published in 2008 by Sun, Albert Y et al. [52]. Two years later, the second review was published by Zhang Feng et al. (2010) [44], providing a detailed exploration of the anti-inflammatory activities of resveratrol in the brain and its role in microglial activation. More recently, publications have shifted their focus to the mechanisms of action of resveratrol on other signaling pathways, such as Keap1/Nrf2/ARE, a biological system within cells that plays a crucial role in the antioxidant response and protection against oxidative stress [53], its modulation of pro-inflammatory cytokines [54], and its role in the enzymatic activity of SIRT1 [55]. Furthermore, additional reviews have examined dietary habits involving polyphenols like resveratrol in relation to lifestyle factors and neurodegenerative diseases, particularly AD [56] and PD [57].
Among the experimental studies, the first articles addressed the role of resveratrol in neuroinflammation and evaluated its effects in microglial cell cultures [58] and dopaminergic neurons [59]. It was observed that resveratrol could reduce the production of prostaglandin E2 and the formation of reactive oxygen species [58]. Furthermore, in the first study on resveratrol, its role in activating SIRT-1 was already mentioned. Researchers linked the neuroprotective and antioxidant effects of resveratrol with its ability to activate this protein [59].
In the subsequent years, most studies continued to examine the effect of resveratrol on microglia-mediated neuroinflammation [25,43,60,61,62,63]. Additionally, researchers explored its impact on neuroinflammation induced by the β-amyloid protein (Aβ), an experimental model of AD [64,65,66]. Recent articles have delved into its role in modulating the SIRT1 response [67,68,69,70] and its involvement in other signaling pathways, such as NF-κB [70,71,72,73,74].
In addition, numerous studies are currently focused on exploring tools aiming to improve the bioavailability of resveratrol. It is noteworthy that the most prolific institution among the evaluated publications is the Federal University of Rio Grande do Sul, where filiated scientists have been concentrating their studies on this aspect. Researchers from this university have assessed the potential of resveratrol as a therapeutic intervention for various neurological conditions using innovative delivery systems, such as lipid nanocapsules [64,75]. These systems show the potential to enhance the effectiveness of resveratrol, which seems to act in reducing neuroinflammation, protecting against neural damage, regulating glial activity, and promoting the release of anti-inflammatory cytokines.
The authorship analysis of publications on resveratrol and neuroinflammation was not conducted because the authors who publish the most on this subject are Chinese and often share the same initials, making a precise analysis challenging. For instance, according to the data analyzed, the most prolific author of publications on resveratrol and neuroinflammation was “Wang, Y”. This name, upon closer examination, could represent individuals like Wang Yan, Wang YP, Wang Yaping, or others such as Wang, XR, which might be the same as Wang Xiangru. Analyzing authorship by full names was also not possible since some records only provided the authors’ first names as initials.
The bubble map presents numerous terms indicating biochemical studies, focusing on oxidative stress, molecular aspects such as signaling pathways involved in the inflammatory process, especially NF-κB, microglial activation, and SIRT-1. The map shows evidence that resveratrol exhibits both antioxidant and anti-inflammatory effects, and that both processes are interconnected.
The overproduction of reactive oxygen species by activated microglia and subsequent oxidative damage induces an inflammatory state. Several studies have demonstrated that oxidative stress exacerbates the expression of inflammatory mediators in neurodegenerative diseases [76,77,78,79], and can activate various transcription factors, such as NF-κB, one of the key terms that appeared in the bibliometric analysis. This factor is sensitive to reactive species; through its phosphorylation, it becomes active and translocate to the cell nucleus, where it induces the expression of various proinflammatory molecules, such as tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1β) and IL-6, which are involved in the inflammatory processes [80,81].
Another term that showed significant occurrence was SIRT-1. Many studies attribute the biological properties of resveratrol to its ability to activate this SIRT-1 [68,82,83,84], an enzyme classified as an NAD+ dependent histone deacetylase, involved in metabolic processes, cellular stress regulation, and longevity [85,86]. In one study, the researchers demonstrated that the activation of SIRT1 by resveratrol (30 mg/kg/day for 8 weeks) reduced Tau protein phosphorylation induced by streptozotocin injection into the brain, confirming its protective role [87]. In another more recent study, it was shown that resveratrol significantly increased SIRT1 expression, inhibiting memory impairment [80]. This keyword analysis reflects the interaction between terms and what has been most studied regarding resveratrol and neuroinflammation in recent years.
The analysis of the most cited documents revealed that a phase 2 clinical study on the effects of resveratrol in patients with mild to moderate AD was the most cited among the articles analyzed [38]. In this study, researchers administered resveratrol (encapsulated) at a dose of 500 mg orally once a day, with a dose escalation every 13 weeks, culminating in 1000 mg twice a day; the total treatment duration was 52 weeks. They assessed the safety and tolerability of resveratrol, as well as its effects on AD biomarkers in plasma and cerebrospinal fluid (CSF). These included analyses of Aβ40 and Aβ42, tau and phospho-tau181. Pro-inflammatory cytokines were also evaluated, and cognitive analyses were conducted. The main results of this study indicated that, although resveratrol treatment did not affect tau protein in CSF, it significantly attenuated declines in Aβ42 and Aβ40 levels in CSF. Moreover, resveratrol was able to mitigate cognitive and functional decline in patients. Additionally, resveratrol reduced plasma levels of pro-inflammatory cytokines such as IL-1R4, IL-12P40, IL-12P70, and TNF-α.
Clinical studies, in general, tend to be highly cited due to their direct implications for clinical practice, especially when they demonstrate promising results, as seen in the study from Moussa et al., 2017. This study holds great relevance for the scientific community, considering its innovative therapeutic approaches and significant advances regarding the effects of resveratrol in AD. Another clinical study with resveratrol appeared in the results; however, this had fewer citations and focused on pathology other than AD [88]. Considering the promising results of resveratrol in preclinical and especially clinical studies, interest in investigating the potential of resveratrol as an intervention to improve brain health and prevent age-related cognitive decline has increased over the years [ClinicalTrials.gov NCT01794351, NCT01010009, NCT02336633]. There is growing interest in combining resveratrol with other therapies in order to potentiate its neuroprotective and anti-inflammatory effects [30,89,90], a future prospect that may offer additional benefits in the treatment of neuroinflammatory diseases.
Review articles are also commonly cited, and this is attributed to their ability to gather and synthesize information from a wide range of studies and sources, providing a comprehensive overview of the topic at hand. The most cited review article was the study by Gonzalez-Reyes, 2017 [39]. In this work, the authors compiled information on the most relevant aspects of the role of astrocytes in the neuroinflammatory changes observed in AD. Additionally, they discussed new neuroprotective and therapeutic measures, emphasizing the importance of astrocytes in this pathology. Although microglia have a fundamental role in neuroinflammation, this study has shown that it is crucial to start considering astrocytes as a new and valuable therapeutic and neuroprotective target for future studies related to the treatment of AD.
The third most cited work was also a literature review, Rahimifard Mahban et al. (2017) [40] explored the role of NF-κB factors in the central nervous system (CNS) through Toll-like receptor (TLR) activation. The researchers demonstrated the therapeutic aspects of polyphenolic compounds, including resveratrol for the treatment of neuroinflammation, by targeting TLR4, an important receptor protein that is essential in the immune system and stimulates various agonists of the inflammatory pathway [91].
A series of articles on the anti-inflammatory effects of resveratrol were collected in this review. It was observed that resveratrol exhibited potent anti-inflammatory effects through a mechanism involving the TLR4/NF-κB pathway and the transcription activation cascade (STAT) in vitro [92]. The resveratrol can prevent the activation of RAW 264.7 rat macrophages and microglial BV-2 cells targeted with a TLR4 ligand and lipopolysaccharide (LPS) [92].
Resveratrol also reduced IL-6, nitric oxide (NO) and TNF-α levels in RAW264.7 cells exposed to pathophysiological concentrations of LPS [93]. Similarly, treatment with resveratrol (5–20 µM) attenuated the increase in TLR4 expression, inhibited NF-κB activation and reduced TNF-α and IL-1β levels in cardiomyocytes exposed to anoxia/reoxygenation injury [94]. The report of resveratrol’s comprehensive mechanisms of action addressed in this review explains the large number of citations of articles that address the mechanisms of action of this molecule, because through these studies it is possible to identify that resveratrol can mediate anti-inflammatory effects by modulating the expression of TLR4 in different signaling pathways, especially NF-κB, which was one of the terms that appeared most in the keyword analyses.

5. Conclusions

In this study, a bibliometric analysis was conducted to identify the profile of publications on resveratrol and its relationship with neuroinflammation over the years, identifying trends, changes, and areas of significant growth. The study maps the most notable scientific contributions, highlighting pioneering studies and the focus of recent research in this domain. Overall, the analyzed manuscripts, especially the more recent ones, predominantly focused on molecular mechanisms and alternatives to enhance the bioavailability of resveratrol, such as studies involving nanoparticles. Early publications often addressed resveratrol as an essential component of the Mediterranean diet, which is rich in polyphenols, and its application in pathologies, with initial studies specifically focusing on PD and a current trend toward AD. This was also observed through the analysis of the most cited documents, being a phase 2 clinical study with mild to moderate AD patients treated with resveratrol that showed promising results from this molecule in the face of this pathology.
Keyword analysis revealed a close association between the terms resveratrol and neuroinflammation with oxidative stress. Considering the antioxidant and anti-inflammatory effects of resveratrol, both processes are interconnected and represent pivotal factors in the development and impairment of neurodegenerative diseases.
Although the term “gut microbiota” appeared in the keyword analysis, it did not rank among the top ten. However, there is a growing body of studies investigating the connection between gut microbiota, inflammation, and resveratrol [95,96,97]. While the precise details of how resveratrol interacts with the microbiota and modulates inflammation are still being clarified, it is known that the intestinal microbiota has the ability to metabolize resveratrol, generating metabolites that can have beneficial effects on the body and influence its bioavailability [97]. Additionally, resveratrol can also modulate the composition of the intestinal microbiota [95]; however, despite the relevance of the topic, the number of these studies is still growing.
The bibliometric analysis conducted in this study revealed research areas and/or gaps within the scientific literature about resveratrol and neuroinflammation. It identified emerging trends and collaborative networks among researchers and institutions that are prominent in publishing on this topic, thereby aiding in the formulation of well-informed decisions grounded in the available evidence within the scientific literature.
The main limitations found in this study are that bibliometric databases may not cover all relevant publications, especially those from non-English sources, and bibliometric analyses often treat all publications equally, regardless of their quality or impact. Bibliometric analyses provide quantitative data, and additional qualitative research is often needed to better complement the study.
Nevertheless, it is expected that the quantitative data analyzed here will contribute to current knowledge in the areas of resveratrol and neuroinflammation, which has increased significantly in recent years, and may help researchers identify promising areas for further study, as well as health policymakers looking for an overview of resveratrol and neuroinflammation research.

Author Contributions

Conceptualization, M.G.d.S. and M.A.H.; methodology and formal analysis M.G.d.S., D.B.d.L., F.B.d.M. and R.F.d.A.; writing -original draft preparation, M.G.d.S., D.B.d.L., F.B.d.M. and R.F.d.A.; writing -review and editing, M.G.d.S., A.M.S., B.D.A. and M.A.H.; supervision, M.A.H.; Funding acquisition: M.A.H. and A.M.S. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES) [Finance Code 001]. M.A.H and A.M.S receives Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) fellowship [research grants 309840/2022-8 and 310989/2021-3].

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Number of publications on resveratrol and neuroinflammation per year.
Figure 1. Number of publications on resveratrol and neuroinflammation per year.
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Figure 2. Bubble map showing words from the titles and abstracts of the 323 publications on resveratrol and neuroinflammation (VOSviewer software). The colors of the bubbles represent the time scale, and the size of the word indicates its frequency of appearance.
Figure 2. Bubble map showing words from the titles and abstracts of the 323 publications on resveratrol and neuroinflammation (VOSviewer software). The colors of the bubbles represent the time scale, and the size of the word indicates its frequency of appearance.
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Figure 3. Articles published by country/region according to number of total citations.
Figure 3. Articles published by country/region according to number of total citations.
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Table 1. The top 10 recurring terms from titles and abstracts.
Table 1. The top 10 recurring terms from titles and abstracts.
KeywordOccurrencesPercentage of Total (323)
Resveratrol21667%
Neuroinflammation17755%
Oxidative stress10533%
Inflammation7624%
Nf-kappa-b7022%
Microglia6019%
Activation5617%
Brain5617%
Sirt13812%
Alzheimer’s disease3711%
Table 2. Ten most-cited research documents.
Table 2. Ten most-cited research documents.
AuthorsTitleType of StudyJournal TitlePublication YearTotal Citations
Moussa Charbel et al. [38]Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s diseaseClinical trialsJournal of Neuroinflammation2017355
Gonzalez-Reyes et al. [39]Involvement of Astrocytes in Alzheimer’s Disease from a Neuroinflammatory and Oxidative Stress PerspectiveReview ArticleFrontiers in Molecular Neuroscience2017304
Rahimifard Mahban et al. [40]Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammationReview ArticleAgeing Research Reviews2017286
Negi Geeta et al. [41]Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: effects on NF-κB and Nrf2 cascadesOriginal articleJournal of Pineal Research2011265
Bureau Genevieve et al. [42]Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammationOriginal articleJournal of Neuroscience Research2008233
Yang Xiaodong et al. [43]Resveratrol regulates microglia M1/M2 polarization via PGC-1α in conditions of neuroinflammatory injuryOriginal articleBrain, Behavior, and Immunity2017211
Zhang Feng et al. [44]Anti-inflammatory activities of resveratrol in the brain: Role of resveratrol in microglial activationReview ArticleEuropean Journal of Pharmacology2010209
Sun Shao-Cong et al. [45]Deubiquitylation and regulation of the immune responseReview ArticleNature reviews immunology2008166
Hurley Laura L. et al. [46]Neuroinflammation, Neurodegeneration, and DepressionReview ArticleNeurotoxicity Research2013165
Mo Xingxing et al. [47]The effects of SIRT1/FoxO1 on LPS induced INS-1 cells dysfunctionOriginal ArticleThe International Journal on the Biology of Stress2020160
Table 3. The top ten countries, organizations and journals contributing to the 323 manuscripts.
Table 3. The top ten countries, organizations and journals contributing to the 323 manuscripts.
ContributorPublication Count
(% of Total)		Citation per
Manuscript
Country
China114 (35.29%)25.5
USA67 (20.74%)51.8
India26 (8.05%)32.5
Brazil24 (7.43%)21.6
Italy18 (5.57%)35.3
Australia12 (3.72%)58.4
Iran12 (3.72%)39.6
Spain10 (3.10%)47.9
Germany9 (2.79%)56.6
South Korea9 (2.79%)12.4
Organization
Federal University of Rio Grande Do Sul10 (3.10%)23.8
Shanghai Jiao Tong University6 (1.86%)78.3
Case Western Reserve University6 (1.86%)57.3
Tehran University of Medical Sciences6 (1.86%)54.3
Nanjing Medical University6 (1.86%)48.5
University of Bari6 (1.86%)30.8
Shenyang Pharmaceutical University6 (1.86%)22.5
The University of New Mexico5 (1.55%)51
Nanjing University5 (1.55%)40.2
China Medical University5 (1.55%)32.2
Journal
Journal of Neuroinflammation13 (4.02%)77.8
International Journal of Molecular Sciences9 (2.79%)18.3
Molecular Neurobiology8 (2.48%)56.8
Cellular and Molecular Neurobiology6 (1.86%)26.5
Journal of Nutritional Biochemistry6 (1.86%)33.1
Neurochemistry International6 (1.86%)58.5
Oxidative Medicine and Cellular Longevity6 (1.86%)27.5
International Immunopharmacology5 (1.55%)39.6
Nutrients5 (1.55%)7.6
Antioxidants4 (1.24%)1.5
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MDPI and ACS Style

dos Santos, M.G.; da Luz, D.B.; de Miranda, F.B.; de Aguiar, R.F.; Siebel, A.M.; Arbo, B.D.; Hort, M.A. Resveratrol and Neuroinflammation: Total-Scale Analysis of the Scientific Literature. Nutraceuticals 2024, 4, 165-180. https://doi.org/10.3390/nutraceuticals4020011

AMA Style

dos Santos MG, da Luz DB, de Miranda FB, de Aguiar RF, Siebel AM, Arbo BD, Hort MA. Resveratrol and Neuroinflammation: Total-Scale Analysis of the Scientific Literature. Nutraceuticals. 2024; 4(2):165-180. https://doi.org/10.3390/nutraceuticals4020011

Chicago/Turabian Style

dos Santos, Michele Goulart, Diele Bopsin da Luz, Fernanda Barros de Miranda, Rafael Felipe de Aguiar, Anna Maria Siebel, Bruno Dutra Arbo, and Mariana Appel Hort. 2024. "Resveratrol and Neuroinflammation: Total-Scale Analysis of the Scientific Literature" Nutraceuticals 4, no. 2: 165-180. https://doi.org/10.3390/nutraceuticals4020011

APA Style

dos Santos, M. G., da Luz, D. B., de Miranda, F. B., de Aguiar, R. F., Siebel, A. M., Arbo, B. D., & Hort, M. A. (2024). Resveratrol and Neuroinflammation: Total-Scale Analysis of the Scientific Literature. Nutraceuticals, 4(2), 165-180. https://doi.org/10.3390/nutraceuticals4020011

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