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Review

Resveratrol in Autism Spectrum Disorders: Behavioral and Molecular Effects

1
Research Center “The Great Senescence”, University of Catania, 95100 Catania, Italy
2
Department of Nursing, University of Valencia, 46010 Valencia, Spain
3
Department of Pharmacy, Abdul Wali Khan University, Marden 23200, Pakistan
4
Frailty and Cognitive Impairment Group (FROG), University of Valencia, 46010 Valencia, Spain
*
Author to whom correspondence should be addressed.
Antioxidants 2020, 9(3), 188; https://doi.org/10.3390/antiox9030188
Received: 14 February 2020 / Revised: 21 February 2020 / Accepted: 22 February 2020 / Published: 25 February 2020

Abstract

Resveratrol (RSV) is a polyphenolic stillbenoid with significant anti-oxidative and anti-inflammatory properties recently tested in animal models of several neurological diseases. Altered immune alteration and oxidative stress have also been found in patients with autism spectrum disorders (ASD), and these alterations could add to the pathophysiology associated with ASD. We reviewed the current evidence about the effects of RSV administration in animal models and in patients with ASD. RSV administration improves the core-symptoms (social impairment and stereotyped activity) in animal models and it also displays beneficial effects in other behavioral abnormalities such as hyperactivity, anxiety and cognitive function. The molecular mechanisms by which RSV restores or improves behavioral abnormalities in animal models encompass both normalization of central and peripheral immune alteration and oxidative stress markers and new molecular mechanisms such as expression of cortical gamma-amino butyric acid neurons, certain type of miRNAs that regulate spine growth. One randomized, placebo-controlled clinical trial (RCT) suggested that RSV add-on risperidone therapy improves comorbid hyperactivity/non-compliance, whereas no effects where seen in core symptoms of ASD No RCTs about the effect of RSV as monotherapy have been performed and the results from preclinical studies encourage its feasibility. Further clinical trials should also identify those ASD patients with immune alterations and/or with increased oxidative stress markers that would likely benefit from RSV administration.
Keywords: antioxidant; animal model; natural compound; nutraceutical; developmental disorders antioxidant; animal model; natural compound; nutraceutical; developmental disorders

1. Introduction

Autism spectrum disorder (ASD) has been defined as a set of developmental disabilities characterized by social impairments, communication difficulties and restricted and stereotyped patterns of behavior [1]. The prevalence of autism is estimated at around 1 in 68 children, with boys 4.5-fold more affected than girls in the United States [2]. Since the first description of clinical features of autism during the 1940’s [3], the molecular basis and the etiology have not been clear to the scientific community. Different research claims that there are a multitude of alterations associated with autism, but 25% of all cases of autism are related to these genes [4]. There are several causes that have been associated to the pathophysiology of ASD (Figure 1), among them the strongest evidence has been proven for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction measured in circulating blood leukocytes [5]. James et al. [6] found differences in the antioxidant capacity and in the concentration of several metabolites related with oxidative stress in 80 subjects with autism compared with healthy children.
Post-mortem brains from autistic subjects have shown altered levels of the transcriptome, some of them related to the inflammation and cytokine production [7]. The inflammation status of the brain is also reflected by an increase in pro-inflammatory cytokines in plasma [8] and the decrease of regulatory T cells [9] of ASD subjects. The impact of the regulatory cells (T-reg) in ASD is consonant with the investigation on the alteration of transcription factors expressed by T-reg cells in ASD spectrum. ASD is conditioned by a wide range of spectrum of behavior effect and despite that the exact molecular effects regarding the pathophysiology have not been identified with precision, oxidative stress and inflammation seem to play a role. For these reason, the natural compound resveratrol (RSV) due to its antioxidant and anti-inflammatory effects in several animal models of diseases has been proposed as a future treatment in ASD [10,11]. To date, the treatment of ASD is mainly based on behavioral therapy and there is not any pharmacological treatment for the core symptoms of ASD. In contrast, there are pharmacological treatments for the psychiatric comorbidities that frequently associate with ASD such as aggressive behaviors, epilepsy, sleep disorders and attention deficit hyperactivity disorder (among the most common comorbidities in ASD) (Table 1).
RSV (3,5,4-trihydroxy-trans-stillbene) is a polyphenolic stillbenoid which acts as a photoalexin and is produced naturally by several plants in response to attack by pathogens like bacteria and fungi [12]. It is commonly found in different fruits like berries and grapes, with direct and indirect antioxidant activity due to its interaction with other signal transduction pathways. In the last three decades, RSV has been extensively studied due to its antioxidant and anti-inflammatory properties [13]. The effects of this molecule have also been recently studied in several neurological diseases [14,15,16] because this molecule crosses the blood–brain barrier [17]. The aim of this review is to summarize the molecular mechanism and the effects of resveratrol on patients and animal models of ASD.
The main objectives of this review were:
(1)
To evaluate the behavioral effects of RSV in animal models of ASD.
(2)
To summarize the molecular mechanisms by which RSV administration improves behavioral deficits in animal models of ASD.
(3)
To review clinical studies with RSV in patients with ASD and its adverse effects.
All original articles in the PubMed/Medline and Scopus electronic bibliographic databases up until December 30 2019 were analyzed for these purposes. The following inclusion criteria were applied: (1) full text in English, (2) primary articles only and (3) identification of data regarding resveratrol administration in animal models of autism or in patients with ASD. The title and abstract were analyzed to determine which articles to include. The full text was retrieved for those that fulfilled the inclusion criteria. Finally, the reference lists of all the relevant articles were manually cross-referenced to identify any additional articles. The primary search terms used were ‘resveratrol’ AND ‘autism*’.

2. Results

2.1. Behavioral Effects of RSV in Animal Models of ASD

Despite the fact that many genetic and environmental factors have been associated to ASD, the pathological mechanism remains unclear. The animal models mostly used to test the effect of potential drugs for ASD are pharmacological or used in genetically modified animals (Table 2). Regarding the pharmacological models, the most used in ASD preclinical research is the valproic acid (VPA) model [18]. VPA is a short-chained fatty acid widely used as an antiepileptic drug [19] and mood stabilizer [20,21]. This model came from epidemiological studies that associated a higher risk of ASD in mothers exposed to VPA during the pregnancy and the development has been associated to autism in humans [22]. For this reason, prenatal exposure to VPA in rats has been used as an approximation of ASD [23]. RSV administration (at doses of 3.6 mg/kg, subcutaneously for 12 to 13 days) prevented or reduced autistic-like social deficits in the VPA model [24,25,26] and sterotipic behaviors [27]. RSV at the same doses also prevented the reduced total reciprocal social interaction with a conspecific, the social transmission of food preference and repetitive self-grooming [26]. Propionic acid (PPA) is a short-chain fatty acid that is endogenous to the human body as both an intermediary of fatty acid metabolism and a fermentation end product of antibiotic-resistant enteric gut bacteria, such as clostridia. There are numerous lines of evidence suggesting that PPA and other enteric short-chain fatty acids may be elevated in ASD. Intracerebroventricular administration of PPA in rats have recently been used as an animal model of ASD [28]. Studies using this model have found that ICV treatment of PPA is capable of inducing numerous behavioral, electrophysiological and neuropathological changes in rats that are consistent with those observed in ASD. In addition, rats with intraventricular infusion of PPA have been demonstrated to be a good model reproducing characterizing molecular alterations found in ASD, such as neuroinflammation and oxidative stress [29]. In the PPA model, oral administration of RSV (5, 10, 15 mg/kg) normalized core symptoms of ASD e.g., the social interaction and stereotypy and also counteracted other behavioral alterations also reproduced in the PPA animal model, such as locomotor hyperactivity, anxiety, spatial learning, memory and depression-like behaviors [30]. The social transmission of food preference task (STFP) is based on the principle that dietary information can be communicated between rodents during social interaction [31]. Briefly, a demonstrator rodent (mice or rats) consumes a novel flavor, and then freely interacts with an observer rodent. The observer rodent is now “socially cued” toward that flavor and will prefer it in a choice paradigm over another novel “un-cued” flavor. Socially relevant cues are required for this transmission of food preference in rodents. VPA-treated rats presented a deficit in this test which is counteracted by RSV administration in rats (at doses of 3.6 mg/kg, administered subcutaneously for 12 days) [26]. Regarding the genetic model of ASD, RSV has been evaluated as a therapeutic agent in the BTBR model [32,33,34,35]. The BTBR is the only genetic model available so far in ASD preclinical research [36]. The BTBR mice model was originally bred for studies on insulin-resistance, diabetes-induced nephropathy and phenyloketonuria, and was identified only a decade ago as displaying strong and consistent autism-relevant behaviors [37,38,39]. The persistent self-grooming (as a surrogate of stereotyped and repetitive behavior observed in ASD patients) displayed by BTBR mice is reduced by RSV (administered intraperitoneally at doses of 20–40 mg/kg).
Among behavioral alterations found in ASD, an abnormal sensory processing is a key feature in ASD [40] and also prenatally VPA-exposed rats displayed such behavioral deficits. RSV administration (at doses of 3.6 mg/kg, subcutaneously) also prevented sensory deficits assessed by nest-seeking behavior and in a whisker nuisance task [25]. However, RSV has no effects on the delayed latency to reach the nest shavings and latency to make any choice (nest or sterile shavings) in VPA-treated animals [27]. More recently, several epidemiological studies showed the possible association between ASD and maternal hormone intervention [41,42]. As a result, prenatal and postnatal exposure with progestins were tested with RSV. RSV treatment at the dose of 20 mg/kg administered through oral gavage for 28 days restored the repetitive behavior tested through a marble burying paradigm in male rats, but not in females, where it was not impaired, and the social interaction in both genders [43].

2.2. Molecular Effects of RSV in Animal Models of ASD

The molecular mechanisms by which RSV prevented or reduced autistic-like behaviors in animal models are diverse and involve antioxidant effects, modulation of synthesis of anti-inflammatory molecules and new mechanisms relevant for ASD, such as those altering neuronal circuits and sensory-processing (Table 3). Regarding the antioxidant effects of RSV in an ASD model have been demonstrated in the PPA model [30]. PPA-treated rats displayed reduced brain glutathione content and enzymatic activities of superoxide dismutase and catalase Regular treatment with resveratrol (5, 10 and 15 mg/kg) produced a significant increase in the glutathione, superoxide dismutase and catalase levels in the brains of PPA-administered rats. Moreover, the daily administration of 15 mg/kg resveratrol produced a positive impact in increasing the reduced glutathione and catalase levels in comparison to 5 mg/kg and 10 mg/kg doses.
Regarding the immune-modulation and anti-inflammatory effects of RSV, several reports showed these effects in ASD models [30,32,33,34,35]. Bakheet et al. [33] studied the effect of RSV (20–40 mg/kg, intraperitoneally administered for 7 days). in the BTBR model by focusing on immune alteration and found that RSV beneficial effects were associated to several immune effects e.g., suppression of T helper 17 (Th17), T helper 2 and T helper 1 cell-related transcription factors and induction of Treg cell-related transcription factor. In another study of the same group, they found that BTBR mice showed higher levels of the chemokine receptors (CCR and CXCR), related to the inflammation, produced and expressed in CD4+ T cells than the B6 control mice did. Resveratrol treatment also decreased the mRNA expression levels of CCR and CXCR in the spleen and brain tissues and downregulated the chemokine receptor levels in CD4+ T cells [32]. This group also studied the impact of RSV treatment on Toll-like receptor pathways, which is increased in in CD4+ cells and brain of BTBR mice. They found that RSV decreased T lymphocytes CD4+, Toll-like receptors TLR2+, CD4+TLR3+, CD4+TLR4+, CD4+NF-κB+, and CD4+iNOS+ levels in spleen cells. RSV treatment decreased TLR2, TLR3, TLR4, NF-κB, iNOS and COX-2 mRNA and protein expression levels in brain tissue [34]. The inflammatory pathway related to the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and the expression of other pro-inflammatory cytokine like interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in brain and in CD4+ cells, is overactivated in BTBR mice. The concentration of pro-inflammatory TNF-α is also increased in the PPA model [30]. Oral administration of RSV (5, 10, 15 mg/kg) antagonizes this molecular pathway and decreases the concentration of pro-inflammatory cytokine such as TNF-alpha, IL-6 and interferon IFN-gamma [30,35], thus counteracting some of the markers of neuroinflammation associated to ASD. Bhandari and Kuhad [30] analyzed several factors in the brain and justified the behavioral results through the beneficial effects of RSV, reducing oxidative stress markers like lipid hydroperoxyde and nitrite, and increasing the endogenous antioxidants: catalase, superoxide dismutase and glutathione. Neuroinflammatory response triggered by stimulation of matrix metalloproteinases (MMPs) also plays pivotal role in the development of autistic phenotype as MMPs stimulate inflammatory cytokines’ release along with mitochondrial deficits, which ultimately leads to neuronal dysfunction and precipitates autistic symptoms [44,45]. Supporting these observations found in ASD patients, oral RSV administration (5, 10, 15 mg/kg) improved the activity of brain mitochondrial complex enzymes and normalized levels of MMP-9 in the PPA model [30].
Bambini-Junior et al. [24] showed an unstable interaction between RSV and VPA by bioinformatics technique, indicating that the effects of RSV are due to its cellular mechanisms. The molecular mechanisms underlying the RSV (3.6 mg/kg, administered subcutaneously) prevention of sensory deficits in the VPA rat model may be through the possible recovery of the altered GABAergic neurons expressing parvalbumin (PVC-neurons) localization and cortical organization impaired in the primary somatosensory area and in the amygdala [25]. These brain areas play a major role on sensory processing of tactile stimulation of the whiskers in rodents [46].
MicroRNAs (miRNAs) are short, endogenous, noncoding RNAs that regulate gene expression through posttranscriptional mechanisms via degradation or inhibition of specific mRNAs targets [47]. Hirsch et al. [48] analyzed the miRNA concentration in the serum of a small group of children affected by ASD (from 5 to 15 years old) and VPA rats and the effects of RSV. They found that of miR134–5p and miR138–5p, both were increased in the serum of ASD patients. VPA rats also showed an augmentation of miR134–5p levels and RSV administration in VPA-treated rats prevented this effect. This miRNA inhibits the LIM domain kinase 1(Rac-LIMK1) pathway determining the reduction of actin polymerization and spine growth and the effects afforded by RSV might also be due to this effect.
Progestins exposure during pregnancy cause reduced the estrogen receptor (ERβ) expression in the amygdala with autism-like behavior in the offspring. Postnatal or prenatal RSV oral treatment (20 mg/kg) significantly reversed this effect with ERβ activation. Xiu et al. [43] showed that RSV activates ERβ and its target genes by demethylation of DNA and histone on the ERβ promoter. It also decreased progestin-induced oxidative stress and ameliorated the impaired mitochondria and lipid metabolism in the amygdala neurons, subsequently improving ASD-like behavior.

2.3. Clinical Studies with RSV in Patients with ASD

Studies on ASD patients are still at the beginning stages. Hendouei et al. [49] recently published the results of a double-blind, placebo-controlled randomized trial (RCT) designed to assess the potential therapeutic effects of RSV plus risperidone on irritability in children (mean age 8 years old) with ASD. Both groups were treated with risperidone (a neuroleptic drug used in ASD to control associated-behavioral deficits) and the experimental group also received RSV 250 mg twice per day from the beginning of the study and the effects was compared to the placebo group that received only risperidone. All patients were assessed for ASD-related behavioral symptoms at baseline, week 5 and week 10 patients in the resveratrol group showed greater decline in hyperactivity/non-compliance score as a secondary outcome measure. In contrast, the improvements in primary outcome measure (irritability) and three secondary outcome measures (lethargy/social withdrawal, stereotypic behavior and inappropriate speech subscales) in the resveratrol group were statistically similar to those in the placebo group, which also improved.
The most frequent side effects observed in the RCT were restlessness (25.8%), constipation (19.3%) and diarrhea (19.3%) in the RSV group, and they were not significantly different form the prevalence of such adverse effects registered in the control group. Importantly, the safety of RSV concerned the frequency of extrapyramidal symptoms and weight gain induced by risperidone, which were similar between resveratrol and placebo groups.

3. Discussion

Apart from several behavioral and cognitive complications arising as a result of central nervous system dysfunction, there are various physiological comorbidities such as immune system deregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction and gastrointestinal complications which can worsen existing behavioral complications. There are no available treatments for these physiological comorbidities. In the last years, several natural compounds like RSV, curcumin, or sulforaphane have been demonstrated to be effective against oxidative stress and immune function [50]. Specifically, RSV has been taken in consideration for brain diseases not just for its interesting biochemical features but also the ability to cross the blood–brain barrier. This compound has long been thought to be the explanation of the “French Paradox”, which consist in a lower incidence of cardiovascular disease despite a high saturated fat diet for its antioxidant properties and multidrug activities [51]. Oxidative stress is deeply involved in ASD pathology [52] because this dysregulation has been found and studied also as a possible biomarker in blood and urine [53,54,55]. There are reports that show the reduction in reduced glutathione, the major endogenous antioxidant, in several brain regions associated with communication, memory, sensory and motor coordination [45,56]. RSV acts as a scavenger against reactive oxygen species and reactive nitrogen species [57]. Moreover, RSV induces an increase of glutathione levels and acts on its metabolism through the activation of the nuclear factor erythroid 2-related factor 2 (NRF2) [58]. When it happens, NRF2 binds to the antioxidant response element (ARE), that increases the expression of different antioxidant enzymes. Glutathione enzymes result as impaired in the cell of the immune system of autistic children [59,60]. The beneficial effect of RSV against the oxidative stress shown in mice [30] may not just be caused from the scavenging activity and antioxidant induction through sirtuin (probably mainly SIRT1), a key regulator of metabolism and against oxidative stress. The activation of the pathway SIRT1/PGC-1α in the ASD lymphoblastoid cell lines determined a decrease in reactive oxygen species and an improvement of mitochondria, impaired in ASD [61]. Mitochondria damage in lymphoblastoid cell lines and the alteration in the fatty acid metabolism are co-factors related to ASD [62]. Peroxisome proliferation-activated receptor gamma (PPARγ), a ligand-activated transcription factor, has a wide spectrum of biological functions: regulating mitochondrial function, mitochondrial turnover, energy metabolism, antioxidant defense and redox balance, immune responses and fatty acid oxidation. Recently, it has been proposed as a therapeutic target to rescue mitochondrial function in neurological disease [63,64] and in ASD, where it was suggested to be modulated with RSV [11].
In order to understand the possible mechanism relative to ASD and the possible therapeutic treatment, it is necessary to analyze preclinical and clinical studies. Unfortunately, the majority of preclinical studies have engaged mainly male animals. Future research directed to the therapeutic effect of RSV are needed also in females. The reason for this choice is mainly epidemiological, in fact, it is well known that ASD affect males more than females by a ratio of 4:1. Hence, it suggests a potential role of sex hormones in the pathophysiology of this disorder. Alterations in the levels of estrogen receptors have been found in subjects with ASD [65,66,67]. This discovery led to the generation of a new animal model of ASD [42]. In fact, the prenatal exposure to progestins decreased ERβ expression in the brain with autism-like behavior, which was partially restored by RSV [43]. RSV interacts with estrogen receptors and act as an ERα ligand, which aids to modulate the inflammatory response but not cell proliferation [68].
The immune system is another important cofactor of ASD. Several reports show that the immunophenotype of ASD patients is altered [69] with an augmented amount of Th17 cells [70]. Different transcription factors related to the immune system have been recently associated to ASD, in fact, it was shown that the maternal Th17 cells, through the interleukin-17a pathway, promote autism-like phenotypes in offspring in mice [71]. Hu et al. [72] reported higher levels of GATA binding protein 3 (GATA-3), a transcription factor, in lymphoblastic cell lines derived from the lymphocytes of autistic children, with respect to that of their non-autistic siblings. In another manuscript, the Toll-like receptor (TLR) pathway is activated during inflammation and neuroinflammation in ASD [73]. These studies highlight the importance of the immune system during the development, its implication on the ASD symptoms and suggest the beneficial implication of a treatment with RSV.
Despite the beneficial effects, RSV during pregnancy may cause abnormalities in the fetus, as shown in Japanese macaques [74]. According to this study, it is necessary to adjust its concentration in order to understand its applicability in clinical trials.
The therapeutic effects of resveratrol on the central nervous system (CNS) have been investigated by a number of clinical trials in neurodegenerative disorders, including mild cognitive impairment (MCI) (NCT01219244), Alzheimer’s disease (AD) (NCT01504854), Parkinson’s disease (PD) (NCT03091543) and Huntington disease (HD) (NCT02336633). The effects of RSV as a monotherapy in ASD patients has not been studied so far. In contrast, its effects on irritability has been evaluated in an RCT performed on children with ASD also receiving the anti-psychotic drug risperidone [49]. Irritability is probably the most damaging associated symptom of ASD, which might complicate treatment of patients both at home and in clinical settings [75,76]. In this RCT, RSV failed to enhance the effects afforded by risperidone and no effects on core symptoms of ASD e.g., social communication deficits and stereotype/limited activities, were observed. ASD is considered as a heterogeneous disorder with considerable variability among ASD subjects. Of note, diversity among ASD patients might lead to different clinical responses, even when the same therapies and interventions are used. Although resveratrol could not improve the majority of ASD-associated behavioral impairments, its alleviation of hyperactivity/non-compliance is an important issue and the resulting molecular mechanisms might be due to its action on several pathological underpinnings of ASD. Comorbid attention deficit hyperactivity disorder (ADHD) with ASD is very common (a prevalence ranging between 26–70%) [77,78,79,80]. The beneficial effects of resveratrol administration co-administered with risperidone on hyperactivity/noncompliance deficits may be beneficial for a subgroup of ASD patients with comorbid ADHD or its subtype (hyperactive/impulsive, inattentive or combinations) and further RCT should focus on this subgroup of ASD patients besides evaluating the drug as a monotherapy.

Author Contributions

Conceptualization, H.K. and O.C.; methodology, M.M. and O.C.; Writing—Original Draft preparation, M.M., H.K. and O.C.; Writing—Review and Editing, M.M. and O.C. All authors have read and agree to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Posar, A.; Resca, F.; Visconti, P. Autism according to diagnostic and statistical manual of mental disorders 5th edition: The need for further improvements. J. Pediatr. Neurosci. 2015, 10, 146–148. [Google Scholar] [CrossRef]
  2. Baio, J.; Wiggins, L.; Christensen, D.L.; Maenner, M.J.; Daniels, J.; Warren, Z.; Kurzius-Spencer, M.; Zahorodny, W.; Robinson Rosenberg, C.; White, T.; et al. Correction and Republication: Prevalence and Characteristics of Autism Spectrum Disorder among Children Aged 8 Years—Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR. Morb. Mortal. Wkly. Rep. 2018, 67, 1279. [Google Scholar]
  3. Kanner, L. Autistic disturbances of affective contact. Nerv. Child. 1943, 2, 217–250. [Google Scholar]
  4. Miles, J.H. Autism spectrum disorders—A genetics review. Genet. Med. 2011, 13, 278–294. [Google Scholar] [CrossRef] [PubMed]
  5. Rossignol, D.A.; Frye, R.E. Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis. Mol. Psychiatry 2012, 7, 290–314. [Google Scholar] [CrossRef] [PubMed]
  6. James, S.J.; Melnyk, S.; Jernigan, S.; Cleves, M.A.; Halsted, C.H.; Wong, D.H.; Cutler, P.; Bock, K.; Boris, M.; Bradstreet, J.J.; et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006, 141B, 947–956. [Google Scholar] [CrossRef]
  7. Garbett, K.; Ebert, P.J.; Mitchell, A.; Lintas, C.; Manzi, B.; Mirnics, K.; Persico, A.M. Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol. Dis. 2008, 30, 303–311. [Google Scholar] [CrossRef]
  8. Ashwood, P.; Krakowiak, P.; Hertz-Picciotto, I.; Hansen, R.; Pessah, I.; Van de Water, J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav. Immun. 2011, 25, 40–45. [Google Scholar] [CrossRef]
  9. Mostafa, G.A.; El-Hadidi, E.S.; Hewedi, D.H.; Abdou, M.M. Oxidative stress in Egyptian children with autism: Relation to autoimmunity. J. Neuroimmunol. 2010, 219, 114–118. [Google Scholar] [CrossRef]
  10. Rossignol, D.A.; Frye, R.E. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front. Physiol. 2014, 5, 150. [Google Scholar] [CrossRef]
  11. Barone, R.; Rizzo, R.; Tabbí, G.; Malaguarnera, M.; Frye, R.E.; Bastin, J. Nuclear Peroxisome Proliferator-Activated Receptors (PPARs) as therapeutic targets of resveratrol for autism spectrum disorder. Int. J. Mol. Sci. 2019, 20, 1878. [Google Scholar] [CrossRef]
  12. Weber, K.; Schulz, B.; Ruhnke, M. Resveratrol and its antifungal activity against Candida species. Mycoses 2011, 54, 30–33. [Google Scholar] [CrossRef] [PubMed]
  13. Malaguarnera, L. Influence of resveratrol on the immune response. Nutrients 2019, 11, 946. [Google Scholar] [CrossRef] [PubMed]
  14. Andrade, S.; Ramalho, M.J.; Pereira, M.D.C.; Loureiro, J.A. Resveratrol brain delivery for neurological disorders prevention and treatment. Front. Pharmacol. 2018, 9, 1261. [Google Scholar] [CrossRef] [PubMed]
  15. Quadros Gomes, B.A.; Bastos Silva, J.P.; Rodrigues Romeiro, C.F.; dos Santos, S.M.; Rodrigues, C.A.; Gonçalves, P.R.; Sakai, J.T.; Santos Mendes, P.F.; Pompeu Varela, E.L.; Monteiro, M.C. Neuroprotective mechanisms of resveratrol in Alzheimer’s disease: Role of SIRT1. Oxid. Med. Cell. Longev. 2018, 2018, 8152373. [Google Scholar] [CrossRef]
  16. Malaguarnera, G.; Pennisi, M.; Bertino, G.; Motta, M.; Borzì, A.M.; Vicari, E.; Bella, R.; Drago, F.; Malaguarnera, M. Resveratrol in Patients with Minimal Hepatic Encephalopathy. Nutrients 2018, 10, 329. [Google Scholar] [CrossRef]
  17. Turner, R.S.; Thomas, R.G.; Craft, S.; Van Dyck, C.H.; Mintzer, J.; Reynolds, B.A.; Brewer, J.B.; Rissman, R.A.; Raman, R.; Aisen, P.S. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 2015, 85, 1383–1391. [Google Scholar] [CrossRef]
  18. Nicolini, C.; Fahnestock, M. The valproic acid-induced rodent model of autism. Exp. Neurol. 2018, 299, 217–227. [Google Scholar] [CrossRef]
  19. Löscher, W. Basic pharmacology of valproate: A review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 2002, 16, 669–694. [Google Scholar] [CrossRef]
  20. Lambert, P.A.; Carraz, G.; Borselli, S.; Bouchardy, M. Dipropylacetamide in the treatment of manic-depressive psychosis. Encephale 1975, 1, 25–31. [Google Scholar]
  21. Emrich, H.M.; von Zerssen, D.; Kissling, W.; Möller, H.J.; Windorfer, A. Effect of sodium valproate on mania. The GABA-hypothesis of affective disorders. Arch. Psychiatr. Nervenkr. 1980, 229, 1–16. [Google Scholar] [CrossRef] [PubMed]
  22. Bromley, R.L.; Mawer, G.; Clayton-Smith, J.; Baker, G.A. Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology 2008, 71, 1923–1924. [Google Scholar] [CrossRef] [PubMed]
  23. Dufour-Rainfray, D.; Vourc’h, P.; Le Guisquet, A.M.; Garreau, L.; Ternant, D.; Bodard, S.; Jaumain, E.; Gulhan, Z.; Belzung, C.; Andres, C.R.; et al. Behavior and serotonergic disorders in rats exposed prenatally to valproate: A model for autism. Neurosci. Lett. 2010, 470, 55–59. [Google Scholar] [CrossRef] [PubMed]
  24. Bambini-Junior, V.; Zanatta, G.; Della Flora Nunes, G.; Mueller de Melo, G.; Michels, M.; Fontes-Dutra, M.; Nogueira Freire, V.; Riesgo, R.; Gottfried, C. Resveratrol prevents social deficts in animal model of autism induced by valproic acid. Neurosci. Lett. 2014, 583, 176–181. [Google Scholar] [CrossRef]
  25. Fontes-Dutra, M.; Santos-Terra, J.; Deckmann, I.; Schwingel, G.B.; Nunes, G.D.F.; Hirsch, M.M.; Bauer-Negrini, G.; Riesgo, R.S.; Bambini-Júnior, V.; Hedin-Pereira, C.; et al. Resveratrol prevents cellular and behavioral sensory alterations in the animal model of autism induced by valproic acid. Front. Synaptic Neurosci. 2018, 10, 1–12. [Google Scholar] [CrossRef]
  26. Hirsch, M.M.; Deckmann, I.; Fontes-Dutra, M.; Bauer-Negrini, G.; Della-Flora Nunes, G.; Nunes, W.; Rabelo, B.; Riesgo, R.; Margis, R.; Bambini-Junior, V.; et al. Behavioral alterations in autism model induced by valproic acid and translational analysis of circulating microRNA. Food Chem. Toxicol. 2018, 115, 336–343. [Google Scholar] [CrossRef]
  27. Fontes-Dutra, M.; Della-Flora Nunes, G.; Santos-Terra, J.; Souza-Nunes, W.; Bauer-Negrini, G.; Hirsch, M.M.; Green, L.; Riesgo, R.; Gottfried, C.; Bambini-Junior, V. Abnormal empathy-like pro-social behaviour in the valproic acid model of autism spectrum disorder. Behav. Brain Res. 2019, 364, 11–18. [Google Scholar] [CrossRef]
  28. Shultz, S.R.; MacFabe, D.F.; Ossenkopp, K.P.; Scratch, S.; Whelan, J.; Taylor, R.; Cain, D.P. Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: Implications for an animal model of autism. Neuropharmacology 2008, 54, 901–911. [Google Scholar] [CrossRef]
  29. MacFabe, D.F.; Cain, D.P.; Rodriguez-Capote, K.; Franklin, A.E.; Hoffman, J.E.; Boon, F.; Taylor, A.R.; Kavaliers, M.; Ossenkopp, K.P. Neurobiological effects of intraventricular propionic acid in rats: Possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav. Brain Res. 2007, 176, 149–169. [Google Scholar] [CrossRef]
  30. Bhandari, R.; Kuhad, A. Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders. Neurochem. Int. 2017, 103, 8–23. [Google Scholar] [CrossRef]
  31. Galef, B.G.; Kennett, D.J. Different mechanisms for social transmission of diet preference in rat pups of different ages. Dev. Psychobiol. 1987, 20, 209–215. [Google Scholar] [CrossRef] [PubMed]
  32. Bakheet, S.A.; Alzahrani, M.Z.; Nadeem, A.; Ansari, M.A.; Zoheir, K.M.A.; Attia, S.M.; AL-Ayadhi, L.Y.; Ahmad, S.F. Resveratrol treatment attenuates chemokine receptor expression in the BTBR T + tf/J mouse model of autism. Mol. Cell. Neurosci. 2016, 77, 1–10. [Google Scholar] [CrossRef] [PubMed]
  33. Bakheet, S.A.; Alzahrani, M.Z.; Ansari, M.A.; Nadeem, A.; Zoheir, K.M.A.; Attia, S.M.; Al-Ayadhi, L.Y.; Ahmad, S.F. Resveratrol Ameliorates Dysregulation of Th1, Th2, Th17, and T Regulatory Cell-Related Transcription Factor Signaling in a BTBR T + tf/J Mouse Model of Autism. Mol. Neurobiol. 2017, 54, 5201–5212. [Google Scholar] [CrossRef] [PubMed]
  34. Ahmad, S.F.; Ansari, M.A.; Nadeem, A.; Alzahrani, M.Z.; Bakheet, S.A.; Attia, S.M. Resveratrol Improves Neuroimmune Dysregulation Through the Inhibition of Neuronal Toll-Like Receptors and COX-2 Signaling in BTBR T+ Itpr3tf/J Mice. Neuromol. Med. 2018, 20, 133–146. [Google Scholar] [CrossRef]
  35. Ahmad, S.F.; Ansari, M.A.; Nadeem, A.; Bakheet, S.A.; Alzahrani, M.Z.; Alshammari, M.A.; Alanazi, W.A.; Alasmari, A.F.; Attia, S.M. Resveratrol attenuates pro-inflammatory cytokines and activation of JAK1-STAT3 in BTBR T(+) Itpr3(tf)/J autistic mice. Eur. J. Pharmacol. 2018, 829, 70–78. [Google Scholar] [CrossRef]
  36. Meyza, K.Z.; Blanchard, D.C. The BTBR mouse model of idiopathic autism—Current view on mechanisms. Neurosci. Biobehav. Rev. 2017, 76, 99–110. [Google Scholar] [CrossRef]
  37. Bolivar, V.J.; Walters, S.R.; Phoenix, J.L. Assessing autism-like behavior in mice: Variations in social interactions among inbred strains. Behav. Brain Res. 2007, 176, 21–26. [Google Scholar] [CrossRef]
  38. Moy, S.S.; Nadler, J.J.; Young, N.B.; Perez, A.; Holloway, L.P.; Barbaro, R.P.; Barbaro, J.R.; Wilson, L.M.; Threadgill, D.W.; Lauder, J.M.; et al. Mouse behavioral tasks relevant to autism: Phenotypes of 10 inbred strains. Behav. Brain Res. 2007, 176, 4–20. [Google Scholar] [CrossRef]
  39. Moy, S.S.; Nadler, J.J. Advances in behavioral genetics: Mouse models of autism. Mol. Psychiatry 2008, 13, 4–26. [Google Scholar] [CrossRef]
  40. Geschwind, D.H. Advances in Autism. Annu. Rev. Med. 2009. [Google Scholar] [CrossRef]
  41. Mamidala, M.P.; Polinedi, A.; Kumar, P.P.; Rajesh, N.; Vallamkonda, O.R.; Udani, V.; Singhal, N.; Rajesh, V. Maternal hormonal interventions as a risk factor for Autism Spectrum Disorder: An epidemiological assessment from India. J. Biosci. 2013, 38, 887–892. [Google Scholar] [CrossRef] [PubMed]
  42. Li, L.; Li, M.; Lu, J.; Ge, X.; Xie, W.; Wang, Z.; Li, X.; Li, C.; Wang, X.; Han, Y.; et al. Prenatal Progestin Exposure Is Associated With Autism Spectrum Disorders. Front. Psychiatry 2018, 9, 611. [Google Scholar] [CrossRef] [PubMed]
  43. Xie, W.; Ge, X.; Li, L.; Yao, A.; Wang, X.; Li, M.; Gong, X.; Chu, Z.; Lu, Z.; Huang, X.; et al. Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation. Mol. Autism 2018, 9, 1–13. [Google Scholar] [CrossRef] [PubMed]
  44. Palmieri, L.; Persico, A.M. Mitochondrial dysfunction in autism spectrum disorders: Cause or effect? Biochim. Biophys. Acta Bioenerg. 2010, 1797, 1130–1137. [Google Scholar] [CrossRef] [PubMed]
  45. Rose, S.; Melnyk, S.; Pavliv, O.; Bai, S.; Nick, T.G.; Frye, R.E.; James, S.J. Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl. Psychiatry 2012, 2, e134. [Google Scholar] [CrossRef] [PubMed]
  46. Chen-Bee, C.H.; Zhou, Y.; Jacobs, N.S.; Lim, B.; Frostig, R.D. Whisker array functional representation in rat barrel cortex: Transcendence of one-to-one topography and its underlying mechanism. Front. Neural Circuits 2012, 6, 93. [Google Scholar] [CrossRef] [PubMed]
  47. Paul, S.; Reyes, P.R.; Garza, B.S.; Sharma, A. MicroRNAs and Child Neuropsychiatric Disorders: A Brief Review. Neurochem. Res. 2020, 45, 232–240. [Google Scholar] [CrossRef]
  48. Hirsch, M.M.; Deckmann, I.; Fontes-Dutra, M.; Bauer-Negrini, G.; Nunes, G.D.F.; Nunes, W.; Rabelo, B.; Riesgo, R.; Margis, R.; Bambini-Junior, V.; et al. Data on social transmission of food preference in a model of autism induced by valproic acid and translational analysis of circulating microRNA. Data Br. 2018, 18, 1433–1440. [Google Scholar] [CrossRef]
  49. Hendouei, F.; Sanjari Moghaddam, H.; Mohammadi, M.R.; Taslimi, N.; Rezaei, F.; Akhondzadeh, S. Resveratrol as adjunctive therapy in treatment of irritability in children with autism: A double-blind and placebo-controlled randomized trial. J. Clin. Pharm. Ther. 2019. [Google Scholar] [CrossRef]
  50. Bhandari, R.; Paliwal, J.K.; Kuhad, A. Dietary Phytochemicals as Neurotherapeutics for Autism Spectrum Disorder: Plausible Mechanism and Evidence. Adv. Neurobiol. 2020, 24, 615–646. [Google Scholar]
  51. Saqib, U.; Kelley, T.T.; Panguluri, S.K.; Liu, D.; Savai, R.; Baig, M.S.; Schürer, S.C. Polypharmacology or Promiscuity? Structural Interactions of Resveratrol With Its Bandwagon of Targets. Front. Pharmacol. 2018, 9, 1201. [Google Scholar] [CrossRef] [PubMed]
  52. Bjørklund, G.; Meguid, N.A.; El-bana, M.A.; Tinkov, A.A.; Saad, K. Oxidative Stress in Autism Spectrum Disorder. Mol. Neurobiol. 2020. [Google Scholar] [CrossRef] [PubMed]
  53. Osredkar, J.; Gosar, D.; Maček, J.; Kumer, K.; Fabjan, T.; Finderle, P.; Šterpin, S.; Zupan, M.; Vrhovšek, M.J. Urinary markers of oxidative stress in children with autism spectrum disorder (ASD). Antioxidants 2019, 8, 187. [Google Scholar] [CrossRef] [PubMed]
  54. El-Ansary, A.; Bjørklund, G.; Chirumbolo, S.; Alnakhli, O.M. Predictive value of selected biomarkers related to metabolism and oxidative stress in children with autism spectrum disorder. Metab. Brain Dis. 2017, 32, 1209–1221. [Google Scholar] [CrossRef]
  55. El-Ansary, A.; Hassan, W.M.; Daghestani, M.; Al-Ayadhi, L.; Ben Bacha, A. Preliminary evaluation of a novel nine-biomarker profile for the prediction of autism spectrum disorder. PLoS ONE 2020, 15, e0227626. [Google Scholar] [CrossRef]
  56. Endres, D.; Tebartz van Elst, L.; Meyer, S.A.; Feige, B.; Nickel, K.; Bubl, A.; Riedel, A.; Ebert, D.; Lange, T.; Glauche, V.; et al. Glutathione metabolism in the prefrontal brain of adults with high-functioning autism spectrum disorder: An MRS study. Mol. Autism 2017, 8, 10. [Google Scholar] [CrossRef]
  57. Salehi, B.; Mishra, A.P.; Nigam, M.; Sener, B.; Kilic, M.; Sharifi-Rad, M.; Fokou, P.V.T.; Martins, N.; Sharifi-Rad, J. Resveratrol: A double-edged sword in health benefits. Biomedicines 2018, 6, 91. [Google Scholar] [CrossRef]
  58. Kode, A.; Rajendrasozhan, S.; Caito, S.; Yang, S.R.; Megson, I.L.; Rahman, I. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 2008, 294. [Google Scholar] [CrossRef]
  59. Al-Yafee, Y.A.; Al-Ayadhi, L.Y.; Haq, S.H.; El-Ansary, A.K. Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia. BMC Neurol. 2011, 11, 139. [Google Scholar] [CrossRef]
  60. Bennuri, S.C.; Rose, S.; Frye, R.E. Mitochondrial dysfunction is inducible in lymphoblastoid cell lines from children with autism and may involve the TORC1 pathway. Front. Psychiatry 2019, 10, 269. [Google Scholar] [CrossRef]
  61. Bu, X.; Wu, D.; Lu, X.; Yang, L.; Xu, X.; Wang, J.; Tang, J. Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder. Neuropsychiatr. Dis. Treat. 2017, 13, 1633–1645. [Google Scholar] [CrossRef] [PubMed]
  62. Siddiqui, M.F.; Elwell, C.; Johnson, M.H. Mitochondrial Dysfunction in Autism Spectrum Disorders. Autism. Open Access 2016, 6. [Google Scholar] [CrossRef] [PubMed]
  63. Corona, J.C.; Duchen, M.R. PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease. Free Radic. Biol. Med. 2016, 100, 153–163. [Google Scholar] [CrossRef] [PubMed]
  64. Agarwal, S.; Yadav, A.; Chaturvedi, R.K. Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders. Biochem. Biophys. Res. Commun. 2017, 483, 1166–1177. [Google Scholar] [CrossRef] [PubMed]
  65. Wang, X.; Liang, S.; Fujisawa, T.X.; Nishitani, S.; Tomoda, A.; Zou, M.; Li, Y.; Wu, L.; Shinohara, K. Association of estrogen receptor alpha polymorphisms with symptoms of autism among Chinese Han children. Neuroendocrinol. Lett. 2016, 37, 439–444. [Google Scholar] [PubMed]
  66. Chakrabarti, B.; Dudbridge, F.; Kent, L.; Wheelwright, S.; Hill-Cawthorne, G.; Allison, C.; Banerjee-Basu, S.; Baron-Cohen, S. Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and asperger syndrome. Autism Res. 2009, 2, 157–177. [Google Scholar] [CrossRef]
  67. Crider, A.; Thakkar, R.; Ahmed, A.O.; Pillai, A. Dysregulation of estrogen receptor beta (ERβ), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects. Mol. Autism 2014, 5, 46. [Google Scholar] [CrossRef]
  68. Nwachukwu, J.C.; Srinivasan, S.; Bruno, N.E.; Parent, A.A.; Hughes, T.S.; Pollock, J.A.; Gjyshi, O.; Cavett, V.; Nowak, J.; Garcia-Ordonez, R.D.; et al. Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network. Elife 2014, 2014, e02057. [Google Scholar] [CrossRef]
  69. Ashwood, P.; Corbett, B.A.; Kantor, A.; Schulman, H.; Van de Water, J.; Amaral, D.G. In search of cellular immunophenotypes in the blood of children with autism. PLoS ONE 2011, 6, e19299. [Google Scholar] [CrossRef]
  70. Basheer, S.; Venkataswamy, M.M.; Christopher, R.; Van Amelsvoort, T.; Srinath, S.; Girimaji, S.C.; Ravi, V. Immune aberrations in children with Autism Spectrum Disorder: A case-control study from a tertiary care neuropsychiatric hospital in India. Psychoneuroendocrinology 2018, 94, 162–167. [Google Scholar] [CrossRef]
  71. Choi, C.H.; Schoenfeld, B.P.; Bell, A.J.; Hinchey, J.; Rosenfelt, C.; Gertner, M.J.; Campbell, S.R.; Emerson, D.; Hinchey, P.; Kollaros, M.; et al. Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models. Front. Behav. Neurosci. 2016, 10, 136. [Google Scholar] [CrossRef] [PubMed]
  72. Hu, V.W.; Nguyen, A.T.; Kim, K.S.; Steinberg, M.E.; Sarachana, T.; Scully, M.A.; Soldin, S.J.; Luu, T.; Lee, N.H. Gene expression profiling of lymphoblasts from autistic and nonaffected sib pairs: Altered pathways in neuronal development and steroid biosynthesis. PLoS ONE 2009, 4, e5775. [Google Scholar] [CrossRef] [PubMed]
  73. Enstrom, A.M.; Onore, C.E.; Van de Water, J.A.; Ashwood, P. Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav. Immun. 2010, 24, 64–71. [Google Scholar] [CrossRef]
  74. Roberts, V.H.J.; Pound, L.D.; Thorn, S.R.; Gillingham, M.B.; Thornburg, K.L.; Friedman, J.E.; Frias, A.E.; Grove, K.L. Beneficial and cautionary outcomes of resveratrol supplementation in pregnant nonhuman primates. FASEB J. 2014, 28, 2466–2477. [Google Scholar] [CrossRef] [PubMed]
  75. Fung, L.K.; Mahajan, R.; Nozzolillo, A.; Bernal, P.; Krasner, A.; Jo, B.; Coury, D.; Whitaker, A.; Veenstra-Vanderweele, J.; Hardan, A.Y. Pharmacologic treatment of severe irritability and problem behaviors in Autism: A systematic review and meta-analysis. Pediatrics 2016, 137, S124–S135. [Google Scholar] [CrossRef]
  76. Howes, O.D.; Group, E.P.F.; Rogdaki, M.; Findon, J.L.; Wichers, R.H.; Charman, T.; King, B.H.; Loth, E.; Mcalonan, G.M.; Mccracken, J.T.; et al. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J. Psychopharmacol. 2018, 32, 3–29. [Google Scholar] [CrossRef]
  77. Goldstein, S.; Schwebach, A.J. The comorbidity of pervasive developmental disorder and attention deficit hyperactivity disorder: Results of a retrospective chart review. J. Autism Dev. Disord. 2004, 34, 329–339. [Google Scholar] [CrossRef]
  78. Ghanizadeh, A. Co-morbidity and factor analysis on attention deficit hyperactivity disorder and autism spectrum disorder DSM-IV-derived items. J. Res. Med. Sci. 2012, 17, 368–372. [Google Scholar]
  79. Lee, D.O.; Ousley, O.Y. Attention-deficit hyperactivity disorder symptoms in a clinic sample of children and adolescents with pervasive developmental disorders. J. Child Adolesc. Psychopharmacol. 2006, 16, 737–746. [Google Scholar] [CrossRef]
  80. Ghanizadeh, A.; Molla, M.; Olango, G.J. The effect of stimulants on irritability in autism comorbid with ADHD: A systematic review. Neuropsychiatr. Dis. Treat. 2019, 15, 1547–1555. [Google Scholar] [CrossRef]
Figure 1. General scheme that summarizes the issues of autism spectrum disorder (ASD).
Figure 1. General scheme that summarizes the issues of autism spectrum disorder (ASD).
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Table 1. Pharmacological treatment for psychiatric comorbidities in autism spectrum disorder (ASD) patients.
Table 1. Pharmacological treatment for psychiatric comorbidities in autism spectrum disorder (ASD) patients.
ComorbidityDrug Class
Hyperactivity/inattentionPsychostimulants
Non-stimulants
Sleep alterationsHormone (Melatonin)
Antihistamines
IrritabilityAtypical antipsychotics
EpilepsyAntiepileptics
AggressionAtypical antipsychotics
MiscellaneousAntidepressants (selective serotonin reuptake inhibitors)
Mood stabilizers
Table 2. Behavioral effects of resveratrol (RSV) in animal models of ASD.
Table 2. Behavioral effects of resveratrol (RSV) in animal models of ASD.
StudyAnimal ModelDose RSV, Treatment Duration and Route of AdministrationBehavioral AlterationsMain Outcome
Bambini-Junior et al., 2014 [24]Prenatal exposure of valproic acid in Wistar rats3.6 mg/kg, subcutaneous. Administered daily for 13 days.Social memory and preferences (Three chamber sociability and social novelty test).RSV prevents autistic-like social behaviors.
Bakheet et al., 2016 [32]BTBR model20–40 mg/kg, intraperitoneally
For 7 days.
Self-Grooming (repetitive behavior).RSV reduced repetitive behavior.
Bhandari and Kuhad 2017 [30]Propanoic acid (PPA) infused into the anterior portion of the lateral ventricle in Sprague-Dawley rats5, 10, 15 mg/kg. Oral treatment. Administered daily for 27 days after PPA infusion.Social interaction, stereotypy, locomotor activity, anxiety, spatial learning, memory, depression-like behaviors.RSV normalizes the social interaction, stereotypy, locomotor activity, anxiety, spatial learning, memory and depression-like behaviors.
Fontes-Dutra et al., 2018 [25,27]Prenatal exposure of valproic acid in Wistar rats3.6 mg/kg, subcutaneous. Administered daily for 12 days.Effect on sensory behavior (Nest-seeking behavior and in whisker nuisance task).RSV improves the percentage of correct choices (reach the nest shavings) per litter.
Hirsch et al., 2018 [26]Prenatal exposure to valproic acid in Wistar rats3.6 mg/kg, subcutaneous. Administered daily for 12 days.Reciprocal social interaction test (Social Transmission of Food Preference test).RSV counteracts the deficit in the social interaction test.
Xie et al. 2018 [43]Prenatal and Postnatal exposure to different progestins, and then just norethindrone (20 mg) in Sprague-Dawley rats20 mg/kg administered through oral gavage for 28 days (two protocol: prenatal and postnatal treatment).Repetitive behavior, anxiety, and social interaction test.RSV recovers the repetitive behavior (Marble burying test) and the deficit found in social interaction test.
Table 3. Molecular effects of RSV in animal models of ASD.
Table 3. Molecular effects of RSV in animal models of ASD.
StudyAnimal Model of ASDDose RSV, Treatment Duration and Route of AdministrationMolecular Effects of RSV in ASD Models
Bakheet et al., 2016 [32]BTBR model20–40 mg/kg, intraperitoneally administered for 7 days.Decreases the expression (mRNA) levels of CCR and CXCR in the spleen and brain tissues and downregulated the chemokine receptor levels in CD4+ T cells.
Bakheet et al., 2017 [33]BTBR model20–40 mg/kg, intraperitoneally administered for 7 days.Suppression of upregulation of T helper 17 (Th17), T helper 2, and T helper 1 cell-related transcription factors and induction of T-reg cell-related transcription factor such as FOX-p3, GATA.
Bhandari and Kuhad 2017 [30]Propanoic acid (PPA) infused into the anterior portion of the lateral ventricle in Sprague-Dawley rats5, 10, 15 mg/kg. Oral treatment. Administered daily for 27 days after PPA infusion.Increase the concentration of reduced glutathione, superoxide dismutase and catalase in the brain.
Reduction of oxidative stress markers (lipid hydroperoxyde and nitrites).
Normalizes brain levels MMP-9 and TNF-alpha.
Ahmad et al., 2018 [34]BTBR model20–40 mg/kg, intraperitoneally administered for 7 days.Decreases TLR2, TLR3, TLR4, NF-κB, iNOS, and COX-2 mRNA and protein expression levels in brain.
Ahmad et al., 2018 [35]BTBR model20–40 mg/kg, intraperitoneally administered for 7 days.Decreases IL-6, TNF-alpha, IFN-gamma and STAT-3 expression in spleen and in the brain.
Fontes-Dutra et al., 2018 [25,27]Prenatal exposure of valproic acid in Wistar rats3.6 mg/kg, subcutaneous. Administered daily for 12 days.Restoration of GABAergic neurons and cortical organization in the primary somato-sensory area and in the amygdala.
Hirsch et al., 2018 [26]Prenatal exposure of valproic acid in Wistar rats3.6 mg/kg, subcutaneous. Administered daily for 12 days.Prevention of the augmentation of miR134–5p levels induced by valproic acid.
Xie et al. 2018 [43]Prenatal and postnatal exposure to different progestins in rats20 mg/kg of through oral gavage for 28 days (two protocol: prenatal and postnatal treatment)Augmentation of estrogen receptor (ERβ) expression and its target genes by demethylation of DNA and histone on the ERβ promoter.
The CCR chemokine receptors are expressed on cells important to allergic inflammation including eosinophils, basophils, lymphocytes, macrophages, and dendritic cells, whereas the CXCR are expressed mainly on neutrophils and lymphocytes. FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. CCR, CXCR: chemokine receptors (or beta chemokine receptors); GATA, STAT-3: transcription factors; COX: Cyclooxygenase; iNOS: Inducible nitric oxide synthase; PPA: propionic acid; GABA: Gamma-amino butyric acid; TLR: Toll-like receptors.
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