Natural Anti-Inflammatory Agents for Autism Spectrum Disorders

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1		Suneel Kumar	--	4177	2023-01-19 14:55:05	\|
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3	format	Jason Zhu	Meta information modification	4175	2023-02-02 02:20:31	\|

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11010115

Autism spectrum disorder (ASD) is a heterogeneous category of developmental psychiatric disorders which is characterized by inadequate social interaction, less communication, and repetitive phenotype behavior. ASD is comorbid with various types of disorders. The reported prevalence is 1% in the United Kingdom, 1.5% in the United States, and ~0.2% in India. The natural anti-inflammatory agents on brain development are linked to interaction with many types of inflammatory pathways affected by genetic, epigenetic, and environmental variables. Inflammatory targeting pathways have already been linked to ASD. However, these routes are diluted, and new strategies are being developed in natural anti-inflammatory medicines to treat ASD.

autism spectrum disorder inflammatory pathway neuropsychiatric disorders natural anti-inflammatory agents

1. Introduction

Autism spectrum disorder (ASD) is a neurodevelopment disorder ^[1] characterized by an inadequate shortfall in social involvement and social communication across various contexts and restricted areas ^[2] and stereotype behavior, especially in early childhood ^[3]. Additionally, male patients are more numerous than females in a 3:1 ratio ^[4]. The current prevalence is investigated at 1% in the United Kingdom, 1.5% in the United States, and ~0.2% in India ^[5]^[6]. According to Freitas et al. (2018), the western nation’s average age of 8 years old has increased by almost 150% between 2000 and 2014, posing a public health concern in North America ^[7]. Studies from North America, Asia, and Europe indicate a 1–2% moderate prevalence of ASD. Numerous causes, including hereditary and environmental toxins, stress, weakened immunological function, mitochondrial dysfunction, and neuroinflammation, are mentioned in the unidentified pathogenesis ^[8]. Classic innate failure of metabolism is a monogenic disease that can affect a subgroup of ASD patients, including 12.73% of children suffering from ASD ^[9]^[10]. Despite the rise in ASD cases ^[10], current treatments only partially alleviate some of the symptoms of ASD rather than curing them. Only 2 drugs, risperidone, and aripiprazole have been approved by the Food and Drug Administration of the United States of America for the treatment of disturbing symptoms in ASD patients. However, factors like (1) the condition of the subject, which may affect various aspects of daily function, (2) the significant direct and indirect reasonable effects of treatments, and (3) the suffering experienced by the subject’s entire family highlight the need for ongoing research into effective interventions. Although there have been many classifications and developments about ASD, its genesis is still unknown, and there are few questions about the straightforward nature of the problem ^[11]. Immunological flaws have been linked to ASD for many years, but they have just reached their pinnacle. The earliest indication of a relationship between the immune system and ASD came from a 1976 study that discovered 5 of 13 autistic infants had undetectable antibody titers despite prior rubella immunization, while every control subject had detectable titers. In the past few decades, research on animal models and human models has revealed evidence of changes in the central and peripheral immune systems’ functioning in ASD, excluding the activation of immune cells, production of autoantibodies, inequality in cytokines and chemokines, and increased permeability of brain regions ^[12]. Several immunological dysfunction and inflammation in ASD have been proposed as potential targets. Tumor necrosis factor alpha (TNF-α), Interleukin-(IL) 6, and monocytes chemotactic proteins 1 (MCP-1), the most potent of which is also mast cells chemotactic, are recognized as biomarkers of inflammation in the brain and cerebrospinal fluids (CSF) of various autistic individuals ^[1]. The brain infection makes pro-inflammatory cytokines and chemokines disposable, and they have been linked to hippocampal and cerebral damage ^[1]. A rich source of a different biomarker is mast cells. Immune cells are stored in mast cells, which can frequently discharge stimulation ^[13]. The observation of inflammation as a probable etiology factor in psychopathology serves more as an inflammatory condition of brain physiology activity which is an integral part of biological mechanisms and environmental factors ^[14].

2. Inflammatory Pathways and Immunoinflammatory Link of ASD

2.1. NF-κB Pathway

The NF-κB family controls the regulation of several genes involved in inflammation, immunological responses, anti-apoptosis, and cell proliferation. More than 500 genes related to inflammation have been shown to be activated by the NF-κB family, which in turn triggers the release of cytokines necessary for inflammation. Some of these cytokines, such as IL-1β and TNF-α, cause the NF-κB to become active, creating a positive feedback loop that, if NF-κB becomes abnormally or continuously active, has the potential to cause chronic and excessive inflammation. The neurological system seems to be where the ubiquitous functions of NF-κB in neuroprotection, apoptosis, and inflammation are most pronounced. The consequences of NF-κB activation on gene expression vary depending on the stimulus that activates it, the type of cell that it targets, and the microenvironment. According to previous research, NF-κB activation in glial cells may result in the loss of neurons, but activation in neurons may increase the likelihood of their survival. Increased expression and enriched NF-κB signaling has been found in some studies performed on the peripheral blood samples and postmortem brains of ASD patients, as well as in studies on animal models ^[15].

IL-17A cytokine produced by a variety of immune cells, engages in both acute and chronic inflammatory reactions by upregulating the expression of pro-inflammatory genes via the NF-κB and MAPK signaling pathways. MAPK containing three subsequently activated protein kinases that are key components of a series of vital signal transduction pathways that regulate processes such as cell proliferation, differentiation and cell death in eukaryotes ^[16]. Evidence already in existence suggests that altering the downward signals coming from IL-17RA in response to IL17A may play a significant role in the neuroinflammation seen in ASD patients. When investigated the IL-17A/IL-17RA associated signaling in monocytes of ASD patients, they discovered elevated IL-17RA expression together with NF-κB and inducible nitric oxide synthase (iNOS) in these patients’ monocytes ^[17].

2.2. JAK/STAT Pathway

It has been shown that the JAK2/STAT3 signaling pathway activates and releases inflammatory cytokines such IL-1, TNF-α, and IL-6 ^[18]. Cognitive impairment could result from abnormal synapse construction and function brought on by a shift in the c-Jun N-terminal kinase (JNK) pathway in response to IL-1. JAK/STAT signaling cascades are triggered by IL-4. Interferon-gamma (IFN-γ) concentration was markedly elevated in the brains of those with ASD. For T-cell activation and differentiation in autoimmune CNS inflammation, IL-9 is crucial. Children with ASD had higher levels of IL-9, which shows that IL-9 may have a role in the emergence of ASD. Children with autism may exhibit behavioral changes as a result of peripheral immunological activation ^[19].

2.3. MAPK Pathway

IL-17 also activates the MAPK pathways, which include the extracellular signal-regulated kinase (ERK), p38, and JNK pathways. The ERK/MAPK signaling is known to play a critical role in brain development, as well as in learning, memory, and cognition ^[20].

2.4. TGF-β Signalling Pathway

Increased TGF-β levels through its receptors TGF-β R1/R2 and putative neuropilin 2 receptors may cause altered brain-derived neurotrophic factor (BDNF)/Tropomyosin receptor kinase B (TrkB) processing such that neurons produce increased pro-BDNF and less full-length TrkB. BDNF is a key molecule involved in plastic changes related to learning and memory processes, while TrkB is well known for its function during the development of nervous system ^[21]. Decreased TrkB signaling combines with decreased fibroblast growth factor (FGF)8/17 signaling to produce additive decreases in PI3K/Akt/mTOR (mammalian target of rapamycin) signaling. TGF-β is a transcriptional activator of BDNF and TrkB ^[22], but IL-1β inhibits BDNF signaling and decreases BDNF levels. Therefore, aberrant neural stem cell growth and differentiation may be caused by inflammation-regulated BDNF signaling through changing the Wnt/-catenin signalling pathway ^[23].

In addition to elevations of specific cytokines, their combinations may be related to specific symptoms and their severity in ASD. In previous studies elevations in IL-1β, IL-6, and reductions in TGF-β were found children with ASD who had more severe symptoms ^[6]. Supporting those results, a combination of reduced IL-6 and IL-1α and elevated IL-17 may help differentiate children with no ASD symptoms from those with ASD symptoms.

3. Significance of Natural Anti-Inflammatory Agents in ASD

The importance of natural anti-inflammatory drugs in ASD has recently come to light. These drugs may have positive effects on autistic patients and greatly reduce maternal infection and brain inflammation in the etiology of neuropsychiatric disorders. There are a variety of naturally occurring anti-inflammatory agents’ studies so far that showed promising results against ASDs through their antioxidant and anti-inflammatory actions. The inflammatory response is the coordinated activation of many signaling pathways that keep track of the amounts of inflammatory mediators in native tissue cells and inflammatory cells from the blood. Many chronic diseases, such as cancer, diabetes, rheumatoid arthritis, cardiovascular disease, and bowel illness, have straightforward pathophysiology that involves inflammation. Although inflammatory response strategies vary depending on the place of the body, they are all based on common mechanisms that can be pictured as follows: Inflammatory pathways are engaged, inflammatory markers are generated, inflammatory cells are attracted, and cell surface pattern receptors detect harmful stimuli ^[24]. Studies have demonstrated the beneficial effects of natural anti-inflammatory agents in an animal model of ASD and autistic children by modulating the signaling molecules of inflammatory pathways. Sachdeva al. demonstrated that curcumin showed beneficial effects in valproic acid-induced-autism in rats by decreasing the IL-6 level ^[25]. Luteolin, an anti-inflammatory agent, also improved the behavioral symptoms in autistic children by reducing IL-6 and TNF-α level ^[26]^[27]. However, more research needs to be done to further investigate the potential beneficial effects of the naturally occurring anti-inflammatory agents for the prevention and treatment of ASD.

4. Preclinical Studies Targeting Inflammatory Pathways

Animal models of the circumstances of biology-based pharmaceutical treatment of ASD clearly show a critical function for ASD. However, ASD is a unique human illness, and there is not a single rodent model that can replicate every essential ASD trait. It can be used to create animal models that provide insights into the brain mechanisms that control behaviors related to ASD and the inheritance of genetic traits that are comparable to ASD ^[28].

Dr. Leo Kanner originally discussed the idea of a link between pro-inflammatory cytokines and ASD in macrophages in 1943. The notion was founded on the fact that macrophage-produced cytokines affect ASD symptoms and the consequences of social and emotional disorders on the brain when administered to active individuals. The risk of ASD is significantly increased by prenatal exposure to the rubella virus, herpes simplex virus, cytomegalovirus, or viral meningitis ^[29]. The non-genetic etiology of autism is infection with germs and viruses prior to delivery. An analysis of all Danish infants born between 1980 and 2005 revealed a higher risk of ASD in cases where mothers were admitted to the hospital for viral illnesses at the beginning of pregnancy or for bacterial and viral infections at the end of the first trimester ^[30]. Children’s chances of developing ASD are increased when their mothers have celiac disease or rheumatoid arthritis ^[31]. Clinical and epidemiological research has correlated early pregnancy maternal infection with the fetus to autism. Recent research suggests that prenatal infection viral-like immune responses can cause permanent hyper- and hypomethylation at signaling genomic regions, which further disrupts the transcription of downstream target genes and may play a role in ASD ^[32].

The level of inflammatory cytokines and the dysregulation of mothers are likely factors contributing to the offspring’s delayed neurodevelopment, according to many findings from studies conducted on both humans and animals ^[33]. Crossing typically worsens behavioral phenotype and increases the probability of developing ASD ^[34]. Aripiprazole and risperidone are the most common psychiatric medications given to children with ASD to reduce their disruptive and violent behavior, although these medications have little effect on the fundamental symptoms of ASD. Studies have called into question the beneficial effects of psychotropic substances and have highlighted fast adverse reactions such as weight gain, sedation, tremor, signal abnormalities, and drooling. Growing polypharmacy has led to an unacceptable danger of drug interactions ^[35].

In addition to reduced social contact and repetitive activity, altered ultrasonic vocalization, a deficit in learning and memory, and pre-impulse inhibition, they indicate behavioral abnormalities related to neuropsychiatric diseases ^[36]. The use of behavioral analysis for various CNS variants is becoming clearer. A model has enabled a convention joint to assess behavior, reinforcement by individual documentation, and utility replacement in the anatomical regions located in CNS under the influence of humans. The injection of a maternal action is essential to the mechanisms of MIA ^[37]. TNF-α, IL-17a, IL-6, and IL-1 are a few examples of pro-inflammatory cytokines. Anti-inflammatory cytokine IL-10 overexpression is sufficient to protect the behavioral phenotype and is associated with neuropsychiatric diseases ^[38]. However, in the absence of IL-10, MIA ^[39] promotes aberrant behavior in the adults. Thus, the equalization of cytokines may be just as significant for the development of the fetal brain as any specific chemical. The maternal fluids, placenta, amniotic fluids, and fetal brain all have higher cytokine concentrations after immune system activation ^[40]. In both rodents and non-rodent primates, the changes in cytokines are region-specific and accompanied by neuropathological abnormalities, with the long events’ effects into adulthood.

The longitudinal effects are suggested to be associated with precise alterations in cytokine receptor distribution, or those that act as the other immune mediating process. Microglia, which act as resident CNS macrophages, are another example. Microglia plays a significant processing and neuromodulator role in neurogenesis, apoptosis, neuronal migration, and synapse remodeling ^[41]. MIA exposure to prenatal microglial expression causes other cytokines to be released and the downstream effects of the magnification factor as well as antioxidants to be activated. As a result, the actions on microglial cells have a long-term effect and may help to fuel the development of an inflammatory intermediate with neurotoxic effects in adults ^[42].

According to Bertolus et al. (2018), MIA leads to an increase in pro-inflammatory conditions in the developing fetal brain, which has wide-ranging effects on gene expression and genetics of neurons as well as excitotoxicity-induced damage to developing neurons. While excessive inflammation appears to increase the likelihood of abnormal cortical evolution, cytokines involved in the pathogenesis of MIA and autism, including IL-6, IL-TNF-, IL-1, and IL-17, are less attentive to TNF-α and IL-6 and play a physiological role in the proliferation of neuronal cells, differentiation, and abidance ^[43]^[44]. One of the important cytokines exposed in MIA is IL-6 in conjunction with IL-17′s downstream signaling. Pro-inflammatory cells’ stability is altered by cytokines in IL-6, which also controls placental T-cell behavior toward them. To clock the mother’s abandonment of the fetus, the placenta is inside an upsurge in regulatory T-cells above the pro-inflammatory Th17 cells at baseline. When MIA occurred, the balance shifted in favor of increased pro-inflammatory Th17 activity and decreased production of regulatory T cells ^[45]. When T cells are activated by IL-6, they produce IL-17, which is only found in the placenta and decidua ^[46].

When given to pregnant mice in the second trimester of pregnancy, poly (I: C) injections cause the serum level of IL-17a to increase. The offspring of the mouse subjected to increased levels of IL-17a had autistic features and displayed abnormal cortical patches. This was done to better understand IL-17a receptor upregulation in the fetal mouse brain. Numerous investigations have found raised IL-17a, which is consistent with human studies showing elevated IL-17a blood levels in ASD children and higher amounts in instances with more severe symptoms ^[47]. TNF-α is another cytokine involved in the pathophysiology of ASD. TNF-α participates in synaptic plasticity, memory and learning, and astrocyte-induced synaptic strengthening by activation of glutamate release at physiological levels ^[48]. Increased TNF-α release can intensify cytotoxicity caused by glutamate by preventing the absorption of glutamate into cells ^[49].

5. Clinical Studies Aimed at Targeting Inflammatory Pathways

5.1. BDNF-TrkB Pathway

BDNF family of nerve growth factors, sometimes referred to as neurotrophins (NT), helps the brain develop both during pregnancy and after birth. BDNF plays a significant role in neuronal plasticity, neurotransmitter release, neuronal growth and survival, long-term potentiation and memory ^[50]. BDNF could be important biomarker to be investigated in the serum and blood of the autistic patients. Some studies have shown the increased level of BDNF in the serum and blood of neonatal autistic patients. However, few studies have shown the decreased level of BDNF in blood and brain tissues of autistic children compared to age-matched control or teenage children ^[51]^[52]^[53]. The downregulation of BDNF in AkT leads to a decrease in attention, which is a growth factor for Akt activities.

TrkB is most significant chemical in brain development, which includes Akt-mTOR, makes autistic individuals a candidate for engagement. A member of the tumor necrosis receptor superfamily called p75 neurotrophic receptor (p75NTR) shares structural similarities with the TrkB family of receptors and collaborates with other Trk family members to regulate the signaling of the TrkB receptor. By forming chimeric heteromeric complexes, different Trk family members and p75 NTR communicate with one another ^[54]. Due to its participation in numerous essential biological processes, has become a particularly attractive molecule of TrkB consequence surveillance in more recent times. TrkB functions as a receptor for NT-3 and NT-4 ligand and BDNF ^[21]. In addition to acting as a NT3 binding initiator, TrkC can also bind TrkB with lower affinity and regulate neurons. The homologous neurotrophin ligand activates the tyrosine kinase receptors, which thereafter dimerize with the unliganded monomeric form thought to be in balance with the phosphorylated dimeric state. While the exact cause of autism is unknown at the molecular level, studies in functional imaging, anatomy, and genetics show that synaptic modification and plasticity restrictions, as well as establishments that impede and improperly maintain the neural system, are what causes autism.

The clinical symptoms of ASD are thought to be fundamentally influenced by improved neuronal complex affinity. Recent research on the etiology of ASD exposed compounds elaborates on synaptic plasticity and evolution. One of the BDNF receptors, TrkB, and proteins that are elaborate in their signaling pathways affect the stability and composition of the dendritic spine. The immune system, cellular homeostasis, and the transformation of the development component are all crucial to inflammation control. A group of children with autism was found to have decreased levels of TGF plasma and a relationship between the plasma level and behavior deterioration estimates ^[23].

5.2. JAK-STAT Pathway

Tyrosin kinase, a non-receptor family of the JAKs pathway, has four members: JAK1, JAK2, JAK3, and Tyk2. JAK1 is the first member of the family. The JAK family of proteins mediates the transmission of several cytokines and hormones, including immune system regulators, hormone growth factors, and many hematopoietic factors. The protein family’s structure is a JAK complex made up of seven homologous JAK and protein kinase domains. JAK3 is mainly found in hematopoietic cells and is one of three proteins that are hypothesized to be present throughout whole tissues. In addition to JAK pathway receptors, other phosphorylated signaling molecules with certain domains also bind cytokines and chemokines. JAK1 and STAT5 are raised in the blood peripheral mononuclear cells of autistic patients, which has major implications for the pathophysiology of diseases and opens the door to the potential use of certain chemicals as biomarkers for autism ^[55]. Signaling on the JAK/STAT pathway, which are the brain-derived neurotrophins that are involved in improving glial cell survival in the central nervous system, has been demonstrated to boost expression.

5.3. mTOR Pathway

mTOR can control important cellular and molecular pathologies like protein production and mRNA translation. This regulation occurs in response to a wide range of external stimuli, including cytokines/chemokines, growth factors, hypoxia, and energy deprivation. Relevance of human illness in mTOR, which is increasingly recognized in oncology, neurology, immunology, and biotransformation/metabolisms, including autism. The role of the mTOR dysregulation signaling pathway in a subset specifically associated with autism and its contribution to the understanding of pharmacological and pathophysiological therapies for autism spectrum disorders are among the comprehensive molecular ASD on pathophysiology associated with the disorders that are accumulating evidence highlight the body ^[56].

5.4. NF-κB Pathway

The NF-κB route plays a major role in the processes of apoptosis, immunological activation, and inflammation. Nuclear kappa factor B can be activated based on the ability to express pro-inflammatory cytokines, which can include chemokines, adhesion molecules, and genes. The NF-κB is a complex player in the etiology of the targeting pathway of ASD, an indication of neuroinflammation that turns out to be crucial both as a marker for the illness treatment and as a selector for therapeutic interposition. A few theories have been developed on the role of NF-κB molecular signaling as the intersection of multiple elaborated pathways in autism. Inflammatory cytokines, both acute and chronic, are produced by the immune system and are involved in responses. Increased cytokine expression in conjugation with NF-κB/iNOS in patients with ASD has been discovered to be connected to autistic subjects’ monocytes. A rise in tyrosine evolution caused by up-regulation of iNOS through activation of the NF-κB signaling inflammatory targeting pathway may increase cytokine expression levels, which may contribute to neuroinflammation in ASD.

The biological and physiological immune system’s protective effects of nuclear factor kappa B activation are currently being outweighed by the detrimental effects of nuclear factor kappa B malfunction. Considerable progress has been made in comprehending the primary function and operation of NF-κB ^[57]. A 2.2-fold increase in NF-κB DNA imperative project was found in ASD when compared with those from the age-matched group after the peripheral blood samples from 67 ASD subjects and 29 matched individuals were electrophoretically portable carry evaluated. This increase was also seen when the metaphysical experimental plan in innate immunity on the role and ROS condition of pathological in autistic patients was combined. Overall, it can be said that the connection between microglia substance and expression in different brain locations elucidates the prospective role of NF-κB in distinguishing the inflammation region of the brain on ASD ^[17].

5.5. Toll-Like Receptor Pathway

A fundamental function of the innate immune system is played by the family of proteins known as toll-like receptors (TLRs) ^[58]. LPS (lipopolysaccharides) is the component of bacterial and virus cell walls. Complex proteins are essential to the process of LPS recognition by TLRs ^[59]. The specialized proteins that bind LPS as a polymeric category medication during viral and bacterial infections create inflammation, which results in brain disruption. The conformational start of dimerization of the toll-like cytoplasmic receptor is altered by extracellular domains. Create a new scaffold with conformational modifications that will allow the post receptor’s adaptor protein to join a signaling complex ^[60]. The receptor, which produces a single domain trans-membrane receptor involved in pattern recognition, is often expressed in a variety of cells, including macrophages, dendritic cells, and numerous non-immune cells, including fibroblasts and epithelial cells ^[61].

5.6. Mitogen-Activated Protein Kinase Pathway

Both threonine and serin are protein kinase types that are MAPK targets on direct cellular responses to several stimuli, including heat shock, mitogens, osmotic stress, and inflammatory biomarkers that regulate cell proliferation, differentiation, and death. An ERK1/2, p38 MAPK, and c-Jun N-terminal kinases are among the MAPKs that are connected with mammalian microtubules ^[62]. Every signaling process includes at least three MAPK components, which include MAPK kinase and MAPK kinase. Activate the MAPKKs and phosphorylate the MAPKKKs to activate the phosphorylated MAPKs. While inflammatory stimuli and stress activate JNK and P38, mitogen and other signals typically activate EKRs ^[63].

The ERK/MAPKs is another pathway that has been tied to autism which is involved in the various intracellular methods and techniques that are regulation of protein, which are the command in the growth of cells and trigger apoptosis. Genetic syndromes are including like neurofibromatosis type 1 and another name is Noonan syndrome. Autistic traits increased prevalence in autistic children RASopathies. There is the equality of PI3K/AKT and mTOR pathway, and various research of interest to treat targeting of ERK/MAPK for cancerous disease. The maturing of neuropsychiatric disorders has been studied in the targeting pathway of the ERK/MAPK in animal models. Micro deletion associated with mice is reconsidered to ASD in humans, which is used in the mice behavior deficits increase of ERK activity. Inhibitors of the ERK pathway are used to treat some animal behavior impairments in mice. The neurodevelopment in which the ERK pathway is affected occurs throughout a crucial time. Phosphorylation of ERK results in a momentary blocking of outcomes based on a postnatal day. Apoptosis in the forebrain caused memory loss and social problems in 6 mice ^[64].

6. Translational Studies Targeting Inflammatory Pathways (Patents)

Plant derived anti-inflammatory agents have contributed significantly in the development of drugs for various neuropsychiatric disorders including anxiety, depression ^[65].

Previous studies have also revealed the involvement of inflammation in the pathogenesis of ASD. Thus, targeting inflammatory pathways could be useful in developing new treatment therapeutics for the amelioration of autistic-like symptoms in children. Although few studies have done so far the investigation of natural anti-inflammatory agents for the treatment of ASD as reviewed recently by Pangrazzi et al. ^[66]. However, there are promising results that encourages the researchers to further explore the potential of these agents for the ASD prevention and treatment. In line with, only two translation work has been completed that demonstrated the effectiveness of natural anti-inflammatory agents against the inflammatory pathway signaling molecules. Most studied flavonoids including sulforaphane, resveratrol, quercetin improved the behavioral symptoms in the autistic patients, modulate pro-inflammatory or anti-inflammatory signaling molecules. These translational studies provided the basis to further explore the potential benefits of plant derived anti-inflammatory agents to treat either core or associated symptoms of ASD ^[67]^[68].

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