Biomarkers-Directed Strategies to Treat Autism

Autism is a neurodevelopmental disorder characterized by social, communication, and behavioral symptoms. Recent research has attempted to identify the potential mechanisms that may contribute to the pathogenesis of autism. Biomarkers as noninvasive quantitative biological measures with accurate indication of a specific mechanism can lead to a better understanding of the pathogenesis required to design the most effective treatments of autism. There is also great hope that the discovery of valid and predictive biomarkers for this disorder will help earlier and more targeted methods for diagnosis and intervention. In this chapter, we discuss some of the current theorized mechanisms contributing to autism, including inflammation, oxidative stress, impaired detoxification, glutamate excitotoxicity, gut-microbiota-brain axis, impaired fatty acid profiling, and serotonin (5-HT)/oxytocin (OT) abnormalities as target to treat autism. Moreover, based on our understanding of the role of these mechanisms, selected treatment strategies are suggested. These strategies include nutraceuticals, probiotics/prebiotics and ω-3 supplementation, targeting glutamate transporters or selective 5-HT reuptake inhibitors, and intranasal OT treatment. Of course, the joint efforts of scientists, caregivers, and other stakeholders must combine to identify valid, clinically useful autism biomarkers that may lead to efficient treatment strategy and/or combined strategies

On the Toxicity of Therapeutically Used Nanoparticles: An Overview

Human beings have been exposed to airborne nanosized particles throughout their evolutionary stages, and such exposures have increased dramatically over the last century. The rapidly developing field of nanotechnology will result in new sources of this exposure, through inhalation, ingestion, and injection. Although nanomaterials are currently being widely used in modern technology, there is a serious lack of information concerning the human health and environmental implications of manufactured nanomaterials. Since these are relatively new particles, it is necessary to investigate their toxicological behavior. The objective of this review was to trace the cellular response to nanosized particle exposure. Therapeutic application of selected nanoparticles together with their range of toxic doses was also reviewed. Effect of therapeutically used nanoparticles on cell membrane, mitochondrial function, prooxidant/antioxidant status, enzyme leakage, DNA, and other biochemical endpoints was elucidated. This paper highlights the need for caution during the use and disposal of such manufactured nanomaterials to prevent unintended environmental impacts

Neurotoxins and Autism

Recently, a great concern has risen about the increasing prevalence of autism as a neurodevelopmental disorder. Environmental factors as significant contributors to children’s health through a wide range of routes are linked to remarkable increases in this disorder. It is well known and accepted that young children are more vulnerable to environmental toxins, compared to adults. Modern day lifestyles with more mercury and lead exposures, fast food, cell phones, and microwaves place children at higher risk of neurotoxicity. Moreover, a huge number of synthetic chemicals termed as high-production-volume (HPV) chemicals are found in many products such as medications, cosmetics, building materials, plastic, and car fuels. These HPVs highly contribute to brain damage in developing infants. Other environmental toxins include thalidomide, valproic acid, misoprostol, and many infectious agents among which are pathogenic bacteria or their metabolites are found to be neurotoxic and/or linked to incidences of autism. This chapter summarizes the most important routes of exposure to environmental neurotoxins and explains how these toxins are related to the remarkable increase in the prevalence of autism through different etiological mechanisms such as oxidative stress, neuroinflammation, impaired neurochemistry and glutamate excitotoxicity

Neuroprotective effect of creatine against propionic acid toxicity in neuroblastoma SH-SY5Y cells in culture

This work aimed to verify propionic acid toxic effects, and to investigate the possible neuroprotective effects of creatine against it. Propionic acid (PA) toxicity together with the effect of creatine (CR) was studied on neuroblastoma SH-SY5Y brain cells in culture. In the first group, cells were divided and treated with different concentrations of PA, while the second group was pre-treated with creatine to test its neuroprotective effect in PA-intoxicated cells. Comet assay and DNA fragmentation studies were used to examine genotoxicity and apoptosis of cells. The results emphasized the neurotoxicity of propionate to neuroblastoma cell line SH-SY5Y by DNA fragmentation that increased in a dose- and time-dependent manner. More importantly, our data confirms a possible neuroprotective effect of creatine against the neurotoxic effect of propionic acid. The obtained in vitro data supports and explains the in vivo neurotoxic effect of PA and proves its DNA damaging effect which could clarify its role in the etiology of autism, a phenomenon recently raised by many researchers. It also supported the accumulating literature which describes creatine as a potential bioactive agent against neurotoxicity. With sufficient research and clinical trials in future, this could prove to be successful in treatment or management of autism as a neurodevelopmental disorder recently related to PA neurotoxicity.Keywords: Propionic acid, creatine, SH-SY5Y, comet assay, DNA fragmentation assay, apoptosis, neuroprotection.African Journal of Biotechnology Vol. 12(31), pp. 4925-493

On the protective effect of omega-3 against propionic acid-induced neurotoxicity in rat pups

<p>Abstract</p> <p>Backgrounds</p> <p>The investigation of the environmental contribution for developmental neurotoxicity is very important. Many environmental chemical exposures are now thought to contribute to the development of neurological disorders, especially in children. Results from animal studies may guide investigations of human populations toward identifying environmental contaminants and drugs that produce or protect from neurotoxicity and may help in the treatment of neurodevelopmental disorders.</p> <p>Objective</p> <p>To study the protective effects of omega-3 polyunsaturated fatty acid on brain intoxication induced by propionic acid (PPA) in rats.</p> <p>Methods</p> <p>24 young male Western Albino rats were enrolled in the present study. They were grouped into three equal groups; oral buffered PPA-treated group given a nuerotoxic dose of 250 mg/Kg body weight/day for 3 days; omega-3 - protected group given a dose of 100 mg/kg body weight/day omega-3 orally daily for 5 days followed by PPA for 3 days, and a third group as control given only phosphate buffered saline. Tumor necrosis factor-α, caspase-3, interlukin-6, gamma amino-buteric acid (GABA), serotonin, dopamine and phospholipids were then assayed in the rats brain's tissue of different groups.</p> <p>Results</p> <p>The obtained data showed that PPA caused multiple signs of brain toxicity as measured by depletion of gamaaminobyteric acid (GABA), serotonin (5HT) and dopamine (DA) as three important neurotransmitters that reflect brain function. A high significant increase of interlukin-6 (Il-6), tumor necrosis factor-α (TNF-α) as excellent markers of proinflammation and caspase-3 as a proapotic marker were remarkably elevated in the intoxicated group of rats. Moreover, brain phospholipid profile was impaired in PPA-treated young rats recording lower levels of phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylcholine (PC).</p> <p>Conclusions</p> <p>Omega-3 fatty acids showed a protective effects on PPA - induced changes in rats as there was a remarkable amelioration of most of the measured parameters (i.e. higher GABA, 5HT, DA, PE, PS and PC) and lower Il-6, TNF-α and caspase-3.</p

Elimination of high-refined-sugar diet as treatment strategy for autistic features induced in a rodent model

Purpose: To investigate the potency of ampicillin in altering gut flora in the presence of a high-sucrose diet in rat pups, and to determine its effect on selected neurotransmitters and a cytokine as markers of the persistent autistic features repeatedly induced in orally administered propionic acid rat pups..Methods: Twenty-eight young male Wistar albino rats were divided into four equal groups. The first group served as a control. The second group received an oral neurotoxic dose of propionic acid (PPA, 250 mg/kg body weight/day) for 3 days. The third group was treated with ampicillin (50 mg/kg for 3 weeks) with a standard diet. The fourth group was given the same dose of ampicillin with a high-sucrose diet for 10 weeks.Results: The results showed a significant (p &lt; 0.001) decrease in the investigated neurotransmitters in PPA- and ampicillin-treated rat pups (norepinephrine by 32.49 and 14.58 %, dopamine by 31.45 and 20.22 %, serotonin by 35.99 and 29.09 %), as well as a remarkable increase (p &lt; 0.001) in the proinflammatory cytokine, IL-6 (30.07and 6.07 %). The high-sucrose diet also significantly (p &lt; 0.001) enhanced the neurotoxic effect of ampicillin.Conclusion: The observed dietary modulation of the gut microbiota, coupled with the subsequent modulation of brain neurochemistry and inflammation, demonstrates the considerable potential of dietary intervention through the elimination of highly refined sugar as a treatment strategy to prevent and treat autism.Keywords: Neurotoxicity, Ampicillin, Propionic acid, Neurotransmitters, Cytokines, High-sucrose die

Proinflammatory and proapoptotic markers in relation to mono and di-cations in plasma of autistic patients from Saudi Arabia

<p>Abstract</p> <p>Objectives</p> <p>Autism is a developmental disorder characterized by social and emotional deficits, language impairments and stereotyped behaviors that manifest in early postnatal life. This study aims to clarify the relationship amongst absolute and relative concentrations of K⁺, Na⁺, Ca²⁺, Mg²⁺and/or proinflammatory and proapoptotic biomarkers.</p> <p>Materials and methods</p> <p>Na⁺, K⁺, Ca²⁺, Mg²⁺, Na⁺/K⁺, Ca²⁺/Mg²⁺together with IL6, TNFα as proinflammatory cytokines and caspase3 as proapoptotic biomarker were determined in plasma of 25 Saudi autistic male patients and compared to 16 age and gender matching control samples.</p> <p>Results</p> <p>The obtained data recorded that Saudi autistic patients have a remarkable lower plasma caspase3, IL6, TNFα, Ca²⁺and a significantly higher K⁺compared to age and gender matching controls. On the other hand both Mg²⁺and Na⁺were non-significantly altered in autistic patients. Pearson correlations revealed that plasma concentrations of the measured cytokines and caspase-3 were positively correlated with Ca²⁺and Ca²⁺/K⁺ratio. Reciever Operating Characteristics (ROC) analysis proved that the measured parameters recorded satisfactory levels of specificity and sensitivity.</p> <p>Conclusion</p> <p>Alteration of the selected measured ions confirms that oxidative stress and defective mitochondrial energy production could be contributed in the pathogenesis of autism. Moreover, it highlights the relationship between the measured ions, IL6, TNFα and caspase3 as a set of signalling pathways that might have a role in generating this increasingly prevalent disorder. The role of ions in the possible proinflammation and proapoptic mechanisms of autistics' brains were hypothesized and explained.</p

Plasma fatty acids as diagnostic markers in autistic patients from Saudi Arabia

<p>Abstract</p> <p>Backgrounds</p> <p>Autism is a family of developmental disorders of unknown origin. The disorder is characterized by behavioral, developmental, neuropathological and sensory abnormalities, and is usually diagnosed between the ages of 2 and 10 with peak prevalence rates observed in children aged 5-8 years. Recently, there has been heightened interest in the role of plasma free fatty acids (FA) in the pathology of neurological disorders. The aim of this study is to compare plasma fatty acid profiles of Saudi autistic patients with those of age-matching control subjects in an attempt to clarify the role of FA in the etiology of autism.</p> <p>Methods</p> <p>26 autistic patients together with 26-age-matching controls were enrolled in the present study. Methyl esters of FA were extracted with hexane, and the fatty acid composition of the extract was analyzed on a gas chromatography.</p> <p>Results</p> <p>The obtained data proved that fatty acids are altered in the plasma of autistic patients, specifically showing an increase in most of the saturated fatty acids except for propionic acid, and a decrease in most of polyunsaturated fatty acids. The altered fatty acid profile was discussed in relation to oxidative stress, mitochondrial dysfunction and the high lead (Pb) concentration previously reported in Saudi autistic patients. Statistical analysis of the obtained data shows that most of the measured fatty acids were significantly different in autistic patients compared to age -matching controls.</p> <p>Conclusions</p> <p>Receiver Operating Characteristic (ROC) curve analysis shows satisfactory values of area under the curve (AUC) which could reflect the high degree of specificity and sensitivity of the altered fatty acids as biomarkers in autistic patients from Saudi Arabia.</p

Neuroprotective Role of Glutathione against Hydrogen Peroxide Induced Toxicity to the Neuronal Cells in Culture

Neuropathophysiology research is receiving considerable attention. Studies have demonstrated that under oxidative stress, reactive oxygen species (ROS) generated at high levels inducing cellular and DNA damage, thereby resulting in apoptosis of neuronal cells. This is implicated in the etiology of several neurodegenerative and neurodevelopmental disorders. This study was undertaken to examine the role of glutathione as a Neuroprotective bioactive compound on hydrogen peroxide-induced apoptosis. Assessment of DNA damage with the help of Comet assay (single cell gel electrophoresis) and DNA fragmentation Assay were carried out on cultured SH-SY5Y neuroblastoma cells. The treatment with glutathione markedly attenuated hydrogen peroxide-induced cell viability loss and apoptotic neuronal cell death. These results provide evidence that glutathione may act as a significantly bioactive compound and support the possibility that it may be important in health and disease, and for protection against DNA damage by oxidative stress