Extracellular Mitochondrial ATP, Suramin, and Autism?

Theoharides, Theoharis C.

doi:10.1016/j.clinthera.2013.07.419

Cited by 9 publications

(4 citation statements)

References 40 publications

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“…This method was previously used to document the effect of other inhibitors on MC activation 40 as well as of resveratrol on passive cutaneous anaphylaxis in mice 55 Moreover, the flavonoid concentrations used here in this mouse “model” (100 mg/kg) have already been shown to have a statistically significant benefit at least for lut in children with autism 56 many of whom have been reported to have “allergic-like” symptoms 57 implicating MC activation. 58 …”

Section: Discussionmentioning

confidence: 99%

The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells

Weng

Patel

Panagiotidou

et al. 2015

Journal of Allergy and Clinical Immunology

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121

114

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Background Mast cells (MCs) are hemopoietic cells that mature in tissues and are involved in allergy, immunity and inflammation by secreting multiple mediators. The natural flavone luteolin (lut) has anti-inflammatory actions and inhibits human MCs. Objective To investigate the ability of lut, and its novel structural analog 3’,4’,5,7-tetramethoxyluteolin (methlut), to inhibit human MCs mediator expression and release in vitro and in vivo. Methods Human LAD2 cells and primary human umbilical cord-blood derived cultured MC (hCBMCs) were stimulated by substance P (SP) or IgE/anti-IgE with or without pre-incubation with lut, methlut or cromolyn (1–100 μM) for 2 or 24 hr following which a mediator secretion was measured. The effect of the compound on MC intracellular calcium levels and NF-κB activation was also investigated. Pretreatment with methlut was also studied in mice passively sensitized with dinotrophenol-human serum albumin (DNP-HSA) and challenged intradermally. Results Methlut is a more potent inhibitor than lut or cromolyn for beta-hexosaminidase (β-hex) and histamine secretion from LAD2 cells stimulated by either SP or IgE/anti-IgE, but only methlut and lut significantly inhibit preformed tumor necrosis factor (TNF) secretion. Methlut is also a more potent inhibitor than lut of de novo synthesized TNF from LAD2, and of chemokine (C-C motif) ligand 2 (CCL2) from hCBMCs. The mechanism of action from methlut may be due to its ability to inhibit intracellular calcium increase, as well as NF-κB induction at both the transcriptional and translational levels in LAD2 cells stimulated by SP without affecting cell viability. Treatment (ip) with methlut significantly decreases skin vascular permeability of Evans blue in mice passively sensitized to DNP-HAS and challenged intradermaly. Conclusion Methlut is a promising MC inhibitor for the treatment of allergic and inflammatory conditions.

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Section: Discussionmentioning

confidence: 99%

The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells

Weng

Patel

Panagiotidou

et al. 2015

Journal of Allergy and Clinical Immunology

Self Cite

121

114

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“…A recent study suggested that antipurinergic drug suramin reversed ASD-like symptoms in offspring of mice treated with poly (IC) by blocking adenosine triphosphate release that have proinflammatory activity [43]. However, these findings are not in line with previous reports and further studies are required to prove its efficacy in human subjects due to side effects and other questions associated with its usage [44].…”

Section: Discussionmentioning

confidence: 51%

Prevalence of antimitochondrial antibodies in autism spectrum subjects

2015

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Objective: Autism is a neurodevelopmental disorder characterized by impairment in verbal and nonverbal communication, repetitive and stereotypic behavior. Dysregulated immune system has a role in the pathogenesis of Autism. This study was designed to measure the prevalence of antimitochondrial (AM) antibodies in a group of autistic children. Methods: AM antibodies subtype 2 (AMA-M2) were evaluated by indirect solid phase enzyme immunoassay in 62 autistic children and 14 age-matched healthy controls. Autistic activity was assessed by using the Childhood Autism Rating Scale. Results: Significantly elevated levels of AMA-M2 were observed in the sera of autistic children (n = 54, 0.221 ± 0.029 IU/ml [mean ± SEM]) compared with healthy controls (n = 14, 0.111 ± 0.010 IU/ml [mean ± SEM], p = 0.0008) and there was no significant difference in patients with moderate to severe autism (p = 0.49). AM antibodies in autistic patients have no correlation with Childhood Autism Rating Scale score. conclusion: The current study demonstrated significantly high levels of AMA-M2 in autistic subjects when compared with healthy controls. Further large-scale studies are required to dissect any pathogenic role of these antibodies in the development of autism.

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“…Similar features are also indicated in a variety of neurodevelopmental disorders, including epilepsy, Rett syndrome, and Fragile X syndrome, which are characterized by dysfunctions in the balance between excitatory and inhibitory neurotransmissions [155, 156]. Evidence indicates an important role of the extracellular ATP and purinergic signaling in ASD [157-159], while abnormalities in purine metabolism and a relationship between adenosine and autism in terms of symptoms and behavior have been reported [160, 161] e.g insufficient adenosine levels may be related to some symptoms such as poor eye contact or repetitive movements [162, 163]. Since locomotor activity and social contacts are behavioural patterns normally controlled by eN activity, main adenosine-producing enzyme in the CNS [105, 134, 164] it is not surprising that the changes in these behavioural patterns contribute to endophenotypes of ASD [165], while eN may be a tool for pharmaceutical intervention in behavioural disorders.…”

Section: Implication Of Ectonucleotidases In Synapse Formation Maturmentioning

confidence: 85%

Role of Ectonucleotidases in Synapse Formation During Brain Development: Physiological and Pathological Implications

Grković

Drakulić

Martinović

et al. 2018

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Extracellular adenine nucleotides and nucleosides, such as ATP and adenosine, are among the most recently identified and least investigated diffusible signaling factors that contribute to the structural and functional remodeling of the brain, both during embryonic and postnatal development. Their levels in the extracellular milieu are tightly controlled by various ectonucleotidases: ectonucleotide pyrophosphatase/phosphodiesterases (E-NPP), alkaline phosphatases (AP), ectonucleoside triphosphate diphosphohydrolases (E-NTPDases) and ecto-5'-nucleotidase (eN). During central nervous system development and in adulthood all ectonucleotidases have diverse expression pattern, cell specific localization and function. Formation, maturation, and refinement of synaptic contacts are influenced by neurotransmitters and neuromodulators, and control of extracellular adenine nucleotide levels by ectonucleotidases are important for understanding the role of purinergic signaling in developing tissues and potential targets in developmental disorders such as autism.

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Extracellular Mitochondrial ATP, Suramin, and Autism?

Cited by 9 publications

References 40 publications

The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells

The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells

Prevalence of antimitochondrial antibodies in autism spectrum subjects

Role of Ectonucleotidases in Synapse Formation During Brain Development: Physiological and Pathological Implications

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