Inflammation and immunomodulation: considerations towards developing treatments for symptoms of autism spectrum disorder

Abstract

Autism Spectrum Disorder (ASD) is an increasingly prevalent developmental disorder characterized by moderate to debilitating social, behavioral, and communicative deficits. It is frequently accompanied with one or more co-occurring conditions that both diminish the quality of life of individuals with ASD and can significantly increase the financial burden on families for medical and care costs. Despite the growing urgency to address ASD, there currently are no broadly accepted treatments or biological diagnostic methods for the disorder. Research into these have been hampered by the high degree of heterogeneity in ASD and the lack of a clear etiology for the disorder. However, studies have identified consistent pathological features – aberrant neuroanatomical structure, chronically altered immunological state, and metabolic dysfunctions – which has driven research towards exploring these avenues for pharmacological intervention. While several therapeutic strategies have demonstrated some clinical promise, there remains large populations of patients whose symptoms either see no improvement or worsen within most trials. This necessitates clarification of both the targeted pathological features and the cellular mechanistic underpinnings of the treatments in order to develop broadly effective pharmacological strategies.The work herein focuses on three pharmaceuticals that have shown some clinical promise for treatment of core symptoms of ASD: 1) cannabidiol (CBD), 2) Tocilizumab (Toc), and 3) suramin (Sura). These three treatments focus on dysregulated components of the immune system that are potentially complicit in the neuroanatomical abnormalities observed in ASD, namely through endocannabinoid, interleukin 6 (IL-6), and purinergic signaling. xv CBD, an anti-inflammatory and anxiolytic phytocannabinoid, targets the endocannabinoid system (eCBS), a short-range signaling pathway with roles in immunomodulation and synaptic depression. As such CBD has shown some efficacy in small clinical trials, but much remains to be elucidated. Towards this, we expand upon previous studies characterizing the anti-inflammatory effects of CBD on peripheral immune cells in terms of secreted cytokines, chemokines, and growth factors as well as provide novel insights into their mechanistic effects on autophagy and oxidative stress. We also explore the effects of CBD on microglia and neurons under ASD-mimetic inflammatory stimuli – IL-6 and purinergic adenosine triphosphate (ATP) – and demonstrate its capacity to ameliorate ASD-mimetic deficits to inflammatory markers and synaptic protein expression. Following, we further explore IL-6 and purinergic targeted treatments with Toc, an anti-IL-6R monoclonal antibody treatment, and general antipurinergic P2 receptor antagonist Sura. This was done in terms of inherent dysregulations exhibited by neurons differentiated from induced pluripotent stem cells derived from individuals with a monogenetic syndromic form of ASD, Fragile X Syndrome (FXS). We demonstrate that Toc and Sura both have similar beneficial effects on the inherent dysregulations to components of the transmethylation and transsulfuration pathways and secreted proteins in FXS neurons.