Role of Neuroinflammation in Autism Spectrum Disorder and the Emergence of Brain Histaminergic System. Lessons Also for BPSD?

Abstract

Many behavioral and psychological symptoms of dementia (BPSD) share similarities in executive functioning and communication deficits with those described in several neuropsychiatric disorders, including Alzheimer's disease (AD), epilepsy, schizophrenia (SCH), and autism spectrum disorder (ASD). Numerous studies over the last four decades have documented altered neuroinflammation among individuals diagnosed with ASD. The purpose of this review is to examine the hypothesis that central histamine (HA) plays a significant role in the regulation of neuroinflammatory processes of microglia functions in numerous neuropsychiatric diseases, i.e., ASD, AD, SCH, and BPSD. In addition, this review summarizes the latest preclinical and clinical results that support the relevance of histamine H1-, H2-, and H3-receptor antagonists for the potential clinical use in ASD, SCH, AD, epilepsy, and BPSD, based on the substantial symptomatic overlap between these disorders with regards to cognitive dysfunction. The review focuses on the histaminergic neurotransmission as relevant in these brain disorders, as well as the effects of a variety of H3R antagonists in animal models and in clinical studies.

Keywords: Alzheimer’s disease; H3R antagonists; autism spectrum disorder; behavioral and psychological symptoms of dementia; central histamine receptors; cytokines; neuroinflammation; schizophrenia.

Figure 1

Schematic depiction of microglia activation neuronal cell death in BPSD, AD, ASD, and SCH. Neuroinflammatory proteins and cytokines due to microglia activation by genetic and different environmental activators, leading to neuron dysfunctions and cell death. BPSD, Behavioral and Psychological Symptoms of Dementia; AD, Alzheimer’s disease; ASD, Autism Spectrum Disorder; SCH, Schizophrenia; NO, Nitric Oxide; LPS, Lipopolysaccharide; ROS, Reactive Oxygen Species; H₂O₂, hydrogen peroxide; IL-1β, Interleukin-1β; IL-6, Interleukin-6; TNF-α, tumor necrosis factor-α; PGE₂, Prostaglandin E2; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells. Modified after (Shabab et al., 2017).

Figure 2

Effect of genetic and environmental factors on neuronal dysfunction and immune response modulating BPSD, AD, ASD, and SCH symptoms. All possibilities contributing to ASD through glia activation (grey arrow), or through directly altering peripheral immune cells (white arrows) which in turn activates glia affecting the neuronal function (black arrows). BPSD, Behavioral and Psychological Symptoms of Dementia; AD, Alzheimer’s disease; ASD, Autism Spectrum Disorder; SCH, Schizophrenia. Adapted from (Depino, 2013).