A Probable Way Vitamin D Affects Autism Spectrum Disorder: The Nitric Oxide Signaling Pathway

Abstract

Vitamin D (VD) deficiency during pregnancy and early brain development is an important environmental risk factor for autism spectrum disorder (ASD). Its specific mechanism of action is still unclear. However, one study on the correlation between metabolomics and VD levels in children with ASD has found that the whole-blood arginine (Arg) levels of children with ASD are significantly negatively correlated with serum VD levels, suggesting that the effect of VD on ASD may be related to the signaling pathway involving Arg. Arg is a precursor of nitric oxide (NO), and changes in its levels most directly affect NO levels and signal transduction pathways. NO, a biologically active free radical, is both a neurotransmitter and a neuromodulator in the central nervous system and is related to the pathogeneses of various neurological diseases. The NO signaling pathway is not only affected by VD levels but also closely related to ASD through a series of mechanisms, such as neurotransmitter imbalance, immune disorders, and oxidative stress. Therefore, the effect of VD on ASD may be achieved via regulation of the NO signaling pathway. The current review discusses the relationship among VD, NO, and ASD as suggested by a large body of evidence in the literature in an effort to provide clues for researchers on the pathogenesis of ASD and the mechanism of VD's impact on ASD.

Vitamins D and E Improve Valproic Acid-Induced Autistic-Like Behaviors and Oxidative Stress in the Rat Offspring

“…Along with our result, another study also reported an increase in the pain threshold in offspring rats caused by maternal VPA treatment, which was decreased using pregabalin (31). It seems that under the influence of VPA, the nitric oxide (NO) signaling pathway is probably affected by imbalances in neurotransmitter release, immune disorders, and oxidative stress (32). Since pain sensation in the periphery depends on the presence of different local inflammatory mediators, including NO (33), therefore, an imbalance in NO production alters the threshold of pain sensation as it happens in autistic patients (34).…”

“…NO directly regulate vitamin D expression through CYP27B1. On the other hand, since inflammatory factors increase the expression of inducible Nitric Oxide synthase (iNOS) and, consequently, produce NO, vitamin D modulates the inflammatory processes and reduces NO production (32).…”

The role of vitamin D deficiency in the development of paediatric diseases

“…The impact of VitD on ASD is still under discussion. In addition to theoretical support that the effects of VitD on ASD may be related to signalling pathways involving whole blood arginine and nitric oxide, researchers also found that ASD is associated with disorders of the dopamine system and abnormalities of the serotonin-melatonin axis, which are caused by insufficient amounts of VitD ( Figure 2 ) [ 38 ].…”