Emerging Role of Long Noncoding RNAs in Perioperative Neurocognitive Disorders and Anesthetic-Induced Developmental Neurotoxicity

Abstract

Preclinical investigations in animal models have consistently demonstrated neurobiological changes and life-long cognitive deficits following exposure to widely used anesthetics early in life. However, the mechanisms by which these exposures affect brain function remain poorly understood, therefore, limiting the efficacy of current diagnostic and therapeutic options in human studies. The human brain exhibits an abundant expression of long noncoding RNAs (lncRNAs). These biologically active transcripts play critical roles in a diverse array of functions, including epigenetic regulation. Changes in lncRNA expression have been linked with brain development, normal CNS processes, brain injuries, and the development of neurodegenerative diseases, and many lncRNAs are known to have brain-specific expression. Aberrant lncRNA expression has also been implicated in areas of growing importance in anesthesia-related research, including anesthetic-induced developmental neurotoxicity (AIDN), a condition defined by neurological changes occurring in patients repeatedly exposed to anesthesia, and the related condition of perioperative neurocognitive disorder (PND). In this review, we detail recent advances in PND and AIDN research and summarize the evidence supporting roles for lncRNAs in the brain under both normal and pathologic conditions. We also discuss lncRNAs that have been linked with PND and AIDN, and conclude with a discussion of the clinical potential for lncRNAs to serve as diagnostic and therapeutic targets for the prevention of these neurocognitive disorders and the challenges facing the identification and characterization of associated lncRNAs.

Figure 1.:. Downstream Molecules of lncRNAs and their role in AIDN pathophysiology.

Exposure to anesthetics alters the expression upregulated (highlighted in Red) & downregulated (highlighted in green) of lncRNAs MALAT-1 (metastasis-associated lung adenocarcinoma transcript 1), BDNF-AS (Brain derived neurotrophic factor antisense RNA transcripts), Rik-203 (LncRNA Rik-203), TUG-1 (Taurine-upregulated gene 1) contributing towards the pathophysiology of AIDN. Changes in the expression of these lncRNAs subsequently influences oxidative stress, inflammation, neuronal apoptosis, cognitive function, and neuronal growth and differentiation.