ABSTRACT
Childhood is recognised as a period of immense physical and emotional development, and this, in part, is driven by underlying neurophysiological transformations. These neurodevelopmental processes are unique to the paediatric brain and are facilitated by augmented rates of neuroplasticity and expanded neural stem cell populations within neurogenic niches. However, given the immaturity of the developing central nervous system, innate protective mechanisms such as neuroimmune and antioxidant responses are functionally naïve which results in periods of heightened sensitivity to neurotoxic insult. This is highly relevant in the context of paediatric cancer, and in particular, the neurocognitive symptoms associated with treatment, such as surgery, radio- and chemotherapy. The vulnerability of the developing brain may increase susceptibility to damage and persistent symptomology, aligning with reports of more severe neurocognitive dysfunction in children compared to adults. It is therefore surprising, given this intensified neurocognitive burden, that most of the pre-clinical, mechanistic research focuses exclusively on adult populations and extrapolates findings to paediatric cohorts. Given this dearth of age-specific research, throughout this review we will draw comparisons with neurodevelopmental disorders which share comparable pathways to cancer treatment related side-effects. Furthermore, we will examine the unique nuances of the paediatric brain along with the somatic systems which influence neurological function. In doing so, we will highlight the importance of developing in vitro and in vivo paediatric disease models to produce age-specific discovery and clinically translatable research.
Subject(s)
Brain Diseases , Chemotherapy-Related Cognitive Impairment , Neoplasms , Adult , Child , Humans , BrainABSTRACT
The neuropsychological symptoms associated with chemotherapy treatment remain a major challenge with their prevention hampered by insufficient understanding of pathophysiology. While long-term neuroimmune changes have been identified as a hallmark feature shared by neurological symptoms, the exact timeline of mechanistic events preceding neuroinflammation, and the relationship between the glial cells driving this neuroinflammatory response, remain unclear. We therefore aimed to longitudinally characterize the neuroimmunological changes following systemic 5-fluorouracil (5-FU) treatment to gain insight into the timeline of events preceding the well-documented chronic neuroinflammation seen following chemotherapy. Eighteen female C57Bl/6 mice received a single intraperitoneal dose of 5-FU and groups were killed at days 1 and 2 (acute timepoint), days 4 and 8 (subacute timepoint), and days 16 and 32 (chronic timepoint). A further six mice were administered with vehicle control with tissues collected from three mice on day 1 and day 32 of the study. The expression of key genes of interest, BCL2, BDNF, TIMP1, MMP-9, MMP-2, TNFα, IL-1ß, and IL-6R were assessed using real time polymerase chain reaction. Levels of neurogenesis were determined through immunofluorescent staining of doublecortin (DCX). The density of microglia and astrocytes were assessed using immunofluorescence staining of Iba1 and GFAP respectively. 5-FU treatment caused significant decreases to DCX staining at acute timepoints (p = 0.0030) which was positively correlated with BCL2 expression levels. An increase to microglial density was observed in the prefrontal cortex (p = 0.0256), CA3 region (p = 0.0283), and dentate gyrus (p = 0.0052) of the hippocampus at acute timepoints. 5-FU caused increases to astrocyte density, across multiple brains regions, at subacute and chronic timepoints which were positively correlated with TNFα, TIMP-1, MMP-2, and IL-6R expression. This study has identified acute objective neuroinflammatory changes suggesting that the role of early intervention should be explored to prevent the development of neuropsychological deficits in the longer-term following chemotherapy.
