Hyperglycemia induces histological abnormalities and dysregulates angiotensin-converting enzymes and inflammatory signaling in zebrafish brain: Possible relationship with memory impairment

Abstract

<title>Abstract</title> Dysregulation of renin-angiotensin system (RAS), through the actions of angiotensin-converting enzymes significantly impacts inflammatory responses. Recent studies have demonstrated the relevance of RAS in Coronavirus Disease 2019 (COVID-19), where outcomes worsen in diabetic patients. We investigate the effects of hyperglycemia on RAS components and inflammatory gene expression in adult zebrafish brain. Hyperglycemia was induced by exposing zebrafish to a 111 mM glucose solution for 14 days. Behavioral tasks were conducted to evaluate learning/memory and anxiety-like behavior. After fasting, blood glucose levels were measured, and brain collected for histological and q-RT-PCR analyses. Exposure to glucose resulted in a significant hyperglycemic state, inducing anxiety-like phenotypes and impairing learning and memory. These alterations were followed by an upregulation of <italic>ace</italic> and a downregulation of <italic>ace2</italic> brain transcripts. Additionally, there was an increase in the transcript levels of the gene <italic>adam17a.</italic> Furthermore, hyperglycemia increased the transcript levels of <italic>il-6, il-10</italic>, and <italic>il-1β</italic>, along with a decrease in <italic>rela</italic> transcripts. Several histological abnormalities were found in the telencephalon, cerebellum and optic tectum of hyperglycemic fish, including neuronal and synaptic loss, gliosis, edema and necrosis. Collectively, our results demonstrate that hyperglycemia significantly disrupts behavioral and cognitive functions in adult zebrafish. These conditions correlate with dysregulated expression of critical components of RAS and inflammatory markers, suggesting a potential neuroinflammatory pathway that may underlie the observed neurodegenerative effects in brain. The dysregulation of angiotensin-converting enzymes signaling, which play critical roles in the pathophysiology of COVID-19, may exacerbate inflammation and contribute to the neurological complications associated with the disease.