Impact of prenatal tramadol exposure on cerebral and cerebellar development and amyloid precursor protein expression in newborn mice

Abstract

Tramadol is a widely prescribed analgesic for pain management in adults, but its safety during pregnancy remains a subject of concern. While previous research has highlighted potential risks associated with Tramadol use during gestation, there is a need for a comprehensive investigation into its effects on foetal brain development. This preclinical study sought to address this gap in knowledge by examining the impact of Tramadol exposure on the cerebral and cerebellar cortices in a murine model. Pregnant mice were subjected to controlled exposure to varying doses of Tramadol during the initial stages of gestation. The foetal brains were examined through a combination of histopathological analysis, assessment of apoptotic changes, and evaluation of amyloid precursor protein (APP) expression. These investigative methods allowed for a detailed examination of structural alterations, cell death patterns, and molecular changes within the foetal brain tissues. The study’s findings were notable for several significant observations. Firstly, there was clear evidence of global shrinkage within the cerebral and cerebellar cortices of foetuses exposed to Tramadol. This shrinkage was associated with disrupted cellular organization, marked apoptosis of neural cells, and a notable upregulation in the expression of APP, particularly within the cerebral cortex. Specifically, a 23% reduction in cerebral cortex size was observed in Tramadol-exposed foetuses compared to the control group. Furthermore, a dose-dependent relationship was established, indicating that higher Tramadol doses corresponded to more pronounced alterations in foetal brain structure and molecular profile. Prenatal tramadol treatment induces neurodegenerative changes in newborn cerebellum with agenesis in the Purkinje cells layer and up regulation of APP in response to the neurotoxic effect that could be considered a neuroprotective role for neurons.

Keywords

• Amyloid precursor protein
• apoptosis
• cerebellar cortex
• purkinje cells agenesis