Related Experiment Video
Updated: Jul 31, 2025
Early Pathological and Magnetic Resonance Detection of Cerebral Injury Using a Rat Model of Neonatal Hypoxic Ischemic Encephalopathy
Published on: October 28, 2022
Neurometabolic changes in a rat pup model of type C hepatic encephalopathy depend on age at liver disease onset
Dunja Simicic1,2, Veronika Rackayova3,4, Olivier Braissant5
1CIBM Center for Biomedical Imaging, Lausanne, Switzerland. dunja.simicic@epfl.ch.
Insights
Neonatal onset chronic liver disease (CLD) in rats at post-natal day 15 causes distinct brain metabolic changes, including delayed glutamine increase and altered lactate levels, compared to later onset. These findings highlight age-dependent vulnerabilities in hepatic encephalopathy (HE).
Area of Science:
- Neuroscience
- Hepatology
- Biochemistry
Background:
- Chronic liver disease (CLD) can lead to hepatic encephalopathy (HE), impacting brain function.
- Children with CLD may face unique developmental vulnerabilities.
- Understanding age-specific neurometabolic changes is crucial for pediatric HE research.
Purpose of the Study:
- To investigate the longitudinal neurometabolic and behavioral effects of early-onset CLD (post-natal day 15) in rats.
- To compare the brain's response to CLD in rats with neonatal onset versus later onset (post-natal day 21).
- To utilize high-field proton Magnetic Resonance Spectroscopy (¹H MRS) for detailed metabolic analysis.
Main Methods:
- Bile Duct Ligation (BDL) was used to induce CLD in Sprague-Dawley rats at post-natal day 15 (p15).
- Longitudinal ¹H MRS was employed to monitor brain metabolite changes.
- Plasma biochemistry (bilirubin, ammonium) was analyzed.
- Results were compared to a previously published cohort of rats with CLD induced at post-natal day 21 (p21).
Main Results:
- Rats with p15 CLD exhibited typical CLD signs (elevated bilirubin, ammonium) and HE-related brain metabolic changes (glutamine increase, osmolytes decrease).
- Compared to p21 CLD rats, p15 rats showed delayed brain glutamine increase and a milder decrease in total choline.
- Neonatal onset CLD resulted in an earlier increase in brain lactate and a distinct antioxidant response in p15 rats compared to p21 rats.
Conclusions:
- Early-onset CLD (p15) in rats induces unique neurometabolic alterations, including delayed glutamine changes and differential lactate responses, compared to later onset.
- These findings suggest age-dependent neurodevelopmental impacts of CLD and HE.
- The study raises questions about potential missed changes in human pediatric HE due to current ¹H MRS limitations.
Abstract:
Chronic liver disease (CLD) is a serious condition where various toxins present in the blood affect the brain leading to type C hepatic encephalopathy (HE). Both adults and children are impacted, while children may display unique vulnerabilities depending on the affected window of brain development.We aimed to use the advantages of high field proton Magnetic Resonance Spectroscopy (1H MRS) to study longitudinally the neurometabolic and behavioural effects of Bile Duct Ligation (animal model of CLD-induced type C HE) on rats at post-natal day 15 (p15) to get closer to neonatal onset liver disease. Furthermore, we compared two sets of animals (p15 and p21-previously published) to evaluate whether the brain responds differently to CLD according to age onset.We showed for the first time that when CLD was acquired at p15, the rats presented the typical signs of CLD, i.e. rise in plasma bilirubin and ammonium, and developed the characteristic brain metabolic changes associated with type C HE (e.g. glutamine increase and osmolytes decrease). When compared to rats that acquired CLD at p21, p15 rats did not show any significant difference in plasma biochemistry, but displayed a delayed increase in brain glutamine and decrease in total-choline. The changes in neurotransmitters were milder than in p21 rats. Moreover, p15 rats showed an earlier increase in brain lactate and a different antioxidant response. These findings offer tentative pointers as to which neurodevelopmental processes may be impacted and raise the question of whether similar changes might exist in humans but are missed owing to 1H MRS methodological limitations in field strength of clinical magnet.
