Ammonia exposition during gestation induces neonatal oxidative damage in the brain and long-term cognitive alteration in rats.

Diogo Dominguini,Renata C Gonçalves,João Quevedo,Felipe Dal-Pizzol,Tatiana Barichello,Cristiane Ritter,Lauro Nogueira,Amanda V Steckert,Monique Michels,Dhébora M Dall’Igna

doi:10.1590/0001-3765202020190925

Abstract

Ammonia is involved in the pathogenesis of neurological conditions associated with hyperammonemia, including hepatic encephalopathy. Few is known about the effects of gestational exposition to ammonia in the developing brain, and the possible long-term consequences of such exposure. We aimed to evaluate the effects of ammonia exposure during the gestation and the possible long-term cognitive alterations on pups. Eight female rats were divided into two groups: (1) control (saline solution); (2) ammonia (ammonium acetate, 2,5mmol/Kg). Each rat received a single subcutaneous injection during all gestational period. The brains from 1-day-old rats were obtained to the determination of thiobarbituric acid reactive species (TBARS), protein carbonyl and nitrite/nitrate levels. Some animals were followed 30 days after delivery and were subjected to the step-down inhibitory avoidance task. It was observed a significant increase in protein carbonyl, but not TBARS or nitrite/nitrate levels, in pups exposed to ammonia. Rats exposed to ammonia presented long-term cognitive impairment. Gestational exposition to ammonia induces protein oxidative damage in the neonatal rat brain, and long-term cognitive impairment.

Highlights

Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans (Davuluri et al 2016)
There was no significant increase in thiobarbituric acid reactive species (TBARS) and nitrite/nitrate levels in ammonia-exposed animals when compared to control group (Figures 2b and 2c)
Since oxidative damage in proteins can be associated with cognitive dysfunction it was determined the performance on the inhibitory avoidance task 30 days after delivery

Summary

Introduction

Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans (Davuluri et al 2016). It is involved in the pathogenesis of neurological alterations associated with hyperammonemia, including hepatic encephalopathy (HE) (Skowronska & Albrecht 2012). Ammonia can induce oxidative stress and disturbances of nitric oxide (NO) production, besides, induces astrocytes and microglia activation in the hippocampus, increasing pro-inflammatory cytokines IL-1β and IL-6 (Cagnon & Braissant 2007, Haussinger & Schliess 2008, Hernandez-Rabaza et al 2016). Several general mechanisms are associated with brain injury in the neonatal period and these include increased levels of intracellular calcium, oxidative stress, inflammation, decreased levels of trophic factors, and mitochondrial

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