The neuroprotective role of melatonin in a gestational hypermethioninemia model

Abstract

Elevated levels of methionine in blood characterize the hypermethioninemia, which may have genetic or non‐genetic origin, as for example from high protein diet. Born rats from hypermethioninemic mothers presented cerebral oxidative stress, inhibition of Na+,K+‐ATPase, memory deficit and ultrastructure cerebral changes. Melatonin is a hormone involved in circadian rhythm and has antioxidant effects. The aim of this study was to verify the possible neuroprotective effects of melatonin administration in hypermethioninemic pregnant rats on damage to biomolecules (Na+,K+‐ATPase, sulfhydryl content and DNA damage index) and behavior (open field, novel object recognition and water maze tasks), as well as its effect on cells morphology by electron microscopy in offspring. Wistar female rats received methionine (2.68 μmol/g body weight) and/or melatonin (10 mg/kg body weight) by subcutaneous injections during entire pregnancy. Control rats received saline. Biochemical analyzes were performed at 21 and 30 days of life of offspring and behavioral analyzes were performed only at 30 days of age in male pups. Results showed that gestational hypermethioninemia diminished Na+,K+‐ATPase activity and sulfhydryl content and increased DNA damage at 21 and 30 days of life. Melatonin was able to totally prevent Na+,K+‐ATPase activity alteration at 21 days and partially prevent its alteration at 30 days of rats life. Melatonin was unable in to prevent sulfhydryl and DNA damage at two ages. It also improved DNA damage, but not at level of saline animals (controls). Regarding to behavioral tests, data showed that pups exposed to gestational hypermethioninemia decreased reference memory in water maze, spent more time to the center of the open field and did not differentiate the objects in the recognition test. Melatonin was able to prevent the deficit in novel object recognition task. Electron microscopy revealed ultrastructure alterations in neurons of hypermethioninemic at both ages of offspring, whose were prevented by melatonin. These findings suggest that melatonin may be a good neuroprotective to minimize the harmful effects of gestational hypermethioninemia on offspring.

Effect of Methionine Diet on Metabolic and Histopathological Changes of Rat Hippocampus

“…Remarkably, disruption of microtubule environment is thought to be an important parameter, which potentially can lead to the progressive neurodegenerative process. Extensive brain damage, as well as an oxidative dysbalance, has also been shown on the animal model of gestational hypermethioninemia [50].…”

“…One limitation of this study was in the actual measurement of metabolites, because their level could fluctuate in chronic conditions due to occurrence of cytotoxic oedema (tissue water), which could result in a lack of correlation between 1H MRI and histological data [50]. Furthermore, different vulnerability to acute or chronic insults in the hippocampal areas [38] could also influence the actual metabolic ratio.…”

Light and Circadian Signaling Pathway in Pregnancy: Programming of Adult Health and Disease

“…As shown in Table 2, rodents have been the dominant animal species used. Various developmental programming models have been examined, including maternal caloric restriction [92], L-NAME induced preeclampsia [98], a maternal high-fructose diet [101], maternal hyperhomocysteinemia [126], maternal phenytoin exposure [127], a maternal high-fructose diet plus a post-weaning high-salt diet [128], maternal constant light exposure [56,108], a maternal high methyl-donor diet [100], prenatal GC exposure [69,112,129,130], and maternal hypermethioninemia [131]. These environmental insults lead to adverse offspring outcomes including cognition deficits [126], neurobehavioral dysfunction [106,127], hypertension [56,92,98,100,101,113], and liver steatosis [129,130].…”

“…Protected hippocampal morphology in 16-week-old rat offspring [70] Drinking water Prevented hypertension and increased nephron number in 16-week-old rat offspring [113] Drinking water Protected liver steatosis in 16-week-old rat offspring [129] Prenatal GC exposure plus post-weaning high-fat diet Drinking waterDrinking water Prevented hypertension in 16-week-old rat offspring [109] Protected liver steatosis in 6-month-old rat offspring [130] Maternal hypermethioninemia Subcutaneous injection Protected impaired recognition and neurons in 30-day-old rat offspring [131] L-NAM E = N G -nitro-L-arginine methyl ester. GC = glucocorticoid.…”

Methionine Diet Evoked Hyperhomocysteinemia Causes Hippocampal Alterations, Metabolomics Plasma Changes and Behavioral Pattern in Wild Type Rats

“…Additionally, experiments with gestational, neonatal or adults hMet with various duration on mice or rats show [ 12 ] an increased number of TUNEL+ cells with the increase in autophagosomes, apoptosis rates, DNA damage and caspase activity [ 59 , 60 , 61 ]. In our experimental design, TUNEL assay was not able to unequivocally detect statistically significant changes in the CA1 region, likely due to the duration of Met treatment (four weeks).…”