Oral administration of trace element magnesium significantly improving the cognition and locomotion in hepatic encephalopathy rats

Abstract

The therapeutic effects of iron, zinc and magnesium trace elements, as well as rifaximin were investigated and compared in HE rats. In this study, HE rats were treated with either ferrous sulfate (HE-Fe, 30 mg/kg/day), zinc sulfate (HE-Zn, 30 mg/kg/day), magnesium sulfate (HE-Mg, 50 mg/kg/day) or rifaximin (HE-Rf, 50 mg/kg/day), which was mixed with water and administered orally for 61 days. The Morris water maze (MWM) and open-field tests were used to evaluate cognitive and locomotor function. The blood ammonia levels before and after administration of the glutamine challenge test, manganese concentration and glutamine synthetase (GS) activity were measured. Significantly longer MWM escape latencies, less locomotor activity, higher blood ammonia levels, higher brain manganese concentrations and higher GS activity were observed in HE rats. However, HE-Mg and HE-Rf rats had significantly shorter MWM escape latencies, increased locomotor activity, lower blood ammonia, lower brain manganese concentrations and lower GS activity. Partial improvements were observed in HE-Fe and HE-Zn rats. The results indicated that oral administration of magnesium can significantly improve the cognitive and locomotor functions in HE rats by reducing the brain manganese concentration and regulating GS activity.Hepatic encephalopathy (HE) is a major complication of cirrhosis and (or) portal-systemic shunting 1 . Its pathogenesis is not completely clear. It has been suggested that nitrogen metabolism dysfunction may cause neurological symptoms 2 . HE significantly affects the quality of daily life and may ultimately lead to death; however, HE can be reversed with the appropriate treatment 1, 2 . HE patients are known to have higher levels of ammonia in their blood. Thus, current HE treatments focus on non-absorbable disaccharides (e.g., lactulose) or antibiotics (e.g., rifaximin) to reduce ammoniagenesis in the intestines and lower blood ammonia levels 3 . Recent studies showed that trace element concentrations varied in cirrhotic patients with HE 4 . Lower serum zinc, magnesium and iron but higher serum manganese and copper were reported in cirrhotic patients [5][6][7] . Zinc, magnesium, and iron are co-enzymes of a variety of metabolic enzymes. Deficiencies in zinc, magnesium and iron levels may lead to metabolic disorders and negatively impact behavior and cognition [8][9][10] . On the other hand, high manganese levels can be neurotoxic. Excessive levels of manganese lead to cognitive impairments and extrapyramidal symptoms 11 . Oral administration of zinc effectively improves HE symptoms 12 . However, whether oral administration of iron or magnesium is also beneficial is not known. Previous studies demonstrated that trace elements, such as iron and magnesium, can influence manganese absorption in the intestines 13,14 . We hypothesize that iron and magnesium supplementation may improve HE by reducing intestinal manganese absorption and subsequently

Interaction of Manganese and Ammonia in the Brain of Hepatic Encephalopathy Rats

“…As we concluded above, the change in ammonia level did not affect brain Mn content, while the change of brain Mn content affected the ammonia level. By further considering previous studies (17,23), which revealed that MgSO 4 could significantly increase fecal Mn excretion to reduce brain Mn content, we speculated that MgSO 4 decreased the blood ammonia level and brain GLN content by increasing the amount of fecal Mn excretion to decrease the brain Mn content and by regulating brain GS activity.…”

“…The latency and the total time of the NBT were recorded. Therefore, MWM, Y maze, and NBT were performed according to the previous protocols (17)(18)(19)(20).…”

“…Paraffin-embedded tissues were serially sectioned (4 microns). Immunohistochemistry was performed according to previous protocols (17). Sagittal sections of tissue were examined for the presence of GS (rabbit polyclonal antibody; Abcam, United States).…”

“…tive role in eclampsia-like seizure rats via significantly reducing the response of inflammatory cytokines in the cerebrospinal fluid (16). Our previous study found that Mg could reduce intestinal Mn absorption and reduce brain Mn deposition in portal-systemic shunt encephalopathy (PSE) rats (17).…”

Effect of proton pump inhibitors on sympathetic hyperinnervation in infarcted rats: Role of magnesium

“…The dose of omeprazole was based on an oral human dose of 40 mg normalized to body surface area, and it was smaller than previously reported study [ 17 ]. The doses of magnesium sulfate [ 18 ] and famotidine [ 19 ] have been shown effective modulation of the biological activities. The rats were kept in cabinets controlled for temperature, humidity, and light.…”