The effect of glial glutamine synthetase inhibition on recognition and temporal memories in the rat

Kant, Deepika; Qureshi, Munazah Fazal; Tripathi, Shweta; Pandey, Sweta; Singh, Gunjan; Kumar, Tankesh; Mir, Fayaz Ahmad; Jha, Sushil K.

doi:10.1016/j.neulet.2013.12.033

Cited by 9 publications

(4 citation statements)

References 28 publications

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“…Inhibition of GS activity could improve cognitive function in HE rats 29 . In this study, we found that GS activity significantly increased in the basal ganglia and cortex of HE rats, which was in accordance with a study conducted by Montes S et al .…”

Section: Discussionmentioning

confidence: 98%

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

Liu

Mei

et al. 2017

Sci Rep

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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

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Section: Discussionmentioning

confidence: 98%

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

Liu

Mei

et al. 2017

Sci Rep

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“…Current evidence, however, suggests that (as with glutamate in general) astrocytic factors also may be important in associative learning. For example, inhibition of glutamine synthetase, an astrocytic enzyme that converts glutamate to glutamine and is involved in normal neuronal glutamate transmission (Rothstein and Tabakoff, 1984, Zhou and Danbolt, 2014), disrupts temporal, but not spatial, memory in an associate trace learning task (Kant et al , 2014). In addition, transgenic knockout mice deficient for gliotransmission also demonstrate decreased reinstatement of cocaine CPP, self-administration of cocaine, and cue-induced reinstatement (Turner et al , 2013).…”

Section: Discussionmentioning

confidence: 99%

Ceftriaxone attenuates acquisition and facilitates extinction of cocaine-induced suppression of saccharin intake in C57BL/6J mice

Freet

Lawrence

2015

Physiology & Behavior

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Growing evidence implicates glutamate homeostasis in a number of behaviors observed in addiction such as acquisition of drug taking, motivation, and reinstatement. To date, however, the role of glutamate homeostasis in the avoidance of natural rewards due to exposure to drugs of abuse has received little attention. The aim of the current study was to evaluate the beta-lactam antibiotic, ceftriaxone, which has been shown to normalize disrupted glutamate homeostasis associated with exposure to drugs of abuse, in cocaine-induced suppression of saccharin intake in C57BL/6J mice. Briefly, C57BL/6J mice received daily injections of either 200 mg/kg ceftriaxone or saline. Mice were then given access to 0.15% saccharin for 1 hour and immediately injected intraperitoneally with either saline or 30 mg/kg cocaine; taste-drug pairings occurred every 24 hours for 5 trials followed by a final CS only trial. One week following taste-drug pairings, extinction was evaluated in a series of one- and two-bottle saccharin intake tests. Individual differences in cocaine-induced suppression were observed (i.e., low and high suppressors) with differential effects of ceftriaxone. Ceftriaxone delayed suppression of saccharin intake in high suppressors but prevented suppression in low suppressors. In addition, ceftriaxone history facilitated extinction in the high suppressors. These data suggest that changes in glutamate homeostasis may be involved in the formation and expression of cocaine-induced suppression of saccharin intake in mice.

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“…Similarly, delivery of methionine sulfoximine into the hyperstriatum of chicks prevents memory consolidation, an effect that is reversed by the administration of glutamine, demonstrating the essential contribution of astrocytic GS to learning and the consolidation of memories (Gibbs et al, 1996 ; Hertz et al, 1996 ; Gibbs and Hertz, 2005 ). In rats the inhibition of GS impairs the temporal component of memories (Kant et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Astrocytic Glutamine Synthetase by Lead is Associated with a Slowed Clearance of Hydrogen Peroxide by the Glutathione System

Robinson

Lee

Bishop

et al. 2015

Front. Integr. Neurosci.

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Lead intoxication in humans is characterized by cognitive impairments, particularly in the domain of memory, where evidence indicates that glutamatergic neurotransmission may be impacted. Animal and cell culture studies have shown that lead decreases the expression and activity of glutamine synthetase (GS) in astrocytes, yet the basis of this effect is uncertain. To investigate the mechanism responsible, the present study exposed primary astrocyte cultures to a range of concentrations of lead acetate (0–330 μM) for up to 24 h. GS activity was significantly reduced in cells following 24 h incubation with 100 or 330 μM lead acetate. However, no reduction in GS activity was detected when astrocytic lysates were co-incubated with lead acetate, suggesting that the mechanism is not due to a direct interaction and involves intact cells. Since GS is highly sensitive to oxidative stress, the capacity of lead to inhibit the clearance of hydrogen peroxide (H2O2) was investigated. It was found that exposure to lead significantly diminished the capacity of astrocytes to degrade H2O2, and that this was due to a reduction in the effectiveness of the glutathione system, rather than to catalase. These results suggest that the inhibition of GS activity in lead poisoning is a consequence of slowed H2O2 clearance, and supports the glutathione pathway as a primary therapeutic target.

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The effect of glial glutamine synthetase inhibition on recognition and temporal memories in the rat

Cited by 9 publications

References 28 publications

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

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

Ceftriaxone attenuates acquisition and facilitates extinction of cocaine-induced suppression of saccharin intake in C57BL/6J mice

Inhibition of Astrocytic Glutamine Synthetase by Lead is Associated with a Slowed Clearance of Hydrogen Peroxide by the Glutathione System

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