Manganese and Epilepsy: Brain Glutamine Synthetase and Liver Arginase Activities in Genetically Epilepsy Prone and Chronically Seizured Rats

Abstract

Low blood manganese (Mn2+) concentration is associated with epilepsy in humans and rats. The low Mn2+ concentration is attributed by some investigators to the seizure activity associated with the epilepsy, whereas others propose that the low Mn2+ concentration may be secondary to genetic mechanisms underlying the epilepsy. To begin to differentiate between these possibilities, Mn(2+)-binding enzymes of liver and brain (i.e., arginase and glutamine synthetase, respectively) were assayed in rats exposed to chronically induced seizures and in genetically epilepsy-prone rats (GEPRs). Chronic seizures caused a decrease in whole blood Mn2+ levels but did not affect brain Mn2+ concentrations. Arginase activity was increased in livers of rats with chronic seizure as compared with controls, but this difference was eliminated when Mn2+ was added to the assay. Brain glutamine synthetase activity was unaffected by chronic seizures, but the activity of this enzyme was significantly lower in GEPR brain than in control brain. Liver arginase activity tended to be lower in GEPRs, although the difference was not statistically significant. These data indicate that seizures affect liver arginase activity through changes in liver Mn2+ concentration, but GEPRs show abnormalities in Mn(2+)-dependent enzymes apparently independent of seizure activity.

Nutritional Requirements for Manganese

“…The high intakes of Mn did not affect glutamine synthetase activity in the brain or seizure occurrence. Nonetheless, Liang et al (2012) 61 supported the findings of Carl et al 68 when they examined the role of Mn deficiency in inducing epilepsy in mice. Animals with low MnSOD activity exhibited increased risk for epileptic seizures that was attributed to oxidative stress, with subsequent mitochondrial dysfunction.…”

“…It is conceivable that Mn is related to epileptic seizures by affecting arginase activity in the liver. 68 In contrast, Critchfield and others 69 investigated the effect of Mn supplementation on seizure development in the offspring of two groups of pregnant mice fed 45 (control) and 1000 mg Mn g À1 diet, respectively. The high intakes of Mn did not affect glutamine synthetase activity in the brain or seizure occurrence.…”

The Role of Autophagy Dysregulation in Manganese-Induced Dopaminergic Neurodegeneration

“…Mn is necessary for a variety of metabolic functions, including lipid, protein, and carbohydrate metabolism, and it serves as a cofactor for various enzymes, including the antioxidant enzyme superoxide dismutase (SOD), as well as enzymes involved in neurotransmitter synthesis and metabolism (Carl et al 1993; Keen et al 2000; Johnson and Giulivi 2005; Aschner et al 2007). However, exposure to high levels of Mn may lead to a neurological disorder that shares many similarities with Parkinson’s disease (PD), and is referred to as manganism.…”

Manganese uptake into rat brain during development and aging

“…Another manganoprotein is mitochondrial superoxide dismutase (Keen et al, 1984). Mn deficiency and the ensuing low Mn concentration in the blood are known to be associated with epilepsy in both humans and experimental animals (Carl et al, 1993). Moreover, Mn ions may be involved in the processes dynamically coupled to the electrophysiological activity of neuronal axons; we demonstrated that Mn is released with neurotransmitters into the extracellular space during stimulation with high K ϩ (Takeda et al, 1998d).…”