Milacemide stimulates deficient glial Na+, K+-ATPase in freezing-induced epileptogenic cortex of cats

Effect of Milacemide on Audiogenic Seizures and Cortical (Na+, K+)‐ATPase of DBA/2J Mice

“…Effect of milacemide administered in vivo (from 0 to 1,000 mg/kg) to DBN2J mice aged 20-22 days. The severity score is defined from 0 to 4 (Schreiber et al, 1980): 0, no response; 1, wild run; 2, clonic phase; 3, tonic phase; and 4, death; p < 0.01, n = 9-16. in basal activity measured at 3 mM K + could be observed between the two strains, supporting previous results (Reichart, 1975;Rosenblatt et al, 1976, Palayoor andSeyfried, 1984;Guillaume et al, 1990~). In C57BL/6J mice but not in DBA/2J mice, (Na+ ,K+)-ATPase activity was increased from 3 to 18 mM K + .…”

“…These changes in (Na+,K+)-ATPase activities are observed at in vitro concentrations of MLM > 10 mg/L. In another study, MLM administered in vitro restored the physiologic K + activation of abnormal glial (Na+ ,K+)-ATPase of epileptogenic cortex of cats with a freeze lesion (Laschet et al, 1990).…”

“…Abnormalities of cortical (Na + ,K+)-ATPase that could be responsible for the spread of seizures from brainstem to the cortex have been previously described in this model (Hertz et al, 1974, Formby, 1975Woodbury et al, 1984. (Na+ ,K+)-ATPase is specifically altered in the nonneuronal or glial membranes, reducing its ability to clear high K + concentrations from the extracellular space during neuronal hyperactivity (Guillaume et al, 1990~). Thus, abnormal glial (Na+ ,K+)-ATPase of DBN2J mice may contribute to the ictal expression of audiogenic seizures by allowing K + to accumulate in the extracellular space of the cortex.…”

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

“…Indeed, the astrocytic enzyme exhibits higher transport capacity and lower affinity for extracellular K + compared with neuronal NKA, the latter being mainly activated by increases in intracellular Na + and already saturated for K + even at basal extracellular K + concentration (see DiNuzzo et al, 2012, 2013). In epileptic tissue, kinetic response to K + and K + removal capacity of astrocytic but not neuronal NKA have been found to be down-regulated (Grisar, 1984; Grisar and Delgado-Escueta, 1986; Grisar et al, 1983; Grisar et al, 1992; Guillaume, 1988; Laschet et al, 1991; Laschet et al, 1990). This decrease in enzyme activity seems to be often paralleled by changes in the expression and subunit composition of astrocytic NKA that at first glance are mutually incompatible.…”