Inositol phosphatase INPP4A inhibits the apoptosis of in vitro neurons with characteristic of intractable epilepsy by reducing intracellular Ca²⁺ concentration

Epilepsy is a chronic neurological disorder characterized by recurrent seizures. Seizures can be controlled for most epilepsy patients after drug therapy, but at least 20% of patients develop intractable epilepsy (IE). The mechanism by which IE causes neuronal damage has not been completely understood. Inositol polyphosphate 4 phosphatase (INPP4A), a magnesium-dependent phosphatase, is shown to be associated with glutamate excitotoxicity. Herein, we show that INPP4A plays an essential role in seizure-induced neuronal apoptosis using an in vitro IE neuron model. In this model, INPP4A expression significantly decreased compared to normal neurons. Our results showed that overexpression of INPP4A significantly inhibited LDH activity and increased cell viability while knockdown of INPP4A markedly increased LDH activity and inhibited cell viability. Similarly, overexpression of INPP4A significantly enhanced G1 phase transition to S phase and inhibited apoptosis while knockdown of INPP4A significantly inhibited cell cycle progression and increased apoptosis in IE neurons. Furthermore, INPP4A-mediated inhibition of apoptosis might be associated with reduced intracellular Ca²⁺ concentration. Our findings thus support the results of the previous in vivo studies that INPP4A is linked to the pathogenesis and progression of intractable epilepsy, which suggest that INPP4A may be an important target against epilepsy, especially IE.