Phenylbutyric acid prevents rats from electroconvulsion-induced memory deficit with alterations of memory-related proteins and tau hyperphosphorylation

Electroconvulsive therapy has been commonly applied in the treatment of refractory depression, but its cognitive side effects are noticed and restrict its application. The molecular mechanisms underlying the side effects remain elusive, and there is no efficient prevention. By employing a recognized electroconvulsive shock (ECS) rat model, we found in the present study that ECS induced spatial memory deficits with simultaneous decreases in synaptic proteins of N-methyl-D-aspartate receptor 2A/B (NR2A/B) and postsynaptic density 95 (PSD95), the immediate early gene c-Fos and cAMP response element binding (CREB) proteins, all of which are memory-related proteins. ECS also caused tau hyperphosphorylation at multiple Alzheimer-related phosphorylation sites with activation of glycogen synthase kinase-3β (GSK-3β), Akt and phospho-PKR-like endoreticulum (PERK), and inhibition of protein phosphatase-2A (PP)-2A. Intraperitoneal injection of phenylbutyric acid (PBA), an aromatic short chain fatty acid with the functions of molecule chaperon, prevented rats from the ECS-induced memory deficits, alterations of the memory-associated proteins, and tau hyperphosphorylation. Our data suggest that PBA may be potentially used for attenuating the side effects caused by electroconvulsive therapy.