Repeated electroconvulsive seizure induces c-Myc down-regulation and Bad inactivation in the rat frontal cortex

Abstract

Repeated electroconvulsive seizure (ECS), a model for electroconvulsive therapy (ECT), exerts neuroprotective and proliferative effects in the brain. This trophic action of ECS requires inhibition of apoptotic activity, in addition to activation of survival signals. c-Myc plays an important role in apoptosis of neurons, in cooperation with the Bcl-2 family proteins, and its activity and stability are regulated by phosphorylation and ubiquitination. We examined c-Myc and related proteins responsible for apoptosis after repeated ECS. In the rat frontal cortex, repeated ECS for 10 days reduced the total amount of c-Myc, while increasing phosphorylation of c-Myc at Thr58, which reportedly induces degradation of c-Myc. As expected, ubiquitination of both phosphorylated and total c-Myc increased after 10 days ECS, suggesting that ECS may reduce c-Myc protein level via ubiquitination-proteasomal degradation. Bcl-2 family proteins, caspase, and poly(ADP-ribose) polymerase (PARP) were investigated to determine the consequence of down-regulating c-Myc. Protein levels of Bcl-2, Bcl-XL, Bax, and Bad showed no change, and cleavage of caspase-3 and PARP were not induced. However, phosphorylation of Bad at Ser-155 and binding of Bad to 14-3-3 increased without binding to Bcl-X L after repeated ECS, implying that repeated ECS sequesters apoptotic Bad and frees pro-survival Bcl-XL. Taken together, c-Myc down-regulation via ubiquitination-proteasomal degradation and Bad inactivation by binding to 14-3-3 may be anti-apoptotic mechanisms elicited by repeated ECS in the rat frontal cortex. This finding further supports the trophic effect of ECS blocking apoptosis as a possible therapeutic effect of ECT.

The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy

“…Bcl-2 and bcl-xl were equally expressed in dying and surviving neurons following kainate-induced SE, but bax protein and mRNA expression increased progressively over time in susceptible neurons (Lopez et al, 1999). Unlike the robust increases in c-myc reported here, previous literature suggests no change or a down-regulation of c-myc following repeated electroconvulsive seizures, kainate-induced SE, and kindled seizures (Jeon, WJ et al, 2008; Azuma, Y. et al, 1996; Simonato M. et al, 1991). Cyclin D1 mRNA increases have been reported following transient global ischemia and kainate-induced seizures in neurons vulnerable to cell death in the CA1, CA3, and DG cell layers of the hippocampus (Timsit, 1999) and in the hippocampus of the El mouse, an epileptic mutant, prior to the onset of spontaneous seizures (Murashima, 2007).…”

Antioxidant-Like Effects and Protective Action of Transcranial Magnetic Stimulation in Depression Caused by Olfactory Bulbectomy

“…Electroconvulsive therapy has been associated with activation of intracellular survival signalling pathways. These effects are characterized by increases in neurotrophic factors and other molecules, enhancing the survival and proliferation of neuronal cells and inhibiting apoptotic signals [26,50]. Published findings regarding oxidative stress differ considerably: [40,51] Jornada et al (2007) found that electroconvulsive therapy in mice prompted an increase in neurotrophic factors together with minimal oxidative damage in brain regions.…”

The effect of electroconvulsive seizure on survival, neuronal differentiation, and expression of the maturation marker in the adult mouse hippocampus

“…It has been reported that ECS increases the expression of anti‐apoptotic factor Bcl‐xl in the hippocampus and inactivates the pro‐apoptotic factor Bad in the prefrontal cortex (Jeon et al . ; Kosten et al . ), suggesting that ECS can suppress the apoptotic pathway in the nervous system.…”

“…The suppression of cell death is considered to be one of the mechanisms of the survival effects of ECS. It has been reported that ECS increases the expression of anti-apoptotic factor Bcl-xl in the hippocampus and inactivates the proapoptotic factor Bad in the prefrontal cortex (Jeon et al 2008;Kosten et al 2008), suggesting that ECS can suppress the apoptotic pathway in the nervous system. In fact, it has been reported that ECS prevents neuronal apoptosis after kainic acid-evoked status epilepticus in the hippocampus (Kondratyev et al 2001).…”