Approximately one out of a hundred people suffer from epilepsy and one out of twenty suffer a seizure at least once during their lifetime. Seizures occur when many nerve cells in the brain fire in synchrony. In epilepsy, nerve cells or neurons lose their usual rhythm, and ion channels, which have a decisive influence on their excitability, are involved. Therefore, scientists are searching for the causes leading to this simultaneous excitation of brain cells. Now, a study from researchers at the University of Bonn has identified a new mechanism for influencing ion channels in epilepsy, namely, spermine inside neurons dampening the neurons excitability. The team state that their findings may be exploited to develop new therapies for epilepsies. The study is published in The Journal of Neuroscience.
Previous studies show that neurons integrate many inputs together to determine an appropriate output, and sodium channels play a key role in both processes. They play an important role in the excitation of nerve cell axons and signal transfer between various cells. Like a type of door, sodium channels allow sodium ions to flow into nerve cells through tiny pores. They consist of large protein complexes located in the membranes of nerve cells.
Earlier studies from the lab found a large increase in a certain sodium influx which significantly increased the excitability of cells in an epileptic animal model. For this reason, the researchers initially compared the sodium channel proteins from the brains of epileptic rats to those of healthy animals. However, this did not reveal any increased formation of sodium channel proteins, which would have explained the overexcitation of nerve cells. After a long search, the team of researchers found a completely different group of substances, the polyamines, to which spermine belongs. Spermine is produced in cells and plugs the pores of the sodium channels from inside the cell membrane. The current study shows that, in this case, the influx of sodium ions is blocked by spermine and the excitation of the nerve cells is reduced.
The current study shows how much of the seizure-inhibiting substance is present in the nerve cells of rats suffering from epilepsy and compared the values to those of healthy animals. Results show that the amount of spermine in the cells of the hippocampus was significantly reduced in diseased animals as compared to the healthy animals. Data findings show that the reduced spermine in the nerve cell led to increased excitability, with the cells more sensitive to input and generating more output.
The researchers validated these findings by adding spermine back into the cell to compensate for the deficiency in the nerve cells of the epileptic rats. Results show that the increase in sodium currents was reversed and the excitability of the neuron returned to normal. The group explain that the lower level of spermine in the epileptic rat’s brain was evidently caused by an upregulation of spermidine/spermine-N(1)-acetyltransferase, an enzyme which breaks down the spermine and important in the control of sodium channels.
The team surmise that their results could be a potential starting point for novel epilepsy therapies. For the future, the researchers state that if a substance was available to reduce the activity of acetyltransferase back to normal levels, the lack of spermine and thus the symptoms of epilepsy could be mitigated. They go on to stress that more study is needed to reach this target.
Source: University of Bonn