Protecting the brain during prolonged seizures

A right-hand facial profile in black with a grey-blue brain shown, on a royal blue background.  The centre of the brain is 'lit' to indicate inflammation. Ref: www.dreamstime.com

Status epilepticus is defined as a seizure or series of seizures that last more than 30 minutes, without full recovery of consciousness during this time period. It affects up to 30,000 people in the UK each year and can be caused by several factors, including inadequately controlled epilepsy (responsible for approximately half of cases), head trauma, infections of the brain, stroke and certain drugs.

Status epilepticus triggers a chain of inflammatory reactions in the brain, as a means of protecting it from the insult. However, some of the signalling molecules that mediate this response can also cause brain injury if they act for too long –  although this usually only becomes noticeable some weeks after the status epilepticus event. In some cases a person might even die, even though their episode was a number of weeks earlier. Researchers at the University of Utah are interested in this delay between status epilepticus and clinical damage, and have been examining the inflammatory pathways that are responsible for it. In a recent study they explored whether, by blocking the action of a specific inflammation-promoting molecule just after status epilepticus, subsequent brain damage could be reduced or even prevented.

For this study, the group decided to focus on a molecule known as prostaglandin E2, which is involved in a range of processes including inflammation, and acts by binding to four receptors – EP1, EP2, EP3, and EP4. EP2 is the most common of these receptors seen in the brain, and here the prostaglandin E2-EP2 interaction has been shown to help the normal development of neurons. However, recent evidence has also linked prostaglandin E2-EP2 signalling to neuronal damage/death during brain inflammation, and this made the researchers wonder if this pathway was also responsible for the damage associated with status epilepticus.

In order to test this, the scientists obtained two groups of rodents, group one and group two, and induced status epilepticus in both using a drug known as pilocarpine. Four hours after status epilepticus induction, they treated group one only with a compound called TG6-10-01, which blocks EP2 and prevents prostaglandin E2 from binding to it.  TG6-10-01 was also administered to group one 21 and 30 hours after status epilepticus induction. The team then observed both groups and noted the one-week survival rate in each, along with other factors such as weight and nesting behaviour (indicators of brain functionality).

The scientists found that 90% of the animals in group one (that received TG6-10-01), but only 60% of those in group two (that did not receive TG6-10-01), survived for one week after status epilepticus induction. They also noticed that four days after status epilepticus induction all of group one displayed normal nest-building behaviour, but that more than a quarter of the animals in group two were unable to build nests. Furthermore, when they examined the brains of the animals more closely, the team saw that the TG6-10-1-treated group had significantly lower levels of inflammatory signalling molecules and less brain injury than the untreated group.

These findings are promising because, if replicated in humans, it may be possible to develop a drug that can reduce the damage to the brain following prolonged seizures.  In the longer term, this may also prove beneficial for people with drug-resistant epilepsy who experience numerous seizures each day.

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