SPMs could have an effect on epileptogenesis
Treatment of epilepsy is based on drugs that treat the symptoms rather than the underlying mechanisms of the disease. There is no treatment to prevent seizures or improve prognosis.
The mechanisms of epileptogenesis involve the production of the proinflammatory cytokines (interleukin 1b (IL-1b) and tumour necrosis factor-α (TNF-α)), which contribute to generating seizures in animal models. Specialised pro-resolving mediators (SPMs) play a key role in controlling inflammation, but this has not been explored in epileptogenesis. Recently, an international team of researchers used a murine epilepsy model to show that SPMs are activated in the epileptic state hippocampus before the onset of spontaneous seizure (as shown by the presence of 5-lipoxygenase, 15-lipoxygenase, two key enzymes in the biosinthesis pathway of SPMs, and lipoxin A4 and chemerin receptors), but with a notable delay compared to the neuroinflammatory response. This supports the hypothesis that the neuroinflammatory response persists due to a failure in the participation of SPMs during epileptogenesis. Lipidomic analysis showed that the levels of lipid mediators needed to resolve neuroinflammation were also significantly altered in the hippocampus during epileptogenesis, with a change in the biosynthesis of various families of SPMs, including protectin D1.
Intracerebroventricular injection of protectin D1 during epileptogenesis reduced expression of IL-1b and TNF-α and this was associated with a notable improvement in weight recovery and cognitive deficiency (based on an object recognition test). On average, the frequency of spontaneous seizures was reduced by half and the mean duration of the seizure was shortened by 40% after discontinuing treatment. In total, treatment with protectin D1 produced a three-fold reduction in seizure time.
These observations show that resolution pathway function is impaired in epilepsy. The fact that boosting the endogenous resolution response produces significant improvements in seizures opens the door to new treatments focussed on resolving the neuroinflammation involving SPMs.