Epilepsy is a chronic neurologic disorder affecting up to 1% of
mankind.
It is defined by recurrent spontaneous seizure-attacks
which, in a proportion of patients, are generated by
synchronous firing of localized groups of neurons – so
called epileptic foci.
Temporal lobe epilepsy (TLE) is the most common type of
epilepsy in adults that also affects children. It is
characterized by the presence of epileptic foci located
within hippocampal formation, amygdala or temporal neocortex.
In most patients, TLE appears to be caused by a single brain
insult, such as seizure episode, trauma or infection,
occurring early in life. This is followed by a seizure-free
(latent) period, that can last for many years. At some
point, a fully expressed epileptic disorder occurs and, if
not properly controlled, it leads, over time, to progressive
cognitive impairment. Unfortunately, in as much as 70% of
patients, TLE is intractable by pharmacologic treatment and
requires brain surgery for seizure control.
Temporal lobe epilepsy is frequently associated with a distinctive histological
alteration, called hippocampal sclerosis. This is characterized by massive loss
of the hippocampal pyramidal neurons. On the other hand, there is no loss of the
granule neurons; instead there is pronounced aberrant sprouting of their axons
(mossy fibers) that reenter the granule cell layer and likely make recurrent
excitatory connections. The latter phenomenon is a prominent example of aberrant
neuronal plasticity. In animals, the condition that closely resembles human TLE
models is a rodent epilepsy that follows kainate-induced status epilepticus or
chronic subthreshold excitatory stimulation called kindling.
In order to explore novel therapeutic avenues for TLE, scientists from the
laboratories of Neuromorphology, and Molecular Neurobiology, of the Nencki
Institute, investigated the role of extracellular proteolysis in the brain of
animals subjected to experimental epilepsy. Synaptic extracellular proteolysis
is a novel important mechanism mediating plasticity of synapses. The major
proteolytic enzyme in the brain is matrix metalloproteinase 9 (MMP-9).
Researchers from the Nencki Institute have discovered that MMP-9 is a synaptic
enzyme playing key role in the development of epilepsy in rats and mice. (Wilczynski i
wsp. J Cell Biol 180: 1021-1035, 2008).
In particular, mice that had been genetically engineered to be deficient of
MMP-9 were more resistant to epileptogenesis than normal mice. Conversely, rats
with increased levels of MMP-9 in neurons were more prone to develop epilepsy
than normal ones. The findings significantly increase our knowledge about the
epilepsy pathogenesis, and indicate possible new directions of research on TLE
therapy.
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