The approach we describe of identifying changes in gene expression during epileptogenesis in critical brain regions and then examining the functional effect of preventing or augmenting these changes, has been applied to a number of genes as described below.
Galanin is a bioactive compound that co-exists with classical neurotransmitters and often inhibits their release. Galanin mediates its action via three types of G protein-linked receptors GaR1-3. It is abundant in several brain structures including hippocampus, where its action is predominantly inhibitory.44
In animal models of SE, there is an acute reduction in the levels of galanin in the hippocampus.44
Galanin injection before induction of SE shortenes the duration of SE,44
whereas, galanin knock out mice have an increased propensity to develop SE.45
Using a gene therapy approach, Haberman and colleagues46
showed that injection of AAV containing coding sequence for active galanin peptide into inferior collicular cortex increased the threshold for seizure generation to electrical stimulation. A recent study by Kanter-Schlifke and colleagues,47
showed that overexpression of galanin by injection of AAV containing a galanin gene in hippocampus decreased duration of afterdischarges and increased the latency to develop generalized seizures in the kindling model of epilepsy. A more direct approach to increase the activity of galanin is to use galanin receptor agonists that can cross the blood brain barrier. Recently galnon, a low-molecular weight (677 Dalton) galanin receptor ligand, has been shown to affect various physiological as well as pathological functions.48
Galnon has been shown to have anticonvulsant activity in the pentylenetetrazol induced seizure model, where galnon injection reduced the seizure score and increased the seizure latency.49
Neuropeptide Y (NPY) is a peptide that has been associated with a number of biologically important functions such as learning and memory. NPY mediates its action through six receptors (Y1-6) that belong to the G-protein coupled superfamily. A number of studies carried out in different animal models of epilepsy have observed that there is an increase in NPY expression in the mossy fiber pathway of the hippocampus suggesting a modulatory role of NPY in epileptic activity.50
Also, mice that lack NPY have a reduced threshold to develop seizures with pentylenetetrazol and develop spontaneous seizures.51
A recent study by Noe and colleagues52
showed that rats that were injected with AAV containing an NYP gene 14 weeks after SE induction halted the progression of seizure activity.
Adenosine is an inhibitory modulator that mediates it action through four G-protein coupled receptors A1
. Decreased adenosine levels53
and long-term reduction in A1
have been observed in different animal models of epileptogenesis. Adenosine antagonists have been shown to reduce the threshold for seizure development.53
In the hippocampal kindling model of epilepsy, rats that were implanted with myoblast grafts that were engineered to release adenosine by inhibiting adenosine kinase, an enzyme that converts adenosine to adenosine 3’,5’-monophosphate, reduced seizure duration for 3 weeks after transplantation.55
Similarly, implantation of human mesenchymal stem cells transduced with lentivirus containing RNAi against adenosine kinase in the hippocampus of mice resulted in a 35% reduction in seizure duration following kainic acid injection compared to control mice that were implanted with scrambled control sequence.56
In another recent study, Wilz and colleagues57
showed that adenosine released from implants over a period of 14 days inhibited development of epilepsy in the kindling model. These studies provide a strong rationale for use of adenosine augmentation as a therapy for intractable epilepsy.
Glial Cell line-Derived Neurotrophic Factor (GDNF) is a member of GDNF family of trophic factors58
that has been shown to increase following seizures59
and intraventricular infusion of GDNF has been shown to suppress seizures in various animal models of epilepsy.60,61
A recent study by Kanter-Shilfke and colleagues62
showed that overexpression of GDNF using recombinant adeno-associated viral (rAAV) vector suppressed generalized seizure activity but could not prevent kindling epileptogenesis.