Felix-Martin Werner


Institute of Neuroscience of Castilla and León Laboratorio de Neuroanatomía, de los Sistemas Peptidérgicos Laboratorio 14 C/Pintor Fernando Gallego, 1, 37007 Salamanca, Spain

Abstract:

Introduction: In generalized epilepsy occurs a disturbance of ion channels and an alteration of neurotransmitters and neuropeptides in the hippocampus, the cortex and the thalamus.

Methods/Materials: In generalized epilepsy alterations of ion channels and neurotransmitter and neuropeptide concentrations can be induced genetically or exogenously.

An enlarged neuronal network is described in order to point out the epileptogenesis as a consequence of the interaction between the corresponding neurotransmitters and neuropeptides.

Results: The neuronal network reads as follows: Dopaminergic neurons in the hippocampus transmit a strong postsynaptic excitatory impulse via D2 receptors to glutaminergic neurons which strongly inhibit serotonergic neurons via NMDA receptors. The glutaminergic neurons have as well an excitotoxic function and transmit a strong postsynaptic excitatory impulse via NMDA, AMPA and kainate receptors to dopaminergic neurons and can enhance epileptogenesis. The serotonergic neurons with a low activity transmit a weak activating impulse via 5-HT2C receptors to GABAergic neurons which weakly inhibit dopaminergic neurons via GABAA receptors. A reduced GABAergic presynaptic inhibition of dopaminergic neurons can cause an epileptic seizure. Other GABAergic neurons weakly inhibit GABAergic neurons via GABAB receptors. In the thalamus, GABAergic neurons weakly inhibit glutaminergic neurons which transmit a strong activating impulse via NMDA receptors to dopaminergic neurons in the cortex. The dopaminergic neurons in the cortex can increase the activity of dopaminergic neurons in the hippocampus via D2 receptors. Galanin containing neurons in the thalamus transmit a weak activating impulse to serotonergic neurons in the hippocampus via Gal1 receptors. Other serotonergic neurons transmit a weak activating impulse to serotonergic neurons via 5-HT7 receptors. Neuropeptide Y containing neurons in the dentate gyrus weakly inhibit glutaminergic neurons via NPY2 receptors and transmit a weak activating impulse to GABAergic neurons via NPY1 receptors. The serotonergic neurons transmit a weak postsynaptic excitatory impulse via 5-HT2C receptors to GABAergic neurons which weakly inhibit adenosine neurons via GABAA receptors. The adenosine neurons with a high activity transmit a strong activiting impulse via A2 receptors to glutaminergic neurons which strongly inhibit serotonergic neurons via the subtype 5 of the glutaminergic metabotropic receptors.

According to the neuronal networks described the following possible pharmacological options could exert an antiepileptic effect:

- Combined GABAA agonists and NMDA antagonists.
- GABAB antagonists, which would enhance GABAergic presynaptic inhibition.
- KA or AMPA receptor antagonists, which would inhibit epileptic glutamate emptying.
- NPY2 receptor agonists, which would inhibit glutamate emptying.
- 5-HT2C receptor agonists.
- Gal1 receptor agonists, which would increase serotonin levels.
- A2 receptor antagonists, which would enhance serotonin levels.
- m5GluR receptor antagonists, which would enhance serotonin levels
- mGlu2/3 receptor agonists, which would reduce glutamate release.
- 5-HT7 receptor agonists, which would increase serotonin levels.
- nAch alpha7 agonists.

Conclusion: It is important to examine neuronal networks in generalized epilepsy in order to optimize a multimodal pharmacotherapy of the disease.