Additional pharmacological options in the therapy of generalized epilepsies

Introduction: In generalized epilepsies exists an altered activity of neurotransmitter and neuropeptide concentrations and a disturbance of ion channels in the hippocampus. A completed neuronal network in the hippocampus will be developed, and additional pharmacological options in the antiepileptic therapy will be derived from the neuronal network.

Material and Methods: In the hippocampus, dopaminergic neurons which have a high activity transmit a strong postsynaptic excitatory impulse upon glutaminergic neurons via D2 receptors. The glutaminergic neurons in their turn strongly inhibit serotonergic neurons via NMDA (N-methyl-D-aspartate) receptors. The glutaminergic neurons have as well an excitotoxic function and transmit a strong postsynaptic excitatory impulse via NMDA receptors upon dopaminergic neurons. A high glutamate release can induce epileptic seizures. The serotonergic neurons which have a low activity transmit a weak activating impulse via 5-HT2C receptors upon GABAergic neurons which weakly inhibit dopaminergic neurons via GABAA receptors. A GABA withdrawal can also cause epileptic seizures.

Results: According to the neuronal network, the following drugs with an antiepileptic effect could be given in generalized epilepsies:

• combined GABAA agonists and NMDA antagonists, since the GABAA agonism and the NMDA antagonism stabilize effectively the neuronal network.

• Further antagonists of ionotropic glutaminergic receptors, i.e. KA (kainate) receptor antagonists or AMPA receptor antagonists which inhibit the epileptogenic glutamate release.

• 5-HT2C agonists which enhance GABAergic presynaptic inhibition of dopaminergic neurons.

• Antagonists of the subtype 5 of the metabotropic glutaminergic receptor, mGluR antagonists which enhance serotonin levels by inhibiting the presynaptic glutaminergic inhibition of serotonergic neurons

• A2A adenosine receptor antagonists which enhance serotonin levels by reducing presynaptic inhibition of serotonergic neurons through metabotropic glutaminergic receptors

• Agonists of the neuropeptide Y2 receptor, i.e. NPY2 receptor agonists which inhibit glutamate release.

Conclusion: Additional pharmacological therapies are important, because they could further stabilize the neurotransmitter and neuropeptide alterations in generalized epilepsies. In this context, the neuronal networks should be investigated and could make clearer the coherence of the involved neurons and subreceptors.