Epilepsy amino acids

NTs it is now appropriate to consider what evidence there is for a malfunction of NT activity in epilepsy, particularly in those responsible for primary excitation and inhibition, i.e. the amino acids. Before doing so the epileptogenesis of absence seizures (petit mal) justifies separate consideration. 

These approaches will be considered in respect of the different NTs although most interest has centred on the amino acids not only because of their possible involvement in the pathology, as already emphasised, but because increased neuronal activity in epilepsy must reflect, even if it is not initiated by, augmented glutamate and/or reduced GABA function. 

There is no shortage of AEDs (Fig. 16.7) but it is not appropriate to consider them in detail in this text other than to see how their mechanisms of action comply with and illustrate those proposed above (Fig. 16.6) for the control of epileptic seizures (see Meldrum 1996 Upton 1994). The decision on which drug to use depends not only on their proven efficacy in a particular type of epilepsy (some drugs are inactive in certain forms) but also what side-effects they have—many are sedative — how they interact with other drugs and how often they need to be taken. Compliance is a problem over a long period if dosing is required more than once a day. It is probably acceptable in reality, if not scientifically, to divide the drugs into old-established AEDs and new AEDs. Only the latter have been developed chemically to modify the known synaptic function of the amino acids. 

R. O., Plasma amino acids in childhood epileptic encephalopathies, Epilepsy Res., 34, 221, 1999. 

In addition to epilepsy, reduced GABA has been recorded in patients with unipolar depression, following alcohol withdrawal and in hepatic encephalopathy. The finding that the concentration of GABA is reduced in depression is unexpected as there is no evidence that the disorder is associated with an increased cortical excitability. One possibility is that the reduction in GABA is a reflection of a decreased availability in its excitatory amino acid precursor glutamate. 

In addition to epilepsy, neuronal death due to the toxic effects of glutamate has also been implicated in cerebral ischaemia associated with multi-infarct dementia and possibly Alzheimer s disease. With the plethora of selective excitatory amino acid receptor antagonists currently undergoing development, some of which are already in clinical trials, one may expect definite advances in the drug treatment of neurodegenerative disorders in the near future. 

Sveinbjornsdottir S, Sander JWAS, Upton D,etal(1993) The excitatory amino acid antagonist d-CPP-ene (sdz eaa-494) in patients with epilepsy. Epilepsy Res 16 165-174 Takano T, Lin JH, Arcnino G, et al (2001) Glntamate release promotes growth of malignant gliomas. Nat Med 7 1010-1015... 

Dingledine, R., McBain, C.J., and McNamara, J.O. (1990) Excitatory amino acid receptors in epilepsy. Trends Tharmacol Set 11 334-338. 

A 61-year-old man with epilepsy had altered consciousness after his dose of valproate was increased because of poor seizure control. Electroencephalography showed triphasic waves and high-amplitude delta-wave activity with frontal predominance. Although serum aspartate transaminase and alanine transaminase were normal, the serum ammonium concentration was high at 960 ng/ml (reference range 30-470). Serum amino acid analysis showed multiple minor abnormalities. Valproate was withdrawn. He improved within 4 days... 

McDonald J. W., Garofalo E. A., Hood T., Sackellares C., Gilman S., McKeever P. E., Troncoso J. C., and Johnston M. V. (1991). Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy. Ann. Neurol. 29 529-541. 

Of the various amino acid neurotransmitters which have been implicated in epilepsy, the inhibitory transmitter glycine has been shown to be present in normal concentrations, or even slightly elevated, in the vicinity of the... 

Richards, D. A., Morrone, L. A., and Bowery, N. G. (2000). Hippocampal extracellular amino acids and EEG spectral analysis in a genetic rat model of absence epilepsy. Neuropharmacology 39, 2433-2441. 

Cyclopropyl-(3-amino acid derivatives, (V), having high binding affinities to the a28 subunit of a calcium channel were prepared by Schwarz (4) and used in the treatment of epilepsy. 

Urbanska, E.M., Czuczwar, S.J., Kleinrok, Z., Turski, W.A. (1998). Excitatory amino acids in epilepsy glutamate, neurodegeneration and neuroprotection more pieces in the puzzle. Restor. Neurol. Neurosci. 13 85-115. 

---