Metabolic manipulation of neural tissue to counter the hypersynchronous excitation of migraine and epilepsy.

Very prominent in the large biochemical data bank on epilepsy, is the almost "universal" finding that a familial or environmental predisposition towards epilepsy, as well as the earliest signs preceding other forms of hypersynchronous excitation, coincide with an altered glutamate metabolism. Hence, it has become increasingly apparent that glutamate occupies a central position in the development of epilepsy or in the onset of a migraine incident. The importance of glutamate is explained by a variety of functions in the CNS: as a dominant constituent of many proteins, by its intermediary role in linking energy metabolism to that of many other amino acids, and as the virtually exclusive precursor of GABA. Moreover, glutamate serves as the primary substrate in ammonia detoxification and the product, glutamine, actively participates in CSF water homeostasis. Finally, by its direct electrophysiological and metabolic actions on neurons and glia, via at least four distinct types of receptor proteins, glutamate is implicated in a number of critical mechanisms of information. These include neuronal excitatory modulation, intracellular Ca2+ redistribution, and key metabolic (phosphorylation) mechanisms. The phenomena, when exaggerated due to excessive extracellular glutamate levels, may cause pathological effects such as hypersynchrony--epilepsy, Spreading Depression-migraine, high internal Ca(2+)--damage, impaired phosphorylation/dephosphorylation-necrosis, among others. Not surprising therefore that severe epilepsy may eventually cause CNS cytoarchitectural and metabolic damage, or conversely, that neural tissue trauma not infrequently gives rise to epilepsy many years later. Both conditions are associated with a persistent, excessive leakage or release of glutamate into the extracellular milieu. An electrophysiological and neurochemical commonality between migraine and epilepsy has also been noted.(ABSTRACT TRUNCATED AT 250 WORDS)