Glutamate enhances brain damage from ischemia and trauma

The amino acid glutamate is a model agent to demonstrate the significance of neurotoxic mediator compounds in secondary brain damage from trauma, ischemia or other adverse conditions. Intensive research of the role of mediator compounds is clinically worthwile as more specific forms of treatment may emerge for the benefit of afflicted patients. In view of the great number of factors, cytokines, etc., which could play a role, it is mandatory that a mediator function in secondary brain damage is identified according to the stringent requirements established for that purpose. Glutamate has been shown - as is the case for only a few other agents - to meet all the criteria of a mediator of secondary brain damage. An excellent basis is thereby provided for the development of specific methods of antagonization. Although recent progress is impressive indeed, a breakthrough of the treatment of secondary brain damage in patients with head injury or cerebral ischemia by glutamate antagonists has not been accomplished so far. There may be various reasons for the delay, such as important side effects of the glutamate antagonists presently available. Some of these may be associated with inhibiting physiological transmitter functions of the amino acid. Another problem relates to the question of whether a complex disorder, such as severe head injury or stroke, can in fact be therapeutically influenced by a single compound. Severe head injury is characterized by an enormous qualitative and quantitative heterogeneity of brain lesions responsible for a clinical course which is often barely predictable. Therefore, detection of the clinical efficacy of a single pharmacological compound might be difficult, particularly in the presence of confounding factors. A trial procedure of targeting subgroups of patients could therefore be a solution. Even then the problem remains, however, that other mediator compounds, such as arachidonic acid or tissue acidosis, play a role as well which attenuate or even annihilate potential treatment effects of a glutamate antagonist. Ultimately, approaches might be required for combining various methods of antagonization which, however, should not be implemented as a rigid treatment protocol but rather as a flexible procedure which can be adjusted from case to case depending on the underlying dominant lesion.