ACTH-related peptides, kindling and seizure disorders

Very small amounts of pituitary hormones and their peptide fragments can profoundly affect learning, memory and other behaviors in both rodents and humans. In addition, several potent pituitary hormone analogs have been developed (e.g. ORG-2766) which retain the behavioral but not the endocrine properties of the parent hormone. The abilities of these peptides to influence nervous system functions suggested that they also may be capable of modifying seizure activity. This possibility is supported by the fact that treatment with adrenocorticotropic hormone (ACTH) represents a major effective therapy for at least one clinical convulsive disorder, infantile spasm. This contention also is reinforced by our findings that ORG-2766 markedly reduces both the behavioral severity and the spread of seizure potentials in an animal model of epilepsy, the kindled rat. By contrast, arginine vasopressin and its non-endocrine desglycyl fragment (DGAVP) facilitates the seizure process in this animal model. Our research also suggests that the behavioral and physiological effects of certain anterior and posterior pituitary hormone fragments depend, in part, on their abilities to modulate permeability mechanisms in brain vasculature. In addition, and especially significant from the standpoint of etiology, is the observation that the kindling process itself appears to alter cerebrovascular permeability. In the kindled rat, "permanent" decreases in permeability (60-75%) are found selectively in the hypothalamic and hippocampal regions, weeks after the last seizure. Several lines of evidence indicate that disruption of normal cerebrovascular function occurs following epileptiform seizures. We propose that an immediate increase in cerebral blood flow and cerebrovascular permeability occurs following a single, acute seizure, and that repeated chronic seizures lead to damage to the cerebrovascular system. Sustained damage would be expected to contribute to the development and maintenance of a chronic seizure focus. Such observations suggest a link between important cerebrovascular disturbances associated with seizures and the existing known and proposed electrophysiological, metabolic and neuropathological substrates of epilepsy. They also point to new strategies for the treatment of seizure disorders by focusing on ways to reduce or prevent cerebrovascular damage.