Kainate-like neurotoxicity of folates

• Published in: Nature (London) 1981-07, Vol.292 (5819), p.165-167
• Main Authors: Olney, John W, Fuller, Terry A, de Gubareff, Taisija
• Format: Article
• Language: English
• Subjects: Amygdala - drug effects; Amygdala - physiology; Animals; brain; Cerebral Cortex - drug effects; Cerebral Cortex - physiology; folic acid; Folic Acid - pharmacology; Humanities and Social Sciences; kainic acid; Kainic Acid - pharmacology; letter; Leucovorin - pharmacology; multidisciplinary; Neurotoxins; Pyrrolidines - pharmacology; Rats; Science; Science (multidisciplinary); seizures; Structure-Activity Relationship; Tetrahydrofolates - pharmacology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/292165a0

Kainic acid (KA) is one of the most powerful of a group of ‘excitotoxic’ analogues of the putative neurotransmitter glu-tamate (Glu) whose neurotoxicity may involve an excitatory mechanism mediated through glutamergic postsynaptic receptors 1–8 . The finding 9 that neural membranes have specific sites where KA binds quite firmly and that Glu inhibits such binding very weakly, however, raises the possibility that KA and Glu receptors may be separate and distinct (see also refs 10, 11). It is in any case known that the neurotoxic properties of K A and Glu are not identical. Thus, when injected into the amygdala, both Glu and KA destroy local neurones but only KA induces sustained limbic seizures and an apparently seizure-mediated pattern of extra-amygdaloid brain damage 12–14 . Ruck et al. 15 , having recently found that the folic acid derivative, methyl-tetrahydrofolate (MTHF), competes powerfully for KA binding sites on rat cerebellar membranes and mimics KA in depolarizing frog spinal neurones, proposed that MTHF may be an endogenous neuromodulator with both excitatory and neurotoxic properties. We have therefore injected MTHF directly into the amygdala of the adult rat and found that at a rather high dose (300 nmol), it reproduces the specific component of KA neurotoxicity that Glu fails to reproduce, namely the limbic seizure/brain damage syndrome. We have also found that folic acid itself (pteroyl-L-glutamic acid, PGA) and one of its reduced derivatives ( N -5-formyltetrahydrofolate, FTHF) are substantially more powerful than MTHF in reproducing this syndrome.