Abstract
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 receptors1–8. The finding9 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 damage12–14. 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Shinozaki, H. & Konishi, S. Brain Res. 14, 368–371 (1970).
Olney, J. W., Rhee, V. & Ho, O. L. Brain Res. 77, 507–512 (1974).
Curtis, D. R. & Watkins, J. C. J. Physiol., Lond. 166, 1–14 (1963).
Olney, J. W., Ho, O. L. & Rhee, V. Expl Brain Res. 14, 61–76 (1971).
Olney, J. W., Sharpe, L. G. & de Gubareff, T. Neurosci. Abstr. 1, 371 (1975).
Watkins, J. C. in Kainic Acid as a Tool in Neurobiology (eds McGeer, E., Olney, J. W. & McGeer, P.) 37–70 (Raven, New York, 1978).
Olney, J. W. in Kainic Acid as a Tool in Neurobiology (eds McGeer, E., Olney, J. W. & McGeer, P.) 95–122 (Raven, New York, 1978).
Schwarcz, R., Scholz, D. & Coyle, J. T. Neuropharmacology 17, 145–151 (1978).
London, E. D., Klemm, N. & Coyle, J. T. Brain Res. 192, 463–476 (1980).
Lambert, J. D. C., Flatman, J. A. & Engberg, I. Adv. Biochem. Psychopharmac. 27, 205–216 (1981).
Watkins, J. C., Davies, J., Evans, R. H., Francis, A. A. & Jones, A. W. Adv. Biochem Psychopharmac. 27, 263–274 (1981).
Ben-Ari, Y., Tremblay, E., Ottersen, O. P. & Meldrum, B. S. Brain Res. 191, 79–97 (1980).
Olney, J. W. Adv. Biochem. Psychopharmac. 27, 375–384 (1981).
Olney, J. W. et al. (in preparation).
Ruck, A., Kramer, S., Metz, J. & Brennan, M. J. W. Nature 287, 852–853 (1980).
Hattori, T. & McGeer, E. G. Brain Res. 129, 174–180 (1977).
Olney, J. W. & de Gubareff, T. in Kainic Acid as a Tool in Neurobiology (eds McGeer, E., Olney, J. W. & McGeer, P.) 201–218 (Raven, New York, 1978).
Olney, J. W., Misra, C. J. & de Gubareff, T. J. Neuropathol. exp. Neurol. 34, 167–177 (1975).
Collins, R. C., Lothman, E. W. & Olney, J. W. Proc. Univ. Calif. Symp. on Status Epilepticus, November 1980 (Raven, New York, in the press).
Nadler, V., Perry, B. W. & Cotman, C. W. Nature 271, 676–677 (1978).
Olney, J. W., Fuller, T. & de Gubareff, T. Brain Res. 176, 91–100 (1979).
Schwob, J. E., Fuller, T. A., Price, J. L. & Olney, J. W. Neuroscience 5, 991–1015 (1980).
Coyle, J. T., McGeer, E. G., McGeer, P. L. & Schwarcz, R. in Kainic Acid as a Tool in Neurobiology (eds McGeer, E., Olney, J. W. & McGeer, P.) 139–160 (Raven, New York, 1978).
Olney, J. W. Adv. Neurol. 23, 609–624 (1979).
Specter, R., Levy, P. & Abelson, H. T. Biochem. Pharmac. 26, 1507–1511 (1977).
Hommes, O. R. & Obbens, E. A. M. T. J. neurol. Sci. 16, 271–281 (1972).
Spector, R. G. Biochem. Pharmac. 20, 1730–1732 (1971).
Corsellis, J. A. N. & Meldrum, B. S. in Greenfields Neuropathology (eds Blackwood, W. & Corsellis, J. A. N.) 771–795 (Arnold, London, 1976).
Olney, J. W., Fuller, T. A., de Gubareff, T. & Labruyere, J. Neuroscience Lett. (in the press).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Olney, J., Fuller, T. & de Gubareff, T. Kainate-like neurotoxicity of folates. Nature 292, 165–167 (1981). https://doi.org/10.1038/292165a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/292165a0
This article is cited by
-
Anticonvulsive Effect of Folic Acid in Homocysteine Thiolactone-Induced Seizures
Cellular and Molecular Neurobiology (2011)
-
Methylfolate modulates potassium evoked neuro-secretion: Evidence for a role at the pteridine cofactor level of tyrosine 3-hydroxylase
Neurochemical Research (1995)
-
Modulation of potassium evoked secretory function in rat cerebellar slices measured by real time monitoring: Evidence of a possible role for methylfolate in cerebral tissue
Neurochemical Research (1993)
-
Folate interactions with cerebral G proteins
Neurochemical Research (1990)
-
Comparison of neural damage induced by electrical stimulation with faradaic and capacitor electrodes
Annals of Biomedical Engineering (1988)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.