Journal of Neuroscience, Vol 13, 5383-5392, Copyright © 1993 by Society for Neuroscience
Effects of the excitatory amino acid receptor antagonists kynurenate and indole-2-carboxylic acid on behavioral and neurochemical outcome following experimental brain injury
DH Smith, K Okiyama, MJ Thomas and TK McIntosh
Division of Neurosurgery, University of Pennsylvania, Philadelphia 19104.
The overactivation of the NMDA receptor is thought to be a major
contributor to the pathophysiologic sequelae of traumatic brain injury
(TBI), which commonly includes memory dysfunction. Uniquely, potentiation
of the NMDA receptor is dependent on the binding of glycine to a distinct
site on the receptor. Despite the potential role of the NMDA receptor in
the development of post-TBI cognitive deficits, no studies to date have
evaluated the efficacy of NMDA receptor antagonists on memory dysfunction
after brain injury. Moreover, glycine site antagonists have not been
employed as potential therapeutic agents in models of TBI. In the present
study, we evaluated the effects of two glycine site antagonists, kynurenate
(KYNA) and indole-2-carboxylic acid (I2CA), on memory and motor
dysfunction, cerebral edema formation, and changes in regional total tissue
brain [Na], [K], [Ca], [Mg], and [Zn], following lateral fluid-percussion
brain injury in the rat. We found that both KYNA (300 mg/kg) and I2CA (50
mg/kg and 20 mg/kg) administered 15 min postinjury dramatically attenuated
trauma-induced cognitive dysfunction (p < 0.01). In addition, both
compounds improved neurologic motor deficits measured at 2 weeks following
injury (p < 0.05). KYNA (300 mg/kg) reduced edema in the cortex,
hippocampus, and thalamus, while I2CA (20 mg/kg) reduced edema formation
only in the thalamus. Differential effects of KYNA and I2CA on cation
concentrations were also noted. KYNA attenuated the postinjury increase in
regional tissue [Ca]; however, it had little effect on other cation
concentrations. I2CA reversed the postinjury regional increases in [Na] and
decreases in [K], [Mg], and [Zn], but had little effect on [Ca] changes.
These results indicate that KYNA and I2CA may have differential, but
beneficial effects on both behavioral and neurochemical sequelae of TBI.
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