Increased homocysteine-induced release of excitatory amino acids in the striatum of spontaneously hypertensive stroke-prone rats

Abstract

Background and purpose: Increased plasma [homocysteine] is associated with stroke but its direct effects on the brain during a stroke are unknown. Since excitatory amino acids are important in inducing brain damage, we examined the effect of homocysteine on the release of various amino acids in the striatum of spontaneously hypertensive stroke-prone (SHSP) rats before and after a stroke. Methods: In vivo microdialysis was carried out in the striatum of anesthetized SHSP rats before and after signs of stroke. Animals were exposed to 20 and 200 μM homocysteine in the microdialysis solution and then the microdialysates were analyzed 30 min later for amino acid content. Brain cryosections were silver-stained to quantify infarcts in the non-ischemic and the damaged tissues in pre-stroke and post-stroke rats. Results: Both pre-stroke and post-stroke animals had similar levels of all amino acids in the striatum. Homocysteine did not alter amino acid release in rats prior to stroke but induced a significant increase in the release of all amino acids tested in the post-stroke rats. However, the increase was significantly greater with the excitatory amino acids glutamate and aspartate, and with tyrosine in post-stroke animals as compared to those in pre-stroke, normal animals. The mean pixel density of the gray matter of post-stroke animals was significantly decreased following homocysteine treatment indicating the presence of neurological damage. Conclusions: Homocysteine-induced neurological damage in post-infarct SHSP rats was associated with a hypersecretion of excitatory amino acids. Patients with hyperhomocysteinemia may be at risk for augmented brain damage from an ischemic infarct due to a selective activation of neuronal excitatory amino acids.