Abstract WP133: L-serine Treatment Confers Neuroprotection Against Permanent Focal Cerebral Ischemia In Rats Via Improving Regional Cerebral Blood Flow

Introduction: L-serine plays critical roles in neuronal development and function. We have recently reported that L-serine protected against ischemic neuronal injury in vivo and in vitro. The mechanism underlying the neuroprotective effect of L-serine remains unclear. L-serine has been documented to induce a fall in mean arterial pressure through activation of small- and intermediate-conductance calcium-activated potassium channels on the endothelium. Such vasodilating action of L-serine in cerebral blood vessels has not been investigated. Hypothesis: Improving regional cerebral blood flow (rCBF) by L-serine contributes to its neuroprotection on the brain after permanent middle cerebral artery occlusion (pMCAO). Methods: Adult male Sprague-Dawley rats were randomly assigned to sham, vehicle or L-serine-treated groups. pMCAO was induced while monitoring rCBF. The neurological deficit scores, brain infarct volumes and physiological parameters were assessed. L-serine and D-serine content in the cortex was measured with high performance liquid chromatography. Results: Compared to vehicle treatment, administration of L-serine improved rCBF in the ischemic cortex and reduced the neurological deficits, infarct volume and cortical neuronal loss in a dose- and time-dependent manner. The improvement of rCBF and neuroprotective effect of L-serine were abolished by apamin plus charybdotoxin, which blocks the calcium-activated potassium channels on the endothelium, but not influenced by strychnine, an antagonist of glycine receptors. HPLC results shows that L-serine treatment increased the content of both L-serine and D-serine in the ischemic cortex. However, inhibiting the conversion of L-serine to D-serine by aminooxyacetic acid did not affect the L-serine-afforded protection, suggesting that the neuroprotective efficacy of L-serine is not related to the conversion of L-serine to D-serine. Conclusions: L-serine displayed a neuroprotective effect in the ischemic brain, at least partly due to an elevation in rCBF through cerebral blood vessel dilation mediated by the calcium-activated potassium channels on the endothelial cells. L-serine may be a potential novel therapy for ischemic brain injury.