Abstract WP256: Paradoxical Neuronal Survival Against Cerebral Ischemia in Lactate Dehydrogenase B Knock-out Mice via Vascular Adaptation

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Abstract

Background: Among several routes of neuronal energy source, astrocyte-neuron lactate shuttle is known to be the main pathway in brain. After lactate is formed in astrocytes, it is transferred into neurons via monocarboxyl transportase. In neurons, lactate is transformed into pyruvate mainly by lactate dehydrogenase (LDH) 1, which consists of 4 units of LDH B (LDHB). To evaluate the effects of lactate shuttle pathway alteration on cerebral ischemia, we developed LDHB knock-out (KO) mouse. We hypothesized that ischemic neuronal damage would be more severe in LDHB KO mice compared with wild-type (WT) mice.

Methods: LDHB KO and WT mice (age, 12-14 weeks) were used for this study. Bilateral common carotid arteries were transiently occluded for 10 minutes, and mice were sacrificed after 3 days. Cresyl violet staining was performed for histological analysis. Immunohistochemistry was performed for GFAP, Iba-1, TUNEL, etc. For evaluation of vascular collateral status, diameters of basilar artery posterior communicating artery, and the ratio of posterior communicating artery diameter to basilar artery was measured.

Results: Contrary to our hypothesis, the ischemic damage was less pronounced in the LDHB KO mice compared to WT mice. The number of surviving neurons in the hippocampal CA 1 region was significantly higher in LDHB KO than in WT. The number of activated astrocytes in the hippocampus was also significantly higher in LDHB KO than in WT. The number of microglia in the hippocampus, however, was significantly lower in LDHB KO group than in WT group. TUNEL-stained neuronal cells in the hippocampus was significantly less in LDHB KO group than in WT group. In analysis of vascular collateral status, the diameter of the basilar artery did not differ; however, the ratio of the posterior communicating artery to basilar artery was significantly higher in LDHB KO group than in WT group. The ratio did not differ in LDHB KO and WT mice without cerebral ischemia.

Conclusions: The brain of LDHB KO mice appeared to be more resistant to ischemic insults compared to WT mice. The mechanism of ischemic resistance in LDHB KO mice is thought to result from better vascular response for collateral supplies. Further analyses to prove the mechanism of ischemic resistance are warranted.

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