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Involvement of d-amino acid oxidase in cerebral ischaemia induced by transient occlusion of the middle cerebral artery in mice.

ABSTRACT: BACKGROUND AND PURPOSE:d-Amino acid oxidase (DAAO) is a flavine adenine dinucleotide-containing flavoenzyme and specifically catalyses oxidative deamination of d-amino acids. This study aimed to explore the association between increased cerebral DAAO expression or enzymic activity and the development of cerebral ischaemia. EXPERIMENTAL APPROACH:A mouse model of transient (90 min) middle cerebral artery occlusion (MCAO) was established, and western blotting, enzymic activity assay, and fluorescent immunostaining techniques were used. KEY RESULTS:The expression and enzymic activity of DAAO increased over time in the cortical peri-infarct area of the mice subjected to transient MCAO. The DAAO was specifically expressed in astrocytes, and its double immunostaining with the astrocytic intracellular marker, glial fibrillary acidic protein, in the cortical peri-infarct area was up-regulated following ischaemic insult, with peak increase on Day 5 after MCAO. Single intravenous injection of the specific and potent DAAO inhibitor Compound SUN reduced the cerebral DAAO enzymic activity and attenuated neuronal infarction and neurobehavioural deficits with optimal improvement apparent immediately after the MCAO procedure. The neuroprotective effect was dose dependent, with ED50 values of 3.9-4.5 mg·kg-1 . Intracerebroventricular injection of the DAAO gene silencer siRNA/DAAO significantly reduced cerebral DAAO expression and attenuated MCAO-induced neuronal infarction and behavioural deficits. CONCLUSIONS AND IMPLICATIONS:Our results, for the first time, demonstrated that increased cerebral astrocytic DAAO expression and enzymic activity were causally associated with the development of neuronal destruction following ischaemic insults, suggesting that targeting cerebral DAAO could be a potential approach for treatment of neurological conditions following cerebral ischaemia.

SUBMITTER: Liu H

PROVIDER: S-EPMC6692583 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Involvement of d-amino acid oxidase in cerebral ischaemia induced by transient occlusion of the middle cerebral artery in mice.

Liu Hao H Zhao Meng-Jing MJ Wang Zi-Ying ZY Han Qiao-Qiao QQ Wu Hai-Yun HY Mao Xiao-Fang XF Wang Yong-Xiang YX

British journal of pharmacology 20190715 17

<h4>Background and purpose</h4>d-Amino acid oxidase (DAAO) is a flavine adenine dinucleotide-containing flavoenzyme and specifically catalyses oxidative deamination of d-amino acids. This study aimed to explore the association between increased cerebral DAAO expression or enzymic activity and the development of cerebral ischaemia.<h4>Experimental approach</h4>A mouse model of transient (90 min) middle cerebral artery occlusion (MCAO) was established, and western blotting, enzymic activity assay, ...[more]

PMID: 31309542

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Project description:BACKGROUND: Anti-inflammatory treatment affects ischemic damage and neurogenesis in rodent models of cerebral ischemia. We investigated the potential benefit of COX-2 inhibition with parecoxib in spontaneously hypertensive rats (SHRs) subjected to transient middle cerebral artery occlusion (tMCAo). METHODS: Sixty-four male SHRs were randomized to 90 min of intraluminal tMCAo or sham surgery. Parecoxib (10 mg/kg) or isotonic saline was administered intraperitoneally (IP) during the procedure, and twice daily thereafter. Nineteen animals were euthanized after 24 hours, and each hemisphere was examined for mRNA expression of pro-inflammatory cytokines and COX enzymes by quantitative RT-PCR. Twenty-three tMCAo animals were studied with diffusion and T2 weighted MRI within the first 24 hours, and ten of the SHRs underwent follow-up MRI six days later. Thirty-three SHRs were given 5-bromo-2'-deoxy-uridine (BrdU) twice daily on Day 4 to 7 after tMCAo. Animals were euthanized on Day 8 and the brains were studied with free-floating immunohistochemistry for activated microglia (ED-1), hippocampal granule cell BrdU incorporation, and neuronal nuclei (NeuN). Infarct volume estimation was done using the 2D nucleator and Cavalieri principle on NeuN-stained coronal brain sections. The total number of BrdU+ cells in the dentate gyrus (DG) of the hippocampus was estimated using the optical fractionator. RESULTS: We found a significant reduction in infarct volume in parecoxib treated animals one week after tMCAo (p < 0.03). Cortical ADC values in the parecoxib group were markedly less increased on Day 8 (p < 0.01). Interestingly, the parecoxib treated rats were segregated into two subgroups, suggesting a responder vs. non-responder phenomenon. We found indications of mRNA up-regulation of IL-1beta, IL-6, TNF-alpha and COX-2, whereas COX-1 remained unaffected. Hippocampal granule cell BrdU incorporation was not affected by parecoxib treatment. Presence of ED-1+ activated microglia in the hippocampus was related to an increase in BrdU uptake in the DG. CONCLUSION: IP parecoxib administration during tMCAo was neuroprotective, as evidenced by a large reduction in mean infarct volume and a lower cortical ADC increment. Increased pro-inflammatory cytokine mRNA levels and hippocampal granule cell BrdU incorporation remained unaffected.

Dataset Information

Involvement of d-amino acid oxidase in cerebral ischaemia induced by transient occlusion of the middle cerebral artery in mice.

Publications

Involvement of d-amino acid oxidase in cerebral ischaemia induced by transient occlusion of the middle cerebral artery in mice.

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