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Involvement of d-amino acid oxidase in cerebral ischaemia induced by transient occlusion of the middle cerebral artery in mice.
Br J Pharmacol 2019; 176(17):3336-3349BJ

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.

Authors+Show Affiliations

King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31309542

Citation

Liu, Hao, et al. "Involvement of D-amino Acid Oxidase in Cerebral Ischaemia Induced By Transient Occlusion of the Middle Cerebral Artery in Mice." British Journal of Pharmacology, vol. 176, no. 17, 2019, pp. 3336-3349.
Liu H, Zhao MJ, Wang ZY, et al. Involvement of d-amino acid oxidase in cerebral ischaemia induced by transient occlusion of the middle cerebral artery in mice. Br J Pharmacol. 2019;176(17):3336-3349.
Liu, H., Zhao, M. J., Wang, Z. Y., Han, Q. Q., Wu, H. Y., Mao, X. F., & Wang, Y. X. (2019). Involvement of d-amino acid oxidase in cerebral ischaemia induced by transient occlusion of the middle cerebral artery in mice. British Journal of Pharmacology, 176(17), pp. 3336-3349. doi:10.1111/bph.14764.
Liu H, et al. Involvement of D-amino Acid Oxidase in Cerebral Ischaemia Induced By Transient Occlusion of the Middle Cerebral Artery in Mice. Br J Pharmacol. 2019;176(17):3336-3349. PubMed PMID: 31309542.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of d-amino acid oxidase in cerebral ischaemia induced by transient occlusion of the middle cerebral artery in mice. AU - Liu,Hao, AU - Zhao,Meng-Jing, AU - Wang,Zi-Ying, AU - Han,Qiao-Qiao, AU - Wu,Hai-Yun, AU - Mao,Xiao-Fang, AU - Wang,Yong-Xiang, Y1 - 2019/07/15/ PY - 2018/11/09/received PY - 2019/05/03/revised PY - 2019/05/16/accepted PY - 2020/09/01/pmc-release PY - 2019/7/17/pubmed PY - 2019/7/17/medline PY - 2019/7/17/entrez SP - 3336 EP - 3349 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 176 IS - 17 N2 - 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/31309542/Involvement_of_d-amino_acid_oxidase_in_cerebral_ischaemia_induced_by_transient_occlusion_of_the_middle_cerebral_artery_in_mice L2 - https://doi.org/10.1111/bph.14764 DB - PRIME DP - Unbound Medicine ER -