ALDH2 Protects Against Ischemic Stroke in Rats by Facilitating 4-HNE Clearance and AQP4 Down-Regulation
Aldehyde dehydrogenase 2 (ALDH2) is a new therapeutic target in the central nervous system. However, the association between ALDH2 and brain edema following ischemic stroke (IS) remains unclear. The present study was investigated to whether active ALDH2 can attenuate brain edema by using a rat model of IS, with the aim of clarifying the underlying mechanisms involved. Rats were administered the ALDH2 agonist Alda-1, vehicle or the ALDH2 inhibitor cyanamide (CYA) 15 min prior to a 1.5 h middle cerebral artery occlusion (MCAO) surgery. The effects of ALDH2 were subsequently investigated 24 h after reperfusion by evaluating neurological function, infarct sizes, brain edema volumes, 4-hydroxy-2-nonenal (4-HNE) levels, and aquaporin 4 (AQP4) protein expression. The results demonstrated that increasing ALDH2 activity significantly improved neurological deficits, reduced infarct sizes, and attenuated brain edema after MCAO. Alda-1 administration led to decreased 4-HNE levels and inhibited AQP4 protein expression in the peri-infarct section of the brain. Whereas, CYA administration increased 4-HNE levels, AQP4 expression, and simultaneously aggravated brain edema following MCAO. In conclusion, increasing ALDH2 activity can improve brain edema, infarct volumes, and reduce neurological impairment in a rat IS model. The therapeutic benefits of ALDH2 are related to 4-HNE clearance and AQP4 down-regulation.
KeywordsALDH2 Middle cerebral artery occlusion Brain edema Aquaporin 4 4-HNE
The project is supported by the National Natural Science Foundation of China (No. 81271456).
Compliance with Ethical Standards
Conflict of interest
No competing interests exist.
- 9.Kato N, Takeuchi F, Tabara Y, Kelly TN, Go MJ, Sim X, Tay WT, Chen CH, Zhang Y, Yamamoto K, Yamori Y, Nakashima E, Jaquish CE, Lee JY, Seielstad M, Isono M, Hixson JE, Chen YT, Miki T, Zhou X, Sugiyama T, Jeon JP, Liu JJ, Takayanagi R, Kim SS, Aung T, Sung YJ, Zhang X, Wong TY, Han BG, Kobayashi S, Ogihara T, Zhu D, Iwai N, Wu JY, Teo YY, Tai ES, Cho YS, He J (2011) Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat Genet 43(6):531–538. https://doi.org/10.1038/ng.834 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Stachowicz A, Glombik K, Olszanecki R, Basta-Kaim A, Suski M, Lason W, Korbut R (2016) The impact of mitochondrial aldehyde dehydrogenase (ALDH2) activation by Alda-1 on the behavioral and biochemical disturbances in animal model of depression. Brain Behav Immun 51:144–153. https://doi.org/10.1016/j.bbi.2015.08.004 CrossRefPubMedGoogle Scholar
- 25.Yang Y, Sharma A, Sharma R, Patrick B, Singhal SS, Zimniak P, Awasthi S, Awasthi YC (2003) Cells preconditioned with mild, transient UVA irradiation acquire resistance to oxidative stress and UVA-induced apoptosis: role of 4-hydroxynonenal in UVA-mediated signaling for apoptosis. J Biol Chem 278(42):41380–41388. https://doi.org/10.1074/jbc.M305766200 CrossRefPubMedGoogle Scholar
- 26.Qi LL, Fang SH, Shi WZ, Huang XQ, Zhang XY, Lu YB, Zhang WP, Wei EQ (2011) CysLT2 receptor-mediated AQP4 up-regulation is involved in ischemic-like injury through activation of ERK and p38 MAPK in rat astrocytes. Life Sci 88(1–2):50–56. https://doi.org/10.1016/j.lfs.2010.10.025 CrossRefPubMedGoogle Scholar
- 27.Arima H, Yamamoto N, Sobue K, Umenishi F, Tada T, Katsuya H et al (2003) Hyperosmolar mannitol stimulates expression of aquaporins 4 and 9 through a p38 mitogen-activated protein kinase dependent pathway in rat astrocytes. J Biol Chem 278(45):44525–44534. https://doi.org/10.1074/jbc.M304368200 CrossRefPubMedGoogle Scholar