Alda 1

IC50: N/A

Alda 1 is an activator of aldehyde dehydrogenase 2 (ALDH2).

Alda 1 increases activity of wild-type ALDH2*1 and variant ALDH2*2 (by ~2-fold and 11-fold respectively), Capable of partly restoring mutant ALDH2*2 activity, and protective against cardiac ischemia.

In vitro: In the present study , Alda-1 increased acetaldehyde oxidation by ALDH2*1 and ALDH2*2 approximately 1.5- and 6-fold, respectively, regarding GTN bioactivation and the effects of Alda-1. To similar extent, Alda-1 induced the esterase activities of both enzymes as the coenzyme NAD. NAD pronounced inhibition occurring at > 5mM, its the effect was biphasic. In the presence of 1 mM NAD, Alda-1 induced ALDH2*2-catalyzed ester hydrolysis 73-fold, whereas the NAD-induced activity of ALDH2*1 was inhibited on account of 20-fold increased inhibitory potency of NAD in the presence of the drug. ALDH2*2 displayed 7-fold lower GTN denitrating activity and GTN affinity than ALDH2*1, but the rate of nitric oxide formation was only reduced 2-fold. Soluble guanylate cyclase (sGC) activation was more pronounced than with wild type ALDH2 at saturating GTN. Alda-1 caused slight inhibition of GTN denitration, and in the presence of either variant, GTN-induced sGC activation was increased. The present results imply that established ALDH2 activities stimulated by Alda-1, which improved NAD binding but does not improve the GTN binding affinity of the Asian variant. In addition, an unexpected discrepancy between GTN reductase activity and sGC activation was revealed, which suggested that GTN denitration and bioactivation may display independent pathways of ALDH2-catalyzed GTN biotransformation [1].

In vivo: Alda-1 (a high-throughput screen yielded a small-molecule activator of ALDH2, administered to rats before an ischemic event) reduced infarct size by 60%, most likely through the inhibition of the formation of cytotoxic aldehydes. Thus, pharmacologic enhancement of ALDH2 activity may be benefit to patients with wild-type or mutant ALDH2 who are subjected to cardiac ischemia, such as during coronary bypass surgery [2].

Clinical trial: Clinical study has been conducted.

References:
[1].  Beretta M, Gorren AC, Wenzl MV, Weis R, Russwurm M, Koesling D, Schmidt K, Mayer B. Characterization of the East Asian variant of aldehyde dehydrogenase-2: bioactivation of nitroglycerin and effects of Alda-1. J Biol Chem. 2010 Jan 8;285(2):943-52.
[2].  Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science. 2008 Sep 12;321(5895):1493-5.

Pretreatment with the ALDH2 agonist Alda-1 reduces intestinal injury induced by ischaemia and reperfusion in mice.[Pubmed:28325855]

Clin Sci (Lond). 2017 Jun 1;131(11):1123-1136.

Many studies demonstrate that activation of aldehyde dehydrogenase 2 (ALDH2) protects against oxidative stress via detoxification of cytotoxic aldehydes, and could attenuate cardiac, cerebral, lung and renal ischaemia-reperfusion (I/R) injuries. However, the effect of ALDH2 in intestinal I/R is unknown. The present study was set up to determine whether an ALDH2 agonist, Alda-1, could alleviate intestinal injury after gut I/R. In a mouse model of intestinal I/R injury, histological grading, proinflammatory cytokines, oxidative stress, cellular apoptosis, chemokine contents, ALDH2 activity, 4-hydroxy-trans-2-nonenal (4-HNE) and malondialdehyde (MDA) were evaluated. The results indicated that I/R treatment conferred elevation in pathological scores, proinflammatory cytokines, oxidative stress, cellular apoptosis and chemokine levels, accompanied by accumulated 4-HNE and MDA. No significant changes in ALDH2 activity were observed after I/R. However, Alda-1 pretreatment significantly decreased these injurious indicators, concomitant with up-regulated ALDH2 activity, and lessened 4-HNE and MDA accumulation. Taken together, our results implicate activation of ALDH2 by Alda-1 in the significant abatement intestinal I/R injury.

Proteomic Analysis of Mitochondria-Enriched Fraction Isolated from the Frontal Cortex and Hippocampus of Apolipoprotein E Knockout Mice Treated with Alda-1, an Activator of Mitochondrial Aldehyde Dehydrogenase (ALDH2).[Pubmed:28218653]

Int J Mol Sci. 2017 Feb 17;18(2). pii: ijms18020435.

The role of different genotypes of apolipoprotein E (apoE) in the etiology of Alzheimer's disease is widely recognized. It has been shown that altered functioning of apoE may promote 4-hydroxynonenal modification of mitochondrial proteins, which may result in mitochondrial dysfunction, aggravation of oxidative stress, and neurodegeneration. Mitochondrial aldehyde dehydrogenase (ALDH2) is an enzyme considered to perform protective function in mitochondria by the detoxification of the end products of lipid peroxidation, such as 4-hydroxynonenal and other reactive aldehydes. The goal of our study was to apply a differential proteomics approach in concert with molecular and morphological techniques to elucidate the changes in the frontal cortex and hippocampus of apolipoprotein E knockout (apoE(-/-)) mice upon treatment with Alda-1-a small molecular weight activator of ALDH2. Despite the lack of significant morphological changes in the brain of apoE(-/-) mice as compared to age-matched wild type animals, the proteomic and molecular approach revealed many changes in the expression of genes and proteins, indicating the impairment of energy metabolism, neuroplasticity, and neurogenesis in brains of apoE(-/-) mice. Importantly, prolonged treatment of apoE(-/-) mice with Alda-1 led to the beneficial changes in the expression of genes and proteins related to neuroplasticity and mitochondrial function. The pattern of alterations implies mitoprotective action of Alda-1, however, the accurate functional consequences of the revealed changes require further research.

In Vivo Post-Cardiac Arrest Myocardial Dysfunction Is Supported by Ca2+/Calmodulin-Dependent Protein Kinase II-Mediated Calcium Long-Term Potentiation and Mitigated by Alda-1, an Agonist of Aldehyde Dehydrogenase Type 2.[Pubmed:27582424]

Circulation. 2016 Sep 27;134(13):961-977.

BACKGROUND: Survival after sudden cardiac arrest is limited by postarrest myocardial dysfunction, but understanding of this phenomenon is constrained by a lack of data from a physiological model of disease. In this study, we established an in vivo model of cardiac arrest and resuscitation, characterized the biology of the associated myocardial dysfunction, and tested novel therapeutic strategies. METHODS: We developed rodent models of in vivo postarrest myocardial dysfunction using extracorporeal membrane oxygenation resuscitation followed by invasive hemodynamics measurement. In postarrest isolated cardiomyocytes, we assessed mechanical load and Ca(2) (+)-induced Ca(2+) release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel fiberoptic catheter imaging system and a genetically encoded calcium sensor, GCaMP6f, to image CICR in vivo. RESULTS: We found potentiation of CICR in isolated cells from this extracorporeal membrane oxygenation model and in cells isolated from an ischemia/reperfusion Langendorff model perfused with oxygenated blood from an arrested animal but not when reperfused in saline. We established that CICR potentiation begins in vivo. The augmented CICR observed after arrest was mediated by the activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban, and ryanodine receptor 2 was detected in the postarrest period. Exogenous adrenergic activation in vivo recapitulated Ca(2+) potentiation but was associated with lesser CaMKII activation. Because oxidative stress and aldehydic adduct formation were high after arrest, we tested a small-molecule activator of aldehyde dehydrogenase type 2, Alda-1, which reduced oxidative stress, restored calcium and CaMKII homeostasis, and improved cardiac function and postarrest outcome in vivo. CONCLUSIONS: Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term potentiation, which support cardiomyocyte contractility in the face of impaired postarrest myofilament calcium sensitivity. Alda-1 mitigates these effects, normalizes calcium cycling, and improves outcome.

The aldehyde dehydrogenase, AldA, is essential for L-1,2-propanediol utilization in laboratory-evolved Escherichia coli.[Pubmed:27938862]

Microbiol Res. 2017 Jan;194:47-52.

Most Escherichia coli strains are naturally unable to grow on 1,2-propanediol (PDO) as a sole carbon source. Recently, however, a K-12 descendent E. coli strain was evolved to grow on 1,2-PDO, and it was hypothesized that this evolved ability was dependent on the aldehyde dehydrogenase, AldA, which is highly conserved among members of the family Enterobacteriacea. To test this hypothesis, we first performed computational model simulation, which confirmed the essentiality of the aldA gene for 1,2-PDO utilization by the evolved PDO-degrading E. coli. Next, we deleted the aldA gene from the evolved strain, and this deletion was sufficient to abolish the evolved phenotype. On re-introducing the gene on a plasmid, the evolved phenotype was restored. These findings provide experimental evidence for the computationally predicted role of AldA in 1,2-PDO utilization, and represent a good example of E. coli robustness, demonstrated by the bacterial deployment of a generalist enzyme (here AldA) in multiple pathways to survive carbon starvation and to grow on a non-native substrate when no native carbon source is available.

Characterization of the East Asian variant of aldehyde dehydrogenase-2: bioactivation of nitroglycerin and effects of Alda-1.[Pubmed:19906643]

J Biol Chem. 2010 Jan 8;285(2):943-52.

The East Asian variant of mitochondrial aldehyde dehydrogenase (ALDH2) exhibits significantly reduced dehydrogenase, esterase, and nitroglycerin (GTN) denitrating activities. The small molecule Alda-1 was reported to partly restore low acetaldehyde dehydrogenase activity of this variant. In the present study we compared the wild type enzyme (ALDH2*1) with the Asian variant (ALDH2*2) regarding GTN bioactivation and the effects of Alda-1. Alda-1 increased acetaldehyde oxidation by ALDH2*1 and ALDH2*2 approximately 1.5- and 6-fold, respectively, and stimulated the esterase activities of both enzymes to similar extent as the coenzyme NAD. The effect of NAD was biphasic with pronounced inhibition occurring at > or = 5 mM. In the presence of 1 mM NAD, Alda-1 stimulated ALDH2*2-catalyzed ester hydrolysis 73-fold, whereas the NAD-stimulated activity of ALDH2*1 was inhibited because of 20-fold increased inhibitory potency of NAD in the presence of the drug. Although ALDH2*2 exhibited 7-fold lower GTN denitrating activity and GTN affinity than ALDH2*1, the rate of nitric oxide formation was only reduced 2-fold, and soluble guanylate cyclase (sGC) activation was more pronounced than with wild type ALDH2 at saturating GTN. Alda-1 caused slight inhibition of GTN denitration and did not increase GTN-induced sGC activation in the presence of either variant. The present results indicate that Alda-1 stimulates established ALDH2 activities by improving NAD binding but does not improve the GTN binding affinity of the Asian variant. In addition, our data revealed an unexpected discrepancy between GTN reductase activity and sGC activation, suggesting that GTN denitration and bioactivation may reflect independent pathways of ALDH2-catalyzed GTN biotransformation.

Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart.[Pubmed:18787169]

Science. 2008 Sep 12;321(5895):1493-5.

There is substantial interest in the development of drugs that limit the extent of ischemia-induced cardiac damage caused by myocardial infarction or by certain surgical procedures. Here, using an unbiased proteomic search, we identified mitochondrial aldehyde dehydrogenase 2 (ALDH2) as an enzyme whose activation correlates with reduced ischemic heart damage in rodent models. A high-throughput screen yielded a small-molecule activator of ALDH2 (Alda-1) that, when administered to rats before an ischemic event, reduced infarct size by 60%, most likely through its inhibitory effect on the formation of cytotoxic aldehydes. In vitro, Alda-1 was a particularly effective activator of ALDH2*2, an inactive mutant form of the enzyme that is found in 40% of East Asian populations. Thus, pharmacologic enhancement of ALDH2 activity may be useful for patients with wild-type or mutant ALDH2 who are subjected to cardiac ischemia, such as during coronary bypass surgery.