Reactive aldehyde species explained

Reactive aldehyde species (RASP), also known as reactive aldehydes, refer to a class of electrophilic organic aldehyde molecules that are generally toxic or facilitate inflammation. RASP covalently react with amine groups (via Schiff base formation) and thiol groups (via Michael addition), particularly in proteins.[1] Following threshold amounts of binding to the electrophile-responsive proteome, RASP modify protein function,[2] as has been described with MAP kinase, protein kinase C, and other proteins that potentiate cytokine release and other aspects of inflammation.[3] Binding of RASP to proteins can also lead to NF-kB activation,[4] autoantibody formation,[5] inflammasome activation,[6] and activation of Scavenger Receptor A.[7] RASP are formed via a variety of processes, including oxidation of alcohols,[8] polyamine metabolism [9] and lipid peroxidation. In addition to binding to proteins and other amine or thiol-containing molecules such as glutathione, RASP are metabolized by aldehyde dehydrogenases or aldehyde reductases. Due to the toxicity of RASP, only a small number of genetic mutations in aldehyde dehydrogenases allow for viable offspring, resulting in Sjögren-Larsson Syndrome, Succinic Semi-Aldehyde Dehydrogenase Deficiency,[10] and other rare diseases.

The two most commonly reported disease-associated pro-inflammatory RASP are malondialdehyde and 4-hydroxynonenal,[11] although many others, including acrolein, crotonaldehyde, acetaldehyde, and hexanal, have been described. The toxicity of RASP include mutagenicity, aggregate formation, and generalized cytotoxicity.[12]

Malondialdehyde, for example, has been associated with many inflammatory and autoimmune diseases, including asthma,[13] psoriasis,[14] and dry eye disease.[15] Only two RASP, retinaldehyde and pyridoxal (or pyridoxal phosphate), appear to effect essential non-inflammatory physiologic functions in animals, though retinaldehyde is highly dependent on protein chaperones to prevent toxicity.[16]

In clinical trials, the RASP inhibitor reproxalap was shown to mitigate inflammation in patients with noninfectious anterior uveitis,[17] dry eye disease[18] [19] and allergic conjunctivitis.[20] [21] [22]

Notes and References

  1. Esterbauer. H.. Schaur. R. J.. Zollner. H.. 1991. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radical Biology & Medicine. 11. 1. 81–128. 10.1016/0891-5849(91)90192-6. 0891-5849. 1937131.
  2. Higdon. Ashlee. Diers. Anne R.. Oh. Joo Yeun. Landar. Aimee. Darley-Usmar. Victor M.. 2012-03-15. Cell signalling by reactive lipid species: new concepts and molecular mechanisms. The Biochemical Journal. 442. 3. 453–464. 10.1042/BJ20111752. 1470-8728. 3286857. 22364280.
  3. Raghavan. Somasundaram. Subramaniyam. Ganesan. Shanmugam. Narkunaraja. 2012. Proinflammatory effects of malondialdehyde in lymphocytes. Journal of Leukocyte Biology. 92. 5. 1055–1067. 10.1189/jlb.1211617. 1938-3673. 22956781. 5472211.
  4. Kalariya. Nilesh M.. Ramana. Kota V.. Srivastava. Satish K.. van Kuijk. Frederik J. G. M.. 2008. Carotenoid derived aldehydes-induced oxidative stress causes apoptotic cell death in human retinal pigment epithelial cells. Experimental Eye Research. 86. 1. 70–80. 10.1016/j.exer.2007.09.010. 0014-4835. 2786271. 17977529.
  5. Thiele. Geoffrey M.. Duryee. Michael J.. Anderson. Daniel R.. Klassen. Lynell W.. Mohring. Stephen M.. Young. Kathleen A.. Benissan-Messan. Dathe. Sayles. Harlan. Dusad. Anand. Hunter. Carlos D.. Sokolove. Jeremy. March 2015. Malondialdehyde-acetaldehyde adducts and anti-malondialdehyde-acetaldehyde antibodies in rheumatoid arthritis. Arthritis & Rheumatology. 67. 3. 645–655. 10.1002/art.38969. 2326-5205. 5469548. 25417811.
  6. Kauppinen. Anu. Niskanen. Henri. Suuronen. Tiina. Kinnunen. Kati. Salminen. Antero. Kaarniranta. Kai. September 2012. Oxidative stress activates NLRP3 inflammasomes in ARPE-19 cells--implications for age-related macular degeneration (AMD). Immunology Letters. 147. 1–2. 29–33. 10.1016/j.imlet.2012.05.005. 1879-0542. 22698681.
  7. Sapkota. Muna. DeVasure. Jane M.. Kharbanda. Kusum K.. Wyatt. Todd A.. 2017. Malondialdehyde-acetaldehyde (MAA) adducted surfactant protein induced lung inflammation is mediated through scavenger receptor a (SR-A1). Respiratory Research. 18. 1. 36. 10.1186/s12931-017-0517-x. 1465-993X. 5307820. 28193223 . free .
  8. Rizzo. William B.. March 2014. Fatty aldehyde and fatty alcohol metabolism: review and importance for epidermal structure and function. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1841. 3. 377–389. 10.1016/j.bbalip.2013.09.001. 0006-3002. 3993971. 24036493.
  9. Wood. Paul L.. Khan. M. Amin. Moskal. Joseph R.. 2007-05-11. The concept of "aldehyde load" in neurodegenerative mechanisms: cytotoxicity of the polyamine degradation products hydrogen peroxide, acrolein, 3-aminopropanal, 3-acetamidopropanal and 4-aminobutanal in a retinal ganglion cell line. Brain Research. 1145. 150–156. 10.1016/j.brainres.2006.10.004. 0006-8993. 17362887. 1228632.
  10. Vogel. Kara R.. Ainslie. Garrett R.. Walters. Dana C.. McConnell. Alice. Dhamne. Sameer C.. Rotenberg. Alexander. Roullet. Jean-Baptiste. Gibson. K. Michael. July 2018. Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies. Journal of Inherited Metabolic Disease. 41. 4. 699–708. 10.1007/s10545-018-0153-8. 1573-2665. 6041169. 29460030.
  11. Fritz. Kristofer S.. Petersen. Dennis R.. 2013-06-01. An overview of the chemistry and biology of reactive aldehydes. Free Radical Biology and Medicine. Methods in Lipid Oxidation. en. 59. 85–91. 10.1016/j.freeradbiomed.2012.06.025. 22750507. 3540155. 0891-5849.
  12. Marchitti. Satori A.. Chen. Ying. Thompson. David C.. Vasiliou. Vasilis. July 2011. Ultraviolet Radiation: Cellular Antioxidant Response and the Role of Ocular Aldehyde Dehydrogenase Enzymes. Eye & Contact Lens. 37. 4. 206–213. 10.1097/ICL.0b013e3182212642. 1542-2321. 3356694. 21670692.
  13. Ochs-Balcom. H. M.. Grant. B. J. B.. Muti. P.. Sempos. C. T.. Freudenheim. J. L.. Browne. R. W.. McCann. S. E.. Trevisan. M.. Cassano. P. A.. Iacoviello. L.. Schünemann. H. J.. 2006. Antioxidants, oxidative stress, and pulmonary function in individuals diagnosed with asthma or COPD. European Journal of Clinical Nutrition. 60. 8. 991–999. 10.1038/sj.ejcn.1602410. 0954-3007. 16482071. free.
  14. Cannavò. Serafinella Patrizia. Riso. Gabriella. Casciaro. Marco. Di Salvo. Eleonora. Gangemi. Sebastiano. 2019. Oxidative stress involvement in psoriasis: a systematic review. Free Radical Research. 53. 8. 829–840. 10.1080/10715762.2019.1648800. 1029-2470. 31392915. 199504425.
  15. Choi. Won. Lian. Cui. Ying. Li. Kim. Ga Eon. You. In Cheon. Park. Soo Hyun. Yoon. Kyung Chul. 2016. Expression of Lipid Peroxidation Markers in the Tear Film and Ocular Surface of Patients with Non-Sjogren Syndrome: Potential Biomarkers for Dry Eye Disease. Current Eye Research. 41. 9. 1143–1149. 10.3109/02713683.2015.1098707. 1460-2202. 26731289. 22720058.
  16. Chen. Yu. Okano. Kiichiro. Maeda. Tadao. Chauhan. Vishal. Golczak. Marcin. Maeda. Akiko. Palczewski. Krzysztof. 2012-02-10. Mechanism of all-trans-retinal toxicity with implications for stargardt disease and age-related macular degeneration. The Journal of Biological Chemistry. 287. 7. 5059–5069. 10.1074/jbc.M111.315432. 1083-351X. 3281612. 22184108. free.
  17. Mandell. Kenneth J.. Clark. David. Chu. David S.. Foster. C. Stephen. Sheppard. John. Brady. Todd C.. December 2020. Randomized Phase 2 Trial of Reproxalap, a Novel Reactive Aldehyde Species Inhibitor, in Patients with Noninfectious Anterior Uveitis: Model for Corticosteroid Replacement. Journal of Ocular Pharmacology and Therapeutics. 36. 10. 732–739. 10.1089/jop.2020.0056. 1557-7732. 7757619. 32955967.
  18. Clark. David. Sheppard. John. Brady. Todd C.. 2021-01-15. A Randomized Double-Masked Phase 2a Trial to Evaluate Activity and Safety of Topical Ocular Reproxalap, a Novel RASP Inhibitor, in Dry Eye Disease. Journal of Ocular Pharmacology and Therapeutics. 37. 4. 193–199. 10.1089/jop.2020.0087. 33450164. 8106247. 1080-7683. free.
  19. Clark. David. Tauber. Joseph. Sheppard. John. Brady. Todd C.. June 1, 2021. Early Onset and Broad Activity of Reproxalap in a Randomized, Double-Masked, Vehicle-Controlled Phase 2b Trial in Dry Eye Disease. American Journal of Ophthalmology. 226. 22–31. 10.1016/j.ajo.2021.01.011. 1879-1891. 33529588. free.
  20. Clark. David. Cavanagh. Bill. Shields. Alan L.. Karpecki. Paul. Sheppard. John. Brady. Todd C.. October 1, 2021. Clinically Relevant Activity of the Novel RASP Inhibitor Reproxalap in Allergic Conjunctivitis: The Phase 3 ALLEVIATE Trial. American Journal of Ophthalmology. 230. 60–67. 10.1016/j.ajo.2021.04.023. 33945820. free.
  21. Clark. David. Karpecki. Paul. Salapatek. Anne Marie. Sheppard. John D. Brady. Todd C. 2022-01-04. Reproxalap Improves Signs and Symptoms of Allergic Conjunctivitis in an Allergen Chamber: A Real-World Model of Allergen Exposure. Clinical Ophthalmology. 16. 15–23. 10.2147/OPTH.S345324. 1177-5467. 8742616. 35018093 . free .
  22. Cavanagh . B . Gomes . PJ . Starr . CE . Nichols . KK . Brady . TC . August 2022 . Reproxalap Activity and Estimation of Clinically Relevant Thresholds for Ocular Itching and Redness in a Randomized Allergic Conjunctivitis Field Trial . Ophthalmology and Therapy. 11 . 4 . 1449–1461 . 10.1007/s40123-022-00520-z . 9253207 . 35585427 .

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