Reactive aldehyde species

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4-hydroxynonenal, a common disease-associated pro-inflammatory RASP 4-hydroxynonenal.png
4-hydroxynonenal, a common disease-associated pro-inflammatory RASP

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. [1] In addition to binding to proteins and other amine or thiol-containing molecules such as glutathione, RASP are metabolized by aldehyde dehydrogenases [8] or aldehyde reductases. [9] 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, [8] 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. [1] The toxicity of RASP include mutagenicity, aggregate formation, and generalized cytotoxicity. [1] [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]

  1. 1 2 3 4 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. doi:10.1016/0891-5849(91)90192-6. ISSN   0891-5849. PMID   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. doi:10.1042/BJ20111752. ISSN   1470-8728. PMC   3286857 . PMID   22364280.
  3. ↑ Raghavan, Somasundaram; Subramaniyam, Ganesan; Shanmugam, Narkunaraja (2012). "Proinflammatory effects of malondialdehyde in lymphocytes". Journal of Leukocyte Biology. 92 (5): 1055–1067. doi:10.1189/jlb.1211617. ISSN   1938-3673. PMID   22956781. S2CID   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. doi:10.1016/j.exer.2007.09.010. ISSN   0014-4835. PMC   2786271 . PMID   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. doi:10.1002/art.38969. ISSN   2326-5205. PMC   5469548 . PMID   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. doi:10.1016/j.imlet.2012.05.005. ISSN   1879-0542. PMID   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. doi: 10.1186/s12931-017-0517-x . ISSN   1465-993X. PMC   5307820 . PMID   28193223.
  8. 1 2 3 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. doi:10.1016/j.bbalip.2013.09.001. ISSN   0006-3002. PMC   3993971 . PMID   24036493.
  9. 1 2 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. doi:10.1016/j.brainres.2006.10.004. ISSN   0006-8993. PMID   17362887. S2CID   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. doi:10.1007/s10545-018-0153-8. ISSN   1573-2665. PMC   6041169 . PMID   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. 59: 85–91. doi:10.1016/j.freeradbiomed.2012.06.025. ISSN   0891-5849. PMC   3540155 . PMID   22750507.
  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. doi:10.1097/ICL.0b013e3182212642. ISSN   1542-2321. PMC   3356694 . PMID   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. doi: 10.1038/sj.ejcn.1602410 . ISSN   0954-3007. PMID   16482071.
  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. doi:10.1080/10715762.2019.1648800. ISSN   1029-2470. PMID   31392915. S2CID   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. doi:10.3109/02713683.2015.1098707. ISSN   1460-2202. PMID   26731289. S2CID   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. doi: 10.1074/jbc.M111.315432 . ISSN   1083-351X. PMC   3281612 . PMID   22184108.
  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. doi:10.1089/jop.2020.0056. ISSN   1557-7732. PMC   7757619 . PMID   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. doi: 10.1089/jop.2020.0087 . ISSN   1080-7683. PMC   8106247 . PMID   33450164.
  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. doi: 10.1016/j.ajo.2021.01.011 . ISSN   1879-1891. PMID   33529588.
  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. doi: 10.1016/j.ajo.2021.04.023 . PMID   33945820.
  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. doi: 10.2147/OPTH.S345324 . ISSN   1177-5467. PMC   8742616 . PMID   35018093.
  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. doi:10.1007/s40123-022-00520-z. PMC   9253207 . PMID   35585427.
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