4-Hydroxynoneal as second messenger of free radicals in the blood-brain barrier
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1
Clinical Hospital Centre, Medical Faculty, Netherlands
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2
Rudjer Boskovic Institute, Netherlands
Excess in production of reactive oxygen species (ROS), process denoted as oxidative stress, is considered to play important role in various pathologies, such as cardiovascular diseases, cancer, metabolic disorders, autoimmune disorders and (neuro)degenerative processes. Although oxidative stress could be moderate and even physiological, as in case of physical exercise or wound healing, thus playing important role in oxidative homeostasis, if excess in production of ROS results in irreversible damage of the structure and function of major bioactive macromolecules, in particular nucleic acids and proteins, it becomes important component of acute and chronic disorders, as mentioned. Of particular relevance is aggressive process of lipid peroxidation, in particular of poly-unsaturated fatty acids (PUFA) in cellular membranous structures, which is a progressive, chain reaction of ROS production resulting in final disintegration of the membranes. The final products of lipid peroxidation, reactive aldehydes, are considered as “second toxic messengers of free radicals” because their biological activities often resemble bioactivities of ROS, although these aldehydes are not ROS. Among the end products of lipid peroxidation of particular relevance is 4- hydroxynonenal (HNE), which acts not only as a second (toxic) messenger of free radicals, but also as a growth regulating factor interfering with the effects of various cytokines [1]. HNE is nowadays considered as major bioactive marker of lipid peroxidation and a signaling molecule involved in proliferation, differentiation and apoptosis [2].
It is well known that HNE has strong affinity to bind to proteins, developing relatively stable and bioactive protein adducts, while recent studies have revealed that HNE-protein adducts are physiologically present in various human and animals tissues, indicating that not only oxidative stress but also lipid peroxidation could contribute to oxidative homeostasis [3]. However, while the physiological roles of such HNE-protein adducts have yet to be clarified, their relevance for various pathologies were intensively studied for year. These studies have shown that HNE-protein adducts could play important roles in neurodegenerative disorders, in particular in Alzheimer’s disease, spongiform encephalopathies and amyotrophic lateral sclerosis (ALS) [4]. Moreover, HNE-protein adducts were also found to be present in brain tumors, in particular astrocytomas, showing the distribution pattern specific for each types of the tumor and positive correlation with the level of malignancy of these neoplasms [5]. Of particular relevance might be findings of association of HNE-protein adducts with the tumor blood vessels, indicating that while HNE could be found physiologically in the blood vessel walls, its spread into the brain tissue might be associated with the development and progression of the tumor. Complementary to that, we have found HNE to be present in the blood-brain barrier (BBB) as presented on Figure 1, but only under pathological circumstances, such as relative hypoxia (reduced blood flow) or inflammation (sepsis) [6]. Biomedical relevance of the presence of HNE in the BBB could be very high, because the use of in vitro model of the BBB has shown that HNE makes the endothelial part of the BBB permeable within 10 minutes of exposure to the aldehyde, while astrocytic part of the BBB starts licking with 10-20 minutes delay after endothelium [7]. Therefore, the presence of HNE in the BBB in vivo might alter the function of the barrier allowing not only exchange of substances otherwise reduced by the BBB but also progressive pathological circumstances allowing secondary brain tissue damage. That could be further enhanced under conditions of hypoxia and/or inflammation, which allow the inflammatory cells, in particular granulocytes, to adhere to the endothelium under hypoxic and to migrate out of the blood vessels undergoing oxidative burst.
Based on these facts we may assume that 4-hydroxynoneal acts as second messenger of free radicals in the BBB under various conditions of oxidative stress and makes preconditions for the disorders of the central nervous system (CNS) function. Accordingly, the use of some antioxidant substances that might attenuate production and bioactivities of HNE might be beneficial for the CNS disorders, while mild lipid peroxidation, within the levels of oxidative homeostasis might eventually also increase the permeability of the BBB and increase efficiency of some medicaments.
References
1. Zarkovic N, Zarkovic K, Schaur RJ, Stolc S, Schlag G, Redl H, Waeg G, Borovic S, Loncaric I, Juric G, Hlavka V. 4-Hydroxynonenal as a second messenger of free radicals and growth modifying factor. Life Sci. 1999, 65, 1901-1904
2. Zarkovic N. 4-Hydroxynonenal as a bioactive marker of pathopysiological processes. Mol. Asp. Med. 2003, 24, 281-291
3. Zarkovic N. Protein-aldehydic adducts as biomarkers of oxidative stress, lipid peroxidation and oxidative homeostasis. Free Radic. Res., 2009, 43: 33-33, Suppl. 1
4. Zarkovic K. 4-Hydroxynonenal and neurodegenerative diseases. Mol. Asp. Med. 2003, 24, 293-303
5. Zarkovic K, Juric G, Waeg G, Kolenc D, Zarkovic N. Immunohistochemical appearance of HNE-protein conjugates in human astrocytomas. Biofactors 2005, 24, 33-40
6. Zarkovic K, Zarkovic N, Schlag G, Redl H, Waeg G. Histological aspects of sepsisinduced brain changes in a baboon model. In: Shock, Sepsis and Organ Failure, 5th Wiggers Bernard Conference (Schlag G., Redl H., Traber D.L., eds.), Springer-Verlag, Heidelberg, 1997, p-146-160
7. Mertsch K, Blasig I, Grune T. 4-Hydroxynonenal impairs the permeability of an in vitro rat blood–brain barrier. Neurosci. Lett. 2001, 314, 135–138
Conference:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.
Presentation Type:
Oral Presentation
Topic:
Presentations
Citation:
Zarkovic
K,
Cindric
M,
Kolenc
D and
Zarkovic
N
(2010). 4-Hydroxynoneal as second messenger of free radicals in the blood-brain barrier.
Front. Pharmacol.
Conference Abstract:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU.
doi: 10.3389/conf.fphar.2010.02.00012
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Received:
25 Feb 2010;
Published Online:
25 Feb 2010.
*
Correspondence:
Kamelija Zarkovic, Clinical Hospital Centre, Medical Faculty, Zagreb, Netherlands, zarkovic@irb.hr