4-hydroxy-2-nonenal and Huntington-Disease

Oxidative stress is involved in various and numerous pathological states including several age-related neurodegenerative diseases. Peroxidation of the membrane lipid bilayer is one of the major sources of free radical-mediated injury that directly damages neurons causing increased membrane rigidity, decreased activity of membrane-bound enzymes, impairment of membrane receptors and altered membrane permeability and eventual cell death. Moreover, the peroxidation of polyunsaturated fatty acids leads to the formation of aldehydes, which can act as toxic by-products. One of the most abundant and cytotoxic lipid -derived aldehydes is 4-hydroxy 2-nonenal (HNE). HNE toxicity is mainly due to the alterations of cell functions by the formation of covalent adducts of HNE with proteins. A key marker of lipid peroxidation, HNE-protein adducts, were found to be elevated in brain tissues and body fluids of Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis subjects and/or models of the respective age-related neurodegenerative diseases. Although only a few proteins were identified as common targets of HNE modification across all these listed disorders, a high overlap of these proteins occurs concerning the alteration of common pathways, such as glucose metabolism or mitochondrial function that are known to contribute to cognitive decline. Within this context, despite the different etiological and pathological mechanisms that lead to the onset of different neurodegenerative diseases, the formation of HNE-protein adducts might represent the shared leit-motif, which aggravates brain damage contributing to disease specific clinical presentation and decline in cognitive performance observed in each case.

Topics: Aging; Aldehydes; Alzheimer Disease; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Apolipoproteins E; Fatty Acids, Unsaturated; Glucose; Humans; Huntington Disease; Lipid Peroxidation; Mitochondria; Nerve Tissue Proteins; Oxidative Stress; Parkinson Disease; Protein Processing, Post-Translational

4-hydroxy-2-nonenal (HNE) is considered to be a strong marker of oxidative stress; the interaction between HNE and cellular proteins leads to the formation of HNE-protein adducts able to alter cellular homeostasis and cause the development of a pathological state. By virtue of its high lipid concentration, oxygen utilization, and the presence of metal ions participating to redox reactions, the brain is highly susceptible to the formation of free radicals and HNE-related compounds. A variety of neuropsychiatric disorders have been associated with elevations of HNE concentration. For example, increased levels of HNE were found in the cortex of bipolar and schizophrenic patients, while HNE plasma concentrations resulted high in patients with major depression. On the same line, high brain concentrations of HNE were found associated with Huntington's inclusions. The incidence of high HNE levels is relevant also in the brain and cerebrospinal fluid of patients suffering from Parkinson's disease. Intriguingly, in this case the increase of HNE was associated with an accumulation of iron in the substantia nigra, a brain region highly affected by the pathology. In the present review we recapitulate the findings supporting the role of HNE in the pathogenesis of different neuropsychiatric disorders to highlight the pathogenic mechanisms ascribed to HNE accumulation. The aim of this review is to offer novel perspectives both for the understanding of etiopathogenetic mechanisms that remain still unclear and for the identification of new useful biological markers. We conclude suggesting that targeting HNE-driven cellular processes may represent a new more efficacious therapeutical intervention.

Topics: Aldehydes; Bipolar Disorder; Cerebral Cortex; Depressive Disorder, Major; Humans; Huntington Disease; Iron; Lipid Peroxidation; Mitochondria; Molecular Targeted Therapy; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Schizophrenia; Substantia Nigra

Huntington's disease (HD) is a rare genetic disease caused by expanded polyglutamine repeats in the huntingtin protein resulting in selective neuronal loss. Although genetic testing readily identifies those who will be affected, current pharmacological treatments do not prevent or slow down disease progression. A major challenge is the slow clinical progression and the inability to biopsy the affected tissue, the brain, making it difficult to design short and effective proof of concept clinical trials to assess treatment benefit. In this study, we focus on identifying peripheral biomarkers that correlate with the progression of the disease and treatment benefit. We recently developed an inhibitor of pathological mitochondrial fragmentation, P110, to inhibit neurotoxicity in HD. Changes in levels of mitochondrial DNA (mtDNA) and inflammation markers in plasma, a product of DNA oxidation in urine, mutant huntingtin aggregates, and 4-hydroxynonenal adducts in muscle and skin tissues were all noted in HD R6/2 mice relative to wild-type mice. Importantly, P110 treatment effectively reduced the levels of these biomarkers. Finally, abnormal levels of mtDNA were also found in plasma of HD patients relative to control subjects. Therefore, we identified several potential peripheral biomarkers as candidates to assess HD progression and the benefit of intervention for future clinical trials.

Topics: Aldehydes; Animals; Behavior, Animal; Biomarkers; Body Fluids; Brain; Case-Control Studies; Disease Progression; DNA Damage; DNA, Mitochondrial; Humans; Huntington Disease; Inflammation; Mice; Mitochondria; Muscle, Skeletal; Oxidation-Reduction; Phenotype; Protein Aggregates

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Oxidative damage has been associated with pathological neuronal loss in HD. The therapeutic modulation of oxidative stress and mitochondrial function using low molecular weight compounds may be an important strategy for delaying the onset and slowing the progression of HD. In the present study, we found a marked increase of 4-hydroxy-2-nonenal (4-HNE) adducts, a lipid peroxidation marker, in the caudate and putamen of HD brains and in the striatum of HD mice. Notably, 4-HNE immunoreactivity was colocalized with mutant huntingtin inclusions in the striatal neurons of R6/2 HD mice. Administration of nordihydroguaiaretic acid (NDGA), an antioxidant that functions by inhibiting lipid peroxidation, markedly reduced 4-HNE adduct formation in the nuclear inclusions of R6/2 striatal neurons. NDGA also protected cultured neurons against oxidative stress-induced cell death by improving ATP generation and mitochondrial morphology and function. In addition, NDGA restored mitochondrial membrane potential, mitochondrial structure, and synapse structure in the striatum of R6/2 mice and increased their lifespan. The present findings suggest that further therapeutic studies using NDGA are warranted in HD and other neurodegenerative diseases characterized by increased oxidative stress and altered mitochondrial function.

Topics: Adenosine Triphosphate; Age Factors; Aldehydes; Analysis of Variance; Animals; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Embryo, Mammalian; Glutamic Acid; Humans; Huntingtin Protein; Huntington Disease; Imaging, Three-Dimensional; In Situ Nick-End Labeling; Indoles; Lipid Peroxidation; Lipoxygenase Inhibitors; Male; Masoprocol; Membrane Potential, Mitochondrial; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Mitochondria; Neostriatum; Nerve Tissue Proteins; Neurons; Nuclear Proteins; Oxidative Stress; Synapses; Tetrazolium Salts; Thiazoles; Trinucleotide Repeat Expansion

Abnormalities in the kynurenine pathway may play a role in Huntington's disease (HD). In this study, tryptophan depletion and loading were used to investigate changes in blood kynurenine pathway metabolites, as well as markers of inflammation and oxidative stress in HD patients and healthy controls. Results showed that the kynurenine : tryptophan ratio was greater in HD than controls in the baseline state and after tryptophan depletion, indicating increased indoleamine dioxygenase activity in HD. Evidence for persistent inflammation in HD was provided by elevated baseline levels of C-reactive protein, neopterin and lipid peroxidation products compared with controls. The kynurenate : kynurenine ratio suggested lower kynurenine aminotransferase activity in patients and the higher levels of kynurenine in patients at baseline, after depletion and loading, do not result in any differences in kynurenic acid levels, providing no supportive evidence for a compensatory neuroprotective role for kynurenic acid. Quinolinic acid showed wide variations in blood levels. The lipid peroxidation data indicate a high level of oxidative stress in HD patients many years after disease onset. Levels of the free radical generators 3-hydroxykynurenine and 3-hydroxyanthranilic acid were decreased in HD patients, and hence did not appear to contribute to the oxidative stress. It is concluded that patients with HD exhibit abnormal handling of tryptophan metabolism and increased oxidative stress, and that these factors could contribute to ongoing brain dysfunction.

Topics: Adolescent; Adult; Aged; Aldehydes; Brain; Female; Humans; Huntington Disease; Kynurenine; Male; Malondialdehyde; Middle Aged; Neopterin; Nerve Growth Factors; Oxidative Stress; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Tryptophan

The effects of the peripheral benzodiazepine receptor (PBR) ligand, PK11195, were investigated in the rat striatum following the administration of quinolinic acid (QUIN). Intrastriatal QUIN injection caused an increase of PBR expression in the lesioned striatum as demonstrated by immunohistochemical analysis. Double immunofluorescent staining indicated PBR was primarily expressed in ED1-immunoreactive microglia but not in GFAP-immunoreactive astrocytes or NeuN-immunoreactive neurons. PK11195 treatment significantly reduced the level of microglial activation and the expression of pro-inflammatory cytokines and iNOS in QUIN-injected striatum. Oxidative-mediated striatal QUIN damage, characterized by increased expression of markers for lipid peroxidation (4-HNE) and oxidative DNA damage (8-OHdG), was significantly diminished by PK11195 administration. Furthermore, intrastriatal injection of PK11195 with QUIN significantly reduced striatal lesions induced by the excitatory amino acid and diminished QUIN-mediated caspase-3 activation in striatal neurons. These results suggest that inflammatory responses from activated microglia are damaging to striatal neurons and pharmacological targeting of PBR in microglia may be an effective strategy in protecting neurons in neurological disorders such as Huntington's disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Antineoplastic Agents; Carrier Proteins; Caspases; Corpus Striatum; Cytokines; Deoxyguanosine; Disease Models, Animal; Ectodysplasins; Encephalitis; Gliosis; Huntington Disease; Isoquinolines; Ligands; Male; Membrane Proteins; Microglia; Nerve Degeneration; Neurotoxins; Nitric Oxide Synthase Type II; Oxidative Stress; Quinolinic Acid; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Tumor Necrosis Factors