Formation of Radicals

Summary

Cerebral formation of oxygen and nitrogen centered radicals including superoxide, hydroxyl radical, nitric oxide, and peroxynitrite is a physiological process originating from enzyme catalyzed redox reactions triggered by the turnover of endogenous and exogenous substrates. Due to the high reactivity of radicals, covalent modifications of lipids, proteins and DNA are likely to occur if radicals are not trapped by scavengers such as tocopherol, ascorbate of glutathione. Lipid peroxidation gives rise to cytotoxic aldehydes that have to be detoxified by glutathionylation. Oxidized proteins are metabolized by proteases and radical-mediated DNA-base modifications may be repaired by specific glycosylases. Incomplete repair of DNA and proteins may however, result in altered transcriptional response and protein aggregation. In chronic neurodegenerative diseases including Alzheimer’s and Parkinson’s disease increased levels of biomarkers of oxidative and nitrosative stress have been identified in the brain. Some of which such as hydroxyalkenals and isoprostanes may even gain diagnostic value for the determination of the degree of neurodegeneration. However, scientific efforts have to be continued to further elucidate the roles of radicals for disease onset and disease progression in neurodegeneration. The search for novel and selective biomarkers of radical-mediated brain damage might provide new diagnostic tools and perspectives for drug development to combat the progression of neurodegeneration. Summary on relevant findings of free radical research in Alzheimer’s disease. In AD neurodegeneration is pathologically first detected in distinct cortical areas including the entorhinal cortex and the hippocampus, leading to the destruction of long axon bearing cholinergic neurons. The majority of degenerating neurons is moderately myelinized, indicating a disturbance of lipid metabolism and selective vulnerability of these neurons. The accumulation of risk factors i.e. alterations in lipid transport by apolipoproteins, as well as amyloid precursor protein (APP) and presenilin mutations overadditively increase the risk for AD. In AD cortical and hippocampal brain regions as well as cerebrospinal fluid show increased susceptibility to damage by reactive species (reactive oxygen and reactive nitrogen species). Enzymatic defence and repair of damage induced by reactive species is upregulated already at early stages of the disease especially in patients with an apolipoprotein-Eε4 genotype. The deposition of amyloid plaques might lead to local formation of reactive species by enhancing transition metal catalyzed redox reactions and to the activation of astrocytes and microglial cells releasing chemokines, cytokines and superoxide. Vice versa plaque formation may be facilitated by reactive species and protein coss links with reactive aldehydes resulting from lipid peroxidation. The products of lipid peroxidation, hydroxyalkenals and isoprostanes, might further react with DNA, alter cellular signaling (hyper-phosphorylated Tau protein) interfere with de novo protein synthesis, transform formally non pathogenic molecules to pathogenic ones (beta amyloid aggregation) e.g. by triggering the formation of advanced glycation end products, and by changing membrane lipid constituents, membrane functions, and fluidity. As a result of fatty acid peroxidation and deacylation of fatty acid peroxides from lipids by phospholipases, increases in levels of prostaglandins and isoprostanes occur in AD that are already considered as peripheral markers in cerebrospinal fluid. Thus, it appears very likely that reactive species play a crucial role for neural degeneration in AD, and therapeutic approaches involving the concept of antagonizing oxidative stress in AD are in progress.

Summary on relevant findings of free radical research in Parkinson’s disease Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the inability to initiate, execute and control movement. Neuropathologically there is a striking loss of dopamine-producing neurons in the substantia nigra pars compacta, accompanied by depletion of dopamine in the striatum. As the disease progresses other neurotransmitters are lost to a minor degree including norepinephrine and serotonin. In PD decreased activities of glutathione peroxidases and catalase, as well as decreased glutathione levels, increased activities of superoxide dismutases, and elevated levels of non-ferritin-bound iron concomitant with a high turnover of catecholamines, may participate in the production of reactive species. All these factors may render substantia nigra cells in PD more susceptible to hereto undefined toxic noxae and may provoke lipid peroxidation as shown by increased levels of hydroxynonenal-modified proteins, consequently lead to increased levels of intracellular Ca²⁺, activation of proteases, lipases, and endonucleases that ultimately execute cell death. Predominantly neuromelanin containing neurons are lost in PD. This suggests the involvement of neuromelanin in the pathogenetic process. It is hypothesized that the antioxidant capacity of neuromelanin is overcome by neuromelanin-bound iron. Interestingly, carbonyl content in the normal human substantia nigra is twofold increased as compared to other brain areas. This points toward an increased carbonyl stress that might be related to catecholamine oxidation and the formation of fatty acid peroxidation products including hydroxynonenal in the substantia nigra. Carbonyl compounds in the form of advanced glycation end products have been identified in Lewy bodies, a pathological hallmark in PD. Another pathological characteristic of Lewy bodies is the ubiquitously expressed presynaptic protein α-synuclein. It has been reasoned that mutations in the α-synuclein gene in autosomal dominant forms of PD might impair storage of presynaptic dopamine making the neuromelanin containing neurons more vulnerable to catechol toxicity. The ocurrence of continuous oxidative stress leads to the inhibition of the proteasome by oxidatively modified proteins. This may further trigger the formation of neurotoxic protein aggregates and extent neuronal damage beyond catecholaminergic brain areas.