Oxidative stress in neurodegenerative diseases: mechanisms and therapeutic perspectives

Abstract

The incidence and prevalence of neurodegenerative diseases (ND) increase with life expectancy. This paper reviews the role of oxidative stress (OS) in ND and pharmacological attempts to fight against reactive oxygen species (ROS)-induced neurodegeneration. Several mechanisms involved in ROS generation in neurodegeneration have been proposed. Recent articles about molecular pathways involved in ROS generation were reviewed. The progress in the development of neuroprotective therapies has been hampered because it is difficult to define targets for treatment and determine what should be considered as neuroprotective. Therefore, the attention was focused on researches about pharmacological targets that could protect neurons against OS. Since it is necessary to look for genes as the ultimate controllers of all biological processes, this paper also tried to identify gerontogenes involved in OS and neurodegeneration. Since neurons depend on glial cells to survive, recent articles about the functioning of these cells in aging and ND were also reviewed. Finally, clinical trials testing potential neuroprotective agents were critically reviewed. Although several potential drugs have been screened in in vitro and in vivo models of ND, these results were not translated in benefit of patients, and disappointing results were obtained in the majority of clinical trials.

Figure 1

Reactions catalyzed by superoxide dismutase (SOD), catalase, and glutathione peroxidases. Superoxide dismutases (SOD) convert O₂ ⁻ to O₂ and H₂O₂. Catalase and glutathione peroxidases convert H₂O₂ to water. Protein structures represented in this figure are available in the Protein Data Bank (PDB; http://www.rcsb.org/pdb/home/home.do). PDB ID, are referred in brackets.

Figure 2

Oxidative damages induced by transition metals. Iron and copper can reduce oxygen leading to ROS generation and subsequent oxidation of proteins, lipids, and nucleic acids.

Figure 3

Cell death induced by zinc. Zinc modulates protein kinases, which activates NADPH oxidase and PARP-1, leading to necrosis.

Figure 4

Neuronal demise in Alzheimer's disease. The pathologic interaction of cerebral Aβ with transition metals induces oxidative stress, perturbed cellular Ca²⁺ homeostasis, and energy metabolism, which in turns generates more ROS leading to neuronal demise.

Figure 5

Nrf2 regulates the expression of antioxidant enzymes. Under physiological conditions, Nrf2 binds to Keap1 and undergoes constitutive proteasome-dependent degradation. However, under oxidative stress, Keap1 changes its conformation and releases Nrf2, which moves to the nucleus and binds to ARE regulating the expression of several antioxidant enzymes.