Apoptotic mechanisms involved in neurodegenerative diseases: experimental and therapeutic approaches.
Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most significant neurodegenerative disorders in the developed world. However, although these diseases were described almost a century ago, the molecular mechanisms that lead to the neuronal cell death associated with these diseases are not yet clear, and vigorous research efforts have failed to identify effective treatment options. In the present review, we evaluate the potential mechanisms underlying apoptosis and neuronal death in neurodegenerative disorders. A role for mitochondria in the release of proapoptotic proteins, such as cytochrome c and apoptosis-inducing factor (AIF) etc., is discussed along with key processes involving oxidative stress and activation of glutamate receptors. We also deliberate the implication of DNA damage, primarily p53 induction and reentry in the cell cycle. Finally, we postulate that multitargeting therapies comprising antioxidants, cell cycle inhibitors and modulating agents of COX-2 or c-JUN kinase pathways could be suitable strategies to prevent or delay the process of neuronal cell death in neurodegenerative disorders. Thus, the aim of this review is to discuss the pathways involved in the pathogenesis of neurodegenerative diseases such as AD, PD and Huntington's disease (HD). Furthermore, current and future pharmacotherapeutics will be considered.
Camins
A
A
Facultat de Farmacia, Unitat de Farmacologia i Farmacognosia, Universitat de Barcelona (UB), Barcelona, Spain.
Pallas
M
M
Silvestre
J S
JS
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D016202:N-Methylaspartate / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology
D000975:Antioxidants; D051033:Apoptosis Inducing Factor; D052246:Cyclooxygenase 2 Inhibitors; D018698:Glutamic Acid; D016202:N-Methylaspartate; D045304:Cytochromes c; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D020169:Caspases