Cells die by a variety of mechanisms. Terminally differentiated cells such as neurones die in a variety of disorders, in part, via parthanatos, a process dependent on the activity of poly (ADP-ribose)-polymerase (PARP). Parthanatos does not require the mediation of caspases for its execution, but is clearly mechanistically dependent on the nuclear translocation of the mitochondrial-associated apoptosis-inducing factor (AIF). The nuclear translocation of this otherwise beneficial mitochondrial protein, occasioned by poly (ADP-ribose) (PAR) produced through PARP overactivation, causes large-scale DNA fragmentation and chromatin condensation, leading to cell death. This review describes the multistep course of parthanatos and its dependence on PAR signalling and nuclear AIF translocation. The review also discusses potential targets in the parthanatos cascade as promising avenues for the development of novel, disease-modifying, therapeutic agents.

The kynurenine pathway is the major route for the oxidative degradation of the amino acid tryptophan. Activity of the pathway is involved in several disease conditions, both in the periphery and the central nervous system, including cancer, inflammatory disorders, neurological conditions, psychiatric disorders and neurodegenerative diseases. Three enzymes are now known to catalyze the first and rate-limiting step in the catabolism of tryptophan along this pathway: tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO, subsequently named IDO1), both of which have been extensively studied, and a third enzyme, indoleamine 2,3-dioxygenase 2 (IDO2), a relative newcomer to the kynurenine pathway field. The adjuvant chemotherapeutic agent, 1-methyl-D-tryptophan, was intially suggested to target IDO2, implying involvement of IDO2 in tumorigenesis. Subsequently this compound has been suggested to have alternative actions and the physiological and pathophysiological roles of IDO2 are unclear. Targeted genetic interventions and selective inhibitors provide approaches for investigating the biology of IDO2. This review focuses on the current knowledge of IDO2 biology and discusses tools that will assist in further characterizing the enzymes of the kynurenine pathway.

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Substantial pieces of direct and indirect evidence have mounted over the years linking the induction of oxidative stress to a plethora of disease conditions, not least those associated with the death of neurons. The causal relationship between oxidative damage and neurodegeneration is, however, not yet clear and still a subject of intense investigation. Nevertheless, the phenomenon of oxidative neuronal death has received considerable attention in a frantic search for efficacious therapies for the management of neurological and neurodegenerative conditions. The redox-active nature of reactive oxygen species (ROS), which in their excessive levels induce oxidative stress, the prevalence of ROS production in biological systems, the complexity of interrelationships among these species, and the context-dependent adequacy and resilience of the antioxidant defense systems are some of the challenges that basic research has to grapple with to advance successfully to the translational stage. Much still has to be understood for research efforts in this field to yield enduring therapies. In this review, we examine the nature (chemistry) of ROS, the relationships between them, their physiological functions, the roles of oxidative stress in neurodegeneration, the mechanisms of cell death induced by oxidant species, and the available means of protecting neurons against oxidative damage.

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