Taken together our results indicated

Taken together, our results indicated that 5-LOX can be induced in mice by MPTP injection, and the 5-LOX inhibitor MK-886 reduced the death of dopaminergic neurons. MK-886 also reduced the LTB4 gtpase induced by MPTP. The development of the novel 5-LOX or FLAP inhibitors may provide a new therapeutic strategy to treat Parkinsonism.
Acknowledgements This work was supported by grants from the National Science Council, Taiwan. There are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Alzheimer’s disease: the neuropathology Through extensive clinical and molecular work over the past several decades, the biochemical pathways that lead to Alzheimer’s disease (AD) pathology have been well characterized. The cardinal pathologies observed in AD are the extracellular deposits of amyloid-β proteins (Aβ) known as Aβ plaques, and intracellular accumulations of the hyper-phosphorylated microtubule-associated tau protein known as neurofibrillary tangles (Iqbal et al., 2010, Holtzman et al., 2011). Current dogma presumes Aβ as the upstream molecular initiator in AD based on the evidence that mutations in the Aβ precursor protein (APP) and presenilins, main components of the protease complex that cleaves it to produce Aβ peptides, are found in early-onset, familial variants of AD. Additionally, patients with Down’s syndrome, in which there is an additional chromosome 21, the locus of the APP gene, have significantly increased rates of AD when compared with the general population (Wilcock and Griffin, 2013). However, some recent clinical data have also found mutations in the APP gene that are protective and reduce the risk to develop the disease (Jonsson et al., 2012). The Aβ peptides are formed by the sequential cleavage of APP by the β-secretase (β APP cleavage enzyme, BACE 1) and the γ-secretase complex composed of the nicastrin, presenilin (PS1), anterior-pharynx defective-1 protein (APH-1), and presenilin enhancer protein (PEN2 or Pen-2), as shown in ​Fig. 1. While APP may be cleaved by α-secretase and then γ-secretase to produce non-amyloidogenic products, this Aβ producing pathway is thought to be privileged in AD. Generation of higher amounts and subsequent aggregation of Aβ peptides through the sequential β- and γ-secretase cleavages is thought to lead to soluble oligomers, followed by longer fibrils, and finally insoluble plaques, which are found abundantly in the vast majority of AD patients on autopsy. Although insoluble plaques have been found in the brains of patients without AD, current thinking is that Aβ oligomers perpetuate the brunt of molecular insults in AD rather than insoluble plaques (Ono and Yamada, 2011).
The 5-lipoxygenase pathway The 5-lipoxygenase (5LO) is an enzyme that inserts molecular oxygen into the carbon in position 5 of free or esterified fatty acids, most notably arachidonic acid. However, in order to carry out the reaction, 5LO also requires the action of the 5LO activating protein, FLAP, which presents the substrate for the enzymatic oxygenation (Rådmark and Samuelsson, 2010). Immediate products of 5LO include unstable 5-hydroperoxyeicosatetraenoic acid which is either reduced to 5-hydroxyeicosatetraenoic acid or leukotriene A4 (LTA4). Depending on the cellular milieu, LTA4 can be metabolized either to leukotriene B4 (LTB4) or C4 (LTC4), with LTC4 further being metabolized to LTD4 and LTE4 (Bishayee and Khuda-Bukhsh, 2013), as shown in Fig. 2. These 5LO final products have potent biological actions mediated by binding to their respective G protein-coupled receptors, such as BLT1 and BLT2 for LTB4 (Yokomizo et al., 2001a, Yokomizo et al., 1997, Yokomizo et al., 2000), and CysLT1 and CysLT2 for LTC4 and LTD4 (Norel and Brink, 2004, Singh et al., 2010). LTB4 is a key mediator of inflammatory processes, immune responses, and host defense against infection (Brock et al., 1995, Yokomizo et al., 2001b) and is known to stimulate chemotaxis, degranulation, release of lysosomal enzymes, and reactive oxygen species (ROS) generation (Palmer et al., 1980, Busse, 1998).