br LO synaptic integrity and memory Interestingly several gr

12/15LO, synaptic integrity, and memory Interestingly, several groups have found that 12/15LO directly modulates synaptic function. Normandin and colleagues reported that pharmacological inhibition of 12/15LO modulates rat hippocampal long-term depression (LTD), a process by which neuronal synaptic activity is reduced in response to stimuli [40]. Other work has also detailed how 12/15LO metabolism is necessary for appropriate metabotropic glutamate receptor signaling, as well as for the induction of long-term potentiation (LTP), a stimulation-dependent process of synaptic strengthening between neurons 41, 42. Because we had already shown changes in the cardinal AD neuropathologies of Aβ and tau in vivo, we were interested to investigate whether, if at all, synaptic changes were present in our 12/15LO model systems. In Tg2576 mice, overexpression of 12/15LO reduced steady-state levels of two main synaptic proteins: post-synaptic density protein 95 (PSD95) and synaptophysin. A similar result was obtained when the dendritic protein MAP2 was also assayed. These results were further confirmed in SB 204990 sections of the same mice when they were tested by immunohistochemical analyses [36]. By contrast, pharmacological inhibition of 12/15LO in 3×Tg mice resulted in a significant increase in both PSD95 and MAP2, suggesting an improvement of synaptic integrity [39]. Because synaptic proteins were found to be modulated in the above studies, we next investigated whether 12/15LO might modulate memory impairments in these AD mouse models. Knockout of 12/15LO in Tg2576 mice significantly improved their learning in the fear-conditioning paradigm which reflects hippocampal functionality [35]. By contrast, overexpression of 12/15LO in Tg2576 mice lead to an exacerbation of contextual and cued-recall memory impairments, suggesting both hippocampal and amygdala involvement [36]. In 3xTg mice, pharmacological inhibition of 12/15LO improved performance on working memory, as assessed by the Y-maze, as well as fear-conditioned memory and spatial memory assessed by the Morris watermaze paradigm [39]. Overall, these data suggest that 12/15LO plays a crucial role not only in synaptic integrity but also in modulating cognitive impairments in AD (Figure 4).
12/15LO and neuroprotection Stroke and ischemic damage share many common pathological mechanisms with AD pathogenesis, including oxidative stress, excitotoxicity, apoptosis, and inflammation 43, 44, 45, 46. In particular, data from various animal stroke models (i.e., multiple infarct embolic strokes, transient focal ischemia), as well as data on brain tissue from stroke patients, have consistently shown that caspase-mediated apoptosis plays a crucial role not only in ischemia but also in AD because APP and tau have been described to be substrates for caspase-mediated cleavage 47, 48, 49, 50. In animal models of ischemia, 12/15LO and its metabolites have been demonstrated modulate cell death, blood–brain barrier permeability, and brain edema because pretreatment with 12/15LO inhibitors reduced infarct size and mitigated resultant apoptosis in these animal 51, 52, 53. Most importantly, beyond reducing the molecular insults, pharmacological inhibition of 12/15LO in stroke has been linked to better functional outcome and improved recovery in animal models 54, 55, 56, 57.
Implications for AD and beyond
Acknowledgments
Introduction Adverse cardiac remodeling is pathological process that develops after myocardial infarction (MI) and alters shape, size, and function of the left ventricle (LV) [1]. Functional and structural changes of the LV are widely associated with defective resolution of inflammation and extracellular matrix (ECM) responses, leading to increased mortality in heart failure patients [2,3]. The post-MI inflammatory response initiates mobilization of immune cells (neutrophils and macrophages) studied in chemokine and cytokine inhibitory approaches. Due to the failure of non-aspirin containing anti-inflammatory products, the FDA recommends limiting the use of inflammation inhibiting agents in the heart failure setting [4]. Thus, it becomes an unmet medical need to resolve inflammation after MI. Resolution in response to MI-induced healing is coordinated by macrophages, lipid mediators and inflammation resolving enzymes such as lipoxygenases (LOXs) cyclooxygenases (COX) and cytochrome P450 epoxygenases (CYP) [5].