**5. Involvement of PLA2 signaling in antidepressants effects**

As mentioned earlier, neuroinflammation is reported to play a key role in neurodegenerative changes of neurological diseases, such as Parkinson's disease and Alzheimer's disease. In addition, the possibility is also discussed that the degeneration of monoamine axons, which is considered to occur in patients with depression, may be due in part to neuroinflammation. In recent years much attention has been paid to the roles of the PLA2 signaling pathway in neuroinflammation in relation to neurodegenerative diseases. It has been reported that cPLA2 releases AA and EPA, while iPLA2 preferentially releases DHA. In addition, AA and its products, such as prostaglandins and leukotrienes, play a major role in pro-inflammatory responses, whereas DHA and EPA and their products, such as resolvins and protectins, are involved in anti-inflammatory responses [55, 76, 77]. Omega-3 fatty acids and their metabolites play a regulatory role in the transition from pro-inflammatory to anti-inflammatory phases by inhibiting pro-inflammatory signaling pathways [55]. Thus, the release of AA and its products in the brain induces inflammatory neuronal damage such as axonal degeneration, whereas omega-3 fatty acids and their metabolites exert anti-inflammatory actions to induce the resolution of inflammation and recovery, including the process of axonal regeneration (**Figure 3**).

*Perspective Chapter: Depression as a Disorder of Monoamine Axon Degeneration May Hold… DOI: http://dx.doi.org/10.5772/intechopen.102340*

#### **Figure 3.**

*A possible mechanism of degeneration and regeneration of monoamine axons related to pro-inflammatory and anti-inflammatory actions of PLA2. In the pro-inflammatory phase, cPLA2 and its pro-inflammatory metabolites cause the degeneration of monoamine axons, whereas iPLA2 and its anti-inflammatory metabolites (omega-3 fatty acids) play pivotal roles in inflammation-resolution and recovery by exerting anti-inflammatory and regenerative actions. There are distinct interactions between pro-inflammatory and anti-inflammatory signaling pathways. Antidepressants are considered to activate iPLA2 signaling pathway and induce antiinflammatory response and the regeneration of monoamine axons through omega-3 fatty acids and their metabolites. PLA2: Phospholipase A2, cPLA2: Cytosolic phospholipase A2, iPLA2: Calcium-independent phospholipase A2.*

Therefore, it is possible, at least in part, that antidepressants, which can activate iPLA2 signaling pathways, induce the axonal regeneration of monoamine neurons by antiinflammatory and regenerative actions of omega-3 fatty acids and their metabolites.

### **6. Biomarkers for axonal degeneration**

As noted in this review, many recent studies have clearly demonstrated that depression is a neurodegenerative disease and shares many similarities with wellknown neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Particularly, axonal degeneration is a common phenomenon that occurs at the early stages of Parkinson's disease and Alzheimer's disease, and possibly in depression. It is thus essential to devise new tools for the detection of axonal degeneration of affected neurons. If this is realized, Parkinson's disease and Alzheimer's disease at early stages, characterized by axonal degeneration without cell death, will be treatable with drugs with the ability to induce axonal regeneration. In depression, one of the promising and powerful tools for detecting monoamine axon degeneration is neuroimaging of monoamine axon terminals using radiotracers of transporters of each monoamine axon. Interestingly, a more recent study reported that plasma phosphoethanolamine is a reliable biomarker of depression because it was significantly decreased in patients with depression and inversely correlated with the severity of depressive symptoms, including depressed mood, loss of interest, and psychomotor retardation [78]. Similarly, plasma levels of ethanolamine and phosphatidylethanolamine were found to

be reduced in early-stage Parkinson's disease [79], while ethanolamine and phosphoethanolamine were also decreased in cerebrospinal fluid [80] and postmortem brains [81, 82] of Alzheimer's disease patients. Because ethanolamine and phosphoethanolamine are the precursors of the phospholipid phosphatidylethanolamine that plays a role in the incorporation of omega-3 fatty acids in the cell membrane, it is possible that phosphatidylethanolamine and its precursors are one of the reliable biomarkers of axonal degeneration of at least a subset of patients with depression as well as neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease.
