Brain Response to Injury and Neurodegeneration

Abstract

Synaptic activity and ischemia/injury promote lipid messenger formation through phospholipase‐mediated cleavage of specific phospholipids from membrane reservoirs. Lipid messengers modulate signaling cascades, contributing to development, differentiation, function (e.g., memory), protection, regeneration, and repair of neurons and overall regulation of neuronal, glial, and endothelial cell functional integrity. Oxidative stress disrupts lipid signaling and promotes lipid peroxidation and neurodegeneration. Lipid signaling at the neurovascular unit (neurons, astrocytes, oligodendrocytes, microglia, and cells of the microvasculature) is altered in early cerebrovascular and neurodegenerative disease. We discuss how lipid signaling regulates critical events in neuronal survival. Aberrant synaptic plasticity (e.g., epileptogenesis) is highlighted to show how gene expression may drive synaptic circuitry formation in the “wrong” direction. Docosahexaenoic acid has been implicated in memory, photoreceptor cell biogenesis and function, and neuroprotection. Free docosahexaenoic acid released in the brain during experimental stroke leads to the synthesis of stereospecific messengers through oxygenation pathways. One messenger, 10,17S‐docosatriene (neuroprotectin D1; NPD1), counteracts leukocyte infiltration and proinflammatory gene expression in brain ischemia‐reperfusion. In retina, photoreceptor survival depends on retinal pigment epithelial (RPE) cell integrity. NPD1 is synthesized in RPE cells undergoing oxidative stress, potently counteracts oxidative stress‐triggered apoptotic DNA damage in RPE, upregulates antiapoptotic proteins Bcl‐2 and Bcl‐xL, and decreases proapoptotic Bax and Bad expression. These findings expand our understanding of how the nervous system counteracts redox disturbances, mitochondrial dysfunction, and proinflammatory conditions. The specificity and potency of NPD1 indicate a potential target for therapeutic intervention for stroke, age‐related macular degeneration, spinal cord injury, and other neuroinflammatory or neurodegenerative diseases.

A More Comprehensive Approach to the Neuroprotective Potential of Long-Chain Polyunsaturated Fatty Acids in Preterm Infants Is Needed—Should We Consider Maternal Diet and the n-6:n-3 Fatty Acid Ratio?

“…Pro-resolving lipid mediators may shorten the times required for cessation of inflammation, possible leading to decreased tissue injury. Experimentally, deficiencies in proresolving mediators as well as high levels of oxidized linoleic acid metabolites have been associated with chronic inflammation and acceleration of associated disease processes (115)(116)(117)(118)(119). A low n-6:n-3 fatty acid ratio, both in the diet and in the blood, is also associated with an increased risk of adult neurological diseases, including stroke and dementia (120)(121)(122).…”

Survival signalling in Alzheimer's disease

“…Exogenously supplied DHA has been shown to attenuate Aβ secretion and neutralize Aβ neurotoxicity in both neural cellular and animal models. When supplied with exogenous DHA, cytokine-stressed human neural cells direct the formation of NPD1 that in turn reduces Aβ peptide secretion and induces both anti-apoptotic and neuroprotective geneexpression programmes (Figure 1) [14,[43][44][45]47,50]. Another important in vivo action of NPD1 may be to neutralize Aβ-mediated neurotoxicity by redirecting βAPP processing and catabolism into favoured production of the nonamyloidogenic, NPD1-inducing sAPPα peptide, and thus promote survival in inflammation-or oxidation-stressed brain cells.…”

“…NPD1 was found to inhibit Aβ42-induced HN cell apoptosis. These results indicate that NPD1 mediates induction of both anti-apoptotic and neuroprotective geneexpression programmes that down-regulate Aβ secretion and modulate intrinsic anti-inflammatory signals that promote neural cell survival in AD brain [41][42][43][44][45][46][47][48][49][50]. The stereospecificity and potency of NPD1 indicate a potential target for therapeutic intervention for stroke, age-related macular degeneration, spinal cord injury and other neuroinflammatory or neurodegenerative diseases.…”

“…The AD Aβ42 peptide induces cell death in human neuroblastoma cells and caspase 3 activation initially via a Bax/Bcl-2 ratio increase [67], and Bcl-2 and Bax induction is related to hyperphosphorylation of tau and neuronal death induced by okadaic acid in rat brain [68,69]. Wide-spectrum gene expression studies show similar depletion of the anti-apoptotic members of the Bcl-2 gene family in AD hippocampus and superior temporal lobe neocortex, and a shift in expression towards the more pro-apoptotic Bcl-2 family species Bax, Bad, Bid and Bik [39,42,44,57,59]. Depletion of these endogenous neuroprotective signals directly contributes to the widespread apoptotic-mediated loss of neurons characteristic of AD brain.…”

“…NPD1 is a novel, stereospecific member of a family of anti-inflammatory neuroprotective bioactive lipids generated from DHA and is the first oxygenated DHA derivative described [41,44,45,47,49,50]. As mentioned previously, DHA has been shown to down-regulate Aβ peptide secretion from aged and cytokine-stressed human neural cells in primary culture, thus lowering Aβ peptide's potential neurotoxic paracrine, aggregative and pro-inflammatory effects [4,14].…”