Biochemical Aspects of Neurodegeneration in Human Brain: Involvement of Neural Membrane Phospholipids and Phospholipases A2

Abstract

Neural membrane phospholipids are hydrolyzed by a group of enzymes known as phospholipases. This process results in the generation of second messengers such as arachidonic acid, eicosanoids, platelet activating factor, and diacylglycerols. High levels of these metabolites are neurotoxic and are associated with neurodegeneration. The collective evidence from many studies suggests that neural membrane phospholipid metabolism is disturbed in neural trauma and neurodegenerative diseases. This disturbance is caused by the stimulation of phospholipases A2. Stimulation of these enzymes produces changes in membrane permeability, fluidity, and alteration in ion homeostasis. Low calcium influx produces mild oxidative stress and results in neurodegeneration promoted by apoptosis, whereas a calcium overload generates high oxidative stress and causes neurodegeneration associated with necrosis. Alterations in phospholipid metabolism along with the accumulation of lipid peroxides and compromised energy metabolism may be responsible for neurodegeneration in ischemia, spinal cord trauma, head injury, and Alzheimer disease. The synthesis of phospholipases A2 inhibitors that cross the blood-brain barrier without harm may be useful for the treatment of acute neural trauma and neurodegenerative diseases.

The Interaction between Cytoplasmic Prion Protein and the Hydrophobic Lipid Core of Membrane Correlates with Neurotoxicity

“…Generally, cPLA2 is involved in the production of eicosanoids and is associated with reactive astrocytes (27,28). To determine the relationship between the increase in cPLA 2 and the reactive astrocytes, we performed immunohistochemical staining with antibodies against both cPLA 2 and GFAP, a marker for reactive astrocytes.…”

Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss

“…Elevated intracellular calcium levels may impair mitochondrial function and compromise a host of cellular functions (Luer et al, 1996). Calcium elevation affects cell membranes by activation of phospholipase A 2 and C, resulting in hydrolysis of membrane phospholipids, release of free fatty acids (Farooqui, et al, 2004) and lipid peroxidation (Sullivan et al, 2004). Disturbance in calcium homeostasis contributes to trauma-induced neuronal injury and age-related neuronal loss (Zipfel et al, 2000;Toescu et al, 2004).…”

Signaling and interplay mediated by phospholipases A2, C, and D in LA-N-1 cell nuclei

“…The mechanism of retinoic acid-mediated apoptosis remains unknown. However, two mechanisms have been proposed [49]. According to the first mechanism, retinoic acid induces apoptosis through mitochondrial dysfunction [50].…”

“…According to the first mechanism, retinoic acid induces apoptosis through mitochondrial dysfunction [50]. The second mechanism involves cytokinemediated stimulation of PLA 2 activity [49], resulting in the generation of excess arachidonic acid. This excess arachidonic acid affects the transcription of many genes, not only through the generation of eicosanoids, but also directly [51,52].…”