Increase in oxidative stress has been postulated to play an important role in the pathogenesis of a number of neurodegenerative diseases including Alzheimer’s disease. There is evidence for involvement of amyloid‐β peptide (Aβ) in mediating the oxidative damage to neurons. Despite yet unknown mechanism, Aβ appears to exert action on the ionotropic glutamate receptors, especially the N‐methyl‐D‐aspartic acid (NMDA) receptor subtypes. In this study, we showed that NMDA and oligomeric Aβ1–42 could induce reactive oxygen species (ROS) production from cortical neurons through activation of NADPH oxidase. ROS derived from NADPH oxidase led to activation of extracellular signal‐regulated kinase 1/2, phosphorylation of cytosolic phospholipase A2α (cPLA2α), and arachidonic acid (AA) release. In addition, Aβ1–42‐induced AA release was inhibited by d(−)‐2‐amino‐5‐phosphonopentanoic acid and memantine, two different NMDA receptor antagonists, suggesting action of Aβ through the NMDA receptor. Besides serving as a precursor for eicosanoids, AA is also regarded as a retrograde messenger and plays a role in modulating synaptic plasticity. Other phospholipase A2 products such as lysophospholipids can perturb membrane phospholipids. These results suggest an oxidative‐degradative mechanism for oligomeric Aβ1–42 to induce ROS production and stimulate AA release through the NMDA receptors. This novel mechanism may contribute to the oxidative stress hypothesis and synaptic failure that underline the pathogenesis of Alzheimer’s disease.

Increased oxidative stress has been regarded as an important underlying cause for neuronal damage induced by cerebral ischemia/reperfusion (I/R) injury. In recent years, there has been increasing interest in investigating polyphenols from botanical source for possible neuroprotective effects against neurodegenerative diseases. In this study, we investigated the mechanisms underlying the neuroprotective effects of curcumin, a potent polyphenol antioxidant enriched in tumeric. Global cerebral ischemia was induced in Mongolian gerbils by transient occlusion of the common carotid arteries. Histochemical analysis indicated extensive neuronal death together with increased reactive astrocytes and microglial cells in the hippocampal CA1 area at 4 days after I/R. These ischemic changes were preceded by a rapid increase in lipid peroxidation and followed by decrease in mitochondrial membrane potential, increased cytochrome c release, and subsequently caspase-3 activation and apoptosis. Administration of curcumin by i.p. injections (30 mg/kg body wt) or by supplementation to the AIN76 diet (2.0 g/kg diet) for 2 months significantly attenuated ischemia-induced neuronal death as well as glial activation. Curcumin administration also decreased lipid peroxidation, mitochondrial dysfunction, and the apoptotic indices. The biochemical changes resulting from curcumin also correlated well with its ability to ameliorate the changes in locomotor activity induced by I/R. Bioavailability study indicated a rapid increase in curcumin in plasma and brain within 1 hr after treatment. Together, these findings attribute the neuroprotective effect of curcumin against I/R-induced neuronal damage to its antioxidant capacity in reducing oxidative stress and the signaling cascade leading to apoptotic cell death.

Phospholipases A2 (PLA2s) belong to a superfamily of enzymes responsible for hydrolyzing the sn-2 fatty acids of membrane phospholipids. These enzymes are known to play multiple roles for maintenance of membrane phospholipid homeostasis and for production of a variety of lipid mediators. Over 20 different types of PLA2s are present in the mammalian cells, and in snake and bee venom. Despite their common function in hydrolyzing fatty acids of phospholipids, they are diversely encoded by a number of genes and express proteins that are regulated by different mechanisms. Recent studies have focused on the group IV calcium-dependent cytosolic cPLA2, the group VI calcium-independent iPLA2, and the group II small molecule secretory sPLA2. In the central nervous system (CNS), these PLA2s are distributed among neurons and glial cells. Although the physiological role of these PLA2s in regulating neural cell function has not yet been clearly elucidated, there is increasing evidence for their involvement in receptor signaling and transcriptional pathways that link oxidative events to inflammatory responses that underline many neurodegenerative diseases. Recent studies also reveal an important role of cPLA2 in modulating neuronal excitatory functions, sPLA2 in the inflammatory responses, and iPLA2 with childhood neurologic disorders associated with brain iron accumulation. The goal for this review is to better understand the structure and function of these PLA2s and to highlight specific types of PLA2s and their cross-talk mechanisms in these inflammatory responses under physiological and pathological conditions in the CNS.

Mitochondrial dysfunction has been implicated in the pathophysiology of Alzheimer's disease (AD) brains. To unravel the mechanism(s) underlying this dysfunction, we demonstrate that phospholipases A 2 (PLA 2 s), namely the cytosolic and the calcium-independent PLA 2 s (cPLA 2 and iPLA 2 ), are key enzymes mediating oligomeric amyloid-␤ peptide (A␤ 1-42 )-induced loss of mitochondrial membrane potential and increase in production of reactive oxygen species from mitochondria in astrocytes. Whereas the action of iPLA 2 is immediate, the action of cPLA 2 requires a lag time of ϳ12-15 min, probably the time needed for initiating signaling pathways for the phosphorylation and translocation of cPLA 2 to mitochondria. Western blot analysis indicated the ability of oligomeric A␤ 1-42 to increase phosphorylation of cPLA 2 in astrocytes through the NADPH oxidase and mitogen-activated protein kinase pathways. The involvement of PLA 2 in A␤ 1-42 -mediated perturbations of mitochondrial function provides new insights to the decline in mitochondrial function, leading to impairment in ATP production and increase in oxidative stress in AD brains.

Plant polyphenols are dietary components that exert a variety of biochemical and pharmacological effects. Recently, considerable interest has been focused on polyphenols because of their antioxidant, anti-inflammatory, and antiproliferative activities. Oxidative stress is thought to be a key event in the pathogenesis of cerebral ischemia. Overproduction of reactive oxygen species during ischemia/reperfusion could cause an imbalance between oxidative and antioxidative processes. Reactive oxygen species can damage lipids, proteins, and nucleic acids, thereby inducing apoptosis or necrosis. There is increasing evidence supporting the hypothesis that plant polyphenols can provide protection against neurodegenerative changes associated with cerebral ischemia. This article reviews the neuroprotective effects of plant extracts and their constituents that have been used in animal models of cerebral ischemia. The use of polyphenols as therapeutic agents in stroke has been suggested.