Cyclooxygenase (COX) catalyses the first committed step in the synthesis of prostanoids, a large family of arachidonic acid metabolites comprising prostaglandins, prostacyclin, and thromboxanes, and is a major target of non-steroidal anti-inflammatory drugs (NSAIDs). COX exists as constitutive and inducible isoforms. COX-2 is the inducible isoform, rapidly expressed in several cell types in response to growth factors, cytokines, and pro-inflammatory molecules. Since its discovery in the early 1990s, COX-2 has emerged as a major player in inflammatory reactions in peripheral tissues. By extension, COX-2 expression in brain has been associated with pro-inflammatory activities, thought to be instrumental in neurodegenerative processes of several acute and chronic diseases. However, 2 major aspects should be borne in mind. First, in the central nervous system, COX-2 is expressed under normal conditions and contributes to fundamental brain functions, such as synaptic activity, memory consolidation, and functional hyperemia. Second, “neuroinflammation” is a much more controlled reaction than inflammation in peripheral tissues, and in many cases is triggered and sustained by activation of resident cells, particularly microglia. In spite of the intense research of the last decade, the evidence of a direct role of COX-2 in neurodegenerative events is still controversial. This article will review new data in this area, focusing on some major human neurological diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease, Creutzfeldt-Jakob disease, and Alzheimer disease. Furthermore, the emerging role of COX-2 in behavioral and cognitive functions will be discussed.

Inflammation is a self-defensive reaction aimed at eliminating or neutralizing injurious stimuli, and restoring tissue integrity. In neurodegenerative diseases inflammation occurs as a local response driven by microglia, in the absence of leucocyte infiltration. Like peripheral inflammation, neuroinflammation may become a harmful process, and it is now widely accepted that it may contribute to the pathogenesis of many central nervous system disorders, including chronic neurodegenerative diseases. This review addresses some of the most recent advances in our understanding of neuroinflammation. The presence of activated microglia surrounding amyloid plaques and increased levels of complement elements, cytokines, chemokines and free radicals support the existence of a self-propagating toxic cycle and provide a rationale for anti-inflammatory approaches to prevent or delay neurodegeneration. Nonetheless, recent studies have provided evidence that chronic stimulation leads microglia to acquire an anti-inflammatory phenotype, characterized by activated morphology and induction of neuroprotective and immunoregulatory molecules. The causes and consequences of this atypical phenotype have just begun to be unravelled. Although significant advances have been made in our knowledge of degenerative diseases, there remains controversy regarding whether neuroinflammation and microglial activation are beneficial or detrimental. Strategies aimed at both preventing and boosting microglial activation are presently under investigation, and these studies might reveal new potentially effective treatments for these neurological disorders.

Curcumin, a lipophilic polyphenol contained in the rhizome of Curcuma longa (turmeric), has been used for centuries in traditional Asian medicine, and nowadays it is widely used in food as dietary spice worldwide. It has received considerable attention for its pharmacological activities, which appear to act primarily through anti-inflammatory and antioxidant mechanisms. For this reason, it has been proposed as a tool for the management of many diseases, among which are gastrointestinal and neurological diseases, diabetes, and several types of cancer. However, the pharmacology of curcumin remains to be elucidated; indeed, a discrepancy exists between the well-documented in vitro and in vivo activities of curcumin and its poor bioavailability and chemical instability that should limit any therapeutic effect. Recently, it has been hypothesized that curcumin could exert direct regulative effects primarily in the gastrointestinal tract, where high concentrations of this polyphenol have been detected after oral administration. Consequently, it might be hypothesized that curcumin directly exerts its regulatory effects on the gut microbiota, thus explaining the paradox between its low systemic bioavailability and its wide pharmacological activities. It is well known that the microbiota has several important roles in human physiology, and its composition can be influenced by a multitude of environmental and lifestyle factors. Accordingly, any perturbations in gut microbiome profile or dysbiosis can have a key role in human disease progression. Interestingly, curcumin and its metabolites have been shown to influence the microbiota. It is worth noting that from the interaction between curcumin and microbiota two different phenomena arise: the regulation of intestinal microflora by curcumin and the biotransformation of curcumin by gut microbiota, both of them potentially crucial for curcumin activity. This review summarizes the most recent studies on this topic, highlighting the strong connection between curcumin and gut microbiota, with the final aim of adding new insight into the potential mechanisms by which curcumin exerts its effects.

Nicotinic acetylcholine (Ach) receptors are ligand-gated pentameric ion channels whose main function is to transmit signals for the neurotransmitter Ach in peripheral and central nervous system. However, the α7 nicotinic receptor has been recently found in several non-neuronal cells and described as an important regulator of cellular function. Nicotine and ACh have been recently reported to inhibit tumor necrosis factor-α (TNF-α) production in human macrophages as well as in mouse microglial cultures. In the present study, we investigated whether the stimulation of α7 nicotinic receptor by the specific agonist nicotine could affect the functional state of activated microglia by promoting and/or inhibiting the release of other important pro-inflammatory and lipid mediator such as prostaglandin E₂. Expression of α7 nicotinic receptor in rat microglial cell was examined by RT-PCR, immunofluorescence staining and Western blot. The functional effects of α7 receptor activation were analyzed in resting or lipopolysaccharide (LPS) stimulated microglial cells pre-treated with nicotine. Culture media were assayed for the levels of tumor necrosis factor, interleukin-1β, nitric oxide, interleukin-10 and prostaglandin E₂. Total RNA was assayed by RT-PCR for the expression of COX-2 mRNA. Rat microglial cells express α7 nicotinic receptor, and its activation by nicotine dose-dependently reduces the LPS-induced release of TNF-α, but has little or no effect on nitric oxide, interleukin-10 and interleukin-1β. By contrast, nicotine enhances the expression of cyclooxygenase-2 and the synthesis of one of its major products, prostaglandin E₂. Since prostaglandin E₂ modulates several macrophage and lymphocyte functions, which are instrumental for inflammatory resolution, our study further supports the existence of a brain cholinergic anti-inflammatory pathway mediated by α7 nicotinic receptor that could be potentially exploited for novel treatments of several neuropathologies in which local inflammation, sustained by activated microglia, plays a crucial role.

The peroxisome proliferator-activated receptor-g (PPAR-γ) belongs to a large group of nuclear receptors controlling reproduction, metabolism, development and immune response. Upon activation by specific agonists, these receptors form dimers and translocate to the nucleus, where they act as agonist-dependent transcription factors and regulate gene expression by binding to specific promoter regions of target genes. The observation that PPAR-γ is involved in the regulation of macrophage differentiation and activation in the peripheral organs has prompted the investigation of the functional role of PPAR-γ in microglial cells, the main macrophage population of the CNS. The present review summarizes the several lines of evidence supporting that PPAR-γ natural and synthetic agonists may control brain inflammation by inhibiting several functions associated to microglial activation, such as the expression of surface antigens and the synthesis of nitric oxide, prostaglandins, inflammatory cytokines and chemokines. Moreover, one of the major natural PPAR-γ agonist, 15d-prostaglandin J2 may contribute to the safe elimination of activated microglia by inducing apoptosis. Synthetic PPAR- g agonists do not entirely reproduce the range of 15d-prostaglandin J2 effects, suggesting that PPAR-γ independent mechanisms are also involved in the action of this prostaglandin. In addition to microglia, PPAR-γ agonists affect functions and survival of other neural cells, including astrocytes, oligodendrocytes and neurons. Although most of the evidence comes from in vitro observations, an increasing number of studies in animal models further supports the potential therapeutic use of PPAR-γ agonists in human brain diseases including multiple sclerosis, Parkinsons disease and Alzheimers disease.