Pro-inflammatory prostaglandin

The effects of LCPUFAs in inflammation have been reviewed by Calder (2006). Briefly, if is h) ofhesized fhaf fhe effecfs of LCPUFA n-3 fatty acids on immune function are mediated by their ability to compete with the metabolism of fhe n-6 fatty AA. AA can be metabolized into the pro-inflammatory prostaglandin-E2 (PGE2) or leukotriene-B4 (LTB4). 

Filipponi et al. [7] studied the differences in the active sites of the two isoforms of cyclooxygenase (COX), an enzyme involved in the biosynthesis of pro-inflammatory prostaglandins. Two isoforms of COX exist a constitutive cyclooxygenase-1 and an inducible cyclooxygenase-2, and it is believed that COX-2 selective inhibitors provide anti-inflammatory agents with a superior safety profile [35]. 

Abner G, Teismann P, Stevie Z, Halaschek-Wiener J, Deecke L, Kos-tic V, Pi zedboi ski S (2002) Ina eased levels of tire pro-inflammatory prostaglandin PGE2 in CSE from ALS patients. Neru ology 58 1277-1279. 

Figueiredo-Pereira et al. discovered that proteasome inhibition leads to accumulation of ubiquitinated proteins [56]. Proteasome inhibition is also connected with the activation of the cellular stress response including an increased expression of HSP 70 and activation of the inflammatory pathway shown by the increase of COX-2 expression and the production of the pro-inflammatory prostaglandin PGE2. An interaction of these two pathways may happen in the cascade of events leading to neurodegeneration [56]. 

Vitamin E (a-tocopherol Figure 37.39) is one of the best antioxidants for cell and organelle membranes. It stabilizes and prevents the destruction of the lipids that make up these membranes, which are very susceptible to oxidation. It blocks the chain reactions that cause intracellular lipoperoxides to form, thus protecting the nucleic acids and proteins. It also inhibits the peroxidation of membrane arachidonic acid, which prevents the subsequent formation of pro-inflammatory prostaglandins. 

Apart from the antimicrobial properties noted above, allyl derivatives such as ajoene have demonstrated activity against platelet aggregation, inhibition of pro-inflammatory prostaglandins, antitumour and hypoglycaemic effects (Reuter 1995). 

Pro-inflammatory mediators, such as prostaglandins (PGs), nitric oxide (NO), and cytokines are involved in carcinogenesis [Kundu and Surh, 2005 Perwez... 

Pro-inflammatory cytokines (see p. 432 et seq.) can also induce sleep, the effect depending on the concentration of the cytokine and the time of day. The effect on the sleep profile (increased non-REM and decreased REM sleep) appears to depend on the increased synthesis of prostaglandin D2 and nitric oxide which then alter the circadian rhythm. It is also known that some pro-inflammatory cytokines can affect the reuptake of 5-HT which plays an important role in regulating the sleep-wake profile. The endogenous fatty acid, oleamide, can cause sedation and induce sleep by activating cannabinoid receptors but also by potentiating the action of benzodiazepines on their receptor sites. Whether such action is of physiological relevance is presently unknown. 

A major signalling pathway involves activation of a protein kinase that phosphorylates inhibitor kB proteins (IkBs) that normally inhibit the function of the nuclear transcription factor NFkB. Phosphorylation of IkB by the serine/threonine-specific IkB kinases (IKKs) leads to NFkB de-inhibition, nuclear translocation and expression of pro-inflammatory proteins such as inducible cyclooxygenase (iCOX) (which generates prostaglandins), inducible nitric oxide synthase (iNOS) (which generates vasodilatory and toxic free radicalgenerating NO) and pro-inflammatory cytokines. 

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