I’ve been in interested in Arachidonic acid for awhile because I have taken COX-2 inhibitors which affect the Arachidonic acid pathway. It seems Arachidonic acid can be good and bad. It’s bad when it produces too many 'bad' prostoglandins and causes inflammation. And when it produces bad cytokines, as opposed to good ones. And when you inhibit COX-2, you upregulate LOX-5 which produces leukotrienes which can be bad (one kind causes asthma). It’s too complicated for me!

From the following article:

“cyclooxygenase-2-dependent arachidonic acid metabolites are essential in the development and maintenance of intestinal immune homeostasis.”

from:

Nature Medicine 5, 900 - 906 (1999)
doi:10.1038/11341
Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen
http://www.nature.com/nm/journal/v5/...m0899_900.html

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doi:10.1016/j.neuron.2005.12.004
Preview
Cannabinoids in Microglia: A New Trick for Immune Surveillance and Neuroprotection
Serge Rivest1, ,

Available online 4 January 2006.

From the article: “cytokine levels were either not changed (e.g., TNF-α) or moderately modified (e.g., IL-6) in the presence of endogenous and exogenous cannabinoids” which is good!

Microglia are the resident immune cells of the brain, and they are under permanent activity to patrol the cerebral microenvironment. A proper inhibitory feedback onto these cells is critical during both intact and injury conditions. In this issue of Neuron, Eljaschewitsch and colleagues report that such feedback is provided by the endogenous cannabinoid anandamine and CB1/2 receptor signaling, which ultimately leads to mitogen-activated protein kinase phosphatase-1 (MKP-1) induction. MKP-1 interferes with lipopolysaccharide-induced toll-like receptor 4 signaling and limits brain damage due to exaggerated microglial reactivity following acute NMDA injury.

http://www.sciencedirect.com/science...1e0b1cd9ba163b

More from the article:

In a series of very elegant studies, Eljaschewitsch and colleagues investigated the intracellular signaling pathways mediating the effects of AEA in BV-2 cells. They observed that the endogenous cannabinoids set microglia into a state of alert by a rapid MAPK phosphorylation and prevent overactivation in the presence of second stimulus. Indeed, MEK phosphorylation is reduced and Erk1/2 dephosphorylation takes place after AEA incubation in LPS-activated BV-2 cells. This is associated with a rapid induction of the mitogen-activated protein kinase-phosphatase 1 and 2 (MKP-1 and MKP-2). Here, MKP expression was not necessarily a direct consequence of the MAPK activation; although AEA alone can activate the MAPK, it switched off this pathway by rapidly upregulating MKP-1 induction following exposure to LPS. The combined treatment of LPS and AEA (not LPS and AEA alone) enhanced histone H3 phosphorylation on the MKP-1 gene sequence. Finally, these authors show that AEA was able to inhibit BV-2 cells in a CB1/2- and MKP-1-dependent manner and that MKP-1 can be found in microglial cells of MS patients. These data provide the first direct evidence that the CB receptors in microglia are coupled to Erk activation in regulating MKP-1 gene expression following histone H3 phosphorylation.

The authors reached the conclusion that the endocannabinoid AEA induces histone H3 phosphorylation, MKP-1 gene expression, and subsequent Erk1/2 dephosphorylation in activated (e.g., LPS) but not in resting microglia, which in turn abolishes NO release and finally leads to neuroprotection. It is however important to keep in mind that all of these studies were performed in culture systems where brain slices were exposed to BV-2 cells and in one occasion to primary cultures of microglia. Direct interaction of these immune cells with CNS tissues taken from another group of animals may not represent the real situation taking place in vivo. Exogenous microglia may be under a different state of immune activation, which may be quite different from endogenous cells behind the BBB. This may modify TLR4 expression, the affinity to its ligand, LPS signaling, and expression of a subset of genes. Also, how these exogenous microglia interfere with their endogenous counterparts still remains to be determined.

The role of microglial cells in neurodegenerative disorders remains a matter of great controversy and debate at the moment. It is clear that LPS-induced proinflammatory signaling in microglia is a natural response that is unlikely to be detrimental to neurons and other cells of the CNS. In contrast, a proper immune response may set the conditions for swiftly eliminating pathogens in cases of cerebral infection, phagocyting cell debris after injuries, and improving brain repair. Recent data support this concept, because inhibition of microglia and TNF-α production was found to cause more damages following acute excitotoxicity (Turrin and Rivest, 2006), delay in remyelination, and inhibit recruitment of progenitors (Arnett et al., 2001). Genes encoding innate immune proteins are induced not only by PAMPs, but also in response to brain injuries and during a variety of neurodegenerative disorders. What comes first (inflammation or cellular degeneration) remains largely unknown, and the role of such an innate immune/inflammatory response in the cerebral tissue has yet to be fully unraveled. It is clear that sustained and unregulated inflammatory reactions are detrimental to neurons, though the acute release of proinflammatory molecules may instead play a leading role in protecting neurons against invading pathogens and restoring homeostasis after the storm. The direction that the inflammatory response is taking and the appropriate inhibitory feedback on microglia may consequently be crucial for determining the ultimate outcome of these events in the CNS.

As shown by Eljaschewitsch and colleagues in this issue, cannabinoid receptor signaling and MKP-1 gene expression in microglia may well be the ultimate trick for allowing these cells to either protect or contribute to neurodegeneration following acute brain damage. Future experiments are nevertheless needed to specifically define the physiological relevance of such a system in the mature as well as developing brain in an in vivo context. Moreover, how cannabinoid receptors interact with TLR4 signaling in microglia remains to be determined. It is possible that such an interaction does not involve the classical LPS-TLR4-NF-κB pathway, but the MyD88-independent signal transduction system. Although AEA had very clear effects on NO release and iNOS gene expression in BV-2 cells, cytokine levels were either not changed (e.g., TNF-α) or moderately modified (e.g., IL-6) in the presence of endogenous and exogenous cannabinoids. This supports the MyD88-independent set of events and the subsequent IFN release, which is a key step for iNOS gene expression and NO biosynthesis (Schilling et al., 2002). As depicted by Figure 1, this pathway may be the direct target of the so-called inhibitory feedback of the AEA/CB1/2, Erk, and MKP-1 cascade. MKP-1 in causing Erk dephosphorylation and switching off MAPK would then lead to IFN gene repression. It is also tempting to propose a direct MKP-1/IRF interaction and dephosphorylation, such as in the case of Erk1/2. These events together are powerful novel mechanisms to prevent the production of type I IFNs and their costimulatory molecules (e.g., iNOS) without interfering with the MyD88-dependent signal transduction pathway and cytokine gene expression. Although still speculative at this point, these data open the door for a potentially new treatment to inhibit specific signaling events with no side effects on those that might have neuroprotective properties in microglia. Of interest is the fact that exogenous cannabinoids (e.g., marijuana) seem to improve recovery, decrease frequency in relapsing, and delay demyelination in MS patients. These frequently discussed beneficial assets of marijuana have to be validated with in-depth studies, but MyD88-independent pathways may well be the indirect target of cannabis through CB1/2 receptors and MKP-1 induction in macroglia and infiltrating macrophages. A new trick, yes indeed!