Microglia/CNS/Pathogens - Modulators

[Guest guest]

Penny, I, and Matt discussed this last year.

And although we never figured out what Benicar was doing for Penny,

we did think it was acting on (chemicals) in the brain.

Here's some interesting stuff on microglia ( microglia are the

inflammatory cells in the brain).

And check out this article.. written almost 15 years ago:

Controversies in neuroborreliosis,

Audrey Stein Goldings, M.D.

Lyme Disease Conference

October 23, 1992

http://www.lymenet.de/literatur/steing.htm

And more currently:

Borrelia burgdorferi induces inflammatory mediator production by

murine microglia.

J Neuroimmunol. 2002 Sep;130(1-2):22-31. Related Articles, Links

Rasley A, Anguita J, Marriott I.

Department of Biology, 9201 University City Boulevard, University of

North Carolina at Charlotte, 28223, Charlotte, NC, USA.

Lyme disease has been associated with damaging inflammation within

the central nervous system. In the present study, we demonstrate that

Borrelia burgdorferi is a significant stimulus for the production of

IL-6, TNF-alpha, and PGE(2) by microglia. This effect is associated

with induction of NF-kappaB, and increased expression of Toll-like

receptor 2 and CD14, receptors known to underlie spirochete

activation of other immune cell types. These studies identify

microglia as a previously unappreciated source of inflammatory

mediator production following challenge with B. burgdorferi. Such

production may play an important role during the development of Lyme

neuroborreliosis.

PMID: 12225885 [PubMed - indexed for MEDLINE]

Sawynok, J. and X. J. Liu (2003). " Adenosine in the spinal cord

> and periphery: release and regulation of pain. " Prog Neurobiol 69

> (5): 313-40.

> >

> > In the central nervous system (CNS), adenosine is an

> important neuromodulator and regulates neuronal and non-neuronal

> cellular function (e.g. microglia) by actions on extracellular

> adenosine A(1), A(2A), A(2B) and A(3) receptors. Extracellular

> levels of adenosine are regulated by synthesis, metabolism,

release

> and uptake of adenosine. Adenosine also regulates pain

transmission

> in the spinal cord and in the periphery, and a number of agents

can

> alter the extracellular availability of adenosine and subsequently

> modulate pain transmission, particularly by activation of

adenosine A

> (1) receptors. The use of capsaicin (which activates receptors

> selectively expressed on C-fibre afferent neurons and produces

> neurotoxic actions in certain paradigms) allows for an

> interpretation of C-fibre involvement in such processes. In the

> spinal cord, adenosine availability/release is enhanced by

> depolarization (K(+), capsaicin, substance P, N-methyl-D-aspartate

> (NMDA)), by inhibition of

> > metabolism or uptake (inhibitors of adenosine kinase (AK),

> adenosine deaminase (AD), equilibrative transporters), and by

> receptor-operated mechanisms (opioids, 5-hydroxytryptamine (5-HT),

> noradrenaline (NA)). Some of these agents release adenosine via an

> equilibrative transporter indicating production of adenosine

inside

> the cell (K(+), morphine), while others release nucleotide which

is

> converted extracellularly to adenosine by ecto-5'-nucleotidase

> (capsaicin, 5-HT). Release can be capsaicin-sensitive, Ca(2+)-

> dependent and involve G-proteins, and this suggests that within C-

> fibres, Ca(2+)-dependent intracellular processes regulate

production

> and release of adenosine. In the periphery, adenosine is released

> from both neuronal and non-neuronal sources. Neuronal release from

> capsaicin-sensitive afferents is induced by glutamate and by

> neurogenic inflammation (capsaicin, low concentration of

formalin),

> while that from sympathetic postganglionic neurons (probably as

> adenosine

> > 5'-triphosphate (ATP) with NA) occurs following more

generalized

> inflammation. Such release is modified differentially by

inhibitors

> of AK and AD. Following nerve injury, there is an alteration in

> capsaicin-sensitive adenosine release, as spinal release now is

less

> responsive to opioids, while peripheral release is less responsive

> to inhibitors of metabolism. Following inflammation, adenosine is

> released from a variety of cell types in addition to neurons (e.g.

> endothelial cells, neutrophils, mast cells, fibroblasts). ATP is

> released both spinally and peripherally following inflammation or

> injury, and may be converted to adenosine by ecto-5'-nucleotidase

> contributing an additional source of adenosine. Release of

adenosine

> from both spinal and peripheral compartments has inhibitory

effects

> on pain transmission, as methylxanthine adenosine receptor

> antagonists reduce analgesia produced by agents which augment

> extracellular levels of adenosine spinally (morphine, 5-HT,

> substance P, AK

> > inhibitors) and peripherally (AK inhibitors, AD inhibitors).

> Increases in extracellular adenosine availability also may

> contribute to antiinflammatory effects of certain agents

> (methotrexate, sulfasalazine, salicylates, AK inhibitors), and

this

> could have secondary effects on pain signalling in chronic

> inflammation. The purpose of the present review is to consider:

(a).

> the factors that regulate the extracellular availability of

> adenosine in the spinal cord and at peripheral sites; and (. the

> extent to which this adenosine affects pain signalling in these

two

> distinct compartments.

> >