A2 (Trophic) astrocytes secrete molecules that provide neurotrophic support and modulate inflammatory responses. This astrocyte phenotype is present following ischemia and has been shown to promote neuronal survival and tissue repair.
So can block them?
There Interleukin_1_receptor_antagonist, which mops up IL-1 but you would need loads of it to get into the brain and being a protein this isn't going to happen very much. Same problem is for the neutralizing antibodies available and as IL-1 has some many function, block this pathway every where long term-isn't going to be good news. As for C1q, well we have the humble aspirin.
There are lots of anti-TNFs that are available, but they can stimulate memory B cells and they can and sometimes do make MS worse.
However this study indicates that you want the anti-TNF need to get into the brain, so antibodies are not the sensible way to go this. However there are anti-TNF chemicals such as thalidomide and less tetragenic (creates deformities in unborn babies) variants. Their are phosphodiesterase 4 inhibitors (PDE4) like rolipram which has made MS worse and ibudilast which has completed a trial in SPMS recently. We showed many years ago that you needed to inhibit the TNF in the brain
These molecules all come from hot microglia, which in this study was mimicked by an infection
Once the A1s had become the bad guys you didn't need to keep giving them the three cytokines to keep them bad. Once formed they were mean bad-ass cells for good.
However they could be salvaged and it was found that it was partially possible to make the cells more astrocyte like again.
So great let's stick TGFbeta into MS and that's sorted?
However, some neuross did this in MS with active cytokine and not the natural cytokine and disaster struct.
The trial was stopped because TGFbeta did not just do what they wanted but it bound to TGFbeta receptor where ever it was and activated the cells it bound to.
This just happened to be fibroblasts (which are involved in tissue modeling), they grew like mad and cause fibrosis of the kidney.
In nature, TGF-beta is not produced as an active molecule. The active site is covered by a latent protein cap/shell that has to be cleaved to make an active molecule. This means it can travel round the body and is not active thing unless there is the right environment, such as inflammation, to cleave the latent protein.
Likewise if we start injecting Fibroblast growth factor,I now think you can what would happen.....yep probably more fibrosis in the kidneys and liver and the lungs which are going to filter the proteins.
A1 astrocytes lose many typical astrocytic functions. They showed that A1 astrocytes no longer promote neuronal survival, outgrowth, and synapse formation, or phagocytize synapses or debris.
Importantly they suggest that A1 astrocytes secrete a compound that is toxic to neural cells. What is it/are they?
Well a recent paper suggests something
Li S, Uno Y, Rudolph U, Cobb J, Liu J, Anderson T, Levy D, Balu DT, Coyle JT. Astrocytes in primary cultures express serine racemase, synthesize d-serine and acquire A1reactive astrocyte features. Biochem Pharmacol. 2018. pii: S0006-2952(17)30735-9.
d-Serine is a co-agonist at forebrain N-methyl-d-aspartate receptors (NMDAR) and is synthesized by serine racemase (SR). A1 reactive astrocytes express SR and release d-serine under pathologic conditions, which may contribute to their neurotoxic effects by activating extra-synaptic NMDA receptors.