Clomipramine is a tricyclic antidepressant (TCA)
I think you can see why it is called a tri cyclic as you can see the three ring structure.
In addition, clomipramine also has anti-adrenergic, anti-histamine, anti-serotonergic, anti-dopaminergic, and ant-icholinergic activities. It is specifically an antagonist of the α1-adrenergic receptor, the histamine H1 receptor, the serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, the dopamine D1, D2, and D3 receptors, and the muscarinic acetylcholine receptors (M1–M5). Like other TCAs, clomipramine weakly blocks voltage-dependent sodium channels as well.
Therefore there are, not surprisingly, side effects.
This study starts with a premise that there is mitochondrial damage, iron accumulation and oxidative stress at the centre of progressive MS. They think B cell follicles may be important and of course the premise that MS is essentially a T cell problem and recognise that there is microglial activation.
In addition they view it essential that the compounds can enter the brain to target the site of tissue damage.
This study looks at the Drug collection from the National Institute of Health of FDA approved (mainly generic) drugs.
Out of 1040 compounds, 123 reduced cytokine production by activated microglia.
Out of the 1040 compounds they threw out compounds that that could not be given as a pill. This excluded 791 compounds
In this study they looked at compounds that affect iron-mediated nerve killing, maintain mitochondrial integrity and scavenge free radicals (which are damaging oxygen species like superoxide and hydrogen peroxide) as well as T & B inhibitors Then asked do the compounds affect EAE.
249 compounds were examined 35 prevented iron-mediated neurotoxicity.
These included drugs such as liothyronine (a thyroid hormone), flunarizine ( a calcium ion channel, carvediol (beta blocker), clozapine (serotonin receptor blocker and other receptors) and a number of tricyclic antidepressants. Liothronine, carvediol were chucked out because they do not enter the brain.
They then looked at influences on inhibiting mitochondrial damage and then in my opinion for some strange reason they looked at the capacity of T cell inhibition and the tricyclics tested at 10 micromolar inhibited T cell proliferation.
Therefore, the tricyclics were studied.
If a drug inhibits T cells then we know they will inhibit EAE, which we know is T cell dependent.
Will it happen? Maybe.
However has the best candidates been thrown away?
Do EAEers have T cell-coloured glasses on. I think so.
The 10uM screening stuff is just one example of why drug company researchers have a dim view of academic drug research.
There's a large element of truth in that, something that has concerned us for many years.
You were not positive about Ibudilast and you proved wrong :/
Atara bio is a T cell immunotherapy and seems to work on progressive MS, so the chapter is not closed yet I guess
Ibudilast…yep may be
T cell immunotherapy is usng T cells to kill virally infected cells…not exactly the same as T cell immunotherapy of MS by targeting T cells
Clonal composition and T cell receptor (TCR) repertoire of CD4
1 and CD8
1 T cells infiltrating
actively demyelinating multiple sclerosis (MS) lesions were determined with unprecedented
resolution at the level of single cells. Individual CD4
1 or CD8
1 T cells were isolated from frozen
sections of lesional tissue by micromanipulation and subjected to single target amplification
of TCRb
gene rearrangements. This strategy allows the assignment of a TCR variable region
(V region) sequence to the particular T cell from which it was amplified. Sequence analysis revealed
that in both cases investigated, the majority of CD8
1 T cells belonged to few clones.
One of these clones accounted for 35% of CD8
1 T cells in case 1. V region sequence comparison
revealed signs of selection for common peptide specificities for some of the CD8
1 T cells
in case 1. In both cases, the CD4
1 T cell population was more heterogeneous. Most CD4
1 and
CD8
1 clones were represented in perivascular infiltrates as well as among parenchymal T cells.
In case 2, two of the CD8
1 clones identified in brain tissue were also detected in peripheral
blood. Investigation of the antigenic specificities of expanded clones may help to elucidate their
functional propertie
Clonal Expansions of CD8
1 T Cells Dominate
the T Cell Infiltrate in Active Multiple Sclerosis
Lesions as Shown by Micromanipulation and
Single Cell Polymerase Chain Reaction
https://www.ncbi.nlm.nih.gov/pubmed/10934227
Are they anti-viral?
Common Anti-Parasitic Agent Eases Motor Symptoms, Aids Remyelination in MS Mouse Model
By promoting the activity of a receptor called P2X4R that is present in microglial cells — immune cells that reside in the brain — ivermectin (marketed as Stromectol, or Soolantra) eased the clinical manifestations of experimental autoimmune encephalomyelitis
http://embomolmed.embopress.org/content/early/2018/07/03/emmm.201708743
The treatment, administrated after disease onset, was found to induce a rapid and significant easing in motor symptoms of the disease. These changes were accompanied by evidence of effective myelin recovery —remyelination — as well as a significant lowering of pro-inflammatory factors and an increase in anti-inflammatory agents.
“The results of our study identify P2X4R as a key modulator of microglia/macrophage polarization, and support the use of IVM [ivermectin] to potentiate a microglia/macrophage switch that favors remyelination in MS,” the researchers concluded.
https://multiplesclerosisnewstoday.com/2018/07/13/anti-parasitic-agent-eases-ms-motor-symtoms-aid-remyelination-in-ms-mice/
What about Ibudilast then?