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.