Miljenko:
I can't respond to all of your post now but some up front points:
1) If you check into the various treatments of Parkinson's disease, they include anticholinergic (trihexyphenidyl/Artane, benztropine/Cogentin, others) as well as procholinergic (i.e. Sibia's) agents. How can this be? The former interact with muscarinic receptors while the latter with NachR. Both appear to act by influencing available dopamine levels, although the muscarinc drugs may directly influence dopamine reuptake. And there is undoubtedly interaction between the two cholinergic systems. The brain is a difficult puppy.
2) My previous post may have left the distorted impression that my description of PD (or AD) approached simplistic completeness. To give a small taste of how inappropriate this interpretation would be: in PD there are also losses, albeit less significant than dopamine, in neurotransmitter systems using other biogenic amines (serotonin, norepinephrine). In fact the drastic reduction in global biogenic amine levels at autopsy was one of the original indicators leading towards the dopamine connection. One more thing: some additional elements of the nigrostriatal system must be mentioned (in the context of cholinergic agents). The dopaminergic cells send connections to the striatum where dopamine (DA) is released. DA then binds to DA receptors in the striatum causing these secondary ('postsynaptic') cells to become either more active or less active. There is a group of cholinergic postsynaptic cells in the striatum. (If you draw a picture of the following, it really does make sense). 1) Assume DA input to the cholinergic cells is inhibitory. 2) Assume the output of the cholinergic cells in excitatory. 3) Assume that one of the net effects of the cholinergic cells is to eventually INHIBIT DA output in a feedback loop design. (in your picture, draw a connection from the cholinergic cell to a cell which uses GABA as a (inhibitory) neurotransmitter. Then draw a connection from the GABA cell all the way back to the DA cell). Put these 'facts' together (in a vacuum): in a 'normal' person, DA blocks cholinergic transmission which has the effect of slowing the GABA cell activity and is thereby part of the feedback/input regulation of DA neuronal activity. This loop is disrupted in PD. Providing anticholinergic agents in this context will (look at your picture) reduce the amount of inhibition on DA activity and allow for greater DA release.
Again, you're dealing with a complex, highly heterogeneous organ here and assuming pharmacologic agents are 'targeting' any single component is risky. You seem willing to learn the necessary biology of Parkinson's to gain a better understanding of Sibia's drugs. I would suggest comparing the long term prospects of Sibia's palliative approach, including esterase inhibitors, with those companies directly addressing neuronal survival. Sibia's approach is likely to bear fruit in the near term. Without addressing the survival issue soon, I would think the extended outlook is less sanguine.
As I mentioned earlier, I too am out for a while. Party lardy.
Peter
PS. Just one other thing. Rats and Monkeys are very different animals. Be careful in confusing potential differences between enantiomers etc and animal distinctions. I would advise researching the MPTP data. I beleive rats are completely unresponsive to this treatment but I may be wrong. |
