Should pregnant women smoke pot?

Well, maybe this is why college board scores have declined so much in recent decades that they’ve been normed upwards. Given sequential MRI studies on brain changes throughout adolescence (with more to come), we know that it is a time of synapse elimination. (this will be the subject of another post). We also know that endocannabinoids, the stuff in the brain that marihuana is mimicking, are retrograde messengers there, setting synaptic tone for information transmission between neurons.

But there’s something far scarier in a paper that just came out [ Proc. Natl. Acad. Sci. vol. 112 pp. 3415 – 3420 ’15 ]. Hedgehog is a protein so named because its absence in fruitflies (Drosophila) causes excessive bristles to form, making them look like hedgehogs. This gives you a clue that Hedgehog signaling is crucial in embryonic development. A huge amount is known about it with more being discovered all the time — for far more details than I can provide see http://en.wikipedia.org/wiki/Hedgehog_signaling_pathway.

Unsurprisingly, embryonic development of the brain involves hedgehog, e,g, [ Neuron vol. 39 pp. 937 – 950 ’03 ] Hedgehog (Shh) signaling is essential for the establishment of the ventral pattern along the whole neuraxis (including the telencephalon). It plays a mitogenic role in the expansion of granule cell precursors during CNS development. This work shows that absence of Shh decreases the number of neural progenitors in the postnatal subventricular zone and hippocampus. Similarly conditional inactivation of smoothened results in the formation of fewer neurospheres from progenitors in the subventricular zone. Stimulation of the hedgehog pathway in the mature brain results in elevated proliferation in telencephalic progenitors. It’s a lot of unfamiliar jargon, but you get the idea.

Of interest is the fact that the protein is extensively covalently modified by lipids (cholesterol at the carboxy terminal end and palmitic acid at the amino terminal end. These allow hedgehog to bind to its receptor (smoothened). It stands to reason that other lipids might block this interaction. The PNAS work shows this is exactly the case (in Drosophila at least). One or more lipids present in Drosophila lipoprotein particles are needed in vivo to keep Hedgehog signaling turned off in wing discs (when hedgehog ligand isn’t around). The lipids destabilize Smoothtened. This work identifies endocannabinoids as the inhibitory lipids from extracts of human very low density lipoprotein (VLDL).

It certainly is a valid reason for women not to smoke pot while pregnant. The other problem with the endocannabinoids and exocannabinoids (e.g. delta 9 tetrahydrocannabinol), is that they are so lipid soluble they stick around for a long time — see https://luysii.wordpress.com/2014/05/13/why-marihuana-scares-me/

It is amusing to see regulatory agencies wrestling with ‘medical marihuana’ when it never would have gotten through the FDA given the few solid studies we have in man.

No longer looking under the lamppost

Time flies. It’s been over 5 years since I wrote https://luysii.wordpress.com/2009/09/25/are-biochemists-looking-under-the-lamppost/, essentially a long complaint that biochemists (and by implication drug chemistry and drug discovery) were looking at the molecules they knew and loved rather than searching for hidden players in the biochemistry and physiology of the cell.

Things are much better now. Here are 3 discoveries from the recent past, some of which should lead to drugable targets.

#1 FAFHA — a possible new way to treat Diabetes. Interested? Take a long chain saturated fatty acid such as stearic acid (C18:0). Now put a hydroxyl group somewhere on the chain (the body has found ways put them at different sites — this gives you a hydroxy fatty acid (HFA). Next esterify this hydroxyl group with another fatty acid and you have a Fatty Acid ester of a Hydroxy Fatty acid (an FAHFA if you will). So what?

Well fat makes them and releases them into the blood, making them yet another adipokine and further cementing fat as an endocrine organ. Once released FAHFAs stimulate insulin release, and increase glucose uptake in the fat cell when they activate GPR120 (the long chain fatty acid receptor).

A variety of fatty acids can form the ester, one of which is palmitic acid (C16:0) forming Palmitic Hydroxy Stearic Acid (PAHSA) which binds to GPR120. if that weren’t enough PAHSAs are anti-inflammatory — interested read more [ Cell vol. 159 pp. 238 239, 318 – 332 ’14 ]. I don’t think the enzymes forming HFA’s are known, and I’m willing to bet that are other HFAs out there.

#2 Maresin1 (7S, 14S dihydroxy docosa 4Z 8E 10E, 12Z 16Z, 19Z hexaenoic acid to you) is the way you start making Specialized Proresolving Mediators (SPMs). Form an epoxide of one of the double bonds and then do an SN2 ring opening with a thiol (glutathione for one) forming what they call a sulfido-conjugate mediator. It appears to be one of the many ways that inflammation is resolved. It helps resolve E. Coli infection in mice at nanoMolar concentration. SPMs further neutrophil recruitment and promote macrophage clearance of apoptotic cells and tissue debris. Wouldn’t you like to make a drug like that? Think of the specificity of the enzyme producing the epoxidation of just one of the 6 double bonds. Also a drug target. For details please see PNAS vol. 111 pp. E4753 – E4761 ’14

#3 Up4A (Uridine Adenosine Tetraphosphate) — as you might expect it’s an agonist at some purinergic receptors (PO2X1, P2Y2, P2Y4) causing vasoconstriction, and vasodilatation at others (P2Y1). It is released into the colon when enteric neurons are stimulated. Another player whose existence we had no idea about. Certainly we have all the GI and vasodilating drugs we need. If nothing else it will be a pharmacological tool. Again the enzyme making it isn’t known — yet another drug target possibly. For details see PNAS vol. 111 pp. 15821 – 15826 ’14.

There is a lot more in these 3 papers than can be summarized here.

Who knows what else is out there, and what it is doing? Glad to see people are starting to look