Brief notes - week of 2020/09/07

These notes are to keep track of things I am reading up on and thinking about and perhaps may write a post on in future. I making them public because - why not? Also, I may never get a chance to write a full post on them.

~~~

MSA, glycine & EPO  

Related references are tagged MSA-EPO-Gly on my zotero account and listed below.

Lithium trial for multiple system atrophy (MSA) had to be stopped as it caused harm - quite severe harm.

One proposed MOA for lithium for biopolar and other disorders where it has been found to be therapeutic is that it increases glycine levels in the brain. However, this hypothesis appears to have been abandoned in recent years and does not have much empirical support - though nothing in the way of  disconfirming findings has turned up so far in literature searches, either.

Elevated levels of glycine in cerebrospinal fluid (CSF) have been found in DLB, ALS and MS. Results of studies on PD patients has been conflicting, but the bulk of evidence indicates no difference in CSF glycine in PD.

In one MSA case report, the patient had hyperglycinemia and was found to have lower mRNA for a glycine transporter. Another study reported increased glycine CSF levels after oral dosing in people with various motor neuron diseases - which included one person with MSA -  as compared to healthy controls (though I don't think MSA should be lumped in with motor neuron diseases). Could timing in relation to meals (and content of meals) have affected results of PD glycine CSF studies?

MSA patients have been found to be anemic and deficient in erythropoietin (EPO). EPO has been used to treat orthostatic hypotension in MSA patients; heme regulates vascular tone and blood pressure through regulation of nitric oxide levels. Anemia has been suggested to be the main cause of OH, however, it seems that a higher proportion of people with MSA have OH than have anemia - so does anemia explain OH in all or even most cases? Probably not.

Glycine is needed for heme synthesis and was found to be rate-limiting. Could EPO increase glycine transporter expression? Would EPO treatment alter glycine CSF levels in MSA patients?

High glycine levels are excitotoxic; magnesium can mitigate glycine excitoxicity. Some hypotheses on  the therapeutic action of Li relate to its interactions with Mg, either through competitive binding or  Li binding in complexes with Mg. Would these types of interactions have an impact on Mg's ability to mitigate glycine excitotoxicity?

Glycine has also been implicated in demyelination.

Glycine is involved in both generation of ammonia and its disposal. MSA patients symptoms often worsen precipitously during UTI infections - this could be due to increased systemic inflammation and/or increased blood ammonia levels.

Would treatments for hyperammonemia benefit MSA patients? Ornithine? Benzoate? Would alpha ketoglutarate be useful?

When searching for the reference on the case report mentioned above I found a pre-publication entry on PubMed for a mouse study that found that sodium benzoate and cinnamon (contains a substance that converts to sodium benzoate in the body) caused a reduction in Lewy body burden in a PD mouse model.

References:

Babinsky, E., & Levene, R. S. (2012). Multisystem atrophy made worse by lithium treatment in a hospice patient: A case report. The American Journal of Hospice & Palliative Care, 29(7), 570–573. https://doi.org/10.1177/1049909111434633

Briggs, K. T., Giulian, G. G., Li, G., Kao, J. P. Y., & Marino, J. P. (2016). A Molecular Model for Lithium’s Bioactive Form. Biophysical Journal, 111(2), 294–300. https://doi.org/10.1016/j.bpj.2016.06.015

Carmans, S., Hendriks, J. J. A., Thewissen, K., Van den Eynden, J., Stinissen, P., Rigo, J.-M., & Hellings, N. (2010). The inhibitory neurotransmitter glycine modulates macrophage activity by activation of neutral amino acid transporters. Journal of Neuroscience Research, 88(11), 2420–2430. https://doi.org/10.1002/jnr.22395

Fakhredin Saba, N. S., & Fakhredin Saba, N. S. (2017). Crosstalk between catecholamines and erythropoiesis. Frontiers in Biology, 12(2), 103–115. https://doi.org/10.1007/s11515-017-1428-4

Garcia-Santos, D., Schranzhofer, M., Bergeron, R., Sheftel, A. D., & Ponka, P. (2017). Extracellular glycine is necessary for optimal hemoglobinization of erythroid cells. Haematologica, 102(8), 1314–1323. https://doi.org/10.3324/haematol.2016.155671

Lane, R. J., Bandopadhyay, R., & de Belleroche, J. (1993). Abnormal glycine metabolism in motor neurone disease: Studies on plasma and cerebrospinal fluid. Journal of the Royal Society of Medicine, 86(9), 501–505.

Lane, R. J., Virgo, L., Lantos, P. L., & de Belleroche, J. (1998). A case of multiple system atrophy with hyperglycinaemia due to a selective deficiency of glycine transporter mRNA. Neuropathology and Applied Neurobiology, 24(5), 353–358.

Molina, J. A., Gómez, P., Vargas, C., Ortiz, S., Pérez-Rial, S., Urigüen, L., Oliva, J. M., Villanueva, C., & Manzanares, J. (2005). Neurotransmitter amino acid in cerebrospinal fluid of patients with dementia with Lewy bodies. Journal of Neural Transmission (Vienna, Austria: 1996), 112(4), 557–563. https://doi.org/10.1007/s00702-004-0202-3

Raha, S., Dutta, D., Roy, A., & Pahan, K. (2020). Reduction of Lewy Body Pathology by Oral Cinnamon. Journal of Neuroimmune Pharmacology: The Official Journal of the Society on NeuroImmune Pharmacology. https://doi.org/10.1007/s11481-020-09955-2

Rao, S. V., & Stamler, J. S. (2002). Erythropoietin, anemia, and orthostatic hypotension: The evidence mounts. Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society, 12(3), 141–143. https://doi.org/10.1007/s10286-002-0031-0

Saccà, F., Marsili, A., Quarantelli, M., Brescia Morra, V., Brunetti, A., Carbone, R., Pane, C., Puorro, G., Russo, C. V., Salvatore, E., Tucci, T., De Michele, G., & Filla, A. (2013). A randomized clinical trial of lithium in multiple system atrophy. Journal of Neurology, 260(2), 458–461. https://doi.org/10.1007/s00415-012-6655-7

van Woerkom, A. E. (2017). A fully integrated new paradigm for lithium’s mode of action – lithium utilizes latent cellular fail-safe mechanisms. Neuropsychiatric Disease and Treatment, 13, 275–302. https://doi.org/10.2147/NDT.S123612

Winkler, A. S., Landau, S., Watkins, P., & Chaudhuri, K. R. (2002). Observations on haematological and cardiovascular effects of erythropoietin treatment in multiple system atrophy with sympathetic failure. Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society, 12(3), 203–206. https://doi.org/10.1007/s10286-002-0009-y

 

 

~~~

Saw a brief video on The Physiological Society YT channel on paternal nutrition and renin-angiotensin function; there seems to be generational effect of protein restriction on ACE expression (? have to watch again and find the reference). I am wondering if this has relevance to apparent lower per capita covid mortality in developing countries.

Here's the reference: https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP278270

It's paywalled and I can't be bothered.

~~~

Transferrin is needed for oligodendrocyte maturation. 

~~~

High salt diet is not associated with disease progression in multiple sclerosis and a multiple system atrophy mouse model study did not see a significant increase in neuroinflammation or in symptoms. Good news as HSD is used to treat orthostatic hypotension  - but these findings are rather puzzling, to say the least. My guess is there must be a mitigating effect. HSD alters urea cycle and decreases liver glycine levels [PMID: 28414295] (skeletal muscle glycine also decreased but not significant). There was that mention in that Medzhitov video on flu & glucose of sodium having a protective effect - but nothing on why. Interesting to note that death from viral inflammation is due to reduction in autonomic function.

Increasing NO blocks the deleterious effects of HSD on tau-induced pathology in a mouse model of Alzheimer's [PMID: 31932732]. Is NO protective against deleterious effects of HSD generally? Perhaps increased levels of NO in MSA is protective - but only a subset of patients have anemia and presumably increased NO ...