The Rhyothemis princeps Brain Externalization Project

Fucoidan is a sulfated polysaccharide found in brown seaweed that varies in molecular weight and composition. Wakame ( Undaria pinnatifida ) is a brown seaweed commonly consumed in Japan and is a main ingredient in miso soup and is also served as a salad.  Recently it as been reported that fucoidan can inhibit SARS-CoV-2 replication in vitro: https://www.nature.com/articles/s41421-020-00192-8 Of course it remains to be demonstrated in humans, but it's a start.  ~ Wakame fucoidan could be useful for Covid-19 since it inhibits thrombosis without increasing bleeding time: https://pubmed.ncbi.nlm.nih.gov/22084059/ The  Min et al. (2011) study also found in comparison to wakame fucoidan, fucoidan from bladder wrack inhibited thrombus formation, but bleeding time was prolonged (but not as much as for heparin).  An important caveat when considering the therapeutic potential of seaweed/fucoidan is that there are differences in biological activities in fucoidans from different species as we

 4-aminopyridine (4-AP, fampridine, dalfampridine) has been used to treat episodic ataxia 2 and downbeat nystagmus; so far it does not seem to have been trialed or even suggested for use in multiple system atrophy: "In recent years, advance has been made in the pharmacological treatment of cerebellar disorders, for example episodic ataxia type 2 (EA2) and in adition downbeat nystagmus (DBN), specifically because of the utilization of aminopyridines (AP) [ 10 - 13 ]. This agent is a nonselective blockers of the Kv family, mainly the Kv1.5 voltage-activated potassium channels, thereby prolonging the duration of action potentials in axons because of delayed repolarization [ 14 ]. In vitro studies showed that 4-aminopyridine (4-AP) increases the resting discharge rate and excitability of cerebellar Purkinje cells (PCs) of the guinea pig cerebellum [ 15 ], and regulates the PC firing in brain slices of the rat [ 16 , 17 ], Due to an increased activity of PC [ 13 ] the GABAe

  Some news on metformin - a study of C. elegans (worms) and human cell cultures found that older individuals had deleterious effects while younger individuals benefited. Co-administering rapamycin alleviated the toxic effects in older individuals: https://medicalxpress.com/news/2020-11-age-decisive-positive-negative-effects.html   Original research article: https://doi.org/10.1038/s42255-020-00307-1 I am curious to know if boosting NAD+ would also mitigate the toxicity. Related: https://www.sciencedaily.com/releases/2018/12/181211113024.htm Coincidentally I also saw yesterday a video presentation on the effects of aging on microRNA production in response to exercise. An enzyme called DICER is involved in RNA processing and it increased in activity in response to exercise; the effect size was found to be much lower in older individuals and the effect is AMPK dependent. https://youtu.be/lN_wJT-EkuA 10:54 there's one young individual at the bottom of the graph - what's up

 "The modern cognitive embodied theory demonstrates that our mental and cognitive processes are embodied in our bodies, depending on our bodies’ specific activity patterns 44 . This means that, cognition is not independent of body movement, but is deeply rooted in the human body and the interaction between the body and our world." https://www.nature.com/articles/s41598-020-73679-9

 Continuing with PON2... found a brand new article which is unfortunately paywalled: https://pubmed.ncbi.nlm.nih.gov/33096292/ "Previously, we have demonstrated that β-estradiol-3-benzoate (EB) has a protective effect on the neurodegenerative experimental model of Parkinson's disease. The protective effect is through the induction of the expression of paraoxonase-2 (PON2) in the striatum. ... EB protective effect against MPP + neurotoxicity is related to antioxidant effect of PON2, pro-inflammatory cytokines and GSHR but not to SOD2, catalase, GPX1 or GPX4." Is the effect all due to estrogen, or is there some contribution from benzoate? Maybe it's good I can't access the article, I have a lot of chores to do today ... ~ PON2 and bladder cancer: https://pubmed.ncbi.nlm.nih.gov/28430636/ ~ TMPRSS2 is up-regulated in rats treated with 6-hydroxydopamine (6-OHDA) to model PD [ PMID: 30713215 ]. ~ The Potential Role of SARS-COV-2 in the Pathogenesis of Parkinson&

 Learned about PON1 and PD yesterday by attending web conference presentation by Beate Ritz: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922777/ Anthocyanins increase PON1 and are thought to protective against PD, but they also increase NO production - hmm .... ~ Vitamin D levels are decreased in PD: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267215/ "After the discovery that the VDR and 1α-hydroxylase, the enzyme that converts vitamin D to its active form, were highly expressed in the substantia nigra, it was hypothesized that inadequate levels of circulating vitamin D may lead to dysfunction or cell death within the substantia nigra ( 25 , 26 )." Active vit D (calcitriol) is mainly produced in the kidneys, as is klotho. a-syn is produced in the kidneys throughout lifespan.  ~ Chronic kidney disease prevalence is lower in PD patients: https://www.mdsabstracts.org/abstract/prevalence-of-chronic-kidney-disease-in-patients-with-idiopathic-parkinsons-disease-in-a-tertia

MCC950, an NLRP3 inflammasome inhibitor, was shown to reverse symptoms in two Parkinson's disease mouse models and was reported to have no toxicity issues. The only reason given in the following article for not pursuing clinical trials is that it is off-patent: https://www.genengnews.com/news/parkinsons-disease-drug-that-cools-brains-on-fire-could-enter-human-trials-in-2020/   Given its mechanism of action it could be broadly effective against neurodegenerative diseases and even spinal cord injury ( https://www.frontiersin.org/articles/10.3389/fmolb.2020.00037/full ).   Infections due to immunosuppression may be a problem, but there are reasons to think that MCC950 would be safer than immunosuppressive agents currently used to treat inflammatory conditions:   "Thus, specific targeting of NLRP3 will not result in the complete blockade of IL-1β during infection and antimicrobial responses may remain intact. MCC950 may therefore have less immunosuppressive effects when compa

Autophagy and Neurodegeneration │ Prof. David Rubinsztein   https://www.youtube.com/watch?v=BgIk9ehY09k 30:00 screening for mTOR independent autophagy inducing drugs 37:08 felodipine, a Ca channel blocker, induces autophagy and clears protein aggregates 46:00 vicious cycle of protein aggregates impairing autophagy -> more protein aggregates ~  Glycine and tryptophan lower uric acid levels in patients with mild hyperuricemia: https://pubmed.ncbi.nlm.nih.gov/30845731/ Glycine is inversely correlated  with serum uric acid in healthy people and in lifestyle-related diseases: https://www.nature.com/articles/s41598-017-17710-6 The Nature article also notes men are more likely to have hyperuricemia and that estrogen promotes uric acid excretion. The SURE-PD trial of inosine to increase serum and CSF urate was halted due to lack of efficacy, BUT inosine was found to be effective in increasing urate and decreased rate of progression in women: https://pubmed.ncbi.nlm.nih.gov/31484712/ Gelatin

  Genetic Mutations in Parkinson's Disease | 2019 Udall Center Research Symposium, presented by Dr Valina Dawson Some very nice slides. 18:18 - 3:00 - 3:26   19:25 It is disappointing to see therapies targeting NLRP3 inflammasome inhibition are not more advanced, considering the success of MCC950 in mouse models and how broadly effective it could be for neurodegenerative diseases as well as spinal cord injury . Index   3:00 autosomal recessive PD (ARPD) genes & their functions   3:26 interaction of ARPD genes - 'linked in circuits' - leading to inactivation of Parkin & activation of PARP1 resulting in death of neurons   4:56 autosomal dominant - point mutations in alpha synuclein which facilitate its misfolding; a- syn can be duplicated or triplicated     6:00 VPS 35 - vacuolar sorting protein     6:54 LRRK2 - sporadic PD - spontaneous mutations occur at high frequency - 1-7% of PD patients of European origin and 20-40% of PD in Ashkenazi Jews and North A

Getting even worse at keeping up with / track of things. So this week I read more about amino acids.   Lysine + arginie was found to help with anxiety and depression in a brief (7 day) trial. https://pubmed.ncbi.nlm.nih.gov/17510493 Lysine, threonine and histidine were found to inhibit mTOR in bone marrow derived mast cells and also ameliorate autism symptoms in a mouse model. https://pubmed.ncbi.nlm.nih.gov/27640900 A bit weird that histidine ameliorated autism symptoms since histidine converts to histamine and there is indirect evidence of mast cell involvement in autism. However, histidine supplements are used by naturopaths to treat allergy since there is apparently a paradoxical effect -  I need to find a peer-reviewed reference source for this. A metabolomics study found threonine to be elevated in a mouse model of PD; glycine was lowered and urea was higher. Mannose was elevated. https://pubmed.ncbi.nlm.nih.gov/32937957 Came across an anecdote on amazon reviews of threonine reli

Read a bit about lipid metabolism in PD https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099649/ "Since oligomers seem to be the toxic species rather than fibrils, we believe that the increasing DHA concentration in the cell could worsen toxicity rather than having a protective role." oh dear Eating fish is associated with reduced risk of PD - but maybe the benefit is from beta parvalbumin?? ~ A clinical trial published in 2019 found omega-3 from flax plus vitamin E to be beneficial in PD - though of course flax does not contain DHA, but ALA which may be converted to DHA - but not very efficiently & there are sex differences (reproductive age women do so more efficiently than others) https://www.sciencedirect.com/science/article/abs/pii/S0303846718304633 ~ Seems like fibrates would be helpful, but one study in a rat models says no https://pubmed.ncbi.nlm.nih.gov/28403913/ but brilliant blue G, a P2X7R anatgonist, was beneficial ~ Cereblon - "Our study reveals a novel

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 d