#676

Solanesol possesses antimicrobial, anti-tumor, anti-inflammatory, and anti-ulcer activities, and it serves as an important pharmaceutical intermediate for the synthesis of coenzyme Q10, vitamin K2, and N-solanesyl-N ,N ′-bis(3,4-dimethoxybenzyl) ethylenediamine (SDB).[3]

Perhaps K2 is cheaper.

I wonder if the smoking issue is more oxygen related.

Molecular weight 631.1 MK7 molecular weight 649.

I can get 4.5g of MK7 for about the same price as 25mg of Solanesol.

Obviously the isoprene residues in Solanesol allow it to embed in the mitochondrial membrane, but whether it can act as electron transport or first needs converting to CoQ10 or MK-n (where n is from 7-13) I don’t know.

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#677

Globally, 25.2 Million Projected to Be Living With Parkinson Disease in 2050

#678

The Gut-Brain Axis in Parkinson disease: Emerging Concepts and Therapeutic Implications 2025

Mounting evidence from preclinical, clinical and post-mortem studies suggests that a subgroup of PD patients present with a range of prodromal symptoms (e.g., autonomic dysfunction, rapid eye movement sleep behaviour disorder) which reflect initial accumulation and later spread of pathological α-synuclein rostrally from the gastrointestinal tract (“body-first” PD). Through neural connections along the gut-brain axis, pathological α-synuclein may spread to the brain, producing clinically manifest disease. Recently, two mechanisms involving the gut-brain axis have attracted increasing attention for their role in PD pathogenesis and progression, namely the perturbation of the composition of the microorganisms living in the gut (the gut microbiome), and the dysfunction of enteroendocrine cells.
Treatments targeting the gut-brain axis, especially the gut microbiome and the enteroendocrine cells pathway, could potentially slow disease progression or even prevent disease onset. Among these, pre/probiotics, faecal microbiota transplantation, and glucagon-like peptide-1 receptor agonists, have entered advanced stages of clinical trials in humans and shown potential symptomatic and disease-modifying effects.

In the last 20 years, research into the gut-brain axis has broadened our understanding of the pathogenesis, phenotypic heterogeneity and clinical trajectories of PD. Building upon the seminal Braak hypothesis, current models of PD pathogenesis support the existence of a body-first subtype of PD where pathological changes might originate in the gut years or even decades prior to brain dysfunction. For this subset of individuals, alterations in the gut microbiome composition and dysfunction of EECs might contribute to the initial pathogenic alterations and potentially affect disease progression.
Research into the microbiome-gut-brain axis has paved the way for the identification of novel therapeutic targets, including symptomatic, disease-modifying and prophylactic treatments, in PD. These treatments might be particularly effective in addressing troublesome, non-motor symptoms such as constipation, but evidence from phase III RCTs, with appropriate study design and patient selection, is needed.

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#679

This is huge: Chronobiotic use of melatonin improves DAT-binding in iRBD

Dieter Kunz1, Jan De Zeeuw2, Sophia Stotz1, Michail Plotkin3, Frederik Bes1
1 Charité – Universitätsmedizin Berlin, Institute of Physiology, Berlin, Germany,
2 Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany,
3 Charité – Universitätsmedizin Berlin, Berlin, Germany
Aims: Isolated REM-sleep behavior disorder (iRBD) is recognized as a prodromal state of clinical α-synucleinopathies such as Lewy-body dementia and Parkinson’s disease. A pathophysiologic hallmark of α-synucleinopathies is nigrostriatal dopaminergic impairment, with dopamine-transporter (DaT)-SPECT imaging considered best available prognostic and monitoring marker. DaT-binding is reported to decrease with healthy aging by 4-10% per decade, accelerated to 4-12% per year iRBD patients. We have introduced melatonin as a treatment option for iRBD. Aim of the study was to evaluate effects of melatonin on DaT-SPECT imaging in iRBD patients.
Methods: In a prospective, longitudinal, observational, single-center study we performed at least two DaT-SPECTs in 97 iRBD patients treated with melatonin as a chronobiotic (i.e. administration always- at-the-the-same-clock-time;10-11p.m.-corrected for chronotype); 28 patients were excluded mainly due to change of psychotropic drugs known to influence DaT.
Results: After mean follow-up of 3.6yrs, only 21/69 patients (11 female; mean age 71±6yrs) showed specific binding ratios (SBR) in most affected region (MAR, predominantly right posterior putamen) comparable to usually reported declines with iRBD. In contrast, 7 had declined SBR at a rate comparable to healthy aging, while 41 had actually improved SBR. Improvement after one year (SBR of MAR; F1,31=23.748;p>0.001) and two years was significant (F1,24=4.648;p=0.041). After four years half of the patients showed a higher SBR than baseline (23 vs. 24 patients), though this was not significant. 47/69 of our patients at baseline met established criteria for an advanced state.
Conclusions: To the best of our knowledge, present data give first evidence for a consistent increase in DaT-binding ratios in nigrostriatum over time in a cohort of patients with iRBD. In addition, the previously reported persisting effect of melatonin on RBD symptoms suggest that melatonin, when used as a chronobiotic, may have a disease-modifying effect in prodromal α-synucleinopathies.

:warning: It’s a conference poster so not peer-reviewed yet but it’s a very serious research team, it’s a decent size, over a long period of time and it uses an objective biomarker :warning:

Their chronobiotic protocol is “2 mg, ≥6 months, always-at-the-same-clock time, 10-11pm, corrected for chronotype”: Treatment of isolated REM sleep behavior disorder using melatonin as a chronobiotic 2021. In this 2021, paper they note:

Patients on concomitant betablocker or antidepressant therapy seemed to respond more slowly at the beginning of melatonin treatment, although they did not differ in general from the no-confounder group. Both antidepressants and betablockers are known to induce secondary RBD as well as to increase RSWA in patients with iRBD. Antidepressants are well known to influence REM sleep, with anticholinergic agents to suppress, but serotoninergic and noradrenergic agents to spoil the quality of REM sleep. As has been known for decades, lipophilic propranolol blocks melatonin secretion from the pineal gland via beta-receptors. The suppression of melatonin with betablockers predominantly affects REM sleep, which can be reversed by exogenous melatonin. Long-term medication with betablockers is likely to have changed melatonin receptor sensitivity, thus delaying response to initial melatonin. The same negative effect could be attributed to recommended increasing dosage of melatonin. Because melatonin influences its own receptor, it is important to have a melatonin-free period over the day. Supraphysiologic melatonin doses, especially in slow metabolizers, prevent the absence of melatonin during the day and could induce insensitivity in melatonin receptors the next evening.
The rationale for this strict schedule is that since our initial pilot studies with RBD patients about 25 years ago, we repeatedly observed that responders and nonresponders were best distinguished by evaluating their sleep hygiene, that is, stable vs. varying bedtimes and times of melatonin intake (summarized in 10, 17). This clinical observation is in agreement with the fact that melatonin is known to feedback on the suprachiasmatic nucleus, the central pacemaker or master-clock. As a consequence, exogenous melatonin should be administered consistently within a rather narrow time span in order to gain optimal effects. Patients are informed that melatonin in RBD rarely exhibits effects during first days of treatment, rather effects occur within the first weeks. Sometimes symptoms even rapidly worsen over the first days, presumably because appointed time of administration induced a transient initial delay or advance of circadian phase. In those patients, in whom melatonin does not show positive effects over the first 3 weeks of treatment, the time of administration is controlled referring to individual chronotype.
The rate of improvement of RBD symptoms with melatonin in previously reported case series varies, and two recent RCTs have shown no effect. Unfortunately, melatonin has been sold worldwide for the past 25 years as a hypnotic to be administered in connection with clock time independent events (eg, “after a meal,” “at bedtime”). Most people who took melatonin—including those in the two recent RCTs with negative results—will therefore not have adhered to a schedule based strictly on clock time. As an example, in our Clinic for Sleep & Chronomedicine, we precisely explain the chronobiotic protocol but even though, still some patients stuck to the aberrant leaflet prescription. Our study indeed demonstrates that beneficial effects of melatonin can easily be disrupted with improper timing of intake, which may well explain lower response rates reported by other groups. In those patients for whom we had a chance to reinstruct, melatonin improved RBD symptoms. On the other hand, melatonin should not be considered a harmless drug or being without side effects. Inadequate timing of melatonin seems likely not only to fail in improvement, but rather to worsen symptomatology due to desynchronization.

What do you think about this potential risk @John_Hemming?

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Melatonin megadoses?
#680

I think a study is needed as to timing of melatonin linked to the timing of the HPA axis.

On the other hand, melatonin should not be considered a harmless drug or being without side effects.

When there have been reports of claimed harm from melatonin I have chased down the case reports and they did not substantiate the claim.

I am not sure the effects in terms of protection of mtDNA are that sensitive to timing, however.

1 Like
#681

Selegiline looks good: Anyone taking Selegiline / Deprenyl For Longevity? - #90 by adssx

Regarding the melatonin conference abstract, although they only looked at DAT imaging, they showed in a previous paper that “Most RWA metrics correlated significantly with DAT-SPECT ratios (eg, Montreal tonic vs most-affected-region: r=−0.525; p<0.001).” (Prognostic biomarkers in prodromal α-synucleinopathies: DAT binding and REM sleep without atonia 2023)

#682

Just published on melatonin @John_Hemming: Clinical features, plasma neurotransmitter levels and plasma neurohormone levels among patients with early-stage Parkinson’s disease with sleep disorders 2025

RBD was associated with dysautonomia and was negatively correlated with the plasma melatonin concentration at 1:00 AM (r = − 0.40, p = 0.002) in early-stage PD patients.
REM sleep behavior disorder (RBD) was linked to dysautonomia and lower levels of melatonin at 1:00 AM, restless legs syndrome (RLS) was associated with poorer sleep quality and lower levels of serotonin and glutamine at different times.
Previous studies have confirmed that the principal neuroendocrine system and the crucial neurotransmitter systems that mediate sleep, including melatonin, acetylcholine, norepinephrine, serotonin, dopamine, and gamma-aminobutyric acid, are disrupted in PD.
In healthy controls, the plasma dopamine level at 1:00 am was significantly lower than that at 9:00 am, and the melatonin level at 1:00 am was significantly greater than that at 9:00 am, which is consistent with the findings of previous studies. Patients with PD had decreased plasma concentrations of Asp, Glu, GABA, MT and epinephrine at 1:00 am and decreased plasma concentrations of Asp, Glu, DA and epinephrine at 9:00 am.
The plasma concentration of melatonin at 1:00 am was significantly lower in PD patients with RBD than in controls and PD patients without RBD (Fig. 2), whereas the levels of DA were elevated in PD patients with RBD compared with those in patients without RBD at this time point. However, no difference in DA levels was observed between the PD-RBD and control groups (Table S9). The plasma melatonin level at 1:00 am was negatively correlated with RBD (r = − 0.40, p = 0.0018), and the DA level was positively correlated with RBD (r = 0.29, p = 0.025) (Fig. 3).

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Our study revealed a lower level of plasma melatonin in PD patients with RBD than in patients without RBD and healthy controls at 1:00 AM. In addition, the plasma melatonin level at this time was negatively correlated with RBD, suggesting that the decrease in the peripheral melatonin level in the early morning might be involved in RBD development. Previous studies using animal experiments reported that α-synuclein reduces acetylserotonin O-methyltransferase-mediated melatonin biosynthesis. Two previous studies reported that patients with PD presented reduced circulating melatonin levels. Furthermore, based on comprehensive clinical observations, 59.9% of 137 RBD patients reported improvements with melatonin treatment across various outcome measures in published studies. Thus, melatonin has been proposed as a preferable treatment for RBD. These results are consistent with previous findings and support the role of melatonin in the incidence of RBD.
EDS: Excessive daytime sleepiness
Videnovic et al. [11] reported that PD participants with EDS had a significantly lower amplitude of melatonin rhythm and 24-h melatonin area under the curve (AUC) than PD participants without EDS. In the present study, the absence of a change in the levels of melatonin among PD patients with or without EDS may have occurred because the patients were enrolled in the early stage of PD when circadian rhythm disruption was less severe than it was in the advanced stage.

#683

I think there could be two separate types of cause
a) Less production by the pineal
b) Some blockage in the CSF that prevents melatonin going into the third ventricle in some way. (or blocks somewhere else in the CSF).

Obviously you could also have a) and b).

#684

18.6% of the PD patients in this study had no sleep disturbances. Presumably, this group had no significant melatonin abnormalities, at least not significant enough to cause any sleep disturbances whatsoever. If almost 20% of PD patients have no melatonin abnormalities, how central can melatonin be to the development of PD, amelioration of PD (by exogenous supplementation, f.ex.) or indeed be a factor in the pathology of PD at all? Perhaps it is one possible downstream effect of PD, but by no means necessarily present in all cases. What physiological features do all PD patients share? It’s not melatonin abnormalities. Substantia nigra gets destroyed, OK. How that happens seems extremely heterogeneous. But what is the grand unifying theory of PD? Are these an extremely diverse set of diseases which happen to share a common presentation despite widely different pathologies leading to that presentation? Maybe it makes no sense to look for a single agent, like, say, melatonin, which governs PD, instead PD is just a set of symptoms stemming from a common area of damage, such as substantia nigra - and how you get there or how you might cure it is going to be all over the map.

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#685

The thing to measure is melatonin in the CSF. This is a much higher concentration than in serum and is right next to the Substantia Nigra. The concentration is perhaps 20x at night.

This is very hard to measure, but has been measured in people with PD as well as people without.

#686

There’s always a % of people in PD cohorts who actually don’t have PD. It’s maybe just 5% but if they sleep well this might lower this % a bit.

Also, here they looked at five sleep disturbances: RBD, RLS, OSA, insomnia, and EDS. They diagnosed them based on

  • “sleep conditions were comprehensively assessed with clinical questionnaires and polysomnography”
  • “All participants underwent examination by movement disorder specialists through face‒to-face interviews and detailed questionnaires.”
  • “All patients underwent night-time video-polysomnography at the Parkinson’s Disease and Movement Disorder Impatient Clinic.”

They note that “The incidence of insomnia (18.6%) was lower than that reported in a previous study”. This other study (Sleep disorders in Parkinson’s disease, an early and multiple problem 2024) found that “Sleep disorders were systematically diagnosed after medical interview and video-polysomnography in 162 participants with early stage PD and 58 healthy controls from the baseline of the longitudinal ICEBERG cohort. […] Sleep disorders were frequent (71%) and combined in half of the patients. The number of sleep disorders increased with disease duration and dysautonomia. Insomnia was the most common (41%), followed by definite RBD (25%), EDS (25%), and RLS (16%).”

If indeed about 20% of people with PD have no sleep issues at all, then this would question melatonin at being causal @John_Hemming, at least in a subset of people with PD.

However, if you would ask people “Do you think you sleep well?” and “Has your sleep worsened since you got PD?” I guess 100% of people would say they have a sleep issue even though some of them would not be properly diagnosed with a sleep disturbance.

#687

I have for a number of years thought the HPA response to melatonin was serum based. That drives the sleep cycles.

#688

For what it is worth… saw thus today.
Parkinson’s Gut Bacteria Link Suggests an Unexpected, Simple Treatment : ScienceAlert

Link: Parkinson's Gut Bacteria Link Suggests an Unexpected, Simple Treatment : ScienceAlert

We know know that many ulcers were bacteria issues. Unfortunately, many had horrible invasive surgeries that never solved the simple issue.

2 Likes
#689

Yes it’s a paper from last year: Parkinson's disease - #464 by adssx

I tried riboflavin without much success…

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#690

Lithium Chloride Rescues Dopaminergic Neurons in a Parkinson’s Disease Rat Model Challenged with Rotenone 2025

:warning: Egyptian paper + Rotenone rodent model :warning:

Rotenone significantly resulted in neurobehavioral deficits, gastrointestinal dysfunction, decreased activities of catalase and superoxide dismutase, depleted glutathione, and increased levels of malondialdehyde. It also caused DNA fragmentation and loss of dopaminergic neurons in substantia nigra and decreased striatal tyrosine hydroxylase staining intensity. Concomitant treatment of rats with rotenone and lithium chloride significantly improved behavioral impairment and markedly alleviated gastrointestinal dysfunction. It also increased catalase activity and decreased malondialdehyde levels, indicating antioxidant effects. Moreover, it decreased DNA fragmentation, rescued dopaminergic neurons, and increased tyrosine hydroxylase immunoreactivity in the striatum compared to the rotenone-treated group.

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#691

Rats. But what about human genes and GWAS?

https://www.sciencedirect.com/topics/medicine-and-dentistry/lithium-chloride

"### 6.2.3.1 Lithium

Lithium chloride, one of the most well-known mood stabilizers with antisuicidal effects, is currently being utilized as an agent for acute mania and as maintenance treatment in bipolar disorder (BD).81,82 Unfortunately, there are few pharmacogenomic studies that address the issue of response to lithium treatment (reviewed in Ref. [83]), while previous GWASs, also dealing with lithium treatment response, have added a few genetic factors affecting lithium response including only limited criteria for the phenotypic characterization of treatment response (Ref. [2] and references therein).

According to published candidate-gene studies, several genomic variants in different genes, such as 5-HTT, TPH, DRD1, FYN, INPP1, CREB1, BDNF, GSK3β, ARNTL, TIM, DPB, NR3C1, BCR, XBP1, and CACNG2 genes, have been shown to be associated with lithium treatment response. Moreover, SLC6A4 and ACCN1 gene variants have also been associated with lithium treatment outcomes in patients with BD.

In recent studies, it has been shown that the rs1800532 variant in the TPH1 gene was associated with poor lithium response in patients with the rs1800532A/A genotype. Furthermore, the rs4532 variant in the DRD1 gene is associated with poor response to lithium.84 The rs3730353 variant in the FYN gene showed prophylactic response to lithium in patients diagnosed with BD, while the c.C973A variant in the INPP1 gene affected lithium treatment efficacy. Notably, an association was also observed in the lithium response and the rs206472 variant85 As for CREB1 gene, two variants (rs6740584/rs2551710) have been correlated with response to lithium treatment, but further investigations are needed to confirm these findings.84 Furthermore, in a large-scale study, including 3874 psychiatric patients from Sweden and the United Kingdom, it was shown that variants in the PLET1 gene are significantly associated with response to lithium treatment.85

Notably, some of the genes, already mentioned to be associated with lithium response, have overlapping effects in response to antidepressants in major depressive disorder and lithium treatment response in BD, such as SLC6A4 genomic variants.85

Unfortunately, despite the large amount of genetic data on lithium response published so far, we still miss conclusive and robust evidence suggesting that certain genomic variants could be reliably used to predict the probability of responding to lithium,84 and currently, there is no single pharmacogenomic biomarker that has been approved by the FDA or the EMA yet."

Looks to me like in this particular case there is a long way from rats to how humans might react to lithium chloride. YMMV.

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#692

Lithium at higher concentrations inhibits some of the citrate transporters. That’s why I am to keep the levels around the 10-50 micromolar level (sadly too low for the labs I use to measure properly).

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#693

This is probably a useful review if anyone can get a copy.

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#694

Automated Imaging Differentiation for Parkinsonism

https://jamanetwork.com/journals/jamaneurology/fullarticle/2831631

My question is how early in the disease can they do this differentiation imaging?

#695

That’s very good! I wonder when it will be commercially available.