Exciting! As noted in the article this is primarily relevant to people with genetic PD (less than 10% of all cases) but “The next step for the research team is to test whether other forms of Parkinson’s disease that are not associated with the LRRK2 genetic mutation could benefit from this type of treatment.” Wait and see…
1 Like
On calcium and PD @CronosTempi (@DrFraser you might also be interested):
Many papers previously found a protective association between calcium-channel blockers (CCB) use and PD.
However, the RCT of isradipine (a brain-penetrant CCB) failed: Isradipine Versus Placebo in Early Parkinson Disease A Randomized Trial 2020
There’s still an ongoing trial of nilvadipine (4 mg twice a day) in Australia, results expected soon.
But a recent Yale preprint shows a different picture: Drug Repurposing for Parkinson’s Disease: A Large-Scale Multi-Cohort Study 2025
They did find a lower risk of PD among amlodipine users: "Two commonly used antihypertensives, amlodipine and losartan, were also linked to a lower PD risk.”
But after diagnosis, they found a faster decline among amlodipine users: “After adjusting for covariates, PD patients who had ever used sildenafil or amlodipine exhibited a significantly faster cognitive decline in MoCA scores (sildenafil: β = –0.13, p = 0.019; amlodipine: β = –0.11, p = 0.027) and a significantly faster motor decline by UPDRS III scores (sildenafil: β = 0.83, p = 0.000073; amlodipine: β = 0.66, p = 0.0032), compared to those who had never used these drugs (appendix p 34).”
So calcium channel blockers protect you before getting PD, but once you get PD, they make you worse off? When does PD even start?
A recent paper sheds a new light on that conundrum: The molecular clock drives motivated locomotion and time-of-day-dependent firing patterns in mouse dopaminergic neurons 2025
They found that the bursting of nigral dopamine neurons in mice is blocked by the L-Type CCB N-nifedipine. According to the paper, this bursting is time-of-day dependent, Bmal1-regulated, and reliant on L-type Ca²⁺ channels (LTCC) during early night periods. This is Grok’s interpretation of the paper:
On one hand, the paper highlights a potential beneficial aspect: Aging increases reliance on LTCCs for pacemaking in substantia nigra pars compacta (SNc) DANs, which elevates cellular stress and has been implicated in the heightened vulnerability of these neurons in PD. This suggests that reducing excessive LTCC activity—possibly through blockers—could mitigate stress and offer neuroprotective effects, aligning with the paper’s discussion of how circadian clock disruptions (e.g., via Bmal1 deletion) might exacerbate metabolic demands and neurodegeneration in PD-relevant pathways.
On the other hand, the study shows a potential detrimental effect: LTCCs are essential for time-of-day-dependent bursting in SNc DANs during the early night (ZT 12–16), which is Bmal1-regulated and critical for phasic dopamine release and motivated locomotion. Experiments using the LTCC blocker nifedipine completely abolished this bursting without affecting tonic firing, implying that acute blockade could impair normal physiological outputs, such as voluntary movement initiation, which are already compromised in PD.
What does this mean for humans? According to Grok again, mice are nocturnal, while humans are diurnal. So you want to block LTCC during the night (to protect the brain) but not during the morning/ early day (to allow for daytime bursts and support motivation and movement).
I noticed this myself: when I’m on amlodipine (a long-acting CCB) I’m better overall but a bit slower and more apathetic. When I’m off amlodipine, I’m more energetic and faster, but I have slight tremors.
So is there a solution? If the paper is correct and applicable to humans, then you want an L-type CCB with a short half-life that you can take once daily in the evening to protect the brain at night while keeping LTTC active during the day. Ideally this CCB should be brain-penetrant. And this brings us back to… isradipine! Indeed: “The half-life of isradipine is biphasic, with an alpha half-life of 1.5 to 2 hours and a terminal half-life of approximately 8 hours.”
So why did the isradipine trial fail then? I think because they used “5 mg of immediate-release isradipine twice daily or placebo for 36 months.” My guess is that the evening dose was beneficial, while the morning dose was detrimental, resulting in a net effect of 0. Would they find benefits with isradipine IR, taken once daily in the evening?
I’d like to try isradipine IR, but it appears to be available only in the US and Canada. I couldn’t find it on IndiaMart or in Turkey. Some countries have isradipine slow-release but this defeats the purpose.
@John_Hemming: Magnesium being a very mild L-type CCB, this might explain why it doesn’t have significant benefits in PD?
3 Likes
Has this been posted? I did a search but couldn’t find it. Very old paper.
Use of Calcium Channel Blockers and Parkinson’s Disease
Not posted but that’s the paper I had in mind when I wrote “Many papers previously found a protective association between calcium-channel blockers (CCB) use and PD.” Others replicated the finding.
1 Like
As usual, a great post!
I think the delay of onset of PD is probably the most relevant item for many individuals - and different approaches may be needed once one has disease, and may need to change with changing severity.
I currently think that the neuroprotective approaches for AD and PD are likely quite similar pre-disease, but need to start 20 years before one would have had a diagnosis of AD or PD.
The big issue is the need to change strategies and when those change, and on what evidence when dealing with early PD, advanced PD, or MCI, then early AD.
Once disease is present, especially once able to be diagnosed as having PD or AD it is more difficult to substantiate what modifies disease/progression. The sluggish movement of studies and data mining is going too slowly for those who have early disease, so many have to take their best guess based on inadequate information.
We know a lot more about how to risk decrease for AD, there is less on PD - however, many of the same interventions show significant risk reduction, such as Mediterranean diet, exercise, vitamin E, statins, CCBs, NSAIDS, baseline cognitive function, and others.
On the CCB question - you may look at these options - especially the first one as it has high penetration to brain:
|Drug|Half-life|BBB Penetration|
|Nimodipine|~1–2 h|High|
|Nicardipine|~2–4 h|Moderate|
1 Like
I was looking at nifedipine as a short acting, and saw that you already posted the paper showing amlodipine with better ACM compared to nifedipine or felo, vera etc.
Calcium channel blockers, survival and ischaemic stroke in patients with dementia: a Swedish registry study
The problem is by the time I come across a paper, more likely than not, you already posted it 
, like below
Brain-penetrant calcium channel blockers are associated with a reduced incidence of neuropsychiatric disorders
I’m keeping my eye out on calcium handling, as I sense that this is the most promising practical approach to ameliorating early PD.
2 Likes
As usual, I agree with you 
Nimodipine needs to be taken on an empty stomach (≥ 1 h before or ≥ 2 h after food) and can cause tachycardia. Nicardipine appears promising, but in many countries, it’s only available in IV form. I’ll have to do more research…
1 Like
Nicardapine 20 mg 90 capsules in U.S. with a GoodRx coupon is not that cheap - but $178 at CVS. ?if India has these?
1 Like
Parkinson’s disease (PD) is a progressive neurodegenerative condition affecting around 1-2% of the population over the age of 60. The lack of disease-modifying therapies highlights the need for insights into the etiology and pathogenesis of PD. Mitochondrial dysfunction is recognized to be a significant contributor to disease pathogenesis, resulting in bioenergetic deficits and subsequent neurodegeneration. Research indicates that changes in non-oxidative phosphorylation (non-OXPHOS) metabolism in PD may serve as an adaptive response to mitochondrial dysfunction, compensating for energetic failure and alleviating disease progression. This review explores mitochondrial dysfunction-driven alterations in non-OXPHOS metabolic pathways, such as glycolysis and the tricarboxylic acid cycle, emphasizing their role in maintaining energy metabolism and their dual contribution to neuroprotection and disease progression. Advances in neuroimaging techniques are also discussed, particularly their role in visualizing metabolic changes in vivo and their potential utility in identifying non-OXPHOS metabolism as a biomarker of mitochondrial dysfunction. By enhancing our understanding of the complex interplay between metabolic pathways in PD, this review underscores the importance of personalized therapeutic approaches that consider individual metabolic variations. Ultimately, these insights aim to pave the way for improved diagnostic utility and personalized treatment strategies that address the metabolic and mitochondrial dysfunctions underlying PD pathogenesis.
Full paper: PDF
@John_Hemming: non-OXPHOS and TCA cycle 
On glycolysis: “The evidence of glycolysis’ role in PD is conflicting, demonstrating the upregulation of specific glycolytic enzymes as a neuroprotective mechanism, while increased glycolytic flux results in the accumulation of toxic end-products, exacerbating neurodegeneration. The dual nature of glycolysis necessitates identifying the threshold balancing the compensatory benefits against neurotoxic effects. The lack of consistency suggests that the glycolytic reprogramming in PD is context-dependent, with factors such as cell type, disease stage, underlying genotype, and threshold of glycolytic flux shaping its contribution to disease progression.”
On TCA cycle: "This process is significantly disrupted in PD, as evidenced by findings from in vivo PD models. PDH catalyzes the first gatekeeping step of the TCA; however, its activity is compromised in PD. […] The consistent evidence of reduced PDH activity suggests TCA cycle decoupling from glycolysis, leading to elevated pyruvate levels and reduced glucose flux through oxidative metabolism. Elevated pyruvate levels are converted to lactate due to increased LDH activity in PD, signifying a metabolic shift towards anaerobic glycolysis. […] MPP±treated SH-SY5Y cells demonstrated reduced citrate synthase (CS) and isocitrate dehydrogenase activity (IDH)
Fatty acid β-oxidation: “Similarly to glycolysis, FAO appears to be differentially affected across disease stages – upregulated in early stages to meet energy demands and declining with the disease progression; however, this pattern remains controversial and not fully supported by all research available. […] Evidence linking dysregulated FAO to pathogenesis is increasing; for instance, protein analysis of post-mortem tissue revealed early-stage FAO upregulation, marked by increased expression of acetoacetyl-CoA thiolase, a key FAO enzyme [37]. Reduced mitochondrial complex I activity correlated with abnormal FAO, marked by increased plasma levels of isobutyrylcarnitine, reinforcing FAO dysregulation as a consequence of mitochondrial dysfunction [38]. Despite the evidence from some studies reporting FAO upregulation, its overall function is disrupted, as indicated by a shift from FA metabolism to lipid storage in PD.”
I need to read this when I have some time, but it all seems to report the consequences of a failing neuron being downstream of damage to Complexes 1 and 3.
I would need to read up on this to say anything of any use. I am too busy at the moment to do this.
Parkinson’s disease (PD) is a neurodegenerative disorder with both genetic and environmental factors contributing to pathogenesis. Viral infections are potential environmental triggers that influence PD pathology. Using ViroFind, an unbiased platform for whole virome sequencing, along with quantitative PCR (qPCR), we identified human pegivirus (HPgV) in 5 of 10 (50%) of PD brains, confirmed by IHC in 2 of 2 cases, suggesting an association with PD. All 14 age- and sex-matched controls were HPgV negative. HPgV-brain positive patients with PD showed increased neuropathology by Braak stage and Complexin-2 levels, while those positive in the blood had higher IGF-1 and lower pS65-ubiquitin, supporting disruption in metabolism or mitophagy in response to HPgV. RNA-Seq revealed altered immune signaling in HPgV-infected PD samples, including consistent suppression of IL-4 signaling in both the brain and blood. Longitudinal analysis of blood samples showed a genotype-dependent viral response, with HPgV titers correlating directly with IL-4 signaling in a LRRK2 genotype–dependent manner. YWHAB was a key hub gene in the LRRK2 genotypic response, which exhibited an altered relationship with immune-related factors, including NFKB1, ITPR2, and LRRK2 itself, in patients with PD who are positive for HPgV. These results suggest a role for HPgV in shaping PD pathology and highlight the complex interplay between viral infection, immunity, and neuropathogenesis.
Press: Groundbreaking study finds possible virus link to Parkinson’s Disease
His team discovered the presence of Human Pegivirus — a virus not previously linked to any known disease — in half of the Parkinson’s patients studied.
“This is a blood-borne virus that can be found in 5-to-10% of healthy blood donors. It’s related to hepatitis C — and we found it in 50% of brains of patients with Parkinson’s disease.”
Because the virus is similar to hepatitis C, researchers now plan to investigate whether existing hepatitis C medications might also help treat or even prevent Parkinson’s.
2 Likes
There is a correlation with a lot of chronic diseases and pathogens, especially with neurodegenerative disease.
This is why laboratory rodents live longer than wild, lack of predators (including pathogens).
This is why if humans were living an environment free of major pathogens and toxins (except for controlled bioflora) assuming good diet, exercise, sleep and lack of major stressors, they would live much longer IMO.
We already have evidence of that with hygiene, proper nutrition, clean water, vaccinations almost tripled the life span in the past 150 years… mainly by reducing premature deaths.
1 Like
I performed a search of the site and did not see this study posted. If it had been, I apologize. I make a special effort to find French papers on PD. Obviously this is in women. Note however, again, it does matter which specific statin is used, here even a broad class effect of lipophilic vs hydrophilic. Rather counter to previous hypothesis, it’s the lipophilic that had a positive effect. Given how long symptomless period for PD can be prior to diagnosis, I wonder if 5 years is enough.
Statin Use and Incidence of Parkinson’s Disease in Women from the French E3N Cohort Study
Yes, lipophilic looks better in this paper but overall association studies are mixed:
High LDL is protective in PD (per MR), so this might just be reverse causation (high LDL => statin use & lower PD risk):
- Protective role of apolipoprotein A and B in Parkinson’s disease: A prospective study from UK Biobank 2025: “Elevated baseline levels of serum ApoA (HR = 0.84, 95 % CI: 0.71–0.99, P = 0.047) and ApoB (HR = 0.67, 95 % CI: 0.57–0.78, P = 3.18E-07) were associated with a reduced risk of incident PD.”
- Association of cholesterol and glycemic state biomarkers with phenotypic variation and Parkinson’s disease progression: The Oxford Discovery cohort 2025: “HDL-C and total cholesterol differed across baseline PD phenotype clusters, with reduced levels associated with the most severe motor and non-motor phenotypes (psychological well-being, cognitive impairment, REM sleep behavior disorder, and daytime sleepiness). Higher HDL-C and total cholesterol, although the latter was attenuated after adjustment for statin use, were associated with better baseline activities of daily living (e.g., UPDRS-II score with 1 SD increase in HDL-C −0.74, 95%CI −1.22 to −0.26, p = 0.002) and non-motor features. Neither predicted the rate of motor or non-motor progression.”
Two RCTs tried lipophilic statins in early PD:
- Simvastatin: worsening motor symptoms in the simvastatin-treated group.
- Lovastatin: no significant difference in motor scores but possible beneficial effect in terms of dopaminergic cell loss.
Confirmed by MR: Causal relationship between PCSK9 inhibitor and common neurodegenerative diseases: A drug target Mendelian randomization study 2024: “HMGCR inhibitors increased the risk of PD (OR [95%] = 1.907 [1.502 to 2.312], p = 0.001)”
Not PD but see also: Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function 2022: “Using a wide range of cognitive function and dementia endpoints, we failed to find genetic evidence of an adverse PCSK9-related impact, suggesting a neutral cognitive profile. In contrast, we observed adverse neurocognitive effects related to HMGCR inhibition, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance.”
Gut disruption of GLP-1 might be the mechanism of action: Cardiovascular Health - #993 by adssx
Association studies + MR + RCT + Mechanistic understanding all point towards statins (and lipid-lowering in general?) being bad in PD.
1 Like
Statins may facilitate Parkinson’s disease: Insight gained from a large, national claims database
As a Black Sabbath fan since I was 14, my very first 8 track was Paranoid, I was saddened when he passed yesterday. I knew he had been ill with Parkinson’s for a while but did not know there are so many version of this disease.
2 Likes
Chinese paper and toxin rodent models but…
Serving as a pivotal hub for cellular metabolism and intracellular signaling, the mitochondrion has emerged as a crucial organelle whose dysfunction is linked to many human diseases, including neurodegenerative disorders, particularly Parkinson’s disease (PD). However, whether mitochondrial quality control (MQC) can be targeted for therapeutic interventions remains uncertain. This study uses clinical samples, molecular biology techniques, pharmacological interventions, and genetic approaches to investigate the significance of NAD+ levels in cross-species models of PD. These results reveal that treatment of rotenone-incubated cells with NAD+ boosters (such as NMN, siCD38, and NAT) increases UPRmt/mitophagy-related MQC, reduces pro-inflammatory cytokine expression, inhibits apoptosis, and strengthen redox reactions. In vivo, NMN supplementation inhibits motor deficit and forestalls the neuropathological phenotypes of MPTP-induced PD mice, which are required for the atf4-related mitochondrial UPR pathway. Notably, bulk omics signatures and metabolomic profiling analyses of the striatum reveal NMN-induced transcriptional changes in genes and proteins involved in mitochondrial homeostasis. Thus, these findings demonstrate that the accelerated pathology in PD models is probably mediated by impaired MQC and that bolstering cellular NAD+ levels alleviates mitochondrial proteotoxic stress and mitigate PD phenotypes.
With a focus on citrate @John_Hemming:
One prevailing strategy for estimating mitochondrial content is to measure the levels of citrate synthase (CS), a common marker of mitochondrial capacity, to normalize a given bioenergetic readout.
Notably, the activity of the CS protein was lower in the rotenone-treated cells than in the vehicle-treated cells, but it significantly increased after treatment with NMN, siCD38, and NAT (Figure 1l–o), indicating that the mitochondrial content was enhanced in the context of NAD+ boosters’ augmentation.
We then visualized the metabolites involved in regulating these pathways in a circos plot and found that citrate regulates multiple metabolic pathways, whereas prolyl, tryptophan, and adenine are involved in multiple sphingolipid pathways (Figure 10f). By combining the MSEA and pathway enrichment results, we preliminarily identified citrate as the key metabolite induced by NMN in the TCA cycle.
Consistent with our previous report, the mice treated with MPTP showed a robust CS decline in the striatum by immunofluorescence and western blot analysis, which was significantly offset by NMN treatment
Without reading the paper I don’t think CS is at the core of the issue. The quoted text is not clear on whether it is the quantity of CS or the activity of CS that they are looking at. The activity will be linked with pyruvate influx.
Mechanical Forces Guide Axon Growth through the Nigrostriatal Pathway in an Organotypic Model
https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202500400
“Reconstructing the nigrostriatal pathway is one of the major challenges in cell replacement therapies for Parkinson’s disease due to the lack of enabling technologies capable of guiding the reinnervation of dopaminergic precursors transplanted into the substantia nigra toward the striatum. This paper examines nano-pulling, as a technology to enable the remote manipulation of axonal growth.”