So hypercapnia occurs in type 2 respiratory failure, you don’t have to be hypoxic. Cigarette smoking does result in increased carbon monoxide, not carbon dioxide with is what is the issue with hypercapnia. The problem is that one can get CO2 narcosis and stop breathing - we see if in the ER and ICU with some frequency.
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Researchers have reported that inhibition of 15-hydroxyprostaglandin dehydrogenase was shown to protect neurons and improve motor function in mouse models of Parkinson’s disease in findings that could support repurposing of drugs currently under development
Full paper that is the subject of this writeup:
Inhibiting 15-PGDH restores redox homeostasis and confers neuroprotection in Parkinson’s disease
https://www.sciencedirect.com/science/article/pii/S2213231726002843?via%3Dihub
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Leucine and whey?
For decades, researchers have focused on finding elaborate ways to get more drugs across the BBB. Montara Therapeutics is taking an alternative approach. Rather than simply trying to force more drugs into the brain, the company is using the BBB to its advantage to achieve brain-selective pharmacology, allowing drugs to remain active in the brain while preventing their activity elsewhere in the body.
The strategy recently attracted approximately $1 million in funding from The Michael J. Fox Foundation (MJFF), which will support the development of a brain-selective mTOR therapy for Parkinson’s disease. More broadly, however, Montara’s approach represents an exciting opportunity to revive promising drug classes that have long been abandoned because of dose-limiting peripheral toxicities.
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The Alpha-Synuclein Reckoning: Why Parkinson’s Biggest Drug Bets Keep Failing, and What Is Quietly Still Standing
This is a narrative review, not a new experiment. Nine authors from Zhejiang Cancer Hospital and the Chinese Academy of Sciences catalogue roughly 40 clinical trials and dozens of preclinical studies aimed at slowing Parkinson’s disease rather than masking its symptoms. Their central observation is bleak and useful: every large, well-funded attempt to attack alpha-synuclein, the misfolded protein at the centre of Parkinson’s pathology, has failed. Cinpanemab, prasinezumab and minzasolmin all missed their primary endpoints. One drug, venglustat, made patients measurably worse. The authors argue the failures are not proof the targets are wrong but proof the trials were designed badly: no genetic stratification, treatment started too late, and a motor rating scale as the primary endpoint that cannot separate a symptom being masked from a disease being slowed. The surviving signals are modest and come from unglamorous places, chiefly repurposed diabetes drugs and cell replacement.
For thirty years the story of Parkinson’s research has been the same story: find the toxic protein, remove the toxic protein, stop the disease. That story has now been tested at scale, and it has not held up.
This review assembles the wreckage. Cinpanemab, a monoclonal antibody against alpha-synuclein, was tested in 357 early-stage patients and showed no benefit at 72 weeks. Prasinezumab, in 316 patients, missed its primary endpoint at 52 weeks. Minzasolmin, a small molecule designed to stop the protein misfolding in the first place, was tested in 450 patients and its extension study was terminated in December 2024 for lack of benefit. Venglustat, aimed at a lysosomal enzyme pathway, did not merely fail; patients on the drug deteriorated faster than those on placebo, and their neurofilament light levels, a marker of neuronal damage, went up.
The authors’ diagnosis is that these trials asked the right question of the wrong people at the wrong time. None of them selected patients by genotype. Parkinson’s is not one disease. Roughly 5 to 10 percent of patients carry a GBA1 mutation and tend to decline faster; about 1 percent of sporadic cases carry the LRRK2 G2019S variant, which raises kinase activity two to three fold and appears to drive damage through lysosomal failure rather than protein clumping. Giving an anti-aggregation antibody to an unselected population dilutes any real effect into statistical noise. The venglustat data make the point vividly: patients with mild GBA1 mutations got substantially worse while those with severe mutations showed no difference, meaning the same drug had opposite consequences in two subgroups enrolled as though they were one.
The second problem is timing. Neurons are dying years before a tremor appears. By the time a patient meets diagnostic criteria, a large fraction of the substantia nigra is already gone. Treating that patient is repair work, not prevention.
What survives is quieter. GLP-1 receptor agonists, the diabetes and obesity drugs, have produced small but repeatable motor signals across four separate trials. Stem cell grafts have produced early open-label improvements in twelve patients. Neither is a cure, and the review is honest that both remain unproven.
Actionable Insights
Almost nothing here translates into something you can do tomorrow, and any report suggesting otherwise is overselling. Three points survive scrutiny.
First, metabolic health is the only lever in this paper with a plausible causal chain and a real-world magnitude. Diabetics carry roughly a 38 percent higher risk of developing Parkinson’s, and among diabetics, those on GLP-1 drugs had about 23 percent lower Parkinson’s incidence than those on a comparator drug. These are observational associations, not proof, but the direction is consistent.
Second, the drug effects themselves are small. Across the GLP-1 trials, the treated group ended up about 3 to 5 points better on a 132-point motor scale. Expressed as a standardised effect size, that is roughly 0.4 to 0.6, meaning a typical treated patient does better than about 67 to 74 percent of untreated patients. That is a real but partial shift, with enormous overlap between the groups. Critically, the definitive phase 3 exenatide trial found nothing at all.
Third, do not self-experiment on the basis of this review. The ambroxol and nicotinamide riboside results everyone cites are uncontrolled, involved 17 and 30 people respectively, and cannot distinguish drug effect from placebo, practice effect, or regression to the mean.
Context and Source
- Open access paper: Progress in Disease-Modifying Therapies for Parkinson’s Disease
- Authors: Shuyuan Zhang, Gang Shao, Bin Wu, Liang Xia, Lei Wang, Liwen Li, Kai Jin, Yangfan Zou, Caixing Sun
- Institutions: Zhejiang Cancer Hospital, Hangzhou; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences; Zhejiang Sci-Tech University
- Country: China
- Funding: National Natural Science Foundation of China (No. 82373842)
- Journal: Aging and Disease, Volume 17, Number 5, pages 2490 to 2508, October 2026.
- Article type: Review. Received 18 May 2025, revised 3 September 2025, accepted 4 September 2025.
- Impact evaluation. The impact score of this journal is 9.6, evaluated against a typical high-end range of 0 to 60+ for top general science journals, therefore this is a Medium impact journal.
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I searched this thread, but found no mention of cannabinoids, ie. cannabis. I will present a short summary of the effects.
While the discovery that cannabis (specifically THC and CBD) promotes hippocampal neurogenesis is scientifically promising, current evidence does not support the conclusion that this equates to a cure for Parkinson’s disease (PD).
The relationship between neurogenesis and PD is complex, and the “curative” potential remains theoretical rather than proven. Here is a summary of the findings:
1. Neurogenesis vs. The Core Pathology of Parkinson’s
Parkinson’s is primarily defined by the death of dopaminergic neurons in the substantia nigra (a part of the midbrain), not the hippocampus.
- Different Brain Regions: While cannabis-induced neurogenesis occurs in the hippocampus (critical for memory and mood), PD pathology destroys cells in the substantia nigra (critical for movement). Generating new neurons in the hippocampus does not automatically replace the lost dopamine-producing cells in the substantia nigra.
- Limited Migration: There is currently no robust evidence that new neurons generated in the hippocampus can migrate to the substantia nigra and functionally integrate to restore motor control.
2. The State of Hippocampal Neurogenesis in PD
Research indicates that hippocampal neurogenesis is actually impaired or altered in Parkinson’s patients, contributing to non-motor symptoms like depression and cognitive decline.
- Potential Benefit: By promoting hippocampal neurogenesis, cannabis might alleviate these non-motor symptoms (depression, anxiety, cognitive fog) and improve quality of life.
- Not a Motor Cure: Improving hippocampal health does not directly address the primary motor symptoms (tremors, rigidity, bradykinesia) caused by substantia nigra degeneration.
3. Neuroprotection vs. Neurogeneration
Current research distinguishes between generating new neurons (neurogenesis) and protecting existing ones (neuroprotection).
- Neuroprotection Evidence: Preclinical studies (in cells and rats) show that CBD and THC have strong antioxidant and anti-inflammatory properties that can protect remaining dopaminergic neurons from further damage. This could theoretically slow disease progression, but it is not a “cure” that reverses existing damage.
- Clinical Gap: Despite promising animal data, human clinical trials have not yet demonstrated that cannabis stops or reverses the neurodegenerative process in humans. A 2026 systematic review concluded that while cannabinoids may offer symptomatic relief, there is no conclusive evidence of disease-modifying (curative) effects in patients.
4. Recent Clinical Findings (2025–2026)
Recent trials highlight the gap between biological potential and clinical reality:
- Symptom Management: Studies confirm cannabis can help with sleep, pain, and psychosis (specifically CBD), but effects on motor symptoms remain inconsistent.
- No Cure Demonstrated: A 2026 meta-analysis of randomized controlled trials found that cannabinoids did not significantly improve motor symptoms or halt disease progression compared to placebo.
- Safety: While generally safe, high doses of THC can worsen cognitive function and balance, posing risks for PD patients.
Conclusion
The fact that cannabis causes hippocampal neurogenesis suggests it could be a valuable adjunct therapy for managing non-motor symptoms (like depression) and potentially offering neuroprotection to slow decline. However, it is not currently considered a cure because:
- It does not regenerate the specific dopaminergic neurons lost in the substantia nigra.
- Human trials have not yet shown it stops or reverses the disease’s progression.
- The neurogenesis observed is in a different brain region than the primary site of PD damage.
/end AI.
I would also refute the claim that cannabis doesn’t affect motor skills since this has already been documented for everyone to see in this video. I suppose it remains inconsistent; maybe something to do with the entourage effect or the carboxylation state of the compounds.
From the recent interview with Alex Colville:
- BlueRock Therapeutics and Aspen Neuroscience have successfully engrafted iPSC-derived dopaminergic neurons in Parkinson’s disease patients, bypassing the need for lifelong immunosuppression.
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Parkinson’s Rates Are Surging. Is Exposure to Poisons to Blame?
To Caroline “Carlie” Tanner, MD, PhD, a neurologist and epidemiologist specializing in movement disorders, it’s no surprise that Parkinson’s disease was first referenced in England in 1817, at the height of the Industrial Revolution when cities were cloaked in smoke and soot.
Today, smoke and soot have given way to more insidious, less visible toxicants. Research shows that exposure to toxicants destroys neurons, including those that produce dopamine, a neurotransmitter that facilitates smooth, balanced movement. Years later, patients developed Parkinson’s symptoms, including tremors that evolve into immobility, cognitive and mood changes, and difficulty swallowing.
Tanner’s groundbreaking population studies have quantified the risks of these toxicants and have highlighted the role of environmental triggers. Her research was instrumental in the Paraquat Prevention Act introduced in the U.S. House of Representatives in June 2026 and the phasing out or banning of other toxicants.
We asked Tanner, whose research is supported by the National Institutes of Health (NIH), about the upsurge.
How much have Parkinson’s cases increased in recent years and why?
From 1990 to 2021, global Parkinson’s disease cases have increased from approximately 3 million to nearly 12 million.
There’s no doubt that toxicants are contributing to the upswing. True, some portion of the increase can be explained by improved diagnostics and disease recognition. Also, people are living longer and reaching the age when they are most vulnerable to Parkinson’s disease — over 50, with peak diagnosis between 60 to 69.
It’s important to note that these are estimates. We don’t have a good system for reporting Parkinson’s disease in most countries and we lack long-term data.
What role do toxicants play in Parkinson’s?
Years ago, genetics and aging were believed to be the underlying causes of Parkinson’s disease. The impact of toxicants became clear in 1983 when a group of drug users rapidly developed Parkinson’s after injecting themselves with a synthetic heroin, biologically similar to paraquat, an herbicide, now proven to increase Parkinson’s disease risk. Today, Parkinson’s disease is believed to be the combined effects of toxicants, age, genetic makeup, and behaviors like diet and exercise.
Our 1989 study in China, when the country was rapidly developing, found that residents who lived in areas where they were exposed to toxicants like weedkillers, pesticides, and industrial solvents, had a higher rate of Parkinson’s than those in rural villages who grew wheat and raised pigs.
https://www.ucsf.edu/news/2026/08/432396/parkinsons-rates-are-surging-exposure-poisons-blame
Two Diabetes Pills, One Poisoned Brain: Metformin and Empagliflozin Team Up Against Parkinsonism in Rats
Egyptian researchers gave rats a mitochondrial poison called rotenone to produce a rapid, laboratory version of Parkinson’s disease, then asked whether two widely prescribed diabetes drugs could blunt the damage. Metformin and empagliflozin each helped on their own. Given together, starting a week before the poison and continuing throughout, the pair produced the largest recovery of movement, the fewest dying neurons in the substantia nigra, and the lowest accumulation of alpha-synuclein, the protein that clumps in Parkinson’s brains. The combination also restored signalling through PI3K/AKT, a survival pathway, and lifted expression of PPAR-gamma, a metabolic transcription factor. On the single measurement that most directly reflects dopamine nerve function, striatal dopamine content, the combination was not statistically better than metformin alone. This is a short, young-animal, prevention-design toxin study, and it does not test whether either drug helps an already damaged brain.
There is a persistent and slightly awkward observation in neurology: people with type 2 diabetes get Parkinson’s disease more often than people without it, and they tend to progress faster once they have it. Insulin resistance, chronic inflammation, oxidative stress and failing mitochondria show up in both conditions. That overlap raises an obvious question. If a drug fixes the metabolic problem, does it also protect the brain?
A team at Kafrelsheikh University in Egypt has just published one of the more direct attempts to answer that question for two specific drugs. Metformin has been the first-line diabetes medicine for decades and is already a favourite of the longevity field. Empagliflozin belongs to a newer class, the SGLT2 inhibitors, which make the kidneys dump glucose into the urine and which have turned out to protect the heart and kidneys in ways nobody predicted from their glucose effects.
The researchers used fifty male Wistar rats and rotenone, a pesticide that blocks complex I of the mitochondrial electron transport chain. Rotenone is the workhorse toxin for modelling Parkinson’s in rodents because it reliably kills dopamine neurons and triggers alpha-synuclein clumping, the two defining features of the human disease. Rats got either nothing, rotenone alone, or rotenone plus metformin, plus empagliflozin, or plus both. Crucially, drug treatment began a week before the poison, so this is a prevention experiment rather than a rescue experiment.
The rotenone did what rotenone does. Untreated poisoned rats travelled 1.4 metres in a five minute open field test, against 30.7 metres for healthy controls. They could hang from an inverted wire grid for 9 seconds instead of 156. Their substantia nigra showed roughly nineteen times more degenerating neurons than healthy tissue, and their striatal dopamine fell by 79 per cent.
Both drugs pulled the animals back from that. Metformin was consistently the stronger of the two, particularly for dopamine, where it restored 71 per cent of the lost content compared with empagliflozin’s 43 per cent. The combination did better still on almost everything: it recovered 59 per cent of the lost grip endurance where metformin alone recovered only 19 per cent, and it cut degenerating neuron counts by 86 per cent relative to poisoned animals.
The mechanistic story the authors tell is that the two drugs converge from different directions on the same protective machinery, metformin through AMPK and PI3K/AKT, empagliflozin through PPAR-gamma and antioxidant signalling. It is a reasonable story. It is also, in this paper, largely untested: the team measured PI3K and PPAR-gamma and nothing else along those chains, ran no blocking experiments, and took no mitochondrial measurements at all in a study built on a mitochondrial poison.
Actionable Insights
Nothing here should change what anyone takes tomorrow. The reasons are specific and worth understanding.
First, dose. The rat metformin dose converts to roughly 1,700 mg per day in a 70 kg human, squarely inside normal clinical use. The empagliflozin dose converts to about 113 mg per day, which is four to eleven times the maximum approved human dose of 10 to 25 mg. The empagliflozin arm of this study is not a test of the dose anyone actually takes.
Second, timing. Drugs were started seven days before the poison. Humans arrive at a Parkinson’s diagnosis having already lost 50 to 70 per cent of their dopamine neurons. A prevention result in rats says nothing about whether a drug helps after damage has occurred.
Third, magnitude. Effect size is just the gap between two groups measured in units of how much the animals naturally vary. A gap of 0.8 standard deviations is conventionally called large. The gaps here run from 3 to 37 standard deviations. Numbers that extreme are a signature of a toxin model that nearly ablates a system, not of a subtle intervention, and they do not translate to human dose-response.
The defensible takeaway is narrow: metformin outperformed empagliflozin on the most meaningful endpoint, and adding empagliflozin to metformin bought measurable extra benefit on motor and histological measures but not on dopamine itself.
Context and Source
- Full title: Neuroprotective effects of empagliflozin and metformin combined therapy on rotenone induced Parkinsonism in Wistar rats via PI3K and PPARγ modulation
- Institution: Kafrelsheikh University, Faculty of Medicine (Departments of Medical Biochemistry and Molecular Biology, and Medical Physiology) and Faculty of Pharmacy, Kafrelsheikh, Egypt
- Country: Egypt
- Journal: Scientific Reports (Nature Portfolio), 2026, volume 16, article 28103
- Impact evaluation: The impact score of this journal is 4.9 (2-year Journal Impact Factor, 2025 JCR data year, as listed by Nature Portfolio), evaluated against a typical high-end range of 0 to 60+ for top general science, therefore this is a Medium impact journal.