adssx
#723
Targeting mitochondria-regulated ferroptosis: A new frontier in Parkinson’s Disease therapy 2025
Mitochondrial dysfunction is a key driver of ferroptosis in PD.
Altered mitochondrial function affects ETC, TCA, and mLIP to promote ferroptosis.
Ameliorating mitochondrial damage-induced ferroptosis holds a great promise for the therapeutic approach for PD
@John_Hemming
I intend writing up a post about melatonin and the levels required to protect neurons some time today.
I have started writing this up, but I think it will take a few days to bring together all the separate research.
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Not sure if this is relevant to Parkinson’s specifically:
Intermittent fasting and neurocognitive disorders: What the evidence shows
Conclusion: Current findings highlight the therapeutic potential of IF for individuals with existing cognitive impairment. While preclinical studies provide robust evidence of neuroprotective mechanisms, human studies remain sparse and require standardization. Further clinical research is necessary to confirm long-term safety and efficacy and to refine IF protocols for broader clinical application.
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adssx
#726
Previous studies have reported no significant differences in circadian phase, as measured by DLMO, between people with PD and healthy controls. However, amplitude of markers of circadian rhythms are blunted. Videnovic and colleagues highlighted significantly reduced melatonin amplitude and melatonin area under the curve throughout the day in people with PD, compared to controls, despite no differences in DLMO timing. Similarly, Bolitho and colleagues observed that circadian phase remained unchanged between PD and control groups.
Comparable findings were evident in relation to the circadian rhythm of core body temperature. While no phase variations have been presented, core body temperature appears to be disrupted in people with PD. Zhong and colleagues highlighted that PD patients have a reduced average core body temperature in conjunction with a blunted nadir, when compared to healthy controls. The reduction in the amplitude of core body temperature and melatonin rhythms, rather than a phase shift (such as delayed or advanced timing), indicates that PD-related circadian disruptions may manifest as weaker or dampened circadian signals rather than as complete phase shifts.
Like dementia and AD, it appears that people with PD experience disrupted rest-activity rhythms. However, the disruption has been specifically associated with disease severity. In early and moderate stages of PD, rest-activity rhythms are preserved, despite reduced overall activity levels compared to healthy controls. Whereas in advanced stages of PD, circadian variation diminishes and activity patterns become more fragmented. Furthermore, alteration in rest-activity rhythms appear to be influenced by common pharmacological treatments. These findings suggest that both disease progression and medication effects contribute to the disruption of rest-activity rhythms in PD.
Due to the growing evidence of an association between circadian rhythm disturbances and cognitive and functional decline, it has been suggested that circadian dysfunction could contribute to early pathogenesis and serve as a surrogate marker of neurodegenerative diseases. Interventions aimed at stabilising these rhythms could potentially mitigate the risk of AD, dementia and PD, and enhance cognitive health in older adults.
Caffeine increases the oral bioavailability of melatonin: Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity - PMC
Smoking seems to decrease melatonin levels.
And yet both caffeine and smoking are protective against PD. So this would argue against low melatonin being causal @John_Hemming ? (unless serum levels don’t matter and only the CSF matters and caffeine and smoking don’t impact it?)
adssx
#727
A bit more complex, per ChatGPT:
However, research findings on this topic have been mixed. Some studies have reported decreased blood melatonin levels in active smokers, suggesting that smoking may lead to lower circulating melatonin. Conversely, other studies have found higher daytime circulating melatonin levels in smokers compared to nonsmokers, indicating a complex relationship that may depend on various factors such as timing of measurement and individual differences.
The serum levels don’t really matter for PD. My hypothesis is that it is the higher CSF levels that are needed. These are really very high compared to serum levels.
Research on SLU-PP-332 and related ERR modulators continues to expand into new therapeutic areas:
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Neurodegeneration: Preliminary studies suggest potential applications in Alzheimer’s and Parkinson’s diseases through improved mitochondrial function
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adssx
#730
World-first trial indicates immunosuppression may help treat Parkinson’s
Participants on the treatment reported an overall improvement in movement-related symptoms. This meant they found it easier to perform tasks such as moving around, writing, washing and dressing. These improvements were greater in female participants compared to males.
Additionally, patients with faster-progressing Parkinson’s disease showed signs of improved memory and thinking skills.
Importantly, the trial did not reveal significant safety concerns around using immunosuppression treatments in Parkinson’s disease This will enable larger research studies of immune therapies for PD in the future.
During the trial, the effect of the drug on the immune system was measured in both the blood and brains of participants. It showed that, although Azathioprine cannot cross the blood-brain barrier, it acts indirectly to slow progression of inflammation in the brain, and this could explain its effects in Parkinson’s disease.
Very interesting @DrFraser @John_Hemming: positive effects of immunosuppression despite no BBB crossing!
This might explain the gender difference: Parkinson's disease - #629 by adssx
Details of the trial: ISRCTN
- 67 participants
- The treatment will be started at a low initial dose of 1 mg/kg.
- At four weeks, the dose of the trial drug will be increased, if appropriate according to the clinical profile (blood results and adverse events). Azathioprine will be increased to 2 mg/kg and the placebo dose will be doubled.
- “Their final visit will occur 6 months after the end of treatment. The MDS-UPDRS III will be performed in the OFF state, and videoed. Immediately following this the participant can take their PD medication. The remainder of the MDS-UPDRS will then be performed. Their medical and medication history will be reviewed. They will complete the Addenbrookes Cognitive Examination-III. They will go through the same questionnaires related to depression, quality of life, activities of daily living and non-motor symptoms. Finally, they will have a blood sample taken.”
So they saw improvements after a 6-month washout period?! That’s impressive!
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