MAO-B inhibitor Rasagiline improves glucose metabolism in the brain (in Alzheimer’s patients)

[KennethKaniff]

Rasagiline is a MAO-B inhibitor currently used for Parkinson’s disease but appears to broadly cognition enhancing and neuroprotective. This may be mediated in whole or in part by metabolic effects. This study found improved glucose metabolism in the brain when administered to Alzheimer’s patients.

Background: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer's disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose-positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points.
Methods: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model.
Results: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P < 0.025), anterior cingulate (P < 0.041), and striatal (P < 0.023) regions. Clinical measures showed benefit in quality of life (P < 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group.
Discussion: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response.
Full text: Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia

 

[Highserotonin90]

I notice this with Eugenol

 

[golder]

Do we think we could extend this finding to its better known cousin Selegiline? I ask because I know these have slightly different MOA’s and Rasagiline doesn’t have the methamphetamine metabolite like selegiline.

 

[David PS]

I am interested in learning more about MAO inhibitors. The article lists a number of natural chemicals and for some the percent MAO inhibition (in red text).

Selective MAO-B inhibitors: a lesson from natural products

 

[KennethKaniff]

I am interested in learning more about MAO inhibitors. The article lists a number of natural chemicals and for some the percent MAO inhibition (in red text).

Selective MAO-B inhibitors: a lesson from natural products

Never knew caffeine acted as a MAO-B inhibitor. Fascinating, but makes sense

 

[KennethKaniff]

Do we think we could extend this finding to its better known cousin Selegiline? I ask because I know these have slightly different MOA’s and Rasagiline doesn’t have the methamphetamine metabolite like selegiline.

Most likely, but I would prefer rasagiline as it doesn’t have the toxic amphetamine metabolites.

 

[Mauritio]

Most likely, but I would prefer rasagiline as it doesn’t have the toxic amphetamine metabolites.

Selegiline only has that metabolite when taken orally, not when take sublingually .

And even when taken orally I'm not sure that it's enough to matter .

It might actually be beneficial since microdosing amphetamines paradoxically resensitizes dopamine receptors.

 

[KennethKaniff]

Selegiline only has that metabolite when taken orally, not when take sublingually .

And even when taken orally I'm not sure that it's enough to matter .

It might actually be beneficial since microdosing amphetamines paradoxically resensitizes dopamine receptors.

At least one study found that selegiline’s metabolites are counter-productive to its neuroprotective effects: Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline

Anecdotally, selegiline gives me a nervous & obsessive energy that rasagaline doesn’t. Selegiline does indeed feel like a small dose of amphetamine, for me.

 

[Mauritio]

At least one study found that selegiline’s metabolites are counter-productive to its neuroprotective effects: Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline

Anecdotally, selegiline gives me a nervous & obsessive energy that rasagaline doesn’t. Selegiline does indeed feel like a small dose of amphetamine, for me.

What's your dose and how do you take it ?

 

[dukesbobby777]

It's easy to get at ADC.

 

[KennethKaniff]

What's your dose and how do you take it ?

Rasagiline? I’ve been taking 1mg daily, oral route. Same as this study. Above 1mg daily and you might start inhibiting MAO-A which I don’t want.

 

[Mauritio]

Rasagiline? I’ve been taking 1mg daily, oral route. Same as this study. Above 1mg daily and you might start inhibiting MAO-A which I don’t want.

No I meant selegiline.

 

[KennethKaniff]

No I meant selegiline.

When I tried selegiline I took 5mg orally

 

[Mauritio]

When I tried selegiline I took 5mg orally

You couldve tried sublingual to avoid the amphetamine metabolites.
But even when you have the amphetamine metabolites through oral administration, they are not a concern as per this review:

"In clinical trials, selegiline was found to be well tolerated with similar side effect profile to that of placebo and no amphetamine-related adverse events were observed (Shoulson 1992; Palhagen et al. 1998; Shoulson et al. 2002; Palhagen et al. 2006; Mizuno et al. 2017). The weaker psychotropic effect and dependence liability of R-amphetamines compared to the S-enantiomers were shown in several preclinical studies supporting the findings of the clinical reports (Nickel et al. 1994; Yasar et al. 1993)."

Having a bad reaction to selegiline might also be due to it's sigma 1 one agonism. Some people don't react well to it.
Pregnenolone and DHEA are sigma 1 agonists as well and some people don't react well to them.

"Behavioral reactions to σ-agonists are rather heterogeneous: some individuals find σ-receptor agonists euphoric with significant anti-depressive effects. Other individuals, however, experience dysphoria and often report feelings of malaise or anxiety."
- Sigma receptor - Wikipedia

 

[golder]

Most likely, but I would prefer rasagiline as it doesn’t have the toxic amphetamine metabolites.

Same really. The small amphetamine metabolite only bothers me due to potential drug tests at work. I see more favourable anecdotal reports from selegiline rather than rasagiline though, although that could just be because it's less popular and well known. Subjectively, how do you think it compares to selegiline?

 

[KennethKaniff]

Same really. The small amphetamine metabolite only bothers me due to potential drug tests at work. I see more favourable anecdotal reports from selegiline rather than rasagiline though, although that could just be because it's less popular and well known. Subjectively, how do you think it compares to selegiline?

Selegiline is older, more well known and more well researched.
In my totally subjective experience, selegiline and rasagiline are both very mild, but selegiline seemed to caused more anxiety and obsessive thoughts for me. I bought both in one order and only tried selegiline a few times before deciding I liked rasagiline better. YMMV