smbleh
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Introduction
Everyone uses GLP-1s like semaglutide to suppress their appetite however did you know they actually have some potent neuroprotective pathways and emerging data.
First it is important to understand not all GLP-1 agonist do this to the same degree , Exenatide and Lixisenatide cross the blood brain barrier (BBB) best so these will be more potent than something like semaglutide which has limited BBB permeability as they shorter-acting, smaller peptide molecules that are not bounded to blood proteins.
Semaglutide is highly modified with a massive C18 fatty-acid chain designed specifically to keep it in the bloodstream for a week however this means it cannot cross the BBB easily
Everyone uses GLP-1s like semaglutide to suppress their appetite however did you know they actually have some potent neuroprotective pathways and emerging data.
First it is important to understand not all GLP-1 agonist do this to the same degree , Exenatide and Lixisenatide cross the blood brain barrier (BBB) best so these will be more potent than something like semaglutide which has limited BBB permeability as they shorter-acting, smaller peptide molecules that are not bounded to blood proteins.
Semaglutide is highly modified with a massive C18 fatty-acid chain designed specifically to keep it in the bloodstream for a week however this means it cannot cross the BBB easily
Tirzepatide
Tirzepatide also suffers from this similar limitation however it does cross the BBB , though very slowly over the course of about 6 hours , but as we know it also hits GIP While GLP-1 receptors are mostly restricted to the brainstem and hunger centers, GIP receptors are densely populated across the cortex and hippocampus (the memory and thinking centers of the brain)
Because GIP receptors are everywhere in higher brain regions, the tiny amount of tirzepatide that does trickle past the BBB over a 6 hour window finds a massive network of receptors waiting for it. It takes very little tirzepatide inside the brain to trigger a huge neuroprotective response
If you want to reap all benefits like potent appetite suppression , insulin sensitivity and neurological effects , this is the most practical option as well as being easily sourceable and having robust data and so is what I will focus on for this post.
Tirzepatide also suffers from this similar limitation however it does cross the BBB , though very slowly over the course of about 6 hours , but as we know it also hits GIP While GLP-1 receptors are mostly restricted to the brainstem and hunger centers, GIP receptors are densely populated across the cortex and hippocampus (the memory and thinking centers of the brain)
Because GIP receptors are everywhere in higher brain regions, the tiny amount of tirzepatide that does trickle past the BBB over a 6 hour window finds a massive network of receptors waiting for it. It takes very little tirzepatide inside the brain to trigger a huge neuroprotective response
If you want to reap all benefits like potent appetite suppression , insulin sensitivity and neurological effects , this is the most practical option as well as being easily sourceable and having robust data and so is what I will focus on for this post.
GLP-1s neuroprotective pathways
To dumb long blocks of text throughout the video I’ve generated images simplifying the pathway but feel free to read the full extract if you’d like.
Myelin is extremely important because it acts like insulation around the wiring of your nervous system and makes makes nerve signalling dramatically faster and more energy-efficient
Autophagy is basically the cell's recycling , Damaged proteins and damaged cell components get collected, broken down and recycled.
GLP-1R activation with exendin-4 increases autophagy and decreases apoptosis (cell death) , this helps injured neurons survive and potentially regenerate their axons , which is the nerve fiber that transmits outgoing signals.
BDNF is a key protein needed neuron survival , growth and repair and even beyond the CNS plays a large role across the entire body.
GLP-1 increases BDNF by by triggering the cAMP-PKA-CREB signaling pathway inside neurons that were displayed in the previous slide
But there is then a much larger network to what BDNF actually does for the brain , BDNF then increases TrkB which activates several intracellular pathways.
Calcium is extremely important for
However excessive calcium is also bad as it leads to ROS which cause neuronal death via excitotoxicity , so they are more so neuroprotective via maintaining intracellular calcium rather than just increasing it.
When the brain becomes insulin resistant downstream insulin signalling through the IRS-1 → PI3K → AKT pathway can become impaired.
This reduces AKT mediated inhibition of GSK3β , meaning GSK3β activity increases , this can contribute to synaptic dysfunction, abnormal tau phosphorylation, cognitive impairment and neuronal vulnerability.
Activation of AKT through GLP-1 receptor agonism may partially restore this impaired signalling and help protect neuronal function.
To dumb long blocks of text throughout the video I’ve generated images simplifying the pathway but feel free to read the full extract if you’d like.
GLP-1 also increase myelination and decrease demyelination , what this means is basically it builds and protects myelin from inflammation
Myelin is extremely important because it acts like insulation around the wiring of your nervous system and makes makes nerve signalling dramatically faster and more energy-efficient
Autophagy + axon regeneration
Autophagy is basically the cell's recycling , Damaged proteins and damaged cell components get collected, broken down and recycled.
GLP-1R activation with exendin-4 increases autophagy and decreases apoptosis (cell death) , this helps injured neurons survive and potentially regenerate their axons , which is the nerve fiber that transmits outgoing signals.
Lastly GLP-1 activates cAMP and PI3K which activate survival mechanisms such as CREB , with results in less ROS , apoptosis and more neuron survival.
On top of protecting neurones GLP-1Ra can also lead to neurite growth via BDNF
BDNF is a key protein needed neuron survival , growth and repair and even beyond the CNS plays a large role across the entire body.
GLP-1 increases BDNF by by triggering the cAMP-PKA-CREB signaling pathway inside neurons that were displayed in the previous slide
But there is then a much larger network to what BDNF actually does for the brain , BDNF then increases TrkB which activates several intracellular pathways.
Intracellular calcium is increased
Calcium is extremely important for
- neurotransmitter release
- synaptic plasticity
- gene transcription
- learning and memory
However excessive calcium is also bad as it leads to ROS which cause neuronal death via excitotoxicity , so they are more so neuroprotective via maintaining intracellular calcium rather than just increasing it.
Insulin in the brain
When the brain becomes insulin resistant downstream insulin signalling through the IRS-1 → PI3K → AKT pathway can become impaired.
This reduces AKT mediated inhibition of GSK3β , meaning GSK3β activity increases , this can contribute to synaptic dysfunction, abnormal tau phosphorylation, cognitive impairment and neuronal vulnerability.
Activation of AKT through GLP-1 receptor agonism may partially restore this impaired signalling and help protect neuronal function.
The effect of GIP
GIP enhances neuronal growth, reducing cortical amyloid plaque deposition, and suppressing chronic neuroinflammation.
It works through a similar range of mechanisms as GLP-1 does but as mentioned previously unlike GLP-1, GIP synthesis is more extensively distributed across the CNS, including the hippocampus, thalamus, cerebral cortex, and brainstem and it functions as a neurotransmitter in neurons.
GIP also largely works via cAMP , AKT and MAPK
GIPR signaling reduces Aβ deposition, suppresses gliocyte activation, and downregulates pro-inflammatory mediators such as TNF-α, IL-1, and nitric oxide synthase. These effects collectively improve synaptic plasticity and cognitive function.
Additionally GLP-1 can potentiate the effect of GIP, and vice versa , making tirz an even better option.
GIP works largely through the same mechanisms that GLP-1 does so I won’t spend much time going over these mechanisms again.
GIP enhances neuronal growth, reducing cortical amyloid plaque deposition, and suppressing chronic neuroinflammation.
It works through a similar range of mechanisms as GLP-1 does but as mentioned previously unlike GLP-1, GIP synthesis is more extensively distributed across the CNS, including the hippocampus, thalamus, cerebral cortex, and brainstem and it functions as a neurotransmitter in neurons.
GIP also largely works via cAMP , AKT and MAPK
GIPR signaling reduces Aβ deposition, suppresses gliocyte activation, and downregulates pro-inflammatory mediators such as TNF-α, IL-1, and nitric oxide synthase. These effects collectively improve synaptic plasticity and cognitive function.
Additionally GLP-1 can potentiate the effect of GIP, and vice versa , making tirz an even better option.
GIP works largely through the same mechanisms that GLP-1 does so I won’t spend much time going over these mechanisms again.
So full the branch of what Tirz would be doing would look something like this which also includes some mechanisms that didn't fit into this single post such as increased NRF2
Outcome Data
Now all this looks like a huge handful of beneficial mechanisms , which it is but what is the actual outcome data like , though unfortunately this is quite limited at the moment but emerging and being investigated actively
In this mice study Tirz not only significantly improved neurological scores but actually was able to repair damage to the BBB after a stroke via modulating Claudin-1 and C/EBP-α pathways
In a mouse middle-cerebral-artery-occlusion model, untreated stroke animals had an infarct volume of 38.5 ± 4.2%
Meanwhile tirzepatide treated animals had 18.7 ± 3.1%
That's approximately a 51% relative reduction in infarct volume
Neurological deficit scores also fell from approximately 3.5 → 1.6 after treatment
And the study wasn't just measuring pAKT , it measured an actual structural brain injury endpoint plus neurological function
Though this is mice data again human data is limited as of now the human data I have found was all observational rather than RCT so I’d rather not include it.
The diabetic rat cognition study
The rats had high-fat diet + streptozotocin which lead to diabetes and so cognitive impairment
They were given tirz at 1.35 mg/kg once weekly for 10 weeks
Human equivalent dose of 0.110mg/kgbw so for a 70kg individual this would be about 7.7mg tirz which is within the studied therapeutic range
Cognitive performance was assessed using the Morris water maze.
By the final training day, diabetic rats were taking roughly 50 seconds to locate the platform, whereas tirzepatide treated diabetic rats were around 20 seconds, approximately back near the control groups.
So they essentially went from severe diabetic cognitive impairment to performance approaching normal controls.
Now all this looks like a huge handful of beneficial mechanisms , which it is but what is the actual outcome data like , though unfortunately this is quite limited at the moment but emerging and being investigated actively
In this mice study Tirz not only significantly improved neurological scores but actually was able to repair damage to the BBB after a stroke via modulating Claudin-1 and C/EBP-α pathways
In a mouse middle-cerebral-artery-occlusion model, untreated stroke animals had an infarct volume of 38.5 ± 4.2%
Meanwhile tirzepatide treated animals had 18.7 ± 3.1%
That's approximately a 51% relative reduction in infarct volume
Neurological deficit scores also fell from approximately 3.5 → 1.6 after treatment
And the study wasn't just measuring pAKT , it measured an actual structural brain injury endpoint plus neurological function
Though this is mice data again human data is limited as of now the human data I have found was all observational rather than RCT so I’d rather not include it.
The diabetic rat cognition study
The rats had high-fat diet + streptozotocin which lead to diabetes and so cognitive impairment
They were given tirz at 1.35 mg/kg once weekly for 10 weeks
Human equivalent dose of 0.110mg/kgbw so for a 70kg individual this would be about 7.7mg tirz which is within the studied therapeutic range
Cognitive performance was assessed using the Morris water maze.
By the final training day, diabetic rats were taking roughly 50 seconds to locate the platform, whereas tirzepatide treated diabetic rats were around 20 seconds, approximately back near the control groups.
So they essentially went from severe diabetic cognitive impairment to performance approaching normal controls.
Retatrutide
As for retatrutide there is not really enough data to conclude how it would perform compared to tirz but it would obviously also exert a similar effect to tirz but there are some older animal studies showing glucagon can be neuroprotective via reducing circulating and CSF glutamate.
As for retatrutide there is not really enough data to conclude how it would perform compared to tirz but it would obviously also exert a similar effect to tirz but there are some older animal studies showing glucagon can be neuroprotective via reducing circulating and CSF glutamate.
