Agmatine, again shown beneficial in some autism

 

Albrecht Kossel discovered Agmatine in 1910. That year he won the Nobel prize for medicine. The Albrecht Kossel Institute for Neuroregeneration, in Rostock Germany, is named after him.

 

For those people who keep an eye on the autism research, a recuring observation will have been how the same therapies keep on coming up, sometimes with a new twist. A good example that came up recently is Agmatine, a cheap supplement.

Agmatine is a naturally occurring compound in the body derived from the amino acid arginine, functioning as a neuromodulator and cellular regulator with benefits spanning neurological, cardiovascular, metabolic, and anti-inflammatory systems.

Monty, now aged 21 with autism, has been taking 750mg of Agmatine daily for eight years. In his case it reverses both mental and physical lethargy, like fitting a new set of alkaline batteries to an old toy.

Agmatine has many biological effects, the one that works in our case is its effect on nitric oxide (NO). Agmatine increase eNOS which improves vascular health, reduces blood pressure, enhances circulation. Agmatine can boost mitochondrial function, which also improves energy production and physical endurance.

Agmatine has many other effects, including:

1. Neurological Effects

Neuroprotection. Agmatine reduces oxidative stress and excitotoxicity by modulating glutamate and nitric oxide pathways.

Mood Enhancement. Agmatine acts as an antidepressant by interacting with serotonin and adrenergic receptors.

Cognitive Support. Agmatine may enhance memory and learning by promoting synaptic plasticity.

Pain Modulation. Agmatine offers analgesic effects by influencing opioid receptors and pain-related neurotransmission.

Seizure Protection. Agmatine demonstrates anticonvulsant properties in some animal studies.

 

2. Metabolic and Hormonal Effects

Insulin Sensitivity. Agmatine improves glucose uptake and reduces insulin resistance, aiding in blood sugar regulation.

Fat Metabolism. Agmatine may support weight management by modulating appetite and energy expenditure.

Stress Response: Agmatine regulates the hypothalamic-pituitary-adrenal (HPA) axis, improving the body’s response to stress.

 

3. Cardiovascular Effects

Blood Pressure Regulation. Agmatine enhances endothelial nitric oxide synthase (eNOS) activity, promoting vasodilation and lowering blood pressure.

Heart Protection. Agmatine may reduce the risk of atherosclerosis by improving endothelial function.

 

4. Anti-Inflammatory Effects

Cytokine Modulation. Agmatine reduces pro-inflammatory cytokines and markers like TNF-α and IL-6.

Oxidative Stress Reduction. Agmatine acts as an antioxidant, reducing damage from reactive oxygen species (ROS).

 

5. Musculoskeletal Effects

Bone Health: Agmatine supports bone remodeling by regulating osteoblast and osteoclast activity.

Muscle Recovery: Improves recovery after exercise by reducing inflammation and oxidative stress.

 

6. Gastrointestinal Effects

Gut Barrier Protection. Agmatine may enhance gut lining integrity and reduce inflammation.

Microbiota Interaction. Agmatine can indirectly influence gut microbiota through anti-inflammatory pathways.

 

7. Immune System Effects

Immunomodulation. Agmatine balances immune responses by reducing excessive inflammation.

Autoimmune Benefits. Agmatine shows potential in alleviating symptoms of autoimmune diseases by modulating iNOS activity.

 

Agmatine has been shown effective in various models of autism, including valproic acid-induced and Fragile X.

Agmatine signalling has been recently been shown to have a bidirectional interaction with the gut microbiome and its neuroprotective and anti-ageing functions have been suggested to depend on the resident microbes in that person’s gut. So it will not work for all.

Agmatine has even shown to have a benefit when given prenatally, to prevent autism.

The recent paper that I stumbled upon is this one below. There are two well-studied chemicals produced in the gut can induce autism, or just make existing autism worse. One is P-cresol and the other is propionic acid. Our reader Stephen is interested in ways to low P-cresol. A recent finding was that nutmeg lowers P-cresol and can indeed modulate colon cancer – no surprise to those who follow Chinese traditional medicine. Reducing propionic acid is the basis for the popular Nemechek Protocol for autism, which involves increasing fiber (inulin) in the gut, to favour butyric acid production over propionic acid. Butyric acid has many positive effects.

In the new paper the researchers looked at how propionic acid causes autism symptoms and they identified reduced agmatine as the problem.

Supplementing agmatine reversed the behavioral and biochemical alterations. Great!

We have already seen that the propionic acid induced model of autism can be reversed by NAC. Later in this post you will see that quercetin is also effective.

 

Postnatal propionic acid exposure disrupts hippocampal agmatine homeostasis leading to social deficits and cognitive impairment in autism spectrum disorder-like phenotype in rats

·        PPA reduced sociability and social preference and impaired learning and memory.

·        PPA treatment decreased agmatine and increase agmatinase in hippocampus.

·        PPA altered the glutamate, GABA, TNF-α, IL-6, BDNF levels and GFAP expression.

·        Agmatine reversed the behavioral and biochemical alterations induced by PPA.

·        Study suggests the role for hippocampal agmatinergic pathway in the etiopathogenesis of ASD.

 

I did then look up the research that has been published since I first investigated Agmatine as a potential autism therapy in humans and indeed started using it. There is a lot of research now existing.

 

Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism

 ·        Single treatment of agmatine rescues social impairment in the VPA-induced animal model of autism.

·        Effect of agmatine in social improvement in the VPA model is induced from agmatine itself, not its metabolite.

·        Agmatine rescues repetitive and hyperactive behavior, and seizure susceptibility in the VPA model.

·        Overly activated ERK1/2 in the brain of the VPA model is relieved by agmatine.

 

Autistic-like behaviors are attenuated by agmatine consumption during pregnancy: Assessment of oxidative stress profile and histopathological changes in the prefrontal cortex and CA1 region of the hippocampus

Conclusion:

Overall, this investigation suggests that agmatine may be a potential candidate for the early treatment and even prevention of appearance of autism symptoms.

  

Agmatine relieves behavioral impairments in Fragile X mice model 

·        Fragile X syndrome showed an exaggerated NMDA receptor signaling, problems in synaptic transmission, and abnormal behaviors.

·        Agmatine is an endogenous polyamine and functions as a synaptic neurotransmitter.

·        Agmatine reversed these problems in the model of fragile X syndrome mice.

 

 

The prenatal use of agmatine prevents social behavior deficits in VPA-exposed mice by activating the ERK/CREB/BDNF signaling pathway

Results

The results showed prenatal use of AGM relieved anxiety and hyperactivity behaviors as well as ameliorated sociability of VPA-exposed mice in the marble burying test, open-field test, and three-chamber social interaction test, and this protective effect might be attributed to the activation of the ERK/CREB/BDNF signaling pathway. 

Conclusion

Therefore, AGM can effectively reduce the likelihood of offspring developing autism to a certain extent when exposed to VPA during pregnancy, serving as a potential therapeutic drug.

  

The Prenatal Use of Agmatine Attenuates Social Behavior Deficits in VPA-Exposed Mice by Improving Neuron Loss

Results: Prenatal use of agmatine alleviated the anxiety behaviors of autistic mice in the marble burying test, open field test and three-chamber social interaction test. Prenatal use of agmatine blocked hippocampal neuronal damage and protected the maturity of neurons in autistic mice. 

Conclusions: The prenatal use of agmatine efficiently attenuated social interaction, learning and memory impairments in VPA-exposed mice by improving neuron loss. Agmatine is useful to block the occurrence of autism in offspring for the VPA-exposed pregnant women to an extent.

 

Neuroprotection by agmatine: Possible involvement of the gut microbiome?

·        Dysfunction of agmatinergic signalling is implicated in neuropathologies.

·        Agmatine is a multimodal neuroprotectant and a potential anti-ageing therapeutic.

·        Agmatinergic signalling elicits a bidirectional interaction with the gut microbiome.

·        Its neuroprotective and anti-ageing functions possibly depend on the resident microbes.

  

Effects of agmatine on radial-arm maze memory performance and autistic-like behaviors in a male rat model of autism

Conclusion

·        In a rat model of autism, spatial learning, and memory did not change. Agmatine rescued social and anxiety-like behavior in autistic animals.

 

Conclusion

I wrote extensively about Agmatine in my blog

https://www.epiphanyasd.com/search/label/Agmatine 

and in my book.

I have used 750mg a day for the last eight years. For me, no further research is needed!

Agmatine is sold as a cheap fitness supplement and is available in many countries, but not all.

You do wonder why more children with autism have not trialed it.

 

A few other interesting papers appeared recently, repeating what has been covered earlier in this blog. 

Oxytocin Improves Autistic Behaviors by Positively Shifting GABA Reversal Potential via NKCC1 in Early-Postnatal-Stage  

Overall, the results demonstrate that the early postnatal stage may be the unique critical period for oxytocin signaling to regulate GABA reversal potential and promote brain development for prosocial behaviors. These findings suggest an earlier intervention window and strategy for the clinical oxytocin treatment of autism.

 

This fits with idea of giving all new-born babies, delivered by C-section, a dose of oxytocin just after birth. These babies missed out on the mother’s surge in oxytocin during birth. The lack of oxytocin means that the GABA developmental switch may never takes place and neurons cannot mature. The result is autism and intellectual disability.

The body does have fall-back mechanisms that can trigger this switch, so not every baby delivered by C-section is autistic. But, humans have evolved to expect a dose of oxytocin at birth – let them have it.

I do like quercetin and it also popped up recently, again in respect to propionic acid induced autism.

 

Antioxidant-Effective Quercetin Through Modulation of Brain Interleukin-13 Mitigates Autistic-Like Behaviors in the Propionic Acid-Induced Autism Model in Rats

These findings, when interpreted together, suggest that quercetin exerts its neuroprotective effects by targeting oxidative stress and neuroinflammation, thereby preventing neuronal cell loss and alleviating behavioral deficits associated with autism spectrum disorders.

 

The final paper is about vagus nerve stimulation (VNS), which has also been extensively covered in this blog. VNS holds promise as a potential adjunctive therapy for autism, especially for symptoms related to autonomic dysregulation, anxiety, and epilepsy. The technology is getting fine-tuned.

 

Vagus Nerve Stimulation Erases PTSD

Prior research shows many PTSD patients fail to respond to standard treatments, making this approach especially promising. Future trials will explore the therapy further, aiming to offer new hope for those resistant to conventional methods.

Key Facts:

·         100% Remission: All participants were free from PTSD diagnosis six months after therapy paired with VNS.

·         Neuroplasticity Boost: VNS enhances brain rewiring, improving outcomes for therapy-resistant PTSD patients.

·         Next Steps: A double-blind Phase 2 trial is underway to confirm findings and move toward FDA approval.