Click on figure to enlarge
Source of text quoted: E-I Balance and Human Diseases – from Molecules to Networking
Interpretation, extrapolation and graphic - Peter
Today’s post is not the one I intended.
It nearly got tucked into long complicated one, that most people might not read.
I should caution that I am perhaps over-simplifying something that is extremely complicated, but no one fully understands the subject.
There is much talk in autism about the imbalance between excitatory and inhibitory processes. In this blog this is normally all about the inhibitory neurotransmitter, GABA, not functioning properly.
There is of course another side to the story. The excitatory neurotransmitter Glutamate signals via receptors including the NMDA receptors. If signaling via these receptors is either up or downregulated, the delicate balance between excitatory and inhibitory can again be lost.
What caught my interest was an experiment on mice that caused downregulation of (excitatory) NMDA signaling. This caused the famous E/I imbalance and resulting autistic behavior.
The interesting part is that the researchers normalized the imbalance and the autism not by targeting NMDA but by targeting GABA. They used baclofen that acts on GABAB receptors. So they made the mouse autistic by adjusting NMDA (Glutamate) signaling, but recovered the mouse by adjusting the GABA signaling. This is really quite compelling and made me look into the E/I imbalance again.
It also neatly explains why anti-epileptics, like valproate, when given during pregnancy can result in autistic off spring. The Valproate increases GABA signaling, i.e. it inhibits neurons from firing too easily. This reduced the tendency towards seizures. It will unfortunately also enter the blood stream of the unborn child. Here again it will shift the E/I balance towards inhibitory, but unlike in the mother, the E/I balance in the child was perfectly fine. The valproate shifts the E/I balance out of the “safe zone” into the inhibitory danger zone. This then can affects critical processes in the developing brain leading to autism.
NMDA hyper/hypo function
In earlier posts we have already seen that in autism NMDA activity be hyper (too much), hypo (too little) or normal. There are drugs that can increase NMDA activity and others that reduce it.
In this post the research shows that reduced NMDAR signaling has been associated with schizophrenia, (some) autism and intellectual disability.
A person with autism might be in this group, but as we saw in earlier posts on NMDA they might be in the opposite group and so have excessive NMDAR signaling. A bit of trial and error would reveal whether the person was hyper, hypo or just right. All three are possible in autism.
GABA/Glutamate imbalance in Autism
The neurotransmitter GABA is supposed to be inhibitory and it is kept in balance by the excitatory neurotransmitter Glutamate. Glutamate binds to NMDA receptors and AMPA receptors. GABA binds to GABAA and GABAB receptors.
In 2003 John Rubenstein and Michael Merzenich published a paper suggesting that autism might be the result of an E/I imbalance that disrupted both the development of the brain at critical periods and also was the underlying cause of some on-going autistic symptoms, including epilepsy (found in 30% of “old” autism) and what I refer to as pre-epilepsy (odd epileptiform activity without seizures – another 40% of “old” autism). Plenty of subsequent research has supported their hypothesis.
Once well-established theory for the development of autism is that the balance of various neurotransmitters is out of balance. GABA, the key inhibitory neurotransmitter in the brain, ceases to inhibit the firing of neurons as it should. The result is chaos in the brain.
In this blog we have concentrated one cause of this so called E/I (excitatory/Inhibitory) imbalance. That cause is the presence of the NKCC1 transporter in the brain beyond the first few weeks of life. This transporter leads to an excess of chloride inside the cells and this shifts GABA away from inhibitory to excitatory. This then results in a GABA/Glutamate imbalance. This impairs cognitive function and logically may be a cause of some seizures.
As Rubenstein and Merzenich observed, the hypothesis of E/I imbalance gives hope that drugs correcting this balance may treat autism. This has already been proved to be the case.
But there are other possible causes of E/I imbalance. Today’s post is about one of those. People who respond to the prescription drug Baclofen and the experimental drug Arbaclofen most likely are affected by this kind of E/I imbalance.
This blog has extensively covered the GABAA-related cause of E/I imbalance, for which the prescription drug Bumetanide is effective.
Baclofen affects the GABAB receptor. One reader of this blog did tell us that in her patients with Asperger’s and anxiety did respond well to Baclofen. They quite possibly have an E/I imbalance of the type covered in this post. If so the underlying cause may well be NMDAR-hypofunction.
Reduced NMDAR signaling has been associated with schizophrenia, autism and intellectual disability. By definition people with Asperger’s do not have and intellectual disability, but the Reduced NMDAR signaling may still be holding back their ever higher potential cognitive function.
As we will see, there may be a simple way to treat the NMDAR-hypofunction.
We have already covered this in an earlier post, when I talked about sodium benzoate and schizophrenia.
Sodium benzoate has multiple effects.
Sodium benzoate is a D-amino acid oxidase inhibitor. It will raise the levels of D-amino acids by blocking their metabolism and in doing so enhance NMDA function. In doing so the E/I balance is shifted towards excitatory.
Sodium benzoate also increases the expression of a protein called DJ-1. This is well known gene/protein because of its role in Parkinson’s disease. The DJ-1 protein plays a supporting role to a key anti-oxidative stress defense called Nrf-1.
At times of oxidative stress, the body activated Nrf-1 which in then turns on key genes that need to respond to the stress. In the absence of enough DJ-1, Nrf-1 is unable to sound the alarm and turn on those genes.
Sodium Benzoate is a common food additive (people with histamine intolerance “should be” allergic to it) but it is also a byproduct of eating cinnamon. This is why cinnamon was shown to have therapeutic value in Parkinson’s disease. Rather surprising it has also been shown to be beneficial in early Alzheimer’s disease.
In the earlier post we also saw that cinnamon had other useful effects like lowing cholesterol and improving insulin sensitivity.
We saw in the earlier post that it is important to use the “purer” cinnamon that come from Sri Lanka, since the related species from China that is commonly used by bakers does actually have side effects in large doses.
The Sri Lankan cinnamon may cost a bit more, but a one year supply is only about $15.
Abstract
Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30–80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory–inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1neo−/− mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABAB-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.
IMPORTANCE In addition to dopaminergic hyperactivity, hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel treatment approach. To date, several trials on adjuvant NMDA-enhancing agents have revealed beneficial, but limited, efficacy for positive and negative symptoms and cognition.
Another method to enhance NMDA function is to raise the levels of D-amino acids by blocking their metabolism. Sodium benzoate is a D-amino acid oxidase inhibitor.
OBJECTIVE To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia.
DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer.
INTERVENTIONS Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo.
MAIN OUTCOMES AND MEASURES The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment.
RESULTS Benzoate produced a 21% improvement in PANSS total score and large effect sizes
(range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms–20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health’s Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects.
CONCLUSIONS AND RELEVANCE Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia.
Abstract
This study underlines the importance of cinnamon, a widely-used food spice and flavoring material, and its metabolite sodium benzoate (NaB), a widely-used food preservative and a FDA-approved drug against urea cycle disorders in humans, in increasing the levels of neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] in the CNS. NaB, but not sodium formate (NaFO), dose-dependently induced the expression of BDNF and NT-3 in primary human neurons and astrocytes. Interestingly, oral administration of ground cinnamon increased the level of NaB in serum and brain and upregulated the levels of these neurotrophic factors in vivo in mouse CNS. Accordingly, oral feeding of NaB, but not NaFO, also increased the level of these neurotrophic factors in vivo in the CNS of mice. NaB induced the activation of protein kinase A (PKA), but not protein kinase C (PKC), and H-89, an inhibitor of PKA, abrogated NaB-induced increase in neurotrophic factors. Furthermore, activation of cAMP response element binding (CREB) protein, but not NF-κB, by NaB, abrogation of NaB-induced expression of neurotrophic factors by siRNA knockdown of CREB and the recruitment of CREB and CREB-binding protein to the BDNF promoter by NaB suggest that NaB exerts its neurotrophic effect through the activation of CREB. Accordingly, cinnamon feeding also increased the activity of PKA and the level of phospho-CREB in vivo in the CNS. These results highlight a novel neutrophic property of cinnamon and its metabolite NaB via PKA – CREB pathway, which may be of benefit for various neurodegenerative disorders.
There are several advantages of NaB and cinnamon over other proposed anti-neurodegenerative therapies. First, both NaB and cinnamon are fairly nontoxic. Cinnamon has been widely used as flavoring material and spice throughout the world for centuries. Cinnamon is metabolized to NaB. NaB is excreted through the urine, if in excess.
Second, cinnamon and NaB can be taken orally, the least painful route.
Third, cinnamon and NaB are very economical compared to other existing anti-neurodegenerative therapies.
Fourth, after oral administration, NaB rapidly diffuses through the BBB. Similarly, after oral administration of cinnamon, we also detected NaB in the brain
Fifth, glycine toxicity is a problem in different neurological diseases because for movement disorders, glycine is one of the factors for inhibiting motor neurons. When impaired, glycinergic inhibition leads to spastic and hypertonic disorders such as featured in PD, multiple sclerosis (MS) and spinal cord trauma. NaB is known to combine with glycine to produce hippurate, a compound that is readily excreted in the urine. Because PD and MS patients exhibit significant elevation in plasma level of glycine, NaB and cinnamon may have added benefits for MS and PD.
Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial.
Abstract
BACKGROUND:
N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD.
METHODS:
We conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250-750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint.
RESULTS:
Sodium benzoate produced a better improvement than placebo in Alzheimer's Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects.
CONCLUSIONS:
Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes.
The implications
There are numerous implications, since cinnamon is very cheap and Sri Lanka Cinnamon is seen as very safe.
· Take cinnamon to lower the risk of Parkinson’s and Alzheimer’s
· Take cinnamon if you have got Parkinson’s or Alzheimer’s
· Take cinnamon if you are type 1 or 2 diabetic to improve insulin sensitivity
· Take cinnamon if you have high cholesterol (perhaps you do not like Statins)
· Rather unexpectedly, it is suggested that cinnamon should also help multiple sclerosis (MS) because it reduces glycine toxicity which otherwise leads to spastic and hypertonic disorders
· Trial cinnamon if you have Asperger’s, Schizophrenia, Autism, MR/ID and even COPD
· Trial cinnamon if (ar)baclofen positively affects your cognitive or emotional function.
Note that some people diagnosed with “autism” have the opposite NMDA dysfunction, they have too much signaling rather than too little.
One method to enhance NMDA function is to raise the levels of D-amino acids by blocking their metabolism. Sodium benzoate is a D-amino acid oxidase inhibitor. Cinnamon is metabolized in the body to sodium benzoate.
Giving cinnamon to someone with hyperfunction of NMDA, should make their symptoms worse.
Sodium Benzoate/Cinnamon also increases the level of BDNF
It is thought that BDNF increases excitatory synaptic signaling partly
“BDNF increases spontaneous network activity by suppressing GABAergic inhibition, the site of action of BDNF is predominantly postsynaptic, BDNF-induced suppression of GABAergic synaptic transmission is caused by acute downregulation of GABAA receptors, and BDNF effects are mediated by its TrkB receptor and require PKC activation in the postsynaptic cell.”
BDNF is commonly elevated in autism.
So you would then expect that some people with autism/schizophrenia would benefit while others would not.
Since some people are allergic to sodium benzoate it would wise to start with a tiny amount of cinnamon.
Cinnamon has been used medicinally for centuries.
Cassia cinnamon from China, Vietnam or Indonesia contains coumarin. Courmarin is not good for you. Cassia cinnamon is what is normally used in food products, to save money.
In an earlier post:
we saw that Clioquinol and D-Cycloserine should help those with those with reduced NMDAR function.
Those with elevated NMDAR function would benefit from Memantine and Ketamine.
So logically Clioquinol and D-Cycloserine should help schizophrenia:-
Nobody seems to have tried Clioquinol on schizophrenia.
Baclofen for Schizophrenia
It is would also be logical that if some people with schizophrenia do have reduced NMDAR signaling then Baclofen should also help them, just as Sodium Benzoate has been shown to do and therefore cinnamon should.
Going back to 1977 Baclofen was indeed found to be effective in some types of schizophrenia
Conclusion
I think that Cinnamon is a better bet than Sodium Benzoate, because you actually may have other substances involved, not just NaB.
The dose at which cinnamon shows tangible biological effects in humans (lowing cholesterol etc.) is around 3g a day. For those who can swallow capsules, that would be 3 large (size 000) gelatin capsules a day, otherwise you have to find a way of eating a teaspoonful of cinnamon a day.
According to the research “cinnamon has been widely used as flavoring material and spice throughout the world for centuries. Cinnamon is metabolized to NaB. NaB is excreted through the urine, if in excess.” So it looks a safe therapy, whether it helps autism will depend on the specific biology of that individual.
