Friday, 31 March 2017

The Glutamate Side of Things

Some readers have suggested that since we have discovered so many ways to treat the GABAA dysfunctions common in autism, it is time to look at the glutamate side of things. Glutamate is the main excitatory neurotransmitter and has to be in balance with the opposing influence of GABA.

The chart below is really a summary of what has already been covered in this blog.  To newcomers it will look complicated, to regular readers it is just bringing together everything we have already covered, even those tauopathies appear. Tau protein tangles appear in Alzheimer’s and some autism.
Glutamate excitoxicity is what happens when things go really wrong, for example in a severe autistic regression.  I doubt you could be in a permanent state like this.

I am beginning to wonder is my son’s summer time raging, though triggered by allergy, develops to a so-called glutamatergic storm.  It fades to nothing  by using a Cav1.2 channel blocker, which does indeed stop those allergy mast cells de-granulating, but it stops the calcium influx in the above chart.  Existing dysfunction in Cav1.2 and Cav1.4 puts you at risk of excitotoxicity.
The oxidative damage to mitochondria causes lipid peroxidation and in particular the 4-HNE produced will cause tau protein, from a recent post and Alzheimer’s, to produce tau tangles, a damaging feature of so-called tauopathies.
The nitrosative stress in particular damages the production of the Complex 1 enzyme leading to mitochondrial disease/dysfunction. The damaging peroxynitrates can be quenched using high doses of calcium folinate. Oxidative stress and the reduced level of GSH can be treated with antioxidants like NAC and ALA.  

Reduced reuptake of glutamate, known to be caused by elevated TNF-α and immune dysfunction, is treatable via upregulating the GLT-1 transporter (beta-lactam antibiotics, riluzole and bromocriptine).
Elevated BDNF is a biomarker of autism and unfortunately this increases the chances of glutamate excitotoxicity.
An inactivated GABA switch that leaves neurons immature, will result in GABA acting excitatory rather than inhibitory, this itself can trigger of glutamate excitotoxicity. Use bumetanide.
Some types of autism feature NMDA hyper-function, this is treatable.  A deviation of NMDA function in either direction (hypo or hyper) leads to autism, but you need to know which way it is, to treat it.

It is also possible to have over/under expression of NMDA receptors.

Wednesday, 29 March 2017

eIF4E inhibitors for Autism – Why not Ribavirin?

Some people find this blog too complicated and would prefer it to be simplified; it would be great if all the science could be accurately described in very simple terms.

This blog has ended up going into far more detail than I had ever intended, because if you want to get to the bottom of a problem you have to keep digging until you get to what is relevant.  The relevant part is not near the surface, as you will see in today’s post, but many potential therapeutic options are sitting there in plain view, obscured only by the scientific jargon.

eIF4E, ADNP, Alzheimer’s, Tauopathy and Autism

In today’s post I am drawing together material from autism, Alzheimer’s and other so-called tauopathies.  The post ends up with the suggestion that an existing antiviral drug called Ribavirin, which affects a very specific part of mTOR signaling, could be a useful autism therapy and should be the subject of a serious clinical trial.

Tauopathies sound interesting.  Tau protein is present in the brains of all humans, but it can dysfunction (hyperphosphorylation) and form tangles. When tau behaves like this it leads to so-called tauopathies, like Alzheimer’s.  Tangles form inside dying cells; they are twisted fibers of a protein tau. In areas where tangles are forming, the twisted strands of tau block nutrients from moving through the cells, causing cell death.

Most people develop some amyloid plaques and tau tangles as they get older, but people with Alzheimer’s tend to develop far more. Plaques and tangles tend to form in a pattern, starting in areas related to learning and memory and then spreading to other regions of the brain.

The question is to what extent are infantile tauopathies present in autism?  Particularly autism with MR/ID?

Tuberous Sclerosis (TSC) is a widely used research model of autism. TSC is a genetic disorder that is usually caused by the TSC2 gene, but can be caused by TSC1. TSC1 and TSC2 are growth supressors and dysfunction leads to the growth of benign tumors.  TSC is associated with seizures, autism, MR/ID and other issues.   TSC is a tauopathy.

It is unkown to what extent tauopathy may be present in autism, or those with mental retardation/intellectual disability. This question was also posed in the blog written by Dr Emily Casanova, wife of the neurologist/blogger Dr Manuel Casanova; the latter normally seems to get the most media attention.

A very expensive drug called Everolimus, is being used to treat TSC. Everolimus is a potent mTOR inhibitor. mTOR is part of a key constellation of signaling pathways implicated in cancer and autism. mTOR is extremely complex and even highly intelligent people will need quite some time to figure it out.  

Eukaryotic translation initiation factor 4E (eIF4E) 

Eukaryotic translation initiation factor 4E (eIF4E), is a protein that in humans is encoded by the EIF4E gene. 

 eIF4E seems to play a critical role in the mTOR pathway to trigger the excitatory/inhibitory imbalance in autism.

There are multiple pathways involved in this process and we previously looked at RORa.

The Purkinje-RORa-Estradiol-Neuroligin-KCC2 axis in Autism
We have already seen that in most autism the mTOR pathway is over active.  The problem is that this pathway is highly complex and affects very many aspects of your body.  You would ideally intervene in a highly selective manner.

eIF4E is just one small part of the mTOR pathway and it appears that by selectively inhibiting it, good things should happen.

In the chart below we would inhibit eIF4E (green box) and then expect a reduction in neuroligins (NLGNS), leading to more inhibition on neurons, resulting in better cognition and milder autism.

Over expression of eIF4E in mice leads to autistic behaviors.

Inhibition of eIF4E works in a mouse model of autism.

Inhibitors of eIF4E exist today.


Activity-dependent neuroprotective protein (ADNP) is the most frequent autism associated gene and the only protein significantly decrease in the serum of Alzheimer's disease patients.

Israeli researchers investigating Alzheimer’s and otherTauopathies identified binding sites on ADNP for eIF4E.

ADNP expression is suggested as a master regulator of key ASD and AD risk genes.

It is also suggested, based on mouse research, that ADNP expression may contribute to the male/female variations in autism and Alzheimer’s (women are more affected by Alzheimer’s, but less by autism).  Increased male ADNP expression was replicated in human postmortem hippocampal samples.

Choice of of eIF4E Inhibitor

Thanks to all the cancer research there is detailed knowledge of eIF4E inhibitors.

As usual a key issue is bioavailability.

I thought ribavirin looks very interesting and I am not the only one (see later studies).  It is an old generic anti-viral medication, often used to treat hepatitis C. An expensive version is being developed as a cancer therapy.


All the evidence points towards eIF4E Inhibitors, but as the professionals would tell us, more research and validation is required. A clinical trial of Ribavirin would seem in order. 

There may be different types of E/I imbalance in autism and different therapies are likely to suit different people. 

The supporting science :-

Researchers at McGill University have mouse data showing a causal link between eIF4E-mediated translational dysregulation and autism-related deficits. The group also corrected the dysregulation—and the associated autistic phenotype—with a small molecule.1

The McGill group, led by Nahum Sonenberg, has been studying the role of eukaryotic translation initiation factor 4E (eIF4E) in protein synthesis for over three decades and has primarily focused on the factor's relevance in cancer. eIF4E binds to the cap structure on mRNA and helps to initiate the translation of the mRNA. Sonenberg is a professor in the Department of Biochemistry and at the Rosalind and Morris Goodman Cancer Research Centre at McGill.

The team previously reported that eIF4E-mediated protein translation is modulated by the phosphoinositide 3-kinase (PI3K), protein kinase B (PKB; PKBA; AKT; AKT1) and mammalian target of rapamycin (mTOR; FRAP; RAFT1) pathway, which is commonly disrupted in cancer.2

He said the initial connection to autism came after other research groups showed that autistic children carry mutations in genes upstream of mTOR. These genes included PTEN (MMAC1; TEP1) and tuberous sclerosis complex tumor suppressor 1 (TSC1).3, 4, 5

Separately, a 2009 study from a research group in the U.K. showed an association between mutations that increased eIF4E promoter activity and autism.6

With multiple studies pointing to eIF4E-dependent processes in autism, the McGill group sought to determine whether dysregulation of eIF4E activity itself could cause an autistic phenotype. Indeed, past studies suggested that dysregulated translation of mRNA could be an underlying cause of autism7 but never showed a causal relationship.

In a new study published in Nature, the McGill researchers showed that increasing eif4e activity in mice—by knocking out the gene encoding an eif4e repressor called eif4e binding protein 2 (eif4ebp2)—led to autism-associated electrophysiological abnormalities and behaviors.

In these mice, as well as mice that overexpressed eif4e, translation of neuroligin proteins was greater than that seen in wild-type controls. Alterations in neuroligin signaling occur in autism.8, 9

In the mouse models, a small molecule inhibitor of eIF4E signaling called 4EGI-1 reversed the electrophysiological abnormalities and decreased autistic behaviors compared with vehicle. Knockdown of neuroligin 1 (Nlgn1) had similar effects.

Importantly, inhibition of eif4e and Nlgn1 activity did not affect electrophysiological and behavioral parameters in wild-type mice.

Autism spectrum disorders (ASDs) are a group of clinically and genetically heterogeneous neurodevelopmental disorders characterized by impaired social interactions, repetitive behaviors and restricted interests. The genetic defects in ASDs may interfere with synaptic protein synthesis. Synaptic dysfunction caused by aberrant protein synthesis is a key pathogenic mechanism for ASDs Understanding the details about aberrant synaptic protein synthesis is important to formulate potential treatment for ASDs. The mammalian target of the Rapamycin (mTOR) pathway plays central roles in synaptic protein. Recently, Gkogkas and colleagues published exciting data on the role of downstream mTOR pathway in autism

Previous studies have indicated that upstream mTOR signaling is linked to ASDs. Mutations in tuberous sclerosis complex (TSC) 1/TSC2, neurofibromatosis 1 (NF1), and Phosphatase and tensin homolog (PTEN) lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly, respectively. TSC1/TSC2, NF1, and PTEN act as negative regulators of mTOR complex 1 (mTORC1), which is activated by phosphoinositide-3 kinase (PI3K) pathway. Activation of cap-dependent translation is a principal downstream mechanism of mTORC1. The eIF4E recognizes the 5′ mRNA cap, recruits eIF4G and the small ribosomal subunit. The eIF4E-binding proteins (4E-BPs) bind to eIF4E and inhibit translation initiation. Phosphorylation of 4E-BPs by mTORC1 promotes eIF4E release and initiates cap-dependent translation. A hyperactivated mTORC1–eIF4E pathway is linked to impaired synaptic plasticity in fragile X syndrome, an autistic disorder caused by lack of fragile X mental retardation protein (FMRP) due to mutation of the FMR1 gene, suggesting that downstream mTOR signaling might be causally linked to ASDs. Notably, one pioneering study has identified a mutation in the EIF4E promoter in autism families, implying that deregulation of downstream mTOR signaling (eIF4E) could be a novel mechanism for ASDs.As an eIF4E repressor downstream of mTOR, 4E-BP2 has important roles in synaptic plasticity, learning and memory. Writing in their Nature article, Gkogkas and colleagues reported that deletion of the gene encoding 4E-BP2 (Eif4ebp2) leads to autistic-like behaviors in mice. Pharmacological inhibition of eIF4E rectifies social behavior deficits in Eif4ebp2 knockout mice. Their study in mouse models has provided direct evidence for the causal link between dysregulated eIF4E and the development of ASDs.Are these ASD-like phenotypes of the Eif4ebp2 knockout mice caused by altered translation of a subset mRNAs due to the release of eIF4E? To test this, Gkogkas et al. measured translation initiation rates and protein levels of candidate genes known to be associated with ASDs in hippocampi from Eif4ebp2 knockout and eIF4E-overexpressing mice. They found that the translation of neuroligin (NLGN) mRNAs is enhanced in both lines of transgenic mice. Removal of 4E-BP2 or overexpression of eIF4E increases protein amounts of NLGNs in the hippocampus, whereas mRNA levels are not affected, thus excluding transcriptional effect. In contrast, the authors did not observe any changes in the translation of mRNAs coding for other synaptic scaffolding proteins. Interestingly, treatment of Eif4ebp2 knockout mice with selective eIF4E inhibitor reduces NLGN protein levels to wild-type levels. These data thus indicate that relief of translational suppression by loss of 4E-BP2 or by the overexpression of eIF4E selectively enhances the NLGN synthesis. However, it cannot be ruled out that other proteins (synaptic or non-synaptic) may be affected and contribute to animal autistic phenotypes.Aberrant information processing due to altered ratio of synaptic excitation to inhibition (E/I) may contribute to ASDs. The increased or decreased E/I ratio has been observed in ASD animal models  In relation to these E/I shifts, Gkogkas et al then examined the synaptic transmission in hippocampal slices of Eif4ebp2 knockout mice. They found that 4E-BP2 de-repression results in an increased E/I ratio, which can be explained by the increase of vesicular glutamate transporter and spine density in hippocampal pyramidal neurons. As expected, application of eIF4E inhibitor restores the E/I balanceFinally, in view of the facts that genetic manipulation of NLGNs results in ASD-like phenotypes with altered E/I balance in mouse models  and NLGN mRNA translation is enhanced concomitant with increased E/I ratio in Eif4ebp2 knockout mice, Gkogkas et al. tested the effect of NLGN knockdown on synaptic plasticity and behaviour in these mice . NLGN1 is predominantly postsynaptic at excitatory synapses and promotes excitatory synaptic transmission. The authors found that NLGN1 knockdown reverses changes at excitatory synapses and partially rescues the social interaction deficits in Eif4ebp2 knockout mice. These findings thus established a strong link between eIF4E-dependent translational control of NLGNs, E/I balance and the development of ASD-like animal behaviors (Figure 1).
In summary, Gkogkas et al. have provided a model for mTORC1/eIF4E-dependent autism-like phenotypes due to dysregulated translational control (Gkogkas et al., 2013). This novel regulatory mechanism will prompt investigation of downstream mTOR signaling in ASDs, as well as expand our knowledge of how mTOR functions in human learning and cognition. It may narrow down therapeutic targets for autism since targeting downstream mTOR signaling reverses autism. Pharmacological manipulation of downstream effectors of mTOR (eIF4E, 4E-BP2, and NLGNs) may eventually provide therapeutic benefits for patients with ASDs.

Ribavirin Inhibitsthe Activity of mTOR/eIF4E, ERK/Mnk1/eIF4E Signaling Pathway and Synergizeswith Tyrosine Kinase Inhibitor Imatinib to Impair Bcr-Abl MediatedProliferation and Apoptosis in Ph+ Leukemia

1. Dr Z Miedzybrodzka, University of Aberdeen, Department of Genetics, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK;


Background: Autism is a common childhood onset neurodevelopmental disorder, characterised by severe and sustained impairment of social interaction and social communication, as well as a notably restricted repertoire of activities and interests. Its aetiology is multifactorial with a strong genetic basis. EIF4E is the rate limiting component of eukaryotic translation initiation, and plays a key role in learning and memory through its control of translation within the synapse. EIF4E mediated translation is the final common process modulated by the mammalian target of rapamycin (mTOR), PTEN and fragile X mental retardation protein (FMRP) pathways, which are implicated in autism. Linkage of autism to the EIF4E region on chromosome 4q has been found in genome wide linkage studies.
Methods and results: The authors present evidence that directly implicates EIF4E in autism. In a boy with classic autism, the authors observed a de novo chromosome translocation between 4q and 5q and mapped the breakpoint site to within a proposed alternative transcript of EIF4E. They then screened 120 autism families for mutations and found two unrelated families where in each case both autistic siblings and one of the parents harboured the same single nucleotide insertion at position −25 in the basal element of the EIF4E promoter. Electrophoretic mobility shift assays and reporter gene studies show that this mutation enhances binding of a nuclear factor and EIF4E promoter activity.
Conclusions: These observations implicate EIF4E, and more specifically control of EIF4E activity, directly in autism. The findings raise the exciting possibility that pharmacological manipulation of EIF4E may provide therapeutic benefit for those with autism caused by disturbance of the converging pathways controlling EIF4E activity.



Activity-dependent neuroprotective protein (ADNP) is a most frequent autism spectrum disorder (ASD)-associated gene and the only protein significantly decreasing in the serum of Alzheimer's disease (AD) patients. Is ADNP associated with ASD being more prevalent in boys and AD more prevalent in women? Our results revealed sex-related learning/memory differences in mice, reflecting hippocampal expression changes in ADNP and ADNP-controlled AD/ASD risk genes. Hippocampal ADNP transcript content was doubled in male vs female mice, with females showing equal expression to ADNP haploinsufficient (ADNP+/−) males and no significant genotype-associated reduction. Increased male ADNP expression was replicated in human postmortem hippocampal samples. The hippocampal transcript for apolipoprotein E (the major risk gene for AD) was doubled in female mice compared with males, and further doubled in the ADNP+/− females, contrasting a decrease in ADNP+/− males. Previously, overexpression of the eukaryotic translation initiation factor 4E (eIF4E) led to ASD-like phenotype in mice. Here, we identified binding sites on ADNP for eIF4E and co-immunoprecipitation. Furthermore, hippocampal eIF4E expression was specifically increased in young ADNP+/− male mice. Behaviorally, ADNP+/− male mice exhibited deficiencies in object recognition and social memory compared with ADNP+/+ mice, while ADNP+/− females were partially spared. Contrasting males, which preferred novel over familiar mice, ADNP+/+ females showed no preference to novel mice and ADNP+/− females did not prefer mice over object. ADNP expression, positioned as a master regulator of key ASD and AD risk genes, introduces a novel concept of hippocampal gene-regulated sexual dimorphism and an ADNP+/− animal model for translational psychiatry.

Sunday, 26 March 2017

Sensory Gating in Autism, Particularly Asperger's

Sensory gating is an issue in autism, schizophrenia and ADHD.   It is the neurological process of filtering out redundant or unnecessary stimuli in the brain; like the child who sits in his classroom and gets bothered by the noise of the clock on the wall.  He is unable to filter out and ignore this sound. He becomes preoccupied by the sound and cannot concentrate on his work.
There are also sometimes advantages to not filtering out environmental stimuli, because you would have more situational awareness and notice things that others miss.
An example of sensory gating is the fact that young children are not waken by smoke detectors that have high pitched siren, but are waken by a recorded human voice telling them there is a fire and to wake up.
There may be times when sensory overload in autism is not a case of too much volume from each of the senses, but rather too many inputs being processed by the brain, instead of some just being ignored.  It is more a case of information overload.
Note that this blog has already covered hypokalemic sensory overload in some depth, which is treatable.
Much is known about sensory gating because it has long been known to be a problem in schizophrenia.
An EEG (Electroencephalography) test measures your brain waves / neural oscillations. Many people with autism have EEGs, but mainly those in which epilepsy is a consideration.
In the world of the EEG, the P50 is an event occurring approximately 50 millisecond after the presentation of an auditory click.  The P50 response is used to measure sensory gating, or the reduced neurophysiological response to redundant stimuli.
Abnormal P50 suppression is a biomarker of schizophrenia, but is present in other disorders, including Asperger’s, post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI).
In more severe autism abnormal P50 suppression was found not to be present in one study.  This might be because cognition and the senses are dimmed by the excitatory-inhibitory imbalance.
More broadly, sensory gating is seen as an issue in wider autism and ADHD.

Correcting P50 gating
It is known that α7 nicotinic acetylcholine receptor (α7 nAChR) agonists can correct the impaired P50 gating. It is also known that people with schizophrenia have less expression of this receptor in their brains than typical people.

One short term such agonist is the nicotine released from smoking.  This likely contributes to why people with schizophrenia can be heavy smokers.  The effect is thought to last for about 30 minutes.
Clinical trials using Tropisetron, a drug that is a α7 nAChR agonist and used off-label to treat fibromyalgia, have shown that it can correct defective P50 gating and improve cognitive function in schizophrenia.

An alternative α7 nAChR agonist that is widely available is varenicline, a drug approved to help people stop smoking.
So you might expect varenicline to improve P50 gating and improve cognition. You might also expect it to help people with fibromyalgia and indeed some other people with chronic inflammation, as shown by elevated inflammatory cytokines.

You may recall that the α7 nAChR is the key to stimulating the vagus nerve and this should be beneficial to many people with inflammatory conditions (from arthritis to fibromyalgia).

Abnormalities in CHRNA7, the alpha7-nicotinic receptor gene, have been reported in autism spectrum disorder. These genetic abnormalities potentially decrease the receptor’s expression and diminish its functional role. This double-blind, placebo-controlled crossover study in two adult patients investigated whether an investigational receptor-specific partial agonist drug would increase the inhibitory functions of the gene and thereby increase patients’ attention. An electrophysiological biomarker, P50 inhibition, verified the intended neurobiological effect of the agonist, and neuropsychological testing verified a primary cognitive effect. Both patients perceived increased attention in their self-ratings. Alpha7-nicotinic receptor agonists, currently the target of drug development in schizophrenia and Alzheimer Disease, may also have positive clinical effects in autism spectrum disorder.

A role for H3 and HI histamine receptors
It has also been suggested that histamine plays a role in sensory gating via the H1 and H3 receptors.

It had also been thought H3 receptors could be targeted to improve cognition in schizophrenia, but that research really did not go anywhere.

Histamine H1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H1 effects on sensorimotor gating to human studies. The effects of the histamine H1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli.

The aim of this study was to investigate an established rat model of decreased PPI induced by administration of the NMDA antagonist, dizocilpine and the reversal of this PPI impairment by the histaminergic H1-antagonist, pyrilamine. H1-antagonism is a potential mechanism of the therapeutic effects of the atypical antipsychotic, clozapine, which improves PPI following dizocilpine administration in rats as well as in patients with schizophrenia. In the present study we show that chronic pyrilamine administration prevents the PPI impairment induced by chronic dizocilpine administration, an effect that is correlated with a reduction in ligand-binding potential of H1 receptors in the anterior cingulate and an increase in nicotinic receptor α7 subunit binding in the insular cortex. In light of the functional anatomical connectivity of the anterior cingulate and insular cortex, both of which interact extensively with the core PPI network, our findings support the inclusion of both cortical areas in an expanded network capable of regulating sensorimotor gating.

The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor-mediated activation of extracellular signal-regulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor-mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling.


Other than nicotine, varenicline would seem a good potential therapy for sensory gating.  There are α7-nicotinic acetylcholine receptor agonists in development.
There are many H1 histamine antagonists.  Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors. Centrally acting H1 antihistamines are sedating.

H3 antagonists have stimulant and nootropic effects. Betahistine is an approved drug in this class, there are many research drugs.

The aim of this study is to investigate the role of the neurotransmitter histamine in sensory and cognitive deficits as they often occur in schizophrenia patients (e.g. hearing voices, planning and memory problems). The ideal location to conduct the study and to obtain a unique learning experience is at the Institute of Psychiatry, London, United Kingdom, where staff comprises of leading experts in the field of schizophrenia and Magnetic Resonance Imaging of pharmacological effects. Current pharmacological treatment of psychotic symptoms including sensory and cognitive deficits remains partially unsuccessful due to side effects and treatment resistance. The neurotransmitter histamine seems to be a very promising target for new treatments. It has been found that histamine neurotransmission is altered in brains of schizophrenics, which may contribute to both the hallucinatory and cognitive symptoms. However, this specific role of histamine has not been investigated before. I will assess the effects of increased histaminergic activity, by administration of betahistine to healthy volunteers, on performance (sensory gating, executive functioning or planning and memory) and associated brain activity using fMRI. Altered performance and brain activity would support the importance of histamine in schizophrenia and would provide a research model and target for new treatments.

Thursday, 23 March 2017

Targeting Angiotensin in Schizophrenia and Some Autism

 A home run? Certainly worth further consideration.

Just when you thought we had run out of hormones to connect to autism and schizophrenia, today we have Angiotensin. 

Angiotensin is a hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs (ACE inhibitors) that lower blood pressure. Angiotensin also stimulates the release of aldosterone, a hormone that promotes sodium retention which also drives blood pressure up.

Angiotensin I has no biological activity and exists solely as a precursor to angiotensin II.

Angiotensin I is converted to angiotensin II  by the enzyme angiotensin-converting enzyme (ACE).  ACE is a target for inactivation by ACE inhibitor drugs, which decrease the rate of Angiotensin II production.  

It turns out that Angiotensin has some other properties very relevant to schizophrenia, some autism and quite likely many other inflammatory conditions. 

Blocking angiotensin-converting enzyme (ACE) induces those potent regulatory T cells that are lacking in autism and modulates Th1 and Th17 mediated autoimmunity.  See my last post on Th1,Th2 and Th17. 

In addition, Angiotensin II affects the function of the NKCC1/2 chloride cotransporters that are dysfunctional in much autism and at least some schizophrenia.  

Drugs that reduce Angiotensin are very widely prescribed, so they are cheap and well understood. This means that yet another cheap generic has the potential to be repurposed to treat neurological disorders. 

As one paper puts it “modulation of the RAAS (renin-angiotensin-aldosterone system) with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.” 

No big profits then for big pharma. 


We learnt all about the inflammatory cytokines IL-17 and IL-17a in a recent post. That post was about autism, but not surprisingly, elevated levels of IL-17a are a feature in big brother schizophrenia. Big brothers do tend to get more research attention.

In schizophrenia there is increased plasmatic Angiotensin Converting Enzyme (ACE) activity in patients compared to healthy controls, which is also associated to poor cognitive functioning. The ACE main product angiotensin II has known pro-inflammatory properties. 

So an ACE inhibitor looks an obvious choice for schizophrenia.  Very slowly research is indeed moving in that direction.

Angiotensin receptor blockers have even been proposed for bipolar disorder, autism’s other elder brother.

What about ACE and Autism? 

As we have got used to, kid bother autism has not had the same level of research attention as given to schizophrenia, but we do have this:- 

Autism is a disease of complex nature with a significant genetic component. The importance of renin-angiotensin system (RAS) elements in cognition and behavior besides the interaction of angiotensin II (Ang II), the main product of angiotensin-converting enzyme (ACE), with neurotransmitters in CNS, especially dopamine, proposes the involvement of RAS in autism. Since the genetic architecture of autism has remained elusive, here we postulated that genetic variations in RAS are associated with autism. 

Our data suggests the involvement of RAS genetic diversity in increasing the risk of autism.

Here is the supporting research:-  

The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-κB1 transcription factor complex and activation of the alternative NF-κB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.

In an effort to find a marker that predicts psychosis, postdoctoral researcher Lindsay Hayes, Ph.D., learned unexpectedly that mice and people with behavior disorders have abnormally low levels of a hormone system tied to blood pressure regulation and inflammation. In the cerebrospinal fluid of patients with first episode psychosis, she noticed abnormally low levels of the enzyme that makes the hormone angiotensin. To see if these results correlated to animals and could be studied in the lab, Hayes, who works in the laboratory of treated brain cells with angiotensin and inflammation activators in their mouse model for behavior disorders, then measured the output of proteins involved in inflammation. Compared to normal mice, the cells from the mouse with behavioral disorders released more inflammation protein when treated with low levels of angiotensin and less when treated with high levels. Next, she looked at gene expression levels of the angiotensin system components in the brain cells of the behavioral disorder mice. The gene expression levels for the receptor that detects angiotensin were abnormally low in a specific type of brain cell. Hayes says these specific cells in the behavior disorder mice seem to be less susceptible to angiotensin’s immunosuppressive properties, because they have less receptor to detect angiotensin than the same brain cells in normal mice. Hayes and Sawa plan to investigate whether targeting angiotensin could control inflammation and perhaps treat psychosis. 

Angiotensin converting enzyme activity is positively associated with IL-17a levels in patients with schizophrenia.


Previous studies of our group showed increased plasmatic Angiotensin-I Converting Enzyme (ACE) activity in schizophrenia (SCZ) patients compared to healthy controls, which was also associated to poor cognitive functioning. The ACE main product angiotensin II (Ang-II) has pro-inflammatory properties. Activated immune-inflammatory responses in SCZ and their association with disease progression and cognitive impairments are also well-described. Therefore, we examined here the association of plasma ACE activity and inflammatory mediators in 33 SCZ patients and 92 healthy controls. Non-parametric correlations were used to investigate the association of the enzyme activity and the peripheral levels of immune inflammatory markers as interleukins, tumor necrosis factor (TNF-α), and interferon (IFN-γ). Although no significant correlations could be observed for ACE activity and measured cytokines levels in healthy controls, a significant positive correlation for ACE enzymatic activity and IL-17a levels was observed in SCZ patients. Correcting for gender did not change these results. Moreover, a significant association for ACE activity and IFN-γ levels was also observed. To our knowledge, this is the first study to show a significant association between higher ACE activity and the levels of cytokines, namely IL-17a and IFN-γ, in patients with SCZ. 

Cerebrospinal fluid angiotensin-converting enzyme (ACE) correlates with length of illness in schizophrenia. 


The aim of the study was to evaluate a possible progression with time of cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) levels in treated schizophrenia patients. CSF ACE was determined in duplicate by a sensitive inhibitor-binding assay (IBA) from morning CSF samples of 56 acute and chronic in-patients with schizophrenic psychoses diagnosed according to DSM-IV. CSF ACE correlated significantly with length of schizophrenic psychosis (r=0.39, p=0.003). There was also a positive significant correlation between CSF ACE and duration of current psychotic episode (r=0.39, p=0.003) as well as duration of current hospitalization (r=0.66, p<0 .001="" span=""> These significances were maintained even when patients who were not treated with antipsychotics at the time of sampling were excluded. The correlations also remained significant when controlling for current neuroleptic dose in chlorpromazine equivalents. Serum ACE did not correlate with any clinical variable. No significant correlations between serum or CSF ACE and age, diagnostic subgroup, gender, serum ACE, CSF to serum albumin ratios, or neuroleptic dose in chlorpromazine equivalents were detected. The elevation of CSF ACE seemed to be confined to a subgroup of chronic patients with few positive symptoms. Elevated CSF ACE may reflect an increased solubilization of ACE from cell membranes in the central nervous system or constitute an increased expression of the ACE gene in response to some stimuli. This may be a function of treatment or a result of the deteriorating schizophrenic process. 

The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-κB1 transcription factor complex and activation of the alternative NF-κB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.

African Americans have been shown to exhibit lower urinary potassium excretion when compared to Caucasians. Angiotensin II regulates both potassium handling by the kidney and the Na-K-2Cl (NKCC) cotransporter in vitro . However, little is known about the role of the reninangiotensin system (RAS) in human NKCC cotransport regulation in vivo. We hypothesized that regulation of RAS would induce concomitant alterations in NKCC activity in humans. The kidney and erythrocyte express NKCC-1 isoform. Therefore, we measured NKCC-1 activity in freshly isolated ex vivo red cells from 12 healthy blacks and 11 healthy whites in high (200 mmol/d) and low (10 mmol/d) salt balance, followed by a measure 24 h-post candesartan [16 mg] to block angiotensin II type I receptors on low salt diet. Baseline NKCC cotransport activity was significantly lower in Blacks when compared to Whites in balance on a typical high salt diet, and was reduced when the subjects were placed on a low salt diet in whites only. Administration of candesartan reversed the reduction seen with low salt diet in whites, where as in blacks there was no significant effect. These data suggest altered in vivo regulation of NKCC-1 via RAS in Blacks when compared to Whites, and provide a mechanism that may in part explain the altered potassium handling observed among otherwise healthy African Americans.


I think it is likely that some sub-types of autism would likely benefit from an ACE inhibitor. As a secondary benefit, it will also reduce any troubling high levels of leptin.

There are other ways to modulate Th1, Th2 and Th17, but if you have elevated Angiotensin Converting Enzyme (ACE), then an ACE inhibitor would appear the logical choice.

How about a clinical trial in adults with Asperger's?