Today’s post covers some practical interventions raised recently either in the research, or in the comments section.
·
Chlorzoxazone
(via Potassium channels – BKCa, SKCa) an old muscle relaxant first
approved in 1958
·
Varenicline
a drug approved in 2006 that targets nicotinic receptors in the brain
·
Nicotine
·
Tropisetron,
an anti-nausea drug that also targets nicotinic receptors in the brain; it was
approved in 1992 in Switzerland and is available in the Europe but not the US.
·
Gallic
acid, a component of numerous plants/foods (grapes, pomegranates, green tea,
red wine etc) that have been used in traditional medicine across different
cultures
The common
link between the first four is the sensory problems usually found across all severities
of autism, and some forms of ADHD/autism-lite. It can be either sound
sensitivity (hyperacusis) or misophonia (impaired sensory gating), both of
which often co-occur in the same person.
We will
refer to some of the excellent research into Fragile X syndrome. This is the
most common single gene type of autism; most autism is polygenic and some is
not of genetic origin at all (hypoxia during birth, sepsis etc).
Let’s start
with the easiest topic.
Gallic
acid
I saw the
recent study below and wondered what is gallic acid.
Autism, a developmental‐neurodegenerative disorder, often manifests as social communication difficulties and has been correlated to oxidative stress in the brain. Vitamins C and gallic acid (GA) possess potent antioxidant properties, making them potential candidates for addressing autism‐related issues. This study examined the influence of vitamin C (Vit C) and GA on behavioral, motor, and cognitive performance, along with the assessment of brain oxidative markers, using an experimental model of autism.
Finding
The prenatal VPA‐induced autism
model increased nociceptive threshold, heightened anxiety‐like behaviors,
impaired balance power, delayed spatial learning, elevated malondialdehyde, and
decreased glutathione and catalase levels in the brains of the male offspring. Administration of Vit C and GA
effectively mitigated these anomalies.
Conclusions
Vit C and GA could potentially alleviate anxiety‐like
behaviors, motor and cognitive deficits, and brain oxidative stress markers in
a prenatal rat autism model. This underscores their viability as potential pharmacological
interventions for treating autistic dysfunction.
Gallic acid
is a naturally occurring organic acid widely found in various plants, fruits,
and foods. It is notable for its antioxidant, anti-inflammatory, and
antimicrobial properties, making it of interest in health and medicine.
For no obvious
reason, gallic acid has never been commercialized as a supplement, but gallic
acid is one of the reasons a glass of red wine a day may well be good for
you. It can give a you a 20 mg dose of
gallic acid.
Red wines
made from grape varieties with higher tannin content, such as Cabernet
Sauvignon or Pinot Noir, tend to have higher levels of gallic acid because
tannins contain gallic acid. Longer aging, especially in oak barrels, can increase
gallic acid due to the extraction from the wood.
The new study suggests that gallic acid is a potential pharmacological intervention for treating autism. It joins an already very long list!
Varenicline and other nicotinic therapies
Our reader Dragos in Romania recently
asked for help obtaining Varenicline, which is also sold as Chantix. This drug
is similar to using a nicotine patch, but different in some important ways.
DAN doctors in the US used to
prescribe nicotine patches to children with autism.
There is a lot of research to support
the use of therapies that target a
specific nicotinic receptor in the brain called the alpha 7 nicotinic
acetylcholine receptor (α7 nAChR).
Nicotine itself activates all
nicotinic receptors, not just α7 nAChR.
Dragos want to trial the smoking
cessation drug Varenicline, which targets
α7 nAChRs and a little bit the one called α4β2 nAChR.
α7 nAChRs
These receptors are well known to be
implicated in diseases such as Alzheimer's, schizophrenia, autism, and
epilepsy.
They affect:
Cognition
and memory
·
α7 nAChRs are
involved in synaptic plasticity, learning, and memory formation due to their
role in calcium signaling and modulation of neurotransmitter release.
·
Highly expressed
in the hippocampus, which is critical for memory processing.
Neuroprotection
·
Calcium influx
through α7 nAChRs activates signaling pathways that promote cell survival and
neuroprotection.
·
Involved in
reducing neuroinflammation and protecting against excitotoxicity.
Modulation
of Neurotransmitter Release
·
Regulate the
release of dopamine, glutamate, GABA, and serotonin, impacting mood, arousal,
and reward mechanisms.
Inflammatory
Regulation
·
Present on immune
cells, where they regulate the release of pro-inflammatory cytokines like TNF-α
via the cholinergic anti-inflammatory pathway.
Sensory Gating
·
α7 nAChRs are crucial for sensory filtering, preventing
sensory overload. Dysfunction in these receptors is linked to conditions like autism
and schizophrenia.
α4β2 nAChRs
These play a role in:
Cognitive
function
·
Involved in
attention, learning, and memory.
·
Enhances synaptic
plasticity in brain regions like the hippocampus.
Dopamine
release
Pain
modulation
Mood
regulation
Research has shown reduced expression
of both α7 nAChRs and α4β2 nAChRs in the brains of people with autism.
Dragos has good reason to trial
Varenicline; not only has another young adult in Romania with severe autism
recently responded well, but there are published case reports to give further
support.
Varenicline
in Autism: Theory and Case Report of Clinical and Biochemical Changes
Objective: To explore the potential benefits of varenicline (CHANTIX®), a highly specific partial agonist of neuronal α4β2 nicotinic acetylcholine receptors (nAChR), for autistic symptoms, and present resulting biochemical changes in light of dopamine-related genotype.
Methods: The clinical and biochemical changes exhibited
by a 19-year-old severely autistic man following the use of low-dose
varenicline in an ABA experiment of nature, and his genotype, were extracted
from chart review. Clinical outcome was measured by the Ohio Autism Clinical
Impression Scale and 12 relevant urine and saliva metabolites were measured by
Neuroscience Laboratory.
Results: With
varenicline, this patient improved clinically and autonomic biochemical
indicators in saliva and urine normalized,
including dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), epinephrine,
norepinephrine, taurine, and histamine levels. In addition, with varenicline,
the dopamine D1 receptor (DRD1) antibody titer as well as the percent of
baseline calmodulin-dependent protein kinase II (CaM KII) activity dropped
significantly. When
varenicline stopped, he deteriorated; when it was resumed, he again improved.
Doses of 0.5, 1, and 2 mg daily were tried before settling on a dose of 1.5 mg
daily. He has remained on varenicline for over a year with no noticeable side
effects.
Conclusion: This report is, to the best of our knowledge,
only the second to demonstrate positive effects of varenicline in autism, the
first to show it in a severe case, and the first to show normalization of
biochemical parameters related to genotype. As with the previous report, these
encouraging results warrant further controlled research before clinical
recommendations can be made.
Varenicline vs
Nicotine
Let’s compare the mechanisms of action:
Varenicline
- Partial agonist at the α4β2 nicotinic
acetylcholine receptor (nAChR) and a full agonist at α7 nAChRs.
- Modulates neurotransmitter release (e.g.,
dopamine, glutamate), which may improve cognitive function and reduce
repetitive behaviors in ASD.
- FDA-approved for smoking cessation.
Nicotine Patches
- Deliver nicotine, a full agonist at
nAChRs.
- Broadly activate multiple nAChR subtypes,
leading to enhanced cholinergic signaling.
- Typically used for smoking cessation
Other
Considerations
Varenicline
· Offers more targeted modulation of nAChRs with less widespread cholinergic activation.
- Varenicline’s mechanism prevents full
desensitization, maintaining its effects over time.
· May be preferred if minimizing side effects like overstimulation is important.
Nicotine Patches:
- Easy to administer and widely available
but less specific in its action, which may lead to more off-target
effects.
- Nicotine can lead to rapid receptor
desensitization and tolerance, especially with continuous delivery via
patches.
Alternatives
There are some theoretical
alternatives, such as:
ABT-126
(Pozanicline)
·
Type: Selective α7 nAChR agonist.
·
Status: Investigated for Alzheimer's disease and
schizophrenia.
·
Cognitive enhancement and
improved sensory gating.
RG3487
(MEM 3454)
·
Type: Partial α7 nAChR agonist and modulator of
glutamate receptors.
·
Status: Investigated for schizophrenia and cognitive
impairment.
· Improves cognition and reduces symptoms like sensory gating deficits.
The one that caught my attention
previously when writing about this subject was Tropisetron.
Tropisetron:
- Already
approved as an antiemetic but also acts as a weak α7 nAChR agonist.
- Potential benefits in cognitive and
inflammatory disorders.
Clinical Evidence
with Tropisetron
Schizophrenia
Early studies show cognitive and
sensory gating improvements in schizophrenia patients treated with tropisetron.
Not to forget Vagus Nerve Stimulation (VNS)
The vagus nerve activates α7 nAChRs on
immune cells, reducing inflammation without immunosuppression.
The vagus nerve indirectly affects α7
and α4β2 nAChRs in the brain by modulating acetylcholine release.
Vagus nerve stimulation is already used
in epilepsy, depression, and inflammatory disorders.
It is worthwhile highlighting the
effect on people with some types of GI disorder. There is a known association
between Asperger’s and ulcerative colitis.
Nicotine and Ulcerative
Colitis (UC)
·
Smoking appears
to have a protective effect on ulcerative colitis.
·
Smokers are less
likely to develop UC, and those who quit smoking are at higher risk of
developing the condition.
·
Current smokers
with UC may experience milder disease with fewer flares and less severe
symptoms.
The suggested mechanism
·
Dysregulated
inflammation in the colonic mucosa leads to ulcerations, diarrhea, and
abdominal pain.
·
α7 nAChR
activation may reduce this inflammation, aiding in mucosal healing and symptom
improvement.
·
Nicotine’s
anti-inflammatory effects may play a role by modulating cytokine release (e.g.,
reduced IL-8 and TNF-α).
·
Nicotine also
stimulates mucus production and increases colonic blood flow, potentially
improving mucosal healing.
·
Smoking-induced
changes in the microbiome may also reduce UC severity.
Note that for Crohn's Disease (CD) and Irritable Bowel Syndrome (IBS) smoking makes the symptoms worse.
So, it would make
sense to use vagal nerve stimulation for inflammatory bowel disease?
Here are results from 2023
Vagus
nerve stimulation reduces inflammation in children with inflammatory bowel
disease
Bioelectronic medicine researchers at The Feinstein Institutes for Medical Research and Cohen Children’s Medical Center published results today, in the journal Bioelectronic Medicine, from a proof-of-concept clinical trial that showed non-invasive, non-pharmacological transcutaneous auricular vagus nerve stimulation (ta-VNS), or stimulating in the ear, significantly reduced inflammation in more than 64 percent of pediatric patients with IBD.
Dr.
Sahn and his team used a commercially available transcutaneous electrical nerve
stimulator (TENS) unit (TENS 7000) and sensor probe for the trial. Two earbuds
on the probes were placed on a small area of the external ear called the cymba
conchae, where the vagus nerve is most accessible. For five-minute intervals,
the patients received the stimulation for a total of 16 weeks.
Let’s have a quick recap on Fragile X.
Fragile-X
Fragile X (FXS) is the most common
single gene cause of intellectual disability (IQ less than 70).
FXS affects approximately 1 in 4,000
males and 1 in 8,000 females.
The condition is very well studied and
the Fragile X gene (FMR1) is considered an autism gene.
I am surprised how rarely (never?) FXS
parents comment in this blog. They are actually the ones who stand to benefit
the most, given how well-studied their syndrome is and how many treatment
options exist. I was recently discussing this exact point with an autism
therapist with an FXS patient – why do parents remain passive and not react?
More severe in
males than females
Males have one copy of the FMR1 gene,
while females have two.
In females with the full mutation,
symptoms are generally less severe than in males due to what is called random
X-inactivation. Since females have two X chromosomes, one of the X chromosomes
in each cell is randomly inactivated. In cells where the X with the mutation is
inactivated, FMRP is produced normally, and in cells where the normal X is
inactivated, no FMRP is produced. The severity of symptoms often correlates
with the proportion of cells in which the mutated X is active.
In a strange twist of fate females with
the milder form of FXS, called premutation, have the greatest chance of being
infertile. This is due to Fragile X-associated primary ovarian insufficiency
(FXPOI).
Testing
The ability to conduct genetic testing
began in the 1990s, became more widespread by the mid-1990s, and became
integrated into routine clinical practice in the early 2000s. Today, genetic
testing for Fragile X is a standard tool used to diagnose FXS, assess carrier
status, and inform genetic counselling.
You can also identify Fragile X based
on facial features and this is a common practice, especially in the early
diagnosis of individuals with the syndrome.
BKCa and SKCa channels in autism and Fragile X
Ion channel dysfunctions play a key
role in all neurological conditions. A great deal is known about them, making
them an excellent target for intervention.
Fragile X is such a well-studied
condition that you can access all the information very easily.
For other single gene autisms and the more common idiopathic (unknown cause) autism it is more a matter of guesswork.
This recent paper is excellent:
Channelopathies in fragile X syndrome
The paper lists all the proven ion
channel dysfunctions and suggests how to treat some of them.
Potassium channels – BKCa, SKCa,
Kv1.2, Kv3.1, Kv4.2,
Calcium channels – Cav1.3, Cav2.1,
Cav2.3,
Misc – HCN, NKCC1, AMPAR, NMDAR, GABAAR
Targeting BKCa, SKCa in Fragile X and for hyperacusis in broader autism
In FXS, hyperexcitability in brain
circuits is thought to contribute to cognitive and behavioral symptoms.
Preclinical studies suggest that SKCa
and BKCa channel activators may correct this hyperexcitability and improve
neural network function.
The therapeutic effects of a cheap
drug called chlorzoxazone in FXS models are believed to stem from its ability
to enhance BKCa channel activity. These channels play a pivotal role in
regulating neuronal firing rates and neurotransmitter release. By activating
BKCa channels, chlorzoxazone may counteract the neuronal hyperexcitability
observed in FXS, leading to improved behavioral and sensory outcomes.
BKCa channels are indispensable for
hearing, as they regulate frequency tuning, temporal precision, and signal
transmission in both cochlear hair cells and auditory neurons. Dysfunctions in
these channels are linked to hearing impairments like frequency discrimination
deficits, tinnitus, and hyperacusis
(sound sensitivity). Modulating
BKCa activity offers a promising avenue for treating auditory disorders.
Therapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model of Fragile X syndrome
Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by several behavioral abnormalities, including hyperactivity, anxiety, sensory hyper-responsiveness, and autistic-like symptoms such as social deficits. Despite considerable efforts, effective pharmacological treatments are still lacking, prompting the need for exploring the therapeutic value of existing drugs beyond their original approved use. One such repurposed drug is chlorzoxazone which is classified as a large-conductance calcium-dependent potassium (BKCa) channel opener. Reduced BKCa channel functionality has been reported in FXS patients, suggesting that molecules activating these channels could serve as promising treatments for this syndrome. Here, we sought to characterize the therapeutic potential of chlorzoxazone using the Fmr1-KO mouse model of FXS which recapitulates the main phenotypes of FXS, including BKCa channel alterations. Chlorzoxazone, administered either acutely or chronically, rescued hyperactivity and acoustic hyper-responsiveness as well as impaired social interactions exhibited by Fmr1-KO mice. Chlorzoxazone was more efficacious in alleviating these phenotypes than gaboxadol and metformin, two repurposed treatments for FXS that do not target BKCa channels. Systemic administration of chlorzoxazone modulated the neuronal activity-dependent gene c-fos in selected brain areas of Fmr1-KO mice, corrected aberrant hippocampal dendritic spines, and was able to rescue impaired BKCa currents recorded from hippocampal and cortical neurons of these mutants. Collectively, these findings provide further preclinical support for BKCa channels as a valuable therapeutic target for treating FXS and encourage the repurposing of chlorzoxazone for clinical applications in FXS and other related neurodevelopmental diseases.
· Chlorzoxazone
In
the FXS research they repurpose a drug called chlorzoxazone to activate BKCa
channels, with positive results
· Mefenamic acid (Ponstan)
In
this blog Ponstan has shown promise to treat hyperacusis. Ponstan is a known
activator of both BKCa and SKCa channels.
Which is “better”
chlorzoxazone or Ponstan?
According to the science chlorzoxazone
is more potent than Ponstan in affecting both BKCa and SKCa channels.
Ponstan has more effects on Kv
channels like Kv7. Kv7 is implicated in autism and epilepsy.
In terms of gene expression Ponstan
has more direct effects on gene expression due to its modulation of
inflammatory pathways and inhibition of prostaglandin synthesis.
Chlorzoxazone primarily acts on ion
channels, and its effects on gene expression are secondary and less pronounced.
In conclusion the two drugs are very
different, both potentially useful, and some of their actions, such as on
hyperacusis, are overlapping.
Conclusion
Chlorzoxazone an inexpensive drug used
to treat muscle spasms is also known for its effects on calcium-activated
potassium channels (BKCa and SKCa).
Some claim that Chlorzoxazone may
affect GABAa and/or GABAb receptors, but that appears not to be the case.
The research suggests that
Chlorzoxazone should have a beneficial effect in FXS and very likely would have
a benefit in some broader autism and in hyperacusis specifically.
The effects of Chlorzoxazone are
likely to overlap with the effects of Ponstan. Ponstan is quite possibly also
going to be effective in FXS, as it is in broader autism.
There are many suggested therapies for
FXS (Metformin, Lovastatin, Baclofen, Acamprosate, Gabapentin, Minocycline,
Memantine, Rapamycin, L-carnitine, Omega 3 etc). None, when taken alone, are
game-changers.
Every parent of a child with Fragile X
should read the paper I have linked to in this post.
Channelopathies in fragile X syndrome
It is full of excellent ideas. If
NKCC1 is overexpressed, as is suggested, trial bumetanide.
As in all autism, polytherapy is going
to be key. No single therapy can be highly effective with so many dysfunctions
present. To quote from the above paper:-
“Ultimately, the most effective
treatment strategies are likely to be multifactorial.”
This means do not be surprised if you
need 5 different drugs, with 5 different targets to produce a game-changing
effect. Better 5 cheap old re-purposed generic drugs than a single brand-new
drug with little overall effect and that costs a king’s ransom, each and every
year.
Unfortunately, a personalized approach
will need to be used to find such a polytherapy. What works at one age may not
be beneficial at another age. Even within single gene autisms, treatment
response can vary widely from person to person.
At a conference, I did ask a clinician
who is an “expert” in Fragile X, does she apply any of the existing therapies
from the research, to her patients. She was rather taken aback by the idea and
said “no, we have to follow the protocols.” So, an expert in exactly what then?
An expert would make the protocols, if none existed.
