The therapeutic effects of apigenin are pleiotropic. Is its effect on sound sensitivity mediated via potassium channels?

Chamomile, a good source of Apigenin

 

Today we return to flavonoids, those healthy chemicals found in fruits, vegetables, flowers etc.

In particular, the focus is on apigenin, found in things like chamomile, parsley, oregano and in medicinal herbs like Bacopa monnieri.

 

Why the interest in Apigenin?

I did discover a while back that sound sensitivity in some autism responds almost immediately to low dose Ponstan (Mefenamic acid), which is a widely used as a pain reliever.

I was recently informed by a reader who responds well to Ponstan (250mg once a day) that he gets exactly the same relief from sound sensitivity from taking the flavonoid Apigenin (500mg a day). 

Both Ponstan and Apigenin are OTC in many countries. In countries like Greece Ponstan is extremely cheap.  In the US Ponstan is very expensive and supplements tend to be cheap. 

For adults with sound sensitivity drinking chamomile tea might be a good source of 50 mg of Apigenin (you would need about 20g of chamomile flowers). Using the dried flowers likely gives better results than ready-made tea bags.

 

Pleiotropic effects

Both Ponstan and apigenin have numerous beneficial effects.  I noted in my earlier posts on Ponstan that it seems to offer protection from Alzheimer’s. Perhaps surprisingly, people who take Ponstan are much less likely to develop Alzheimer’s. Nobody has studied apigenin in human Alzheimer’s, but in animal studies, apigenin has been shown to improve cognitive function, reduce amyloid plaques, and protect neurons from damage.

 

Other Flavonoids used in Autism

Dr Theoharides wrote a lot about flavonoids to treat autism and mast cell disorders.  His product Neuroprotek is a combination of three flavonoids: luteolin, quercetin, and rutin, which are found in plants such as celery, onions, and citrus fruits.

Epigallocatechin gallate (EGCG) is a flavonoid found in green tea. The Spanish like doing research on EGCG and they believe it has promise as an autism therapy. One of the effects is to modify the gut microbiome. EGCG has also been shown to accumulates in mitochondria making it an interesting therapeutic candidate for neurodegenerative diseases involving neuronal apoptosis triggered by mitochondrial oxidative stress. It has been studied in Down syndrome, Rett syndrome and some other models of autism.

 

A very detailed overview is available in the paper below:-

The Emerging Role of Flavonoids in Autism Spectrum Disorder: A Systematic Review

Although autism spectrum disorder (ASD) is a multifaceted neurodevelopmental syndrome, accumulating evidence indicates that oxidative stress and inflammation are common features of ASD. Flavonoids, one of the largest and best-investigated classes of plant-derived compounds, are known to exert antioxidant, anti-inflammatory, and neuroprotective effects. This review used a systematic search process to assess the available evidence on the effect of flavonoids on ASD. A comprehensive literature search was carried out in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. A total of 17 preclinical studies and 4 clinical investigations met our inclusion criteria and were included in the final review. Most findings from animal studies suggest that treatment with flavonoids improves oxidative stress parameters, reduces inflammatory mediators, and promotes pro-neurogenic effects. These studies also showed that flavonoids ameliorate the core symptoms of ASD, such as social deficits, repetitive behavior, learning and memory impairments, and motor coordination. However, there are no randomized placebo-controlled trials that support the clinical efficacy of flavonoids in ASD. We only found open-label studies and case reports/series, using only two flavonoids such as luteolin and quercetin. These preliminary clinical studies indicate that flavonoid administration may improve specific behavioral symptoms of ASD. Overall, this review is the first one to systematically report evidence for the putative beneficial effects of flavonoids on features of ASD. These promising preliminary results may provide the rationale for future randomized controlled trials aimed at confirming these outcomes.

 

It seems that the many flavonoids have numerous beneficial effects - this is why it is important to include them in your diet.

 

Sytrinol

Years ago, I wrote about Sytrinol, a dietary supplement that is made from citrus peel extract. It contains polymethoxylated flavones (PMFs), which are a type of flavonoid. It mainly contains nobiletin and tangeritin, flavones that are found in citrus fruits, such as lemons, oranges, and grapefruits. They have been shown to have a number of health benefits, including lowering cholesterol, reducing inflammation, and protecting cells from damage.

The idea was of interest because these flavones are known to activate PPAR-gamma, which seemed potentially beneficial in autism.  Readers did confirm Sytrinol provided a cognitive benefit, but it only lasts a few days and is then lost.

 

Sources of Apigenin

Apigenin is sold as a supplement.

Chamomile is one of the oldest, most widely used and well documented medicinal plants in the world and has been recommended for a variety of healing applications for centuries. Apigenin is thought to be one of the most potent substances found within it.

Bacopa monnieri is another rich source of flavonoids being a good source of luteolin and apigenin. An extract of Bacopa monnieri, a nootropic herb, has been used to evaluate its neuroprotective effect in a valproic acid (VPA) model of ASD. The results showed that B. monnieri extract may attenuate VPA-induced damage by restoring antioxidant enzymes and reducing inflammatory cytokines in the hippocampus and prefrontal cortex.

 

The biological effects of Apigenin

 What does the Google AI (artificial intelligence) program Bard have to say:-

 

Apigenin is a flavonoid that is found in a variety of plants, including chamomile, parsley, celery, and citrus fruits. It has several potential health benefits, including:

Antioxidant. Apigenin is an antioxidant, which means it can help protect cells from damage caused by free radicals. Free radicals are unstable molecules that can damage DNA, proteins, and other cellular structures.

Anti-inflammatory. Apigenin has anti-inflammatory properties, which can help reduce inflammation in the body. Inflammation is a contributing factor to many diseases, including heart disease, cancer, and arthritis.

Cancer prevention. Apigenin has been shown to have cancer-fighting properties in both animal and human studies. It may help prevent cancer by blocking the growth and spread of cancer cells.

Brain health. Apigenin may be beneficial for brain health. It has been shown to improve cognitive function in animal studies, and it may also help protect against Alzheimer's disease and other neurodegenerative diseases.

Heart health. Apigenin may help improve heart health. It has been shown to lower blood pressure and cholesterol levels, and it may also help protect against heart arrhythmias.

Hormone modulation. Apigenin may modulate the production of hormones, such as estrogen and testosterone. This could have benefits for women's health, such as reducing the risk of breast cancer and improving menopausal symptoms.

Immune health. Apigenin may boost the immune system. It has been shown to increase the production of white blood cells, which help fight infection.

Other benefits. Apigenin may also have other health benefits, such as relieving anxiety, promoting sleep, and strengthening bones.

When you push Bard a little bit you get more:

Apigenin and ion channels, Bard?

Apigenin is a flavonoid that has been shown to interact with a variety of ion channels in the body. These include:

Voltage-gated calcium channels. Apigenin has been shown to inhibit the activity of voltage-gated calcium channels, which are involved in the regulation of many cellular processes, including muscle contraction, cell growth, and cell death.

Transient receptor potential vanilloid 4 (TRPV4) channels. TRPV4 channels are activated by heat and inflammation, and they play a role in pain perception, thermoregulation, and inflammation. Apigenin has been shown to activate TRPV4 channels, which could have potential implications for the treatment of pain and inflammation.

Nicotinic acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channels that are activated by acetylcholine. They are involved in a variety of functions, including learning, memory, and muscle contraction. Apigenin has been shown to potentiate the activity of nAChRs, which could have potential implications for the treatment of Alzheimer's disease and other neurodegenerative diseases.

Potassium channels: Potassium channels are responsible for the efflux of potassium ions from cells. Apigenin has been shown to activate some types of potassium channels, which can have cardioprotective effects.

Gamma-aminobutyric acid (GABA)A receptors. GABAA receptors are ligand-gated ion channels that are activated by GABA. They are involved in the regulation of anxiety, sleep, and epilepsy. Apigenin has been shown to modulate the activity of GABAA receptors, which could have potential implications for the treatment of anxiety and epilepsy.

 

Which potassium channels, Bard? 

Apigenin has been shown to activate some types of potassium channels, including:

Small conductance calcium-activated potassium channels (SK channels): SK channels are activated by calcium ions and play a role in regulating cell excitability. Apigenin has been shown to activate SK channels in a number of cell types, including neurons, smooth muscle cells, and cardiac cells.

Large conductance calcium-activated potassium channels (BK channels): BK channels are also activated by calcium ions and play a role in regulating cell excitability and blood pressure. Apigenin has been shown to activate BK channels in some cell types, but the effects are less well-studied than the effects on SK channels.

Transient receptor potential vanilloid 4 (TRPV4) channels: TRPV4 channels are activated by a variety of stimuli, including heat, inflammation, and mechanical stress. Apigenin has been shown to activate TRPV4 channels in some cell types, but the effects are less well-studied than the effects on SK and BK channels.

 

The effect of mefenamic acid on potassium channels, Bard? 

Mefenamic acid has been shown to have effects on a variety of ion channels, including potassium channels.

In vitro studies have shown that mefenamic acid can activate certain types of potassium channels, such as small conductance calcium-activated potassium channels (SK channels) and large conductance calcium-activated potassium channels (BK channels). This activation of potassium channels can lead to a decrease in the excitability of cells, which can be beneficial in conditions where excessive cell excitability is a problem, such as epilepsy and arrhythmias.

 However, mefenamic acid can also inhibit certain types of potassium channels, such as ATP-sensitive potassium channels (KATP channels). This inhibition of KATP channels can lead to an increase in the excitability of cells, which can be harmful in conditions where excessive cell excitability is a problem, such as heart arrhythmias.

The effects of mefenamic acid on potassium channels are complex and depend on the type of channel, the concentration of mefenamic acid, and the cell type. More research is needed to fully understand the mechanisms by which mefenamic acid interacts with potassium channels and the implications for its potential therapeutic applications.

 

Apigenin in Down syndrome

 

Plant Compound Apigenin Reduces Cognitive Deficits in Mouse Model of Down Syndrome

Mice treated with apigenin had better memory and developmental milestone scores.

The plant compound apigenin improved the cognitive and memory deficits usually seen in a mouse model of Down syndrome, according to a study by researchers at the National Institutes of Health and other institutions.

Apigenin is found in chamomile flowers, parsley, celery, peppermint, and citrus fruits. The researchers fed the compound to pregnant mice carrying fetuses with Down syndrome characteristics and then to the animals after they were born and as they matured.

The findings raise the possibility that a treatment to lessen the cognitive deficits seen in Down syndrome could one day be offered to pregnant women whose fetuses have been diagnosed with Down syndrome through prenatal testing. The study appears in the American Journal of Human Genetics.

Down syndrome is a set of symptoms resulting from an extra copy or piece of chromosome 21. The intellectual and developmental disabilities accompanying the condition are believed to result from decreased brain growth caused by increased inflammation in the fetal brain.

Apigenin is not known to have any toxic effects, and previous studies have indicated that it is an antioxidant that reduces inflammation. Unlike many compounds, it is absorbed through the placenta and the blood brain barrier, the cellular layer that prevents potentially harmful substances from entering the brain.

Compared to mice with Down symptoms whose mothers were not fed apigenin, those exposed to the compound showed improvements in tests of developmental milestones and had improvements in spatial and olfactory memory. Tests of gene activity and protein levels showed the apigenin-treated mice had less inflammation and increased blood vessel and nervous system growth.

 

Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. In vitro, T21 cells cultured with apigenin had significantly reduced oxidative stress and improved antioxidant defense response. In vivo, apigenin treatment mixed with chow was administered prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, and males showed significantly more improvement than females. We demonstrated that the therapeutic effects of apigenin are pleiotropic, resulting in decreased oxidative stress, activation of pro-proliferative and pro-neurogenic genes (KI67, Nestin, Sox2, and PAX6), reduction of the pro-inflammatory cytokines INFG, IL1A, and IL12P70 through the inhibition of NFκB signaling, increase of the anti-inflammatory cytokines IL10 and IL12P40, and increased expression of the angiogenic and neurotrophic factors VEGFA and IL7. These studies provide proof of principle that apigenin has multiple therapeutic targets in preclinical models of DS.

 

Conclusion 

I am still delighted to have found a treatment for my son’s sound sensitivity, which got much more extreme almost overnight a couple of years ago.

I had already established long ago that he got short term sound sensitivity relief from taking a potassium supplement.  Some readers found a potassium supplement provided long term relief.

I thought that Ponstan might provide a good longer term solution and indeed it worked from the first pill.  This low dose therapy also works for other people with sound sensitivity, even one adult who has no autism.  The effective adult dose is 250 mg once a day.

Unlike other fenamate class drugs, like Diclofenac, Ponstan seems to be free from GI side effects at this low dose in most people.

Apigenin is an interesting alternative for those who do not tolerate Ponstan well, or who cannot access it.

A common link between what seems to improve sound sensitivity:

•                    Oral potassium

•                    Ponstan (Mefenamic acid)

•                    Apigenin

is potassium ion channels. 

If you ask Google’s AI program Bard, he will tell you:

“It is possible that all 3 substances could affect the same potassium ion channel in some cell types, but this has not been definitively shown. More research is needed to fully understand the effects of these substances on potassium ion channels.”

Technically Bard is genderless, but he is a reflection of the programmers behind the software. In our house he is called Bart anyway.

Bart does make mistakes, contradicts himself in the same answer and he gives you different answers if you ask the same question more than once. He is also prone to mixing things up, just like humans do.

Low dose Clonazepam for MIA Autism, Ponstan and TRPM3 in Intellectual Disability, Clemastine to restore myelination in Pitt Hopkins, Improving Oxytocin therapy with Maca, Lamotrigine for some autism

 

Monty in Ginza, Tokyo

Today’s post comes from Tokyo and looks at 5 therapies already discussed in previous posts and follows up on recent coverage in the research. They all came up in recent conversations I have been having.

·      Low dose Clonazepam  – Maternal Immune Activation model of autism

·      Ponstan – TRPM3 causing intellectual disability  (ID/MR)

·      Clemastine – improving myelination in Pitt Hopkins syndrome model

·      Oxytocin – Maca supplement to boost effect

·      Lamotrigine (an anti-epilepsy drug) to moderate autism

The good news is that many of same therapies keep coming up.

Ponstan and TRPM3 caused ID/MR

There is a lot in this blog about improving cognition, which is how I called treating ID/MR.  There are very many causes of ID and some of them are treatable.

ID/MR was always a part of classic autism and in the new jargon is part of what they want to call profound autism.

I was recently sent a paper showing how the cheap pain reliever Ponstan blocks the TRMP3 channel and that this channel when mutated can lead to intellectual disability and epilepsy.

Mefenamic acid selectively inhibits TRPM3-mediated calcium entry.

My own research has established that mefenamic acid seems to improve speech and cognition, as well as sound sensitivity.  The latter effect I am putting down to its effect on potassium channels. 

De novo substitutions of TRPM3 cause intellectual disability and epilepsy

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3’s S4–S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3’s flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.

 

Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3

This study reveals that mefenamic acid selectively inhibits TRPM3-mediated calcium entry. This selectivity was further confirmed using insulin-secreting cells. K_ATP channel-dependent increases in cytosolic Ca²⁺ and insulin secretion were not blocked by mefenamic acid, but the selective stimulation of TRPM3-dependent Ca²⁺ entry and insulin secretion induced by pregnenolone sulphate were inhibited. However, the physiological regulator of TRPM3 in insulin-secreting cells remains to be elucidated, as well as the conditions under which the inhibition of TRPM3 can impair pancreatic β-cell function. Our results strongly suggest mefenamic acid is the most selective fenamate to interfere with TRPM3 function. 

Here, we examined the inhibitory effect of several available fenamates (DCDPC, flufenamic acid, mefenamic acid, meclofenamic acid, niflumic acid, S645648, tolfenamic acid) on the TRPM3 and TRPV4 channels using fluorescence-based FLIPR Ca²⁺ measurements. To further substantiate the selectivity, we tested the potencies of these fenamates on two other TRP channels from different subfamilies, TRPC6 and TRPM2. In addition, single-cell Ca²⁺ imaging, whole-cell voltage clamp and insulin secretion experiments revealed mefenamic acid as a selective blocker of TRPM3.

  

Oxytocin

 Oxytocin does increase how emotional you feel; the difficulty is how to administer it in a way that provides a long lasting effect.  The half-life of oxytocin is a just minutes. The traditional method uses a nose spray.

I favour the use of a gut bacteria that stimulates the release of oxytocin in the brain.  The effect should be much longer lasting. Even then the effect is more cute than dramatic.

The supplement Maca does not itself produce oxytocin, but “it restores social recognition impairments by augmenting the oxytocinergic neuronal pathways”.

So Maca looks like an interesting potential add-on therapy to boost the effect of oxytocin.

One reader wrote to me with a positive report on using Maca by itself, without any oxytocin.

 

Oral Supplementation with Maca Improves Social Recognition Deficits in the Valproic Acid Animal Model of Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a congenital, lifelong neurodevelopmental disorder whose main symptom is impaired social communication and interaction. However, no drug can treat social deficits in patients with ASD, and treatments to alleviate social behavioral deficits are sorely needed. Here, we examined the effect of oral supplementation of maca (Lepidium meyenii) on social deficits of in utero-exposed valproic acid (VPA) mice, widely used as an ASD model. Although maca is widely consumed as a fertility enhancer and aphrodisiac, it possesses multiple beneficial activities. Additionally, it benefits learning and memory in experimental animal models. Therefore, the effect of maca supplementation on the social behavioral deficit of VPA mice was assessed using a social interaction test, a three-stage open field test, and a five-trial social memory test. The oral supplementation of maca attenuated social interaction behavior deficit and social memory impairment. The number of c-Fos-positive cells and the percentage of c-Fos-positive oxytocin neurons increased in supraoptic and paraventricular neurons of maca-treated VPA mice. These results reveal for the first time that maca is beneficial to social memory and that it restores social recognition impairments by augmenting the oxytocinergic neuronal pathways, which play an essential role in diverse social behaviors.

Maca (Lepidium meyenii) belongs to the cruciferous family and grows at high altitudes in Peru. In 2002, it was transplanted from Peru to the Yunnan Province of China. It is rich in dietary fiber; has many essential amino acids and nutrients including vitamin C, copper, and iron; and its root contains bioactive compounds. It is globally consumed and is popularly used as a fertility enhancer and aphrodisiac. On the other hand, with its potential to possess multi-nutritious components, it is reported to have diverse functions, including immunomodulation, antioxidant, antidepressant, antirheumatic, UV radiation protection, hepatoprotective, anti-fatigue, and neuroprotective effects. Interestingly, although the mechanism of the neuronal effect of maca is unclear, the uptake of maca extract improves learning and memory in memory-impaired model mice induced by either ethanol, ovariectomy, or scopolamine. However, the effects of maca on social memory impairment in neurodevelopmental disorders, including ASD, have not yet been tested.

In this study, the effects of maca on ASD animal models, in utero VPA-exposed mice, were investigated. The effect on social recognition by maca uptake with gavage was assessed using the social interaction test, a three-stage open field test, and the five-trail social recognition test. We also explored whether maca intake affects oxytocinergic signaling pathways, which play an important role in various social behaviors.

In this study, we showed that maca uptake rescues the deficits of social behavior and social recognition memory in VPA mice, a mouse model of autism. The c-Fos immunoreactivity of oxytocinergic neurons in SON and PVN increased significantly after maca treatment in VPA mice. Following previous studies indicating that OT administration ameliorates the impairment of social behavior in VPA mice, maca may also have improving effects on the deficit of social behavior and social recognition memory of VPA mice, probably by activating the OT neuronal pathway. Previous studies showed that maca could improve cognitive function in the mice model of impaired cognitive memory induced by either ovariectomy, ethanol, or scopolamine. Further studies are necessary to elucidate the potential link between maca and OT and to determine which components are involved in improving social recognition memory.

We have shown that maca improves the impairment of social memory and social behavioral deficits through oxytocinergic system modulation in this study. Although maca may not have an immediate effect on social behavioral deficits and takes days or weeks to demonstrate the effects, behavioral improvements, were visible regardless of the time of oral intake. The time between the very last oral intake of maca and the start of the social behavioral experiments in this study was more than 16 h. The duration of the maca’s effect on social behavioral deficits after the supplementation period is being investigated in our follow-up experiments. The possibility of the persistent effect of maca is very appealing, given that OT does not have a sustained effect due to its rapid metabolism, despite its immediate effects. Therefore, taking maca as a supplement while also receiving repeated OT treatment may have a synergistic, sustainable effect on improving social impairment in patients with ASD. Maca is already being used as a dietary supplement worldwide and has a high potential for practical applications.

 

This study showed for the first time that maca supplementation improves the impairment of social recognition memory in ASD model mice. We added the mechanism that social memory improvement may occur through the upregulation of oxytocinergic pathways. Maca highlights the possibility of treating social deficits sustainably in individuals with ASDs.

 

Low dose clonazepam

Professor Catterall was the brains behind low dose clonazepam for mice, I just translated it across to humans. It is one way to modify the E/I (excitatory/inhibitory) imbalance in autism.

I found that it gave a boost to cognition. Not as big as bumetanide, but worth having nonetheless.

I do not believe you have to be a bumetanide responder to respond well to low dose clonazepam.

Several people have written to me recently to say it works for their child.

Our reader Tanya is interested in the Maternal Immune Activation (MIA) trigger to autism. She highlighted a recent study showing how and why clonazepam can reverse autism in the MIA mouse model of autism. 

Clonazepam attenuates neurobehavioral abnormalities in offspring exposed to maternal immune activation by enhancing GABAergic neurotransmission

Ample evidence indicates that maternal immune activation (MIA) during gestation is linked to an increased risk for neurodevelopmental and psychiatric disorders, such as autism spectrum disorder (ASD), anxiety and depression, in offspring. However, the underlying mechanism for such a link remains largely elusive. Here, we performed RNA sequencing (RNA-seq) to examine the transcriptional profiles changes in mice in response to MIA and identified that the expression of Scn1a gene, encoding the pore-forming α-subunit of the brain voltage-gated sodium channel type-1 (Na_V1.1) primarily in fast-spiking inhibitory interneurons, was significantly decreased in the medial prefrontal cortex (mPFC) of juvenile offspring after MIA. Moreover, diminished excitatory drive onto interneurons causes reduction of spontaneous gamma-aminobutyric acid (GABA)ergic neurotransmission in the mPFC of MIA offspring, leading to hyperactivity in this brain region. Remarkably, treatment with low-dose benzodiazepines clonazepam, an agonist of GABA_A receptors, completely prevented the behavioral abnormalities, including stereotypies, social deficits, anxiety- and depression-like behavior, via increasing inhibitory neurotransmission as well as decreasing neural activity in the mPFC of MIA offspring. Our results demonstrate that decreased expression of Na_V1.1 in the mPFC leads to abnormalities in maternal inflammation-related behaviors and provides a potential therapeutic strategy for the abnormal behavioral phenotypes observed in the offspring exposed to MIA.

 

Pitt Hopkins – Clemastine and Sobetirome

Poor myelination is a feature of much autism and is a known problem in Pitt Hopkins syndrome.

I did cover a paper a while back where the Pitt Hopkins researchers showed that genes involved in myelination are down-regulated not only in Pitt Hopkins, but in several other popular models of autism.

From the multiple sclerosis (MS) research we have assembled a long list of therapies to improve different processes involved in myelination. Today we can add to that list sobetirome (and the related Sob-AM2). Sobetirome shares some of its effects with thyroid hormone (TH), it is a thyroid hormone receptor isoform beta-1 (THRβ-1) liver-selective analog.

Some people do use thyroid hormones to treat autism, and indeed US psychiatrists have long used T3 to treat depression.

The problem with giving T3 or T4 hormones is that it has body-wide effects and if you give too much the thyroid gland will just produce less.

One proposed mechanism I wrote about long ago is central hypothyroidism, that is a lack of the active T3 hormone just within the brain. One possible cause proposed was that oxidative stress reduces the enzyme D2 that is used to convert circulating prohormone T4 to T3. The result is that your blood test says your thyoid function is great, but in your brain you lack T3.

It looks like using sobetirome you can spice up myelination in the brain, without causing any negative effects to your thyroid gland.

Rather surprisingly, sobetirome is already sold as a supplement, but it is not cheap like Clemastine, the other drug used in the successful study below.

 

Promyelinating drugs promote functional recovery in an autism spectrum disorder mouse model of Pitt–Hopkins syndrome

Pitt–Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process caused by murine Tcf4 mutation is a cell autonomous reduction in oligodendrocytes and myelination. In this study, we show that the promyelinating compounds, clemastine, sobetirome and Sob-AM2 are effective at restoring myelination defects in a Pitt–Hopkins syndrome mouse model. In vitro, clemastine treatment reduced excess oligodendrocyte precursor cells and normalized oligodendrocyte density. In vivo, 2-week intraperitoneal administration of clemastine also normalized oligodendrocyte precursor cell and oligodendrocyte density in the cortex of Tcf4 mutant mice and appeared to increase the number of axons undergoing myelination, as EM imaging of the corpus callosum showed a significant increase in the proportion of uncompacted myelin and an overall reduction in the g-ratio. Importantly, this treatment paradigm resulted in functional rescue by improving electrophysiology and behaviour. To confirm behavioural rescue was achieved via enhancing myelination, we show that treatment with the thyroid hormone receptor agonist sobetirome or its brain penetrating prodrug Sob-AM2, was also effective at normalizing oligodendrocyte precursor cell and oligodendrocyte densities and behaviour in the Pitt–Hopkins syndrome mouse model. Together, these results provide preclinical evidence that promyelinating therapies may be beneficial in Pitt–Hopkins syndrome and potentially other neurodevelopmental disorders characterized by dysmyelination.

 

Sobetirome  (also called GC-1)

Sobetirome is a thyroid hormone receptor isoform beta-1 (THRβ-1) liver-selective analog.

In humans, sobetirome lowers plasma LDL cholesterol and reduced plasma triglycerides, while its liver-selective activity helped avoid the side effects seen with many other thyromimetic agents.

 

Myelin repair stimulated by CNS-selective thyroid hormone action

Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.

 

Compound protects myelin, nerve fibers

 

Research could be important in treating, preventing progression of multiple sclerosis, other neurodegenerative diseases

A compound appears to protect nerve fibers and the fatty sheath, called myelin, that covers nerve cells in the brain and spinal cord. The new research in a mouse model advances earlier work to develop the compound - known as sobetirome - that has already showed promise in stimulating the repair of myelin.

Lead author Priya Chaudhary, M.D., assistant professor of neurology in the OHSU School of Medicine who is focused on developing therapies for neurodegenerative diseases, said that the technique is a common step in drug discovery.

"It is important to show the effectiveness of potential drugs in a model that is most commonly used for developing new therapies," Chaudhary said.

The researchers discovered that they were able to prevent damage to myelin and nerve fibers from occurring, by stimulating a protective response in the cells that make and maintain myelin. They also reduced the activity of migroglia, a type of inflammatory cell in the brain and spinal cord that's involved in causing damage in multiple sclerosis and other diseases.

"The effects are impressive and are at least in part consistent with a neuroprotective effect with particular inhibition of myelin and axon degeneration, and oligodendrocyte loss," the authors write.

The discovery, if proven in clinical trials involving people, could be especially useful for people who are diagnosed with multiple sclerosis early in the disease's progression.

"The drug could protect the nervous system from damage and reduce the severity of the disease," Bourdette said.

 

Does Lamotrigine have the potential to 'cure' Autism?

Recently headlines appeared like this one:-

Scientists 'CURE autism' in mice using $3 epilepsy drug

It referred to the use of the epilepsy drug Lamotrigine to treat a mouse model of autism, caused by reduced expression of the gene MYT1L.

What the tabloid journalists failed to notice was that there has already been a human trial of Lamotrigine in autism.  That trial was viewed as unsuccessful by the clinicians, although the parents did not agree.

There were many comments in the media from parents whose child already takes this drug for their epilepsy and they saw no reduction in autism. There were some who found it made autism worse.

 

MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention

 

Lamotrigine therapy for autistic disorder: a randomized, double-blind, placebo-controlled trial

In autism, glutamate may be increased or its receptors up-regulated as part of an excitotoxic process that damages neural networks and subsequently contributes to behavioral and cognitive deficits seen in the disorder. This was a double-blind, placebo-controlled, parallel group study of lamotrigine, an agent that modulates glutamate release. Twenty-eight children (27 boys) ages 3 to 11 years (M = 5.8) with a primary diagnosis of autistic disorder received either placebo or lamotrigine twice daily. In children on lamotrigine, the drug was titrated upward over 8 weeks to reach a mean maintenance dose of 5.0 mg/kg per day. This dose was then maintained for 4 weeks. Following maintenance evaluations, the drug was tapered down over 2 weeks. The trial ended with a 4-week drug-free period. Outcome measures included improvements in severity and behavioral features of autistic disorder (stereotypies, lethargy, irritability, hyperactivity, emotional reciprocity, sharing pleasures) and improvements in language and communication, socialization, and daily living skills noted after 12 weeks (the end of a 4-week maintenance phase). We did not find any significant differences in improvements between lamotrigine or placebo groups on the Autism Behavior Checklist, the Aberrant Behavior Checklist, the Vineland Adaptive Behavior scales, the PL-ADOS, or the CARS. Parent rating scales showed marked improvements, presumably due to expectations of benefits.

One reader of this blog who heard all about the news and was sceptical, since after all it is a mouse model. Her 8 year old non-verbal child was not happy taking the drug Keppra and was already scheduled to try Lamotrigine. 

“Within a week his teacher called to say he was saying his ABCs, the next week he was counting out loud, the following month he’s attempting to repeat words of interest and this week he’s spelling animals by memory, dolphin, duck, wolf, chicken, pig, etc.

We are 2 months in and at 50mg, our target dose is 100mg bid. Obviously with our success, I’ve been working with his doctor and will continue to.”

 

Conclusion

Even though every day new autism research is published, there is so much already in this blog that not much appearing is totally new to regular readers.

We saw several years ago that low dose clonazepam should be beneficial to some people with autism, in particular Dravet syndrome. Today we learnt a little more about why Nav1.1 might be disturbed beyond those with Dravet syndrome. In the maternal immune activation model it seems to be a winner. It seems to benefit many of those who have trialed it.

Treating myelination deficits has been well covered in this blog. In previous posts we saw how Pitt Hopkins syndrome researchers showed how myelination gene expression was disturbed in a wide range of autisms. Today we saw evidence to support such therapy and we discovered a new drug.

Oxytocin does help some people with autism, but not as much as you might expect. Today we learnt of a potential add on therapy, a supplement called Maca.

The idea that anti-epilepsy drugs might help some autism has been well covered. From low dose valproate to low dose phenytoin from Dr Philip Bird in Australia.

Treatment of Autism with low-dose Phenytoin, yet another AED

Recent research suggested that Lamotrigine should help some with autism and today you learned that it really does help in one case. The fact that a tiny study a few years ago suggested no responders just tells us that only a small subgroup are likely to benefit.

We already know that some people's autism is made worse by their epilepsy therapy. This is just what you would expect. Time to find a different epilepsy therapy.

My favorite new therapy, low dose mefenemic acid / ponstan has numerous effects. One reader without autism, but with an unusual visual dysfunction (visual snow syndrome) and a sound sensitivity problem contacted me a while to see if NKCC1 might be the root of his problem. I suggested he try Ponstan, which did actually work for him and is easy to buy where he lives. Now he sends me research into all its possible modes of action. One mode of action relates to a cause of intellectual disability (ID/MR). Is this a factor in why Ponstan seems to improve speech and cognition in some autism? I really don't mind why it works - I just got lucky again, that is how I look at it. The more I read the luckier I seem to get.

Pleiotropy - your new BFF? SGLT2 inhibitors and targeting the NLRP3 inflammasome to target neurological disorders from Autism to ALS and Alzheimer’s

Pleiotropy 

from Greek πλείων pleion, 'more'

and τρόπος tropos, 'way'

 

 

Today’s post introduces a new term – SGLT2.

Depending how old you are, you will be aware of the term BFF – Best Friend Forever.  These days you can have several BFFs, not just one. 

Pleiotropy (play-o-tropy) is a rather nice sounding word that was brought into use in science and medicine by a German geneticist Ludwig Plate in 1910. Pleiotropic effects of a drug are any beneficial secondary effects.

Statins are the classic example. They were developed to lower cholesterol, but many of the positive effects experienced by users have nothing to do with cholesterol, they lower inflammation (and more besides).  It is now thought that inflammation in your arteries triggers a protective layer of cholesterol to be deposited. As the decades pass, this protective layer grows and ends up causing all kinds of problems.

When you repurpose an old drug for a new use, you are taking advantage of its pleiotropic effects.  For readers of this blog pleiotropy is a friend, and quite possibly a BFF.

 

SGLT2

Today we look at repurposing a class of drugs that lowers blood sugar for those with type 2 diabetes to treat a wide range of brain disorders.

We also look at a cheap pain killer that can be used to disrupt an inflammatory pathway key to most brain disorders and even some cancers.

Our reader Eszter did recently highlight a very well written paper about the potential to repurpose SGLT2 inhibitors to treat autism. Eszter knows a lot about neurology, I should point out.

Eszter has previously commented on the interesting overlap between drugs that provide a benefit in Alzheimer’s and those that benefit some autism.  She will likely find the link at the very end of this post of interest.

 

Repurposing SGLT2 Inhibitors for Neurological Disorders: A Focus on the Autism Spectrum Disorder 

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a substantially increasing incidence rate. It is characterized by repetitive behavior, learning difficulties, deficits in social communication, and interactions. Numerous medications, dietary supplements, and behavioral treatments have been recommended for the management of this condition, however, there is no cure yet. Recent studies have examined the therapeutic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitors in neurodevelopmental diseases, based on their proved anti-inflammatory effects, such as downregulating the expression of several proteins, including the transforming growth factor beta (TGF-β), interleukin-6 (IL-6), C-reactive protein (CRP), nuclear factor κB (NF-κB), tumor necrosis factor alpha (TNF-α), and the monocyte chemoattractant protein (MCP-1). Furthermore, numerous previous studies revealed the potential of the SGLT2 inhibitors to provide antioxidant effects, due to their ability to reduce the generation of free radicals and upregulating the antioxidant systems, such as glutathione (GSH) and superoxide dismutase (SOD), while crossing the blood brain barrier (BBB). These properties have led to significant improvements in the neurologic outcomes of multiple experimental disease models, including cerebral oxidative stress in diabetes mellitus and ischemic stroke, Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy. Such diseases have mutual biomarkers with ASD, which potentially could be a link to fill the gap of the literature studying the potential of repurposing the SGLT2 inhibitors' use in ameliorating the symptoms of ASD. This review will look at the impact of the SGLT2 inhibitors on neurodevelopmental disorders on the various models, including humans, rats, and mice, with a focus on the SGLT2 inhibitor canagliflozin. Furthermore, this review will discuss how SGLT2 inhibitors regulate the ASD biomarkers, based on the clinical evidence supporting their functions as antioxidant and anti-inflammatory agents capable of crossing the blood-brain barrier (BBB).

 

Recently I was asked by one researcher reader where is the evidence to support my suggestion that Ponstan (Mefenamic Acid) can enhance cognition.  I was not sure that I would find evidence that relates to actual humans, but I did. This took me back to the time this blog looked into the NLRP3 inflammasome.

Just like the new generation of type 2 diabetes drugs have pleiotropic effects on the brain, so do Fenamate class NSAIDs, specifically Ponstan.

There are four SGLT2 inhibitors approved to treat type 2 diabetes

·        Invokana (canagliflozin)

·        Farxiga (dapagliflozin)

·        Jardiance (empagliflozin)

·        Steglatro (ertugliflozin)

To be effective inside the brain such a drug would need to be small and lipid (fat soluble) enough to get across the blood brain barrier.

If the idea of a diabetes drug helping brain disorders sounds strange, consider what we have already come across in previous posts in this blog.

  

Other Type 2 drugs with pleiotropic effects

 

Metformin

Metformin was discovered exactly 100 years ago, in 1922.  It is not a new drug and it is the world’s most common therapy for type 2 diabetes.

It has been suggested metformin can delay the onset of aging and also the onset and development of Alzheimer’s.

The use of metformin has repeatedly associated with the decreased risk of the occurrence of various types of cancers, especially of the pancreas and colon and hepatocellular carcinoma.

Metformin has been shown to raise IQ in children with Fragile-X syndrome by about 10%.

Some people with autism do take metformin, in others it provides no benefit.

 

Glitazones

Glitazones are a class of anti-diabetic drug that started to get popular from the year 2000. They  work by stimulating  peroxisome proliferator-activated receptor gamma (PPAR-γ) receptor. They will activate PGC-1 alpha, which we know is the key regulator of mitochondrial biogenesis. For some strange reason, glitazone drugs are not used to treat mitochondrial disease.

Glitazones have broad anti-inflammatory pleiotropic effects.

Pioglitazone has been researched in autism and I have used it for several years as a spring and summertime add-on therapy in Monty’s PolyPill.

 

Back to Eszter’s paper

 

I highlight some of the tables, which do summarize the beneficial effects.

 

Inflammatory signals promote inflammation by activating the microglia and astrocytes within the brain in ASD. SGLT2 inhibitors influence on the inflammation and neuroinflammation, SGLT2 inhibitors decrease the inflammatory factors levels, such as the M1 macrophages, STAT1 inflammatory transcription factor, cytokine interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), and vascular cell adhesion protein (VCAM) in neurodevelopmental diseases

 

 

Distribution of the SGLT receptors in the CNS. 1. Brain cortex (pyramidal cells); 2. Purkinje neurons; 3. Hippocampus; 4. Hypothalamus; 5. Micro vessels; 6. Amygdala cells; 7. Periaqueductal gray; 8. Dorsomedial medulla.

 

Such a distribution of the SGLT2 receptors [114] could potentially be responsible for their intriguing neuroprotective qualities, which could be beneficial in several neurological disorders, including ASD [99]. The SGLT2 inhibitors’ proposed mechanisms are presented in Figure 3. The antioxidant effect of the SGLT2 inhibitors can be attributed to their stimulatory action on the nuclear factor erythroid 2 (Nrf2)- related factor 2 pathway [115]. This displays the antioxidant activity because of their genetic expression of the antioxidant proteins, including glutathione-s-transferase (GST), SOD, and NADPH quinone dehydrogenase-1 to protect against cellular apoptosis [116]. The anti-inflammatory characteristics of the SGLT2 inhibitors could be accredited to the downregulation of NF-KB, which decreases IL-1β and the TNF-α expression [117]. Empagliflozin has the highest selectivity for the SGLT2 receptors (2500-fold) when compared to dapagliflozin which has (1200-fold) selectivity, and canagliflozin (250-fold) [118,119]. Therefore, in the context of the neuroprotective effects associated with the SGLT1 and SGLT2 receptors’ inhibition, canagliflozin was hypothetically preferred over other SGLT2 inhibitors, due to its dual SGLT1/SGLT2 inhibition capability [120].

 

SGLT2 inhibitors have the potential to improve ASD patients’ behavioral and brain disruptions by increasing the cerebral brain derived neurotrophic factor and reducing the cerebral oxidative stress, including elevated the GSH and catalase activity, reduced MDA, amyloid β levels, plaque density, and acetylcholinesterase

 

ASD remains a global health dilemma, as it is a chronic condition, and is incurable, leading to a reduced quality of life. It is crucial to find the mutual molecular mechanisms of ASD and redefine the indications for the well-studied medication with numerous pleiotropic effects to find a solution. This review has disclosed the impact of the SGLT2 inhibitors in neurological diseases, which could relate to ASD as it shares multiple pathways and mutual biomarkers. SGLT2 inhibitors display several neuroprotective properties, highlighting their therapeutic potential for ASD patients, as these agents have the capability to inhibit the acetylcholinesterase enzyme, reduce the elevated levels of the oxidative stress in the brain, and restore the anabolism and catabolism balance. Moreover, clinical intervention studies are vital to determine whether the displayed methods are useful as the SGLT2 inhibitors have never been tested on ASD directly. Currently, our research team is conducting a preclinical experiment to assess the effects of canagliflozin on the VPA-induced ASD in Wistar rats.

  

Back to the NLRP3 Inflammasome

Ponstan (Mefenamic acid) is one of the few available drugs that is known to be a potent inhibitor of an inflammatory pathway called the NLRP3 inflammasome.  It is mainly present macrophages, a type of white blood cell in the immune system.  The role of macrophages includes gobbling up pathogens.  

In the brain the microglia are the resident macrophages.  The microglia have multiple functions in the brain and we know that in autism they can be stuck in an overactivated state and then do not fulfil their other functions.

In many diseases activation of the NLRP3 inflammasome in local macrophages occurs.  Inhibiting this process can disrupt the disease process.

My guess is that this is the mechanism by which Ponstan is improving cognition in some of the people with autism who are taking it.

In the paper below we see that people taking Ponstan to treat their prostate cancer (PCa) experience an improvement in their cognition.

 

Improve cognitive impairment using mefenamic acid non-steroidal anti-inflammatory therapy: additional beneficial effect found in a controlled clinical trial for prostate cancer therapy 

Inflammation is an essential component of prostate cancer (PCa), and mefenamic acid has been reported to decrease its biochemical progression. The current standard therapy for PCa is androgen deprivation therapy (ADT), which has side effects such as cognitive dysfunction, risk of Alzheimer’s disease, and dementia. Published results of in vitro tests and animal models studies have shown that mefenamic acid could be used as a neuroprotector. Objective: Examine the therapeutic potential of mefenamic acid in cognitive impairment used in a controlled clinical trial. Clinical trial phase II was conducted on patients undergoing ADT for PCa. Two groups of 14 patients were included. One was treated with a placebo, while the other received mefenamic acid 500 mg PO every 12hrs for six months. The outcome was evaluated through the Mini-Mental State Examination (MMSE) score at six months. At the beginning of the study, both groups had similar MMSE scores (mefenamic acid vs. placebo: 26.0±2.5 vs. 27.0±2.6, P=0.282). The mefenamic acid group improved its MMSE score after six months compared with the placebo group (27.7±1.8 vs. 25.5±4.2, P=0.037). Treatment with mefenamic acid significantly increases the probability of maintained or raised cognitive function compared to placebo (92% vs. 42.9%, RR=2.2, 95% CI: 1.16-4.03, NNT=2.0, 95% CI: 1.26-4.81, P=0.014). Furthermore, 42.9% of the placebo group patients had relevant cognitive decline (a 2-point decrease in the MMSE score), while in patients treated with mefenamic acid, cognitive impairment was not present. This study is the first conducted on humans that suggests that mefenamic acid protects against cognitive decline.

 

In the AEA mouse model of MS (multiple sclerosis) we see the role again of NLRP3 on cognition. 

Inhibition of the NLRP3-inflammasome prevents cognitive deficits in experimental autoimmune encephalomyelitis mice via the alteration of astrocyte phenotype 

Some studies have indicated that NLRP3 inflammasome activation is involved in mediating synaptic dysfunction, cognitive impairment, and microglial dysfunction in AD models, and that the inhibition of the NLRP3 inflammasome attenuates spatial memory impairment and enhances Aβ clearance in AD model.  However, there is no research on NLRP3 inflammasome in MS-related cognitive deficits. In our study, we found that microglia and NLRP3 inflammasome were activated in the hippocampus of EAE mice, while pretreatment with MCC950 inhibited the activation of microglia and NLRP3 inflammasome

 

Again, we see a benefit from inhibiting NLRP3 in Alzheimer’s. 

Novel Small-Molecule Inhibitor of NLRP3 Inflammasome Reverses Cognitive Impairment in an Alzheimer’s Disease Model

Aberrant activation of the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays an essential role in multiple diseases, including Alzheimer’s disease (AD) and psoriasis. We report a novel small-molecule inhibitor, NLRP3-inhibitory compound 7 (NIC7), and its derivative, which inhibit NLRP3-mediated activation of caspase 1 along with the secretion of interleukin (IL)-1β, IL-18, and lactate dehydrogenase. We examined the therapeutic potential of NIC7 in a disease model of AD by analyzing its effect on cognitive impairment as well as the expression of dopamine receptors and neuronal markers. NIC7 significantly reversed the associated disease symptoms in the mice model. On the other hand, NIC7 did not reverse the disease symptoms in the imiquimod (IMQ)-induced disease model of psoriasis. This indicates that IMQ-based psoriasis is independent of NLRP3. Overall, NIC7 and its derivative have therapeutic prospects to treat AD or NLRP3-mediated diseases.

 

What about sepsis (blood poisoning)? 

Mitochondrial protective effects caused by the administration of mefenamic acid in sepsis

The pathophysiology of sepsis may involve the activation of the NOD-type receptor containing the pyrin-3 domain (NLPR-3), mitochondrial and oxidative damages. One of the primary essential oxidation products is 8-oxoguanine (8-oxoG), and its accumulation in mitochondrial DNA (mtDNA) induces cell dysfunction and death, leading to the hypothesis that mtDNA integrity is crucial for maintaining neuronal function during sepsis. In sepsis, the modulation of NLRP-3 activation is critical, and mefenamic acid (MFA) is a potent drug that can reduce inflammasome activity, attenuating the acute cerebral inflammatory process. Thus, this study aimed to evaluate the administration of MFA and its implications for the reduction of inflammatory parameters and mitochondrial damage in animals submitted to polymicrobial sepsis. To test our hypothesis, adult male Wistar rats were submitted to the cecal ligation and perforation (CLP) model for sepsis induction and after receiving an injection of MFA (doses of 10, 30, and 50 mg/kg) or sterile saline (1 mL/kg). At 24 h after sepsis induction, the frontal cortex and hippocampus were dissected to analyze the levels of TNF-α, IL-1β, and IL-18; oxidative damage (thiobarbituric acid reactive substances (TBARS), carbonyl, and DCF-DA (oxidative parameters); protein expression (mitochondrial transcription factor A (TFAM), NLRP-3, 8-oxoG; Bax, Bcl-2 and (ionized calcium-binding adaptor molecule 1 (IBA-1)); and the activity of mitochondrial respiratory chain complexes. It was observed that the septic group in both structures studied showed an increase in proinflammatory cytokines mediated by increased activity in NLRP-3, with more significant oxidative damage and higher production of reactive oxygen species (ROS) by mitochondria. Damage to mtDNA it was also observed with an increase in 8-oxoG levels and lower levels of TFAM and NGF-1. In addition, this group had an increase in pro-apoptotic proteins and IBA-1 positive cells. However, MFA at doses of 30 and 50 mg/kg decreased inflammasome activity, reduced levels of cytokines and oxidative damage, increased bioenergetic efficacy and reduced production of ROS and 8-oxoG, and increased levels of TFAM, NGF-1, Bcl-2, reducing microglial activation. As a result, it is suggested that MFA oinduces protection in the central nervous system early after the onset of sepsis.

  

Conclusion

One reader of this blog attributes her son’s autism to his sepsis (blood poisoning) at birth. It is pretty clear from one of today’s papers that perhaps babies with sepsis should be treated with Ponstan (Mefenamic acid) to prevent damage to their brain.  I was recently contacted by another parent where sepsis occurred at birth. 

I think the researchers make a strong case that the pleiotropic effects of SGLT2 inhibitors that benefit Alzheimer’s, Parkinson’s and ALS very likely will also be beneficial in some autism.  They plan to test canagliflozin on rats with valproic acid-induced autism.

I have to say to Eszter that I actually think inhibiting the NLRP3 inflammasome might be the Neurologist’s best friend forever (BFF), perhaps even better than an SGLT2 inhibitor.

What is for sure is that both (SGLTi and NLRP3i) should be subject of clinical trials in autism. I suggest going straight humans rather than rats.

I have had positive feedback so far on my suggestion that low dose (250 mg) Ponstan/Mefenamic acid could be an effective long term autism therapy.  We do have to mention that Knut Wittkowski has patented its use in autism; he proposed it as a preventive measure in 2-3 year olds to redirect severe non-verbal autism towards Asperger’s. I selected it to treat extreme sound sensitivity, but later witnessed its pleiotropic effects.

If anyone has experience on the use of an SGLT2 inhibitor in autism, I would be very interested to read about it.

We should add Ponstan to the long list of drugs in this autism blog that may be beneficial in MS (Multiple sclerosis). (ALA, Clemastine, NAG, Ibudilast, DMF, Ponstan etc).

P.S.

A last word from Google

Having noted my recent googling activity, I was today sent the following news item by Google. 

Harnessing the Brain’s Immune Cells to Stave off Alzheimer’s and Other Neurodegenerative Diseases

Researchers have identified a protein that could be leveraged to help microglia in the brain stave off Alzheimer’s and other neurodegenerative diseases

But how does SYK protect the nervous system against damage and degeneration? We found that microglia use SYK to migrate toward debris in the brain. It also helps microglia remove and destroy this debris by stimulating other proteins involved in cleanup processes. These jobs support the idea that SYK helps microglia protect the brain by charging them to remove toxic materials.