MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

nemoci-sympt/METABOLISMUS/downuv-syndrom/90-podpurna-terapie

Možné terapeutické úrovně při DS

  • Most of these therapies have been tested in the Ts65Dn mouse
  • Therapies, which have been selected according to different rationales, can be variously classified
  • Five major classes

(A) Therapies targeted to transmitter systems

  • More than one half of the studies (32 out of a total of 55) that have attempted to rescue DS brain phenotypes have used drugs that act on transmitter systems
  • Many transmitter systems are altered in DS
  • By correcting altered synaptic function it may be possible to reinstate signal transfer
    • Activity-dependent cellular functions

(i) Therapies enhancing cholinergic trasmission

  • In order to counteract age-related damage of the cholinergic systems;
  • Therapies acting on the cholinergic system may belong to class A of this review as well as to class B

(ii) Therapies antagonizing GABAergic transmission

  • In order to reduce excessive inhibition
  • Most of the studies belonging to class A focus on the GABAergic system
    • Excessive inhibition characterizes the trisomic brain
    • It may be possible to normalize its function by reducing inhibition
  • Memory can be improved by antagonizing GABA receptors

(iii) Therapies enhancing noradrenergic transmission

  • In order to compensate for dysfunctions of noradrenergic afferents to the hippocampus

(iv) Therapies targeted to the glutamate NMDA receptor

(v) Therapies targeted to the serotonergic system

(vi) Therapies targeted to the endocannabinoid system

  • In order to increase its activity

(B) Therapies employing neuroprotective agents

  • Antioxidants, and free radical scavengers
  • In order to reduce neurodegeneration
    • A typical feature of the DS brain
  • Second most numerous group of therapies belongs to class B
  • Rationale for the wide use of neuroprotective agents or antioxidants depends on the fact that the trisomic brain undergoes neurodegeneration and develops an Alzheimer's-like pathology with age
  • Neuroprotective agents may prevent or delay neurodegeneration

(C) Therapies targeted to perturbed signaling pathways.

(D) Therapies to normalize the expression of proteins coded by triplicated genes

(E) Therapies that are known to have a proneurogenic effect.

Limitace klinických studií

  • Calculated the minimumsample size required to detect a 6-point (half a standard devi-ation) difference in IQ to be 170 individuals with DS (i.e. 85in each of the treatment and control groups), assuming apower of 90% and 5% level of significance
  • Most of the studies were of short duratio
  • Načasování - po skončení maximální fáze neurogeneze už nemusí fungovat výrazně ani jiank celkem účinné látky


Užívaná suplementace při DS

  • 49% of responders currently/previously gave their child supplement
  • Average child received 3 supplements (ranging from 1-18)
    • Nutrivene,
    • curcumin,
    • Green tea extract
  • Were most common
  • Over 150 different products were reported
  • Supplementation began most often in infancy,
    • Generally between age 4 and 6 months.
  • Average cost was $90.53/month.
  • 87% of users noted improvement, mainly in speech, immunity, and attention
  • 17% reported side-effects
    • Predominantly gastrointestinal disturbance
  • Lack of improvement and cost were the main reasons for discontinuation.
  • Most parents learned of supplements through a parent group or friend.
  • In almost 20%, the pediatrician was unaware of the supplement use.
  • www.jpeds.com/article/S0022-3476(18)30735-2/fulltext

Úvahy

Nejlepší kompenzační zásahy budou přímo potlačovat konkrétní geny/enzymy, které jsou zmnožené:

  • Dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1 A (DYRK1A)
      • Brain development and learning and memory (Altafaj et al., 2001; Park et al., 2009)
  • Regulator of calcineurin 1 (RCAN1)
    • Role in cell growth and immune responses , in cognition (Dierssen et al., 2011; Mendez-Barbero et al., 2013)
  • Cystathionine beta-synthase (CBS)
    • Homocysteine/folate/transulfuration pathways (Iacobazzi et al., 2014);
  • Superoxide dismutase 1 (SOD1)
  • Triplication of some microRNAs (miRNAs)
    • Particular miR-155 (Mashima, 2015)
      • Modulate target genes (Quinones-Lombrana and Blanco, 2015)
  • Formimidoyltransferase cyclodeaminase (FTCD)
    • Enzyme that participates in histidine and folate metabolism
  • Phosphofructokinase (PFK)
  • ADAMTS1
  • APP (amyloid-beta precursor protein)
  • GABPA
  • HSPA13
  • LIPI
  • NRIP1
  • Hsa-mir-99a
  • www.frontiersin.org/articles/10.3389/fnins.2020.00670/full
  • SOD1 (superoxide dismutase-1)
  • DYRK1A (dual specificity tyrosine Y-regulation kinase 1A)
  • EURL (beta-catenin signaling modulator)
  • CBS (cystathionine-beta synthase)
  • OLIG1 and OLIG2 (oligodendrocyte transcription)
    • OLIG1/2 responsible for myelinating cells and oligodendrocyte differentiation
  • IFNAR (alpha-interferon receptor)
  • CBR1 and CBR2 (carbonyle reductase)
  • S100B (glial function in neurons)
  • ERG (regulator of hemato-immune cells)
    • Triplication contributes to dysregulation of the homeostatic proportion of the populations of immune cells in the embryonic brain and decreases prenatal cortical neurogenesis in a mouse model.
  • DSCR1 (inhibitor of calcineurin-mediated signaling)
  • RCAN1 (calcineurin regulator)
  • ETS2 (encoding a transcription factor)
  • Hsa21 harbors four major types of micro RNAs
    • MiRNA-99a, miRNA-125b, miRNA-155, and miRNA-802
      • Short non-coding RNAs mediating post-transcriptional gene silencing

Úvaha po čtení

  • Některé geny i když jsou zmnoženy, nemusí nutně konstantně být přepisovány a tvořit nadbytečné proteiny/enzymy - ale za určitých situací se to může a dít a pravděpodobně děje
  • Utišení přepisu genů - tedy metylace ap. jako epigenetický vliv bude tedy možná důležitý prvek
  • Podpora metylace nadbytečné DNA by mohla pomáhat mírnit nerovnováhy vlivem trizomie a inhibice nadměrné demetylace / konzumace demetylátorů by pak mohly být také součástí nějakých podpůrných opatření

7,8-dihydroxyflavone (7,8-DHF)

  • Possesses powerful antioxidant properties independent of its actions on the TrkappaB receptor

Ts65Dn mice in the postnatal period (from P3 to P15)

  • Restores their hippocampal neurogenesis and dendritic spine development
  • Since 1 month after cessation of the treatment
    • These mice did not show any learning and memory improvement
  • Administered from P3 to adolescence
    • Enhanced the learning and memory abilities of Ts65Dn mice
  • no benefits on the cognitive abilities of these animals were found when they received 7,8-DHF during adulthood (from 5 months of age for a period of 6 weeks)
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7464577/
  • 7,8-DHF
    • A natural mimetic of BDNF
    • Activating the TRKB receptor may compensate for the reduced levels of BDNF in the DS brain
  • 7,8-DHF administered neonatally caused restoration of hippocampal development.
  • Administration of 7,8-DHF from postnatal day 3 to adolescence led to a restoration of memory.
  • amsdottorato.unibo.it/8353/

ALGERNON (altered generation of neurons)

Murine models of DS

  • Restored NSC proliferation
    • Increased the number of newborn neurons

DS mouse dams and embryos

  • ALGERNON to pregnant dams rescued aberrant cortical formation
    • Prevented the development of abnormal behaviors in DS offspring
  • A growth inducer newly identified in our screen of neural stem cells (NSCs)
  • Potent inhibitory activity against dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A)
  • Found to rescue proliferative deficits in Ts65Dn-derived neurospheres and human NSCs derived from individuals with DS !!!
  • Oral administration of this compound, named ALGERNON (altered generation of neurons)
    • Neurogenic phenotype of DS can be prevented by ALGERNON prenatal therapy

ARN23746

  • New chemical class of selective NKCC1 inhibitors
  • Restores the physiological intracellular Cl- in murine Down syndrome neuronal cultures,
  • Has excellent solubility and metabolic stability
  • Displays no issues with off-target activity in vitro.
  • Recovers core symptoms in mouse models of Down syndrome and autism,
    • no diuretic effect, nor overt toxicity upon chronic treatment in adulthood.
  • ARN23746 is ready for advanced preclinical/manufacturing studies toward the first sustainable therapeutics for the neurological conditions characterized by impaired Cl- homeostasis.
  • www.sciencedirect.com/science/article/pii/S2451929420302989

Alpha-lipoic acid and L-cysteine

Supplementation for several treatment cycles

Aminocure

  • Long-term experience in administration of amino acids in infants with Down syndrome
    • Well pronounced results in all cases
  • Improve in speech,
  • Cognitive function,
  • Physical developments
  • Social behavior.
  • In many cases the typical face features of this group of infants who have received amino acids become less expressed.
  • All children who received amino acids in the long-term do well attending neighborhood schools alongside peers who don't have Down syndrome.
  • Some of the infants with Down syndrome could develop mild speech and mental retardation, whilst some of them could have severe forms of mental and speech retardation (some of them never learn to speak).
  • Getting amino acid treatment early – often when they are just babies
    • Can lead to healthier, happier and more independent lives
  • Children treated with amino acids usually attend schools, do well alongside other children, do sports, develop well physically and some of them have only slight, unapparent features of a Down syndrome person.
  • www.aminocure.net/Down-syndrome-and-other-hereditary-diseases

Aminooxyacetate (AOAA)

  • Inhibition of CBS by aminooxyacetate (AOAA), which interferes with the pyridoxal phosphate in the catalytic site
      • CBS je enzym, který je nadměrně aktivní a z methioninu a cysteinu syntetizuje nadbytek H2S, které je toxické (jako CO)
    • Restored Complex IV activity and ameliorated mitochondrial electron transport and cell proliferation !!!

Synonyma

  • Aminooxyacetic,
  • Aminooxyacetic Acid
  • Carboxymethoxyamine
  • 2-aminooxyacetate
  • 2-aminooxyethanoate
  • 2-(aminooxy)acetate
  • Hydroxylamine-O-acetic acid
  • CHEBI:157642, A20598, ...
  • O-(Carboxymethyl)hydroxylamine hemihydrochloride
  • (Aminooxy)acetic acid hemihydrochloride
  • Hydroxylamine-O-acetic acid hemihydrochloride
  • (Carboxymethoxy)amine hemihydrochloride

NÚ

  • Blokáda alanine transaminase
  • Těžko tedy říct, zda je to použitelné in vivo a jestli je to benfit nebo riziko - dohledat...

Antagonizing GABA receptors


Antagonizing the NMDA receptor


Apigenin

  • FDA-approved antioxidant small molecule, when administered to pregnant female mice, significantly improved the postnatal exploratory behavior in the open field of their Ts1Cje pups, and thus it may serve as a potential candidate for prenatal therapy
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7464577/
  • Tedy hodně petržele aj. nebo prášek do jídla...
  • apigenin, a natural antioxidant and anti-inflammatory compound found in
    • Citrus fruit
    • Green leafy vegetables
  • High-priority candidate molecule to reverse the gene expression pattern observed in second-trimester fetuses with DS
  • Amniocytes from fetuses with trisomy 21 with different concentrations of apigenin
    • Up to 2 µm are not toxic (i.e., they do not affect cell proliferation)
    • Concentration statistically significantly reduced oxidative stress
  • Ts1Cje dams were fed 200 mg/kg/d of apigenin with powdered laboratory chow from the time of conception throughout their pregnancies
    • Apigenin treatment normalized brain gene expression in some differentially regulated genes
    • Shortened the time it took to achieve neonatal developmental milestones
    • Improved performance on the open field test
  • Preliminary data provide proof of principle that functional genomic analysis of the human fetal transcriptome can provide a rational basis for drug discovery in DS.
  • www.jneurosci.org/content/35/41/13843

Astaxanthin


Vitamin B12 and folate

  • Tyto reakce má DS asi zvýšené
    • Nižší hladina homocysteinu asi riziko není
    • Ale možná zvýšeným metabolismem hrozí deplece vit. B12 (nezbytný kofaktor pro buněčné dělení - to je další věc, která může limitovat rozvoj nerovvé soustavy a růst) a k. listové do jiných reakcí (?)
  • Dá se někde dohledat, jak je to s hladinou B12 u DS (?)

Vitamin B6

  • Alternative pathway to convert homocysteine to sulfur amino acids
  • Sirné sloučeniny, těch má také vyšší množství
    • Tedy zase může hrozit deficit vit. B6
    • V detoxikaci a deoxidaci sirnýchsloučenin se uplatňuje i molybden (může být citlivější na jeho deficit) (?)
      • Dá se to někde dohledat (?)

Basmisanil

  • A longitudinal validation study of several cognitive scales (for example, the Leiter Performance Scale-Revised and the Clinical Evaluation of Language Fundamentals-Preschool-2) currently used to assess memory, executive function, and language in individuals with DS [66] served for optimizing trial design and endpoint selection in a clinical trial testing
  • A negative allosteric modulator of GABA receptor alpha5-subtype.
  • The trial revealed no improvement of cognitive abilities in individual with DS.
  • www.aimspress.com/article/doi/10.3934/Neuroscience.2020012?viewType=HTML


Bumetanide

  • FDA-approved potent loop diuretic (LD) that acts by antagonizing sodium-potassium-chloride (Na-K-Cl) cotransporters, NKCC1 (SLc12a2) and NKCC2
  • NKCC1 is expressed both in the CNS and in systemic organs
  • NKCC2 is kidney-specific
  • Bumetanide
    • Reduces (Cl-)i levels
    • Restores GABAergic inhibition
    • Attenuates the severity of electrical or behavioral manifestations in many pathological conditions
  • Used since 1975 in adults
  • Since 1986 in children to treat
    • Hypertension,
    • Bronchopulmonary dysplasia,
    • Nephritic syndromes
    • Congestive heart failure
  • It failed to meet efficacy criteria for hypoxic-ischemic encephalopathy (HIE) neonatal seizures.
  • Positive outcomes in temporal lobe epilepsy (TLE), autism, and schizophrenia trials

Autistické děti (2–18 years old)

  • 88 dětí - in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months
  • Mean CARS value was significantly improved in the completers group (P: 0.015)
  • 23 treated children had more than a six-point improvement in the CARS x placebo
  • Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02).
  • The most frequent adverse events were
    • Hypokalemia,
    • Increased urine elimination,
    • Loss of appetite,
    • Dehydration
    • Asthenia
  • Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily
    • Improved gradually with oral potassium supplements.
  • Incidence of adverse event were directly correlated with the dose of bumetanide

Butyrát

  • Neuroprotekce před glutamátovou excitotoxicitou
    • Zklidňuje a zlepšuje soustředění
  • Zároveň hojí střevo

Pozor na krční páteř

  • Parents should be counseled about sports with increased risk of spinal injury, such as football, soccer, and gymnastics.
  • Children with C1-C2 instability or subluxation may require specific teraphy

Coenzyme Q10 treatment

4 mg/kg/day for 20 months to children and teenagers with DS Tiano et al.

  • Reduction in DNA damage in peripheral blood leukocytes

long-term supplementation (4 years) of this coenzyme

  • Did not affect RNA or DNA oxidation in children with DS
  • Different results reported between these studies may be due to the
    • Different biomarkers used to quantify oxidative stress and antioxidant activity
    • Different cells or tissues used for each study
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7464577/

ELND006

  • An inhibitor of gamma-secratase
  • Blocks the formation of a small APP-derived peptide which inhibits the activity of the SHH pathway
    • Thereby reducing neurogenesis
  • ELND006 restored neurodevelopment of the hippocampal formation of Ts65Dn mice
    • Most of these effects were retained at one month after treatment cessation
  • amsdottorato.unibo.it/8353/

Epigallocatechin gallate (EGCG) - CAVE - bude důležitá správná dávka

  • Major catechin in green tea
  • Induce neuronal plasticity (Martinez Cue and Dierssen, 2020)
  • And mitochondrial function (Valenti et al., 2016)
  • Leading to cognitive rehabilitation in young adult DS (De La Torre et al., 2016).
  • DYRK1A is one of the triplicated genes that is thought to be strongly involved in brain alterations

Dyrk1A transgenic mice

  • Epigallocatechin gallate (EGCG), an inhibitor of DYRK1A, improves cognitive performance
  • Suggesting that EGCG may represent a suitable treatment of DS

Ts65Dn mouse model of DS

  • EGCG restores hippocampal development, although this effect is ephemeral
  • no effects of treatment on hippocampus-dependent memory

Pilot study in young adults with DS !!

  • EGCG transiently improves some aspects of memory
  • EGCG plus cognitive training engenders effects that are more prolonged. !!

Lymphoblast and fibroblast cultures from DS subjects

A child (10-year and 3-monh-old) with DS

  • Treated with ECCG (10 mg/kg/day) plus fish oil daily for six months
  • Treatment was safe and improved mitochondrial function

young adults with DS (29 subjects) aged 14–29 years

  • Green tea extracts in capsule form (Mega Green Tea Extract, Lightly Caffeinated, Life Extension®, USA)
    • Containing EGCG (mean EGCG oral dose of 9 mg/kg/day) (6 females, 7 males)
  • Or a placebo (8 females, 8 males)
  • For three months
  • Neuropsychological performance were examined
    • After 3 months of treatment
    • 3 months after treatment discontinuation
  • After 3 months of treatment, EGCG-treated individuals showed
    • A significantly higher percentage of correct answers in visual memory recognition x placebo
  • Three months after treatment discontinuation
    • This effect declined returned to baseline measures
  • Treatment with EGCG has a positive effect on cognition in DS, albeit relatively moderate and transitory

84 subjects of adults (age: 16–34 years) with DS

  • Enrolled and treatment lasted 12 months
  • 23 the same group examined the effect of cognitive training alone or cognitive training plus green tea extract supplement
    • 45% EGCG (Life Extension Decaffeinated Mega Green Tea Extract; Life Extension ®, USA)
    • Mean EGCG oral dose was 9 mg/kg/day
  • Tested with a battery of neuropsychological tests periodically during treatment, at 12 months
    • Immediately following treatment cessation
    • 6 months after treatment discontinuation
  • At 12 months, there were significant differences between the two groups in two of the 15 tests developed for testing cognitive performance and in one of the nine adaptive skills
  • Subjects that received cognitive training plus EGCG
    • Had a better performance in these three tests in comparison with the group that received cognitive training only.
  • Some of these effects persisted in the cognitive training plus EGCG group
  • Treatment has gender- and/or age-dependent effects

2016 study by De la Torre et al., treatment with EGCG was combined with cognitive training

  • Green tea extracts contain various polyphenols in addition to EGCG
    • Contribution of these polyphenols to cognitive improvement remains to be clarified

Various rodent models

  • Positive impact of EGCG on brain and behavior
    • Other studies show no effect
    • Possibly due to heterogeneity of protocols/timing/species
  • EGCG seems to exert some beneficial effects on the brain
  • Among the several inhibitors of DYRK1A, epigallocatechin gallate (EGCG) is one of the most specific
  • EGCG, which is the major catechin in the leaves of green tea
    • Can cross the blood- and placental barrier

Treatment of Dyrk1A transgenic mice with a polyphenol-based diet

  • From gestation to adulthood
    • Correct brain morphogenesis alterations

Dyrk1A transgenic mice

  • Treated with EGCG for one month starting from 21 d of age
    • Undergo restoration of hippocampal neurogenesis

Adult Dyrk1A transgenic mice

  • A 4–6 week administration of green tea extracts rescues defective long-term potentiation in the prefrontal cortex

adult mBACtgDyrk1A mice

  • Treatment with extracts containing EGCG
    • Restores components of GABAergic and glutamatergic pathways in the cortex and hippocampus
    • Improves behavioral deficits
  • EGCG-improved-three-areas-of-cognitive-function">www.medicalnewstoday.com/articles/310799#Daily-dose-of-EGCG-improved-three-areas-of-cognitive-function
  • Recent studies show the protective effect of EGCG, the major catechin in green tea
    • Induce neuronal plasticity (Martinez Cue and Dierssen, 2020)
    • mitochondrial function (Valenti et al., 2016)
    • Leading to cognitive rehabilitation in young adult DS (De La Torre et al., 2016)
  • Takže o to lepší by to mohlo být u malých dětí...
  • www.frontiersin.org/articles/10.3389/fnins.2020.00670/full
  • EGCG, the most common bioactive catechin present in green tea
    • Potent and selective inhibitor of DYRK1A activity
  • Administration of these polyphenols restores the impairment of mitochondrial bioenergetics and biogenesis
    • Improving the activity of mitochondrial respiratory chain complexes and ATP production
    • Promotes the proliferation of neuronal progenitor cells isolated from the hippocampus of the Ts65Dn mouse

Oral administration of EGCG to Ts65Dn mice (2–3 mg/day)

  • Normalizes the activity of DYRK1A
  • Improves the cognitive abilities of these mice

Administration of EGCG to adults with DS (9 mg/kg/day) for 6 months

  • Also produced benefits in different cognitive parameters

EGCG during prenatal stages to Ts65Dn mice

  • Exerted beneficial effects on neurogenesis
  • Immediately after the discontinuation of the treatment, these effects were not maintained 1 month later

EGCG administered at early postnatal stages to Ts65Dn mice

  • Failed to improve cognition
  • Induced skeletal anomalies

EGCG in children with this syndrome

  • Must carefully choose the dosage and duration of the treatment at different life stages
    • In order to obtain beneficial effects on cognition while avoiding undesirable side-effects.

A randomized, double-blind, placebo-controlled, phase 2 trial conducted with young adults with DS

  • Treated with EGCG (9 mg/kg/day)
  • For 12 months
  • Improved visual recognition memory, inhibitory control, and adaptive behavior

Case report, Vacca and Valenti

  • EGCG, a natural inhibitor of the kinase DYRK1A, whose overactivity in the DS brain negatively affects neurogenesis
  • EGCG had short-term but not long-term effects on hippocampal development and behavior
  • amsdottorato.unibo.it/8353/

“Egcg, a dyrk1a Inhibitor as Therapeutic Tool for Reversing Cognitive Deficits in Down Syndrome Individuals” (ClinicalTrials.gov Identifier: NCT01394796)

“Normalization of dyrk1A and APP Function

  • As an Approach to Improve Cognitive Performance and Decelerate AD Progression in DS Subjects: Epigallocatechin Gallate as Therapeutic Tool” (ClinicalTrials.gov Identifier: NCT01699711)
  • ClinicalTrials.gov/show/NCT01699711

  • High doses of EGCG have hepatotoxic effects (Lambert et al., 2009)
  • EGCG administered to pregnant rats does not have teratogenic effects (Isbrucker et al., 2006)
  • Not known whether EGCG may have adverse effects during pregnancy in humans
  • A clinical trial for young adults with DS (De la Torre et al., 2014)
    • Positive effect of treatment with EGCG on behavior tends to disappear with time.
  • Neonatal treatment with EGCG rescued hippocampal development in the Ts65Dn mouse model, similarly to that with fluoxetine.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4594009/

Fluoxetine (Prozac), Dexmethylphenidate (Focalin XR) and Ginkgo biloba, Phosphatidylcholine, 'Body Bio Balanced Oil' and folinic acid

  • Families and healthcare professionals should understand that use of the protocol at this time is essentially experimental
    • None of the benefits of a controlled trial
  • Monitoring for adverse effects would be the responsibility of the prescribing physician

Fluoxetine (Prozac)

  • Used to treat depression, obsessive-compulsive disorder, bulimia nervosa and panic disorder
  • The action of fluoxetine on the growth of new nerve cells seen in one part of the brain of Ts65Dn mice has not been replicated in humans.
  • Potential impact on developing minds of babies and young children is unknown

Dexmethylphenidate (Focalin XR)

  • Used for the treatment of attention deficit and hyperactivity disorder (ADHD)
  • Initiated and monitored by an appropriately qualified physician
  • no scientific evidence to support the use of any of this protocol with people with Down syndrome of any age
  • Nor is there any evidence that this protocol is safe for routine use with people who have Down syndrome.
  • The few studies referenced in support of this protocol are studies of mice
  • Changing Minds Foundation promotional videos do not prove the claims of benefit from the protocol
    • People shown are clearly doing well
    • None of the individuals shown are functioning beyond the wide range seen in others with the syndrome

Bilobalide, a component of Ginkgo Biloba


Fluoxetine

Euploid and Ts65Dn mice - fluoxetine during the first two postnatal weeks

  • 45–60 days after treatment cessation
  • In treated Ts65Dn mice all aberrant features were fully normalized
    • Indicating that fluoxetine can rescue functional connectivity between the DG and CA3
  • Fluoxetine - full recovery of neurogenesis of granule cell precursors in the DG, consistently with evidence from adult Ts65Dn mice
  • Positive effects of fluoxetine on the DG-CA3 system suggest that early treatment with this drug could be a suitable therapy, possibly usable in humans, to restore the physiology of the hippocampal networks and, hence, memory functions.
  • Mice received a daily subcutaneous injection (at 9–10am) of fluoxetine (Sigma-Aldrich)
    • In 0.9% NaCl solution from P3 to P15 (dose: 5 mg/kg from P3 to P7; 10 mg/kg from P8 to P15)
    • Maximum daily dose of 10 mg/kg because, due to the extremely short half-life of fluoxetine in rodents compared to humans
    • Dose is thought to produce a brain concentration of a magnitude similar to that of 20–60 mg taken daily by humans
  • journals.plos.org/plosone/article?id=10.1371/journal.pone.0061689

  • “Other parents whose kids are taking Prozac also feel that their kids are performing ahead of their peers with Down syndrome,” says Watson. “But we don’t really know. That’s why we want a drug trial. We wanted to legitimize it with a formal study.”
  • Fluoxetine works by increasing the availability of serotonin, a neurotransmitter, which plays a role in mood but also in regulating the formation of neurons in the developing brain.
  • www.technologyreview.com/2016/01/12/247076/parents-turn-to-prozac-to-treat-down-syndrome/
  • Fluoxetine use in early pregnancy
    • Has been associated with a slightly increased risk of specific cardiovascular malformations (Reefhuis et al., 2015)
  • Another recent study conducted on a large cohort of subjects
    • Approximately 36,700 exposed infants and 2,200,000 unexposed infants
    • Indicates that there is not a substantial teratogenic effect of SSRI
      • Including fluoxetine, during the first trimester of pregnancy (Furu et al., 2015)
  • Exposure to antidepressants (including fluoxetine) during the second and third trimester
    • Does not have substantial effects on milestones of development (Einarson et al., 2009; Pedersen et al., 2010).
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4594009/

Perinatal fluoxetine treatment at the Southwestern Medical Center of the University of Texas

Rizika

  • Fluoxetine did not measurably improve behavioral impairments of Ts65Dn mice.
  • Seizures and mortality in fluoxetine-treated Ts65Dn mice
    • Raising the possibility of a drug × genotype interaction with respect to these adverse treatment outcomes.
  • Future studies should re-address this in larger animal cohorts and determine if fluoxetine treatment is associated with adverse treatment effects in individuals with Down syndrome.
  • www.hindawi.com/journals/np/2012/467251/
  • Compounds that inhibit RCAN1 can restore normal mitochondrial function. One target for her research is the common antidepressant fluoxetine (brand name Prozac)
    • Already given off-label by some parents to children with Down syndrome.
  • Although fluoxetine is widely known as a selective serotonin reuptake inhibitor (SSRI)
    • It can also have direct effects on mitochondria, according to Dr. Rothermel.
  • www.utsouthwestern.edu/ctplus/stories/2019/rothermel-nih-grant.html

Kontrola a kompenzace hormonů štítnice


Hyperphenylalaninemia

  • Hyperphenylalaninemia is the term used to describe the mildest manifestation of phenylalanine hydroxylase deficiency
  • Broadly defined blood phenylalanine exceed the limits of the upper reference range (2 mg/dL or 120 µmol/L)
    • Without treatment
  • Phenylalanine levels that exceed 20 mg/dL (1200 µmol/L)
    • Considered typical of classic PKU (see Phenylketonuria)
  • 2014, the American College of Medical Genetics and Genomics released a practice statement that recommended that PKU and hyperphenylalaninemia both be considered part of the spectrum of phenylalanine hydroxylase (PAH) deficiency.
  • Phenylalanine levels of 6 mg/dL (360 µmol/L) or less in patients consuming an unrestricted diet
    • Generally considered to be a benign condition
    • No dietary phenylalanine restrictions are usually recommended in this instance
  • Dietary restriction is generally indicated among patients whose phenylalanine levels are more than 12 mg/dL (725 µmol/L)
    • Chronic phenylalanine levels in this range reportedly cause measurable intellectual impairment in children !!!
  • Dietary treatment vary in children with phenylalanine levels in the intermediate range of 7-11 mg/dL (425-660 µmol/L)
  • Most centers in the United States recommend restricting dietary phenylalanine when levels exceed 10 mg/dL (600 µmol/L)
  • Some also recommend treatment for levels that exceed 8-9 mg/dL (480-545 µmol/L)
  • The British Medical Research Council Working Party on PKU recommends dietary phenylalanine restriction when levels consistently exceed 6.6-10 mg/dL (400-600 µmol/L)


INDY

  • Novel Dyrk1A inhibitor
  • Benzothiazole derivative
  • Showing a potent ATP-competitive inhibitory effect with IC50 and Ki values of 0.24 and 0.18 mcM,
  • Dyrk1A/INDY complex revealed the binding of INDY in the ATP pocket of the enzyme
  • INDY
    • Effectively reversed the aberrant tau-phosphorylation
    • Rescued the repressed NFAT (nuclear factor of activated T cell) signalling induced by Dyrk1A overexpression

proINDY

  • A prodrug of INDY
  • Effectively recovered Xenopus embryos from head malformation induced by Dyrk1A overexpression
    • Resulting in normally developed embryos and demonstrating the utility of proINDY in vivo.
  • www.nature.com/articles/ncomms1090

Inhibice MMP 9

  • Overexpression of metalloproteinase 9 (MMP-9) in DS
    • Tedy rychlejší mizení vaziva i kostí !!!
  • Mnohé fenolické látky blokují MMP-9 (Dr. Landa může namíchat čaj)
    • Samotný epigalokatechin gallát ze zelného čaje je jedna taková
  • pubmed.ncbi.nlm.nih.gov/29342922/

Interact with GSK3beta


Inverse agonists selective for the ?5-subunit containing receptor

  • Reduce inhibitory GABAergic transmission
  • Could rescue learning and memory deficits in Ts65Dn mice
  • Improve cognition without inducing seizures
    • Remains particularly difficult when using GABA antagonists

Intranasal insulin administration při rozvoji Alzheimerovy demence (tedy kognitivní zhoršení)

  • Brain insulin resistance could be one of these molecular pathways in AD
  • Proved to ameliorate cognitive decline in AD subjects
  • Effects are even better when insulin is administered in the early stages of the pathology (e.g., MCI) (Craft et al., 2012, 2017; Claxton et al., 2013, 2015)

Kofein

Study by De la Torre et al. on mBACtgDyrk1A mice





Kurkumin

  • Malé dávky podporují hypermetylaci a uspání některých genů (těch má o 21. chormozom navíc) a angioneogenezi
  • Velké dávky jsou rizikové - podporují demetylaci DNA - odkrytí (a mohly by se ev. víc přepisovat enzymy, které jsou navíc) a blokují novotvorbu cév
  • Curcumin protects the brain by directly
    • Binding with toxic metals
    • Protects the brain from oxidative damage and inflammation
  • Bind effectively metals such as iron and copper giving it a neuroprotective role with enhanced radical scavenging efficacy.

Ts65Dn mouse prenatally or during early postnatal stages

  • Increased the brain weight, density of proliferating and mature hippocampal cells
  • Produced a long-term improvement of cognition in the Ts65Dn mouse

Postnatal administration

  • Did not induce any beneficial effect in the altered phenotypes of these animals
  • curcumin is currently being evaluated in clinical trials, its antioxidant and pro-cognitive effects should also be assessed in the DS population.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7464577/

Large neutral aminoacids (LNAA)

  • Součást diety při vyšší hladině fenylalaninu
  • Ratio of tryptophan to LNAA
    • Fairly good indicator of central serotonin synthesis

Leucovorin - folinic acid

The intent-to-treat analysis (113 patients)

  • Did not show a positive effect of +++leucovorin treatment daily dose of 1.0+/-0.3 mg/kg+++ on cognitive function
  • Per protocol analysis of 87 patients (43 LV-treated vs. 44 patients on placebo) revealed a positive effect of leucovorin on
    • Developmental age (DA)
    • DA was 53.1% the normal value with leucovorin and only 44.1% with placebo (p<0.05)
    • This positive effect of leucovorin was particularly strong in patients receiving concomitant thyroxin treatment (59.5% vs. 41.8%, p<0.05)
  • No adverse event related to leucovorin was observed.
  • Results suggest that leucovorin improves the psychomotor development of children with Down's syndrome, at least in some subgroups of the DS population, particularly those on thyroxin treatment.
  • pubmed.ncbi.nlm.nih.gov/20084109/

Selenium 10 mug, zinc 5 mg, vitamin A 0.9 mg, vitamin E 100 mg, and vitamin C 50 mg), folinic acid (0.1 mg) x placebo

  • Vzhledem k váze takto starých dětí (3 a více kg), v této studii podávali 3 a vícekrát nižší dávku leukovorinu oproti té předchozí - možná je to příčina toho, proč jejich výsledky nebyly signifikantní



Lithium


Luteolin

  • Induces hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome
  • [ Wen-Bo ZhouZong-Ning MiaoBin ZhangWei LongFang-Xiu ZhengJing KongBin YuORCID ID ] 2019
  • Natural flavonoid luteolin

mouse model of Down syndrome Ts65Dn mice

  • Neurotrophic activity
  • Intraperitoneally injected with 10 mg/kg luteolin for 4 consecutive weeks starting at 12 weeks of age
  • Luteolin improved learning and memory abilities as well as novel object recognition ability
  • Enhanced the proliferation of neurons in the hippocampal dentate gyrus
  • Luteolin increased expression of nestin and glial fibrillary acidic protein
  • Increased the number of DCX+ neurons in the granular layer and NeuN+ neurons in the subgranular region of the dentate gyrus
  • Increased the protein levels of BDNF and p-ERK1/2 in the hippocampus
  • Luteolin improves behavioral performance and promotes hippocampal neurogenesis in Ts65Dn mice
  • Effects might be associated with the activation of the BDNF/ERK1/2 pathway
  • journals.scholarsportal.info/details/16735374/v14i0004/613_lihnittmmods.xml&sub=all
  • V jablku aj. rosltinách, možná už jde sehnat i v doplňku

Melatonin

  • Pokud je snížená hladina serotoninu bude málo i melatoninu a ten je důležitý proti oxidačnímu stresu a k regeneraci !!!
  • melatonin could serve as a potential therapeutic agent for age-related neurodegeneration and cognitive decline in adults with DS.
    • Due to a variety of physiological and metabolic advantages, the protective effects of this indoleamine against oxidative damage are more potent than those induced by vitamins C or E
  • Approved for human use, it is normally well tolerated in adults
  • Does not cause significant adverse events
  • It is already used in the treatment of other neurodegenerative diseases in which OS is enhanced.
  • Clinical trials should assess the efficacy of melatonin to reduce OS, to restore neuronal function and to delay the age-related progression of cognitive alterations in the DS population.

Memmantine

“Down Syndrome Memantine Follow-up Study”

“Efficacy and Safety of Memantine Hydrochloride in Enhancing the Cognitive Abilities

“Memantine and Down's Syndrome”

“Down Syndrome Memantine Follow-up Study”

  • Study participants were men and women with Down syndrome aged 40 years or older or individuals of any age with Down syndrome and an established diagnosis of dementia.
  • Jan 2012 disappointing turn for Down's syndrome (DS) research, a trial
  • January 10 in the Lancet
    • Neither improved cognition nor activities of daily living in people with DS, aged 40 and older
    • Clear lack of benefit in these individuals [ Clive Ballard, Kings College London, UK]
  • Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist
    • Supposed to prevent excitotoxicity that occurs when excess glutamate is released at the synapse in diseases such as Alzheimer's
  • Memantine improved activities of daily living and cognitive function in people with advanced Alzheimer's
  • In transgenic mouse models of DS, memantine rescued learning and memory deficits and improved spatial learning and memory (see AbstractCosta et al., 2008; Rueda et al., 2010; Lockrow et al., 2011)
  • 173 DS patients over the age of 40, many with clinically diagnosed dementia
    • 88 receive memantine 10 mg daily x 85 placebo for 52 weeks
  • Small, heterogenous sample (some of whom did not have dementia) gave the study only enough statistical power to pick up a moderate to large effect, he said
    • Failed to find one, but "that doesn't mean there can't be a small effect," said Schneider.
  • Lotta Granholm-Bentley, Medical University of South Carolina, agreed that the heterogeneity of the subject pool may have influenced the results. "
  • Memantine in DS, led by Alberto Costa, University of Colorado, Denver
    • Efficacy of the drug in 40 young adults (aged 18-30) with DS
  • www.alzforum.org/news/research-news/memantine-strikes-out-downs-syndrome

Aktivní studie

  • Problém samozřejmě může být dán tím, že u dospělých je neurogeneze už za zenitem...

Metformin

  • metformin and GLP1 mimetics
    • Promising results in animal models of AD (Jha et al., 2017; Holscher, 2018)
  • Insulin signaling activation regulates mitochondrial functions (Butterfield et al., 2014a; Abad et al., 2019; Wardelmann et al., 2019)
    • Mitochondria are dysfunctional in DS (Mollo et al., 2020)
    • Rescuing insulin signaling activation in DS would be beneficial
  • Metformin, a well-known drugs used to treat insulin resistance
    • Was effective in recovering mitochondrial structure and functions in trisomic cells (Izzo et al., 2018)!!

Minocycline

  • Seems to have neuroprotective effects and inhibit neuron apoptosis. Three months of treatment in 10-month old Ts65Dn mice significantly improved performance in cognitive tasks (p < 0.05) [71]. Chen et al. [72] observed that glial cells (astrocytes) supplying nutrients to the neurons and detoxifying the extracellular milieu in neutralizing excess glutamate, induced in vitro from stem cells derived from fibroblasts of persons with DS, do not favor in vivo neurogenesis when transplanted into iPSCs mice brains. Minocycline corrects this deficiency by modulating the expression of gene S100B, located on chromosome 21 at locus 21q22.3. This gene regulates various cellular processes including the glial function.
  • www.aimspress.com/article/doi/10.3934/Neuroscience.2020012?viewType=HTML

N-acetyl cystein

  • NAC reduces oxidative stress, protects neurons, and increases intracellular glutathione
    • Benefit Alzheimer’s, Parkinson’s, Down’s, and other neurodegenerative diseases

In vitro

  • NAC has been shown to protect neuronal migration in Down’s models


NAP and SAL

  • The neuroprotective peptides
  • Can be orally administered
  • NAP penetrates cells and crosses the blood-brain barrier after nasal or systemic administration.
    • This would make treatment of individuals with DS easily feasible.
  • Peptides do not seem to have adverse effects in animal models
  • Functional behavioral assays in rats show no adverse side effects with NAP concentrations that are approximately 500-fold higher than the biologically active dose (see Gozes et al., 2008)
  • Beneficial effects of embryonic treatment on learning and memory in the Ts65Dn mouse model suggest that these peptides may be employed for prenatal treatment in DS.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4594009/

Nikotin ribosid + pterostilben


Oleic acid

  • Early postnatal oleic acid administration enhances synaptic development and cognitive abilities in the Ts65Dn mouse model of Down syndrome
  • Because oleic and linolenic fatty acids
    • Enhance neurogenesis, synaptogenesis, and cognitive abilities in rodents and humans
  • Administration of oleic or linolenic acid did not modify cell proliferation immediately after treatment discontinuation or several weeks later.
  • Oleic acid
    • Increased the total number of DAPI+ cells (+ 26%),
    • The percentage of BrdU+ cells that acquired a neural phenotype (+ 9.1%),
    • The number of pre- (+ 29%)
    • Post-synaptic (+ 32%) terminals
    • Cognitive abilities of TS mice (+ 18.1%)
  • In contrast, linolenic acid only produced a slight cognitive improvement in TS mice. (+12.1%).
  • www.tandfonline.com/doi/full/10.1080/1028415X.2020.1861897
  • Tedy olivový olej... !! (spolu s rybím tukem)


Dieta s mírným omezením fenylalaninu

  • Asi zdaleka nebude muset být tak náročná jako při PKU, pokud screening nezachytil jasnou PKU
    • Nicméně co zmiňované defekty biopterinového metabolismu a snížené aktivity fenylalanin hydroxylázy
  • Vhodná konzultace v metabolické poradně stran diety / suplementace

Pentylenetetrazole


Pyrimethamine

  • Is safe and well tolerated in ALS
  • Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations.
  • Ann Neurol 2017;81:837–848
  • Pyrimethamine was supplied in 25mg tablets (CorePharma, Middlesex, NJ)
  • Target dose was 75mg, based on our experience in the first study
    • 100mg was poorly tolerated
    • But 75mg was deemed to be a dose that most patients could tolerate over an extended period of time
  • Started taking a 25mg tablet daily together with 5mg leucovorin twice daily
  • Leucovorin remained at the same dose for the duration of the study
  • Pyrimethamine dose increased to 37.5mg at 3 weeks, 50mg 6 weeks, 62.5mg at 9 weeks, and 75mg at 12 weeks
  • Patients remained at 75mg for the duration of the study (36 weeks) if tolerated.
  • www.readcube.com/articles/10.1002%2Fana.24950

RG1662

“A Study of RG1662 in Adults and Adolescents With Down Syndrome (CLEMATIS)”

“A Study of RG1662 in Individuals With Down Syndrome”

  • RG1662, a GABAA?5 (GABRA5) negative allosteric modulator (NAM), on quantitative EEG (qEEG) in young adults with Down syndrome (DS)
  • Gamma oscillations are generated by synchronization of pyramidal neurons by fast-spiking GABAergic interneurons
  • RG1662 is a highly selective NAM of GABA-A receptors containing the GABRA5 subunit, a target for enhancement of cognition

Randomized, double blind, placebo-controlled, multiple ascending dose study in young adults with DS aged 18-30 years

  • Received placebo, 80, 160, or 370 mg BID of RG1662 for 5 weeks (n = 8 per group)
  • EEG recordings were obtained at baseline, day 1, and day 10
  • There were no EEG signs of epileptiform abnormality
  • Statistically significant (p < 0.001) dose-dependent increases in gamma power after 10 days of dosing with RG1662
  • Dose-dependent lowering of the DS index
  • RG1662 modulated carbachol-induced gamma oscillations in hippocampal brain slices of WT mice, but not GABRA5 KO mice
  • GABRA5 inhibition results in clear qEEG effects in young adults with DS
    • May be a useful pharmacodynamic biomarker for this class of compounds
  • n.neurology.org/content/84/14_Supplement/P6.273
  • A Phase 1 clinical trial will look at the safety and tolerability of compound RG1662 in people with DS
  • Sponsored by F. Hoffmann-La Roche Ltd., Basel, Switzerland
  • An inverse agonist of the GABAA receptor
    • Evidence suggests is overactive in the DS brain
  • Earlier work demonstrating rescue of cognition and long-term potentiation in mouse models of DS (see ARF related news story)
  • www.alzforum.org/news/research-news/memantine-strikes-out-downs-syndrome

Recombinant human growth hormone

Treatment of children with Down syndrome and growth retardation with (C Torrado 1 , W Bastian, K E Wisniewski, S Castells)

  • Recombinant human growth hormone on children with Down syndrome who had growth retardation and microcephaly was examined.
  • 13 children with trisomy 21 without congenital heart disease who were
    • Short for age (-1.19 to -3.5 standard deviation score)
    • Microcephalic (-1.58 to -6.60 standard deviation score)
  • Were given recombinant human growth hormone, 0.1 mg/kg subcutaneously, 3 days a week for 1 year
  • Before treatment, peak serum growth hormone concentrations were less than 10 micrograms/L
    • After levodopa and clonidine stimulation tests in 5 patients
    • After clonidine in 3 patients
    • After levodopa in 3 patients
  • Patients had nocturnal integrated growth hormone concentrations of 0.5, 1.5 and 0.65 micrograms/L, respectively
  • Mean growth rate before treatment was 5.4 +/- 1.6 cm/yr
    • Increased to 12.2 +/- 3.2 cm/yr (p less than 0.001) after 12 months of recombinant human growth hormone treatment
  • Mean head circumference standard deviation score before treatment was -3.1 +/- 1.3
    • Increased to -2.3 +/- 1.2 (p less than 0.001) at 12 months
  • Bone age before and 1 year after treatment increased in correspondence with chronologic age
  • Insulin-like growth factor I at baseline and at 12 months were 0.54 +/- 0.19 U/ml
    • 1.25 +/- 0.97 U/ml po terapii (p less than 0.02)
  • Recombinant human growth hormone therapy can result in a significant increase in annual growth rate and head circumference in children with Down syndrome, without significant side effects
  • Vzhledem k tomu, že růst obvodu hlavičky velmi úzce souvisí s růstem i mozku, očekávala bych i zlepšení mentálního stavu a o terapii bych měla zájem. Dohledat víc.

GH on linear growth and psychomotor development in young children with Down's syndrome

  • Fifteen children with Down's syndrome 3 years from the age of 6 to 9 months (mean, 7.4)
  • GH treatment results in normal growth velocity in Down's syndrome
    • But does not affect head circumference or mental or gross motor development.
    • Growth velocity declines after treatment stops.
  • pubmed.ncbi.nlm.nih.gov/10086938/
  • Aha, tak žádná sláva
  • Both GH and GnRH have demonstrated potent neurotrophic, neuroprotective, and neuroregenerative action.
  • Positive behavioral and cognitive effects are also associated with GH and GnRH administration. Increasing evidence suggests the possibility of a multifactorial therapy that includes both GH and GnRH.
  • It is very likely that the improvement in the fine-tuning control of movement observed in Down’s syndrome patients treated with GH involves the action of GH and IGF-I in the cerebellum
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC5855597/
  • no vida, něco přecijen může dělat...
  • Hippocampal neurotransmission is improved by GH administration, facilitating the excitatory activity of glutamate receptors (AMPA and NDMA) in both young and old rats and enhancing basal and long-term potentiation (LTP)
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC5855597/

Resveratrol

  • A polyphenol isolated from
    • Grapes,
    • Red wine,
    • Peanuts,
    • Berries
  • Low bioavailability, and so far its efficacy on the DS population has not been assessed
    • Proto by šlo místo toho zkusit podat PTEROSTILBEN (analog, který lépe vleze do CNS)
      • Synergicky funguje s nikotinribosidem
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7464577/

SAG - synthetic activator of the Sonic hedgehog (Shh) pathway

  • The cerebellum is disproportionately small in the Ts65Dn mouse
  • Individuals with DS and has a reduced number of granule neurons and Purkinje cells
  • Trisomic granule cell precursors show a reduced response to the Sonic hedgehog protein signal in vitro (Roper et al., 2006)
  • Trisomic mice a single systemic treatment with SAG at birth
    • Was found to increase neurogenesis
    • Restore granule cell precursor populations if mice were tested at 6 days old (Roper et al., 2006)
  • Effect of a single neonatal injection of SAG
    • Resulted in normal cerebellar morphology in tests carried out when mice reached 4 months of age (Das et al., 2013)
  • 6 days after a single neonatal injection of SAG
    • There was no improvement in the dentate gyrus proliferation deficit in Ts65Dn mice (Das et al., 2013)
    • SAG may differentially affect different neural precursor cell populations
  • Neonatal treatment with SAG
    • Restored performance in a hippocampal-dependent task (MWM) and LTP at the synapse Schaffer collaterals-CA1 when mice were 4 months old (Das et al., 2013)
  • Newborn mice received a single injection of SAG
  • SAG treatment failed to rescue long-term cerebellar-based learning in mice aged 4 months.
  • The lack of effect may be attributable to the persistence of altered granule cell electrophysiological properties and to the fact that in Ts65Dn mice there are fewer Purkinje cells
    • The proliferation of which cannot be affected by treatment in view of their embryonic birth date (Sillitoe and Joyner, 2007; Sudarov and Joyner, 2007).

Selen

  • Component of GSH-Px which is part of thebody’s endogenous antioxidant system

10 mcg of selenium/kg/day was administered to 48 individuals with DS aged 1 to 16 years for 6 months

  • Immunoglobulin G2 and G4 increased by up to 33% and 75% respectively
  • Participants also reported fewer infections during the study

15- 25 mcg of selenium/kg/day to 7 individuals with DS aged 1 to 54 years

  • As an essential micronutrient with important antioxidant actions through the modulation of the activity of antioxidant enzymes such as GPx

Supplementation over a period of 6 months to children with DS

Pokud to nebylo spojené se zvýšením oxidačního stresu, tak to nemuselo znamenat nic zlého, třeba jen že volné radikály začal deaktivovat i jiný na selenu závislý enzym...

Selenium, zinc, vitamins A, E, and C and folinic acid (leukovorin)

Infants less than 7 months old with trisomy 21 for 3–8 months

  • Did not produce any effect on language acquisition, psychomotor development, or in the levels of certain biochemical markers of OS
  • Authors propose could be due to the low dose of the supplements or the short duration of the treatment (18 months)

Folate

Later study, oral daily long-term (12 months) folate supplementation at high doses to children with DS

  • (aged between 3 and 30 months)
  • Slightly improved their psychomotor development
  • But did not produce any changes in sociability, language, or coordination

Zinc, vitamins A, C, E, B1, B2, B3, B6, B9, B12

Another study, after 6 months of supplementation with a mixture of different nutrients

  • To older children with ages ranging between 5 and 16 years
  • Cholinesterase activity increased in the serum of children with DS
  • Significant improvement in their cognitive skills and behavioral patterns
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7464577/

Symptomatická terapie při DS

  • MDD, we typically begin with selective serotonin reuptake inhibitors (SSRIs)
  • Bipolar disorder - often use carbamazepine
  • Psychotic symptoms - begin with risperidone or aripiprazole
  • Anxiety - buspirone
  • Obsessional slowness/OCD - begin with an SSRI
  • Stereotypical repetitive behavior - tend to use buspirone
  • ADHD - begin with guanfacine
  • Irritability of comorbid ASD - risperidone or aripiprazole
  • Dementia in DS - refer to a neurologist for medical work-up and medication management
  • Catatonia-like ‘regression’ - lorazepam
    • If ineffective, we use memantine or clozapine
  • Electroconvulsive therapy is considered if pharmacotherapy is ineffective
  • ‘regression’ with symptoms of MDD ± psychosis - antidepressant and an antipsychotic if needed
  • Randomized controlled trials of medications for comorbid psychiatric disorders in DS are warranted
  • www.semanticscholar.org/paper/Pharmacotherapy-of-Down-syndrome-Palumbo-McDougle/064bd445d100e400be0fe4927216d717d0f4ccd9

Tarenflurbil


Tetrahydrobiopterin dihydrochloride

  • Administration of a single dose 10-20 mg/kg orally
  • To a patient with dihydrobiopterin deficiency
  • Led to disappearance of clinical symptoms for 4 days
  • A dose-dependent stimulation of serotonin production was observed
  • Patient is now under monotherapy with tetrahydrobiopterin . 2 HCl 2.5 mg/kg daily
  • Other patients with this disease may not respond as well

L-sepiapterin

  • A similar effect was noted with even lower doses
  • Biopterin biosynthesis in human kidney and liver proceeds via a dioxo compound and L-sepiapterin
  • pubmed.ncbi.nlm.nih.gov/7094929/

Vitamin A (retinol) in DS

  • Trial was conducted on the basis of reports of poor absorption and reduced serum vitamin A concentration in DS
  • Rationale is weak as impaired absorption of vit-amin A was not reported in a larger study
  • Others havenot found reduced serum vitamin A concentrations

23 individuals with DS aged 3 to 15 years



Inhibition of CB1R

  • Pharmacological inhibition of CB1R restored memory deficits, hippocampal synaptic plasticity and adult neurogenesis in the subgranular zone of the dentate gyrus
  • Blockade of CB1R also normalized hippocampal-dependent memory in female Ts65Dn mice.
  • CB1R pharmacological blockade similarly improved cognitive performance, synaptic plasticity and neurogenesis in transgenic male Dyrk1A mice
  • Novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.
  • journals.scholarsportal.info/details/09699961/v125icomplete/92_ctrbrnitmfds.xml&sub=all

Prevence zbytečně dál zvýšené lipoperoxidace

  • Bude tedy zvýšeně citlivý na zátěž těžkými kovy, tranzitními kovy a jakýmikoliv dalšími toxiny
  • Zlé budou i smažené / jinak zoxidované tuky nebo cholesterol = zákaz smažení na oleji, oleje přidávat do jídla až po dokončení tepelné úpravy
  • There are increased intracellular free radi-cals and enhanced apoptosis in neurons of fetuses with DS, which can be prevented by addition of antioxidants
  • Kontrola T3 štítnice - dělá supersi SOD
    • Nemít deficit tyrosinu
  • Dostatek zinku a selenu !

Early enviromental stimuli - EE

Mouse Ts65Dn

ZINC SUPPLEMENTATION

  • Part of the cytosolic copper-zinc-SOD enzyme
  • Justified mainly because of reports of relatively low serum zinc in DS
  • Significantly reduced zinc concentrations in individuals with DS
  • Othr study found no significant difference
  • Amino acids and their binding to trace elements (notably Zn)
    • Help maintain proper trace elements levels
    • Histidine is among amino acids which particularly contribute to the formation of amino acid-metal complex
      • Reduction in histidine levels in brain tissues of people with DS
  • journals.plos.org/plosone/article?id=10.1371/journal.pone.0175437#pone-0175437-g002

Clinical randomised trial DS

  • 64 individuals with DS
  • Aged 1 to 19 years
  • Receive 25 to 50 mg of zinc/day (depending on age) or placebo
  • For 6 months
  • Found no significant changes in lymphocyte function, complement levels, or number of infections
  • Trend was in favour of the zinc-treated group (p=0.07) for days coughed
    • Significantly (p=0.03) fewer episodesof cough
  • Children less than 10 years old
    • Zinc-treated group had significantly fewer cough days(p=0.01) than placebo

7 uncontrolled zinc trials with pre-and posttreatment measurements

  • Total of 168 individuals with DS aged 2 to 22 years
  • Beneficial effects of zinc supplementation on the immune function of individuals with DS
  • Adding zinc to the serum of individuals with DS
    • Increased their serum thymic factor (FTS) to levels normally seen in individuals without DS
    • Reduced the concentration of FTS inhibitory factor

In vitro

  • 4 months with 1 mg of zinc/kg/day
  • Increase in the in vitro incorporation of thymidine into phytohaemagglutinin (PHA) stimulated of DS lymphocytes
    • Similar to individuals without DS
  • Following gamma-radiation induced damage to DS cells
    • Zinc supplementation reduced the abnormally high DNA repair rate (which predisposes to mutations and increases malignant potential) in DS cells
  • Selenium is a cofactor in glutathione peroxidase, an enzyme that helps scavenge oxygen radicals.
  • quackwatch.org/11ind/down/
    • Takže glutathion a jeho prekurzory se budou také rychleji spotřebovávat = doplnit je ?


O úroveň výše

Poslední aktualizace: 30. 9. 2024 22:17:01