MHGCJ – 2020

Mental Health: Global Challenges Journal

https://mhgcj.org ISSN 2612-2138

Mithridatism for dementia? Hypoxic - Hyperoxic

training in dementia

Christos Tsagkaris

, Rehab Α. Rayan

, Eleni Konstantara

, Lolita Matiashova

Valeriia Danilchenko

University of Crete, Heraklion, Greece

Alexandria University, Alexandria, Egypt

Medical University of Sofia, Sofia, Bulgaria

GI “L.T.Malaya Therapy National Institute of the NAMS of Ukraine, Kyiv, Ukraine

Kharkiv Regional Perinatal Center, Department of Post-Intensive Care, Rehabilitation and Nursing of Premature Newborns, Kharkiv,

Ukraine

Abstract

Introduction: Intense research on dementia has been conducted during the last years. As

advances in the field have started changing the landscape of dementia treatment, it is

necessary to assess the impact of novel therapeutic modalities.

Purpose: The current evidence about hypoxic – hyperoxic treatment for dementia is reviewed in

this article.

Methods: We conducted a thorough PubMed/MEDLINE and Google Scholar search.

Results: Preclinical and clinical data are available. Hypoxic – hyperoxic treatment is

encouraged in the context of the multimodal treatment of dementia. There are concerns

about the recovery of memory with regard to specific modalities of this treatment. Future

perspectives are highlighted in the light of potentially useful biomarkers and health policy.

Conclusion: While constant updates and further research is critical to understand the impact of

hypoxic – hyperoxic treatment in dementia, the available studies are limited and, hence,

research that is more extensive is necessary. Currently, it is important to assess the current state

of knowledge highlighting the success but also the stalemates of this treatment.

Keywords

Intermittent hypoxia, Hypoxic – hyperoxic training, Cognitive performance, Dementia.

Address for correspondence:

Christos Tsagkaris, University of Crete, Faculty of Medicine, Heraklion, Greece, e-mail:

chriss20x@gmail.com

This work is licensed under a Creative Commons Attribution-

NonCommercial 4.0 International License (CC BY-NC 4.0).

©Copyright: Tsagkaris, Rayan, Konstantara, Matiashova, Danilchenko, 2020

Licensee NDSAN (MFC- Coordinator of the NDSAN), Italy

DOI: http://doi.org/10.32437/mhgcj.v3i1.82

Submitted for publication: 15

June 2020

Received: 15 June 2020

Accepted for publication: 19

September 2020

MHGCJ – 2020

Mental Health: Global Challenges Journal

https://mhgcj.org ISSN 2612-2138

Introduction

The concept of Mithridatism dates back to

Mithridates the 6th, king of Pontos during the 1st

century BC. Mithridates would consume non-

lethal amounts of poison to protect himself from

poisoning in the future. By taking the poison in

gradually increased doses, the king made

himself “immune” enough to the poison to make

it ineffective when he would attempt to take his

life some years later after a defeat in battle.

Mithridates would have to order one of his

bodyguards to take his head eventually. In a

vague sense, he managed to create tolerance

against a toxic factor. (Valle et al., 2017)

The pattern of Mithridatism has been classic in

toxicology and pharmacology throughout the

years. Interestingly, hypoxic - hyperoxic treatment

seems to abide by this concept. Essentially,

hypoxic - hyperoxic treatment consists of the use

of hypoxia, a genuinely toxic factor for neuronal

integrity and memory, as a training stimulus to

create tolerance against ischemia and

safeguard human memory. Scientists have come

to investigating such treatment modalities due to

the prevalence and morbidity of neurocognitive

disorders.

Neurocognitive disorders, especially major

neurocognitive disorders (dementias), have

serious effects on patients, families, the health

system, and the economy (Hugo & Ganguli,

2014). Alzheimer’s disease (AD) is a major risk for

mortality (Murphy et al., 2013), admission to

hospitals and nursing facilities, and home

healthcare in the United States (US). The expanses

of health services and the informal expanses of

non-paid caregiving of dementia patients’ are

high and escalating. Caregivers from the family

suffer high affective pressure, depression among

other health issues (“2020 Alzheimer’s Disease

Facts and Figures,” 2020). Globally, In 2010,

almost 35.6 million individuals were assumed to

be surviving with dementia, a number

anticipated to grow to about 115.4 million

individuals by 2050 (Prince et al., 2013).

Pathophysiology of dementia

Amyloid plaques and neurofibrillary tangles

are featured abnormalities, which determine AD.

Amyloid plaques comprise mainly a 40-42 amino

acid peptide called amyloid-β (Aβ), which is

accumulated in fibrils including a high β-sheet

structure. Plaques turn insoluble and sediment in

the brain’s outside cell spaces. Amyloid plaques

are usually linked to distended, dystrophic

neurites, astrogliosis, and activated microglia that

make a neuritic plaque. However, amyloid

plaques and neurofibrillary tangles aggregate

inside the cell in neurons. (Prince et al., 2013). A-β

is naturally created by neurons inside the brain

and released in the brain’s outside cell spaces

where during the pathogenicity of AD it shifts

configuration, turns insoluble, and sediment as

plaques. A-β does not have an identified,

physiologic role, yet an increasing evidence has

shown that under specific testing circumstances,

A-β could regulate synaptic transmission. Yet, the

function of A-β in natural synaptic role or in the

disease's context is unknown (Chavez et al.,

2000).

The role of hypoxia in neurodegeneration

and dementia

Hypoxia regulates metapolyzing amyloid

plaque protein (APP), causing a growing

production of Aβ through the amyloidogenic

mechanism. Time-reliant hypoxic upregulation of

APP has been further proven at the mRNA and

protein levels, following 10–180 mins of ischemia,

which might function as a guarding pathway to

raise the levels of neuroprotective soluble APPα

(Serebrovska et al., 2019). Yet, most times the

growing APP leads to more levels of Aβ, not

soluble APPα since hypoxia prefers metapolizing

APP through the amyloidogenic mechanism

(Urike Bayer et al., 2017)

Purpose

To review the current evidence about Hypoxia

– Hyperoxia treatment for dementia.

Methodology

This is a literature review study. We searched

Pubmed and Google Scholar with the following

strategy: ((prospective[Title/Abstract] OR

cohort[Title/Abstract] OR follow-up[Title/Abstract]

OR review[Title/Abstract] OR

longitudinal[Title/Abstract] OR meta-

analysis[Title/Abstract] OR systematic

review[Title/Abstract]) AND (hypoxia – hyperoxia

treatment[Title/Abstract] OR

dementia[Title/Abstract])) AND (hypoxia OR

hyperoxia OR dementia) AND

"humans"[MeSH Terms], up until

August 30 2020. This search strategy aims to

identify: 1) Clinical trials involving hypoxia –

hyperoxia treatment; 2) Other original studies or

metanalyses related to the use of this treatment.

Original, peer-reviewed studies in English and

Russian were included.

Results

There has been encouraging evidence from

the field of basic research that supported the

methods that led to their studying in clinical

context. There are studies, both clinical and basic

researches that show that intermittent hypoxic-

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hyperoxic treatment can reduce dementia and

more specifically Alzheimer’s disease (AD) or mild

cognitive impairment which is a precursor of AD.

It is known that in AD the pathological

evidence is the presence of amyloid plagues.

Clinical data has showed that is AD patients the

reduction of cerebral perfusion happens before

memory and cognitive impairment. Hypoxia is

the direct consequence of hypoperfusion.

Improving oxygen supply in the brain might have

a positive impact on AD pathology. Normobaric

hyperoxia (NBO), not only provides more oxygen

but was also found to be protective in recent

experimental and clinical pilot studies. Morris

water maze tests showed that NBO treatment

improved the spatial learning and memory

problems in AβPP/PS1 transgenic mice.

Immunohistochemical and thioflavin S staining

showed that NBO treatment significantly

decreased Aβ deposition and neuritic plaques

formation in the cortex and hippocampus of

AβPP/PS1 transgenic mice. Immunoblotting and

ELISA assay revealed that NBO treatment

reduced Aβ production by inhibiting γ-secretase

cleavage of AβPP. From the above it is suggested

that NBO may have a potential therapeutic

effect at the early stages of AD. (Gao et al.,

2011)

A study conducted by Malle et al. focused on

the effects of normobaric hypoxia (NH) exposure

has on memory and physiology of the human

body as well as the physiological and cognitive

effects of oxygen breathing before and after the

NH exposure.

For this study 86 healthy men divided randomly

into 4 groups, were used. The groups were: the

Normoxia-Air group (N = 23), where subjects

were breathing air, the Hypoxia-Air group (N =

22), NH exposure was preceded and followed by

air breathing, the Normoxia-O₂ group (N = 21),

similar to the Normoxia-Air group, except with the

addition of 100% O₂ breathing periods and the

Hypoxia-O₂ group (N = 20), whose participants

were exposed to 100% O₂ before and after NH

exposure. The Paced Auditory Serial Addition Test

was performed to test their memory. Moreover,

peripheral oxygen saturation (Spo₂), heart rate

(HR), and electroencephalogram (EEG) were

recorded. (Malle et al., 2016)

The results from this study showed that acute

NH exposure caused a typical physiological

response like decreased Spo₂ and increased HR,

but not the same as the physiological response

to acute hypobaric hypoxia. Impairment in

working memory was also caused by the acute

NH. Oxygen breathing after NH exposure caused

a slowing in the EEG which is associated with

making working memory ability worse. For this

reason, NH is suggested to be surrounded by air

breathing. (Malle et al., 2016)

In another study, researchers used quantitative

proton magnetic resonance spectroscopy to

evaluate the regional metabolic alterations, after

a 24-hour hypoxic or hyperoxic exposure on the

background of ischemic brain insult, in a total of

60 female Wistar rats which were divided in two

age-groups of rats of equal number: young - 3

months old and aged - 24 months old. Each age

group was further subdivided into three subgroups

of 10 rats each. Two of these subgroups were

anesthetized with Nembutal (30 mg·kg-1), after

overnight fast, and by ligation of the right

common carotid artery, cerebral ischemia was

induced to them. After taking extracts from three

different brain regions (fronto-parietal and

occipital cortices and the hippocampus) from

both hemispheres concentrations of eight

metabolites (alanine, choline-containing

compounds, total creatine, γ-aminobutyric acid,

glutamate, lactate, myo-inositol and N-

acetylaspartate) were measured. This showed

that in the control normoxic condition, there were

significant increases in lactate and myo-inositol

concentrations in the hippocampus of the aged

rats, in comparison with the young ones. In the

ischemia-hypoxia condition, the most

predominant changes in the brain metabolites

were found in the hippocampal regions of both

young and aged rats, but the effects were more

evident in the aged animals. The ischemia-

hyperoxia procedure caused less changes in the

brain metabolites, which may indicate more

limited tissue damage. (Watanabe et al. 2019)

As it is already well-known, chronic hypoxia

stimulates angiogenesis in brain and other tissues.

Therapeutic IHT (intermittent hypoxic training)

then, can improve the vascularity of the brain

and prevent AD. When in hypoxia, cerebral

angiogenesis starts by the transcription factor,

hypoxia-inducible factor-1 (HIF-1) when genes

with promoter regions containing hypoxic

response elements, including the vascular

endothelial growth factor (VEGF) gene, are

activated. (Takashi et al. 2019)

There are also clinical studies that support

these findings. More specifically, Urike Bayer et al.

in a clinical study in 2017 studied thirty-four

patients from the Geriatric Day Clinic aged

between 64 and 92 years old who participated in

a controlled trial. These patients received

randomly MTP and IHHT (experimental group-EG)

or MTP and placebo-breathing with machine

face mask (experimental group-CG) in a double-

blind fashion. Before and after the 5- to 7-week

intervention period (MTI + IHHT vs. MTI + ambient

air), cognitive function was evaluated by the

Dementia-Detection Test (DemTect), the

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Sunderland Clock-Drawing Test (CDT), and

functional exercise capacity by the total distance

of the 6-Minute Walk Test (6MWT). (Bayer et al.,

2017)

Results from other studies showed that after

MTI + IHHT was administered, DemTect showed

important improvement (+16.7% vs. -0.39%, P <

0,001) as well as the 6MWT with a larger increase

in EG than CG (+24.1% vs. +10.8%, P = .021).

Furthermore, the CDT showed similar results with

DemTect with an increase in EG but decrease in

CG (+10.7% vs. -8%, P = 0,031). Also, there was

found to be a relation between the changes of

the 6MWT, the DemTect and the CDT. The studies

concluded that, IHHT is easy in application and

well tolerated by geriatric patients up to 92 years

and, helped in the improvement in cognitive

function and exercise capacity in geriatric

patients after MTI (CIRRITO & HOLTZMAN, 2008)

(Lall et al., 2019).

Bayer et al. in 2019 updated the previous

study by performing some additional tests and

including new results. Like before, she studied

thirty-four patients (64-92 years old) who

participated in the double-blind clinical trial. The

patients took part in a 5–7 weeks lasting MTI

(strength, endurance, balance, reaction,

flexibility, coordination, and cognitive exercises)

and performed IHHT (breathing 10–14% oxygen

for 4–7 min followed by 2–4 min 30–40% oxygen)

in the Hypoxic Group (HG) or placebo treatment

with ambient air in the Normoxic Group (NG).

Before and after all treatments, mobility was

assessed by the Tinetti Mobility Test (TMT), the

Timed-Up-and-Go Test (TUG) and Barthel-Index,

while perceived health was evaluated by one

part of the EQ-5D Test, the EQ visual analogue

scale (EQ VAS).

These tests showed that after the MTI plus IHHT

or normoxia sessions, results of the TMT, TUG,

Barthel Index and EQ-VAS revealed no significant

difference between HG and NG (Bayet et al.,

2019)

Another study indicated that, IHHT added to

MTI did not cause any additional improvements

in patient’s health and mobility compared to MTI

alone (Pichiule & Lamanna, 2002).

Serebrovska et al. also conducted a study in

2019 which examined the effects of intermittent

hypoxic-hyperoxic training (IHHT) on elderly

patients with mild cognitive impairment (MCI)

which is a precursor of AD. The study used twenty-

one participants between 51 and 74 years of

age which were divided into three groups:

Healthy Control (n = 7), MCI+Sham (n = 6), and

MCI+IHHT (n = 8). IHHT was performed five times

per week for three weeks which means a total of

15 sessions. Each IHHT session had four cycles of

5-min hypoxia (12% FIO2) and 3-min hyperoxia

(33% FIO2). Cognitive parameters, Aβ and

amyloid precursor protein (APP) expression,

microRNA 29, and long non-coding RNA in

isolated platelets as well as NETs in peripheral

blood were investigated. (Serebrovska et al.,

2019)

The study found an initial decline in cognitive

function indices in both MCI+Sham and

MCI+IHHT groups and important connections

between cognitive test scores and the levels of

circulating biomarkers of AD. IHHT resulted in the

improvement in cognitive test scores, along with

significant increase in APP ratio and decrease in

Aβ expression and NETs formation one day after

the end of three-week IHHT. These effects on Aβ

expression and NETs formation remained more

pronounced one month after IHHT. In conclusion,

the results from this pilot study suggested a

potential usage of IHHT as a new therapy to

improve cognitive function in pre-AD patients and

slow down the development of AD (Serebrovska

et al., 2019).

Discussion

In this review, we elaborated on hypoxic -

hyperoxic treatment in the context of dementia.

We retrieved information from original studies

spanning from preclinical to clinical research. The

existing evidence seems to back the use of

hypoxic - hyperoxic treatment, however there are

few preclinical and clinical studies. With regard to

mechanisms, the effects of hypoxia on the

nervous system and the prevention or progression

of dementia vary from study to study, indicating

that the results also depend on the design of the

studies.

A previous review study of Lall et al,

concluded that hypoxia can prevent and treat

AD (Lall et al., 2019). Our review has reached the

same conclusion with regard to improving the

status of patients with AD but we cannot reach

the conclusion that hypoxic - hyperoxic treatment

can prevent AD among healthy individuals.

Another review has indicated that intermittent

hypoxia has not always beneficial effects on

patients with AD. Genetic traits might have

contributed in the variability of the results

(Manukhina et al., 2016). We have also reached

the same conclusion.

The interplay between preclinical and clinical

studies is also notable. Preclinical studies were

conducted first encouraging the design of

clinical interventions. With clinical studies initiated,

basic research kept proceeding unraveling key

information for the personalization of hypoxic -

hyperoxic treatment. Interestingly, in a study on

40 male mice where 40% oxygen with normal

atmospheric pressure was utilized in the early

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stage of Alzheimer disease, there was a notable

improvement in AβPP/PS1 transgenic mice after

1-2 months of treatment. The same treatment

had no effect in wild-type mice. Such findings

support the hypothesis of genetic interference

that was suspected in clinical studies.

Translational clinical studies may detect

biomarkers determining the individuals who will

benefit more from hypoxic - hyperoxic treatment.

In another study, normobaric hypoxia (NH)

appeared to decrease γ-secretase cleavage of

AβPP and Aβ in mice (Gao et al., 2011). Taking

into account the involvement of these factors in

the pathogenesis of dementia, and particularly

AD, this finding indicates that IHHT can hinder the

further progression of the disease. Provided that

large clinical studies verify these outcomes,

hypoxic - hyperoxic treatment can be used as a

dementia stabilizer, while cognitive training can

improve the functionality and the quality of life of

the patients.

The interplay of clinical and preclinical

research is highlighted in the study of Marci et al.

Their data indicated that hypoxia leads to

cerebral ischemia resulting in the damage of the

hippocampus-controlled functions (Macri et al.,

2010) and then a study on healthy young men

verified that NH and hypobaric hypoxia (HH) can

have adverse effects on memory. In both cases,

the damage was attributed to physiological

response to acute NH and HH. These modalities

are different and using oxygen after acute NH

can slow cerebral activity down harming the

recovery of memory (Malle et al., 2016). This

finding, a synergy between preclinical and

clinical research, suggests a serious adverse

effect of this treatment. Participants of future

studies should be properly warned and

monitored.

Other studies have identified further

biomarkers in patients with AD. Exercise capacity,

cognitive performance and safety in geriatric

patients have been correlated with an increase in

APP130 and APP110 fractions in platelets,

decrease in Aβ expression and downregulation of

lncRNA BACE-AS and NETs formation (Serebrovska

et al., 2019) (U. Bayer et al., 2017).

Hypoxic - hyperoxic treatment and

contemporary healthcare

The early diagnosis of dementia spectrum

diseases is a challenge for modern biomedicine.

When it comes to hypoxic - hyperoxic treatment,

the necessary assessment and monitoring of

patients or healthy individuals undergoing such

interventions will require improved imaging

techniques. Watanabe et al. have suggested the

visualization of A2 noradrenergic neurons with MRI

based on the detection of noradrenaline groups

of cells in the brain by T1-weighted MRI with

magnetization transfer (Watanabe et al., 2019).

Hypoxic - hyperoxic treatment would face cost

and implementation issues. With small studies,

absence of long-term results and a need for

expensive additional genetic testing, Hypoxic -

hyperoxic treatment can be expensive and

inaccessible to patients in the future. Regulatory

and legal parameters are also implicated.

University hospitals and centers of excellence can

offer this treatment to large number of patients to

verify its efficacy and define the eligible

population. If this intervention proves to be cost

effective, the necessary regulatory steps can be

taken. Licensing procedures ought to take into

account the multimodal approach of providing

this treatment.

Limitations of the study

Currently it seems that preclinical and clinical

evidence regarding hypoxic - hyperoxic

treatment is encouraging but limited. Systematic

approaches on studies with small populations or

short follow up time would not lead to credible

conclusions. Future studies will need to study the

effect of hypoxic - hyperoxic treatment in larger

population sets. On the other hand, the

indication that hereditary traits might affect the

efficacy of hypoxic - hyperoxic treatment

represents an opportunity of tracking genetic

biomarkers. In this context hypoxic - hyperoxic

treatment could be reserved as a precision

medicine modality in the future.

Conclusions

In the existing studies, hypoxic - hyperoxic

treatment appears as a beneficial additional

treatment for dementia. It may contribute in

preventing dementia in healthy individuals. It

seems that genetic factors are involved in the

efficacy of the treatment. Normobaric and

hyperbaric hypoxia modalities can be used in

patients with damage of the nervous system,

which leads to benefits in cognitive function,

however depending on the administration of

hypoxic - hyperoxic treatment memory recovery

may be impaired especially in healthy individuals

(Serebrovska et al., 2019) (Malle et al., 2016).

Mithridates has managed to determine the

optimal way of self-poisoning to avoid adverse

effects. Nowadays, the same challenge falls

upon contemporary scientists with regard to the

use of hypoxic – hyperoxic treatment in

dementia.

Conflict of interest

MHGCJ – 2020

Mental Health: Global Challenges Journal

https://mhgcj.org ISSN 2612-2138

The authors declare no conflict of interest with

regard to this study.

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