Neuroregeneration Journal Reading

8/10/2019 Neuroregeneration Journal Reading

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JOURNAL READING

Presented by : FK UKI

Supervisor : dr. Sabar Siregar,

SpKJDepartment of Psychiatry Faculty of medicineChristian University of Indonesia,Jakarta


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ABSTRACT


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ABSTRACT

In the last years,physiological aging became

a general concept thatincludes all the changes

that occur in organism withold age

One of these majorconcerns is probably

dementia.

Sooner or later, all forms ofdementia lead to learningdeficit, memory loss, low

attention span, impairmentof speech and poor

problem solving skills.

In this review, try tohighlight some of thenewest aspects of

therapeutic strategiesthat can improve natural

neuroregeneration


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Introduction


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INTRODUCTION

In developing and developed countries, new health

problems concerning specific needs of older

populations arise. One of the major health concerns

in this aspect is dementia.

Dementia is a clinical term used to characterize a

number of diseases with neuropsychiatricsymptoms, that are not explained by delirium or

major psychiatric disorder


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INTRODUCTION

All changes that occur in all organs and systems

associated with old age is now generally accepted

as physiological ageing


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INTRODUCTION

Brain ageing is associated with structures and functionsdecline both is neurons and glia. This is generallyreferred as neurodegeneration

It is a normal process that can lead to reductions incommunication and in memory function but also to poorrecovery after stroke

Neurodegeneration is a progressive process that occursbecause of a decline in the total number of neurons;generally, this process is due to apoptosis and is associatedwith a loss of neuronal structure and function


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INTRODUCTION

AIMEDand by discussing

contradictory resultsof different

researcher groups

summarizing up

to-date findingsdescribed

evaluated by anumber of

different authors


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Neuroregeneration and aging


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AGEING

Physiological ageing is now generally accepted as a concept

that includes all the changes that occur in all organs and

systems associated with old age, characterized by the

declining ability to respond to different types of stress,

homeostatic imbalance and diseases.

The phenomena involved in brain ageing are associated with a

decline of the neuronal and glial structures and functions,

which can lead to reductions in communication and in

memory function and also to poor recovery after stroke


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NEURODEGENERATION

Neurodegeneration is a process is due to apoptosis

and is associated with a loss of neuronal structure

and function.

Ageingis considered the most important risk factorfor brain degeneration and age-related cognitive

disorders


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NEUROGENERATION

An increasing susceptibility to poor recovery from brain

injury has been observed in the elderly. Regeneration of

neuronal tissue makes no exception however the pathways for

the cellular processes that characterize these phenomena have

yet to be found.

The concept of neurogeneration can be also defined as the

superposition of three distinctive processes including

neurogenesis, neuroplasticity and neurorestoration


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However, older organisms, including humans, have reported a

decline in the rate of neurogenesis. Hippocampal neurogenesis

seems to persist also in adult age. With ageing, the

proliferation and differentiation of neural progenitors are

significantly decreased with a higher number of newborndeath neurons.


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The neural stem cells are enteringin a quiescent state.

Another possibility can be that theexpression of some transcription

factors (Er81 and Dlx2) associatedwith neural development are

reduced in the elderly

Another effect can be thereduction in telomerase activity.

supported by the hypothesis thataged neural stem cells areintrinsically different from theyounger one

A study on adult mice deficient intelomerase activity, reported poorneurogenesis in hippocampal areas,associated with a lower number of

proliferation (Ki67+) or immature(Dcx+) cells


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Potential mechanisms

responsible for the age-

related decline in

neurogenesis

Artegiani B, Calegari F. Age-

related cognitive decline:

can neural stem cells help

us?. 2012 (1)

A-E :

SCHEMATIC

REPRESENTATION OF

ADULT NEUROGENESIS

IN THE YOUNG (A) AND

OLD (B-E)


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Nevertheless, extrinsic factors from the local environment

neurogenic niche) can regulate neurogenesis. In old age, lower

levels for different growth factors that can facilitate

neurogenesis (fibroblast growth factor-2, insulin growth

factor-1 or vascular endothelial growth factor) wereregistered in the hippocampal area.


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Ageing and dementia


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DEMENTIA

Dementia has many different causes. Dementia is seen as a

clinical term used to characterize a number of diseases such as

Alzheimer's disease dementia, Lewy bodies dementia, vasculardementia, behavior variant frontotemporal dementia, primary

progressive aphasia or any cognitive/behavioral changes with

neuropsychiatric symptoms, that are not explained by

delirium or major psychiatric disorder and interfere with one'sability to function with usual activities


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Disease such as alzheimer, parkinson, huntington all have in common theformation of aggregates of abnormal proteins in the cells of the brain.

In young individuals,autophagy take care of continually eliminating the

abnormal proteins.

How ever, with age, the reduced activity of autophagy contributes to building

up of these abnormal proteins that eventually intoxicate


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PREVALENCE

At the moment it isestimated that 35.6

million peopleworldwide arediagnosed with

dementia

It is predicted thatin approximately

20 years thisnumber will

double

triple in the next40 years


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Based on all the information the scientific community hasgathered, the diagnostic criteria for dementia has becamemore accurate .

Treatment and management of dementia are generated byresearch based on results from studies.

Test subjects are patients with early stages of dementia.

As the population gets older, new criteria for diagnosing oldelderly persons (>75 years old) are needed because theborder between non pathological aged brain and dementiabrain is becoming more unclear with age


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- Broken line shows

patients that were

included in clinical

research of diagnostic

methods and

theurapeutic trials

- Solid line shows

demented patients age

distribution from the

general population of

the netherlands


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As one gets older, multiple risk factors varyingfrom:

- childhood IQ ,

- obesity in middle age,- smoking,

- hypertension,

- high cholesterol- diabetes at midlife to stroke

- atrophy in old age

contribute

to dementia in

the elderly


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Scientific progress has found that a small number ofhighly conserved genes can have a positive effect on thelength of a life span.

These genes act through a number of metabolic processeslike the reactive oxygen species (ROS) representingone of the most incriminated and poorly understoodcontributors to brain ageing.

Acquiring defense from dietary antioxidants canprotect against ROS induced damage


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Regardless of the risk factors, dementia is still a

consequence of neuronal populations loss that

cannot be compensated. It is unclear as to why

there is such large individual variability in ourpopulation.


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Studies done on old elderly persons

As people get older harder to distinguishbetween a normal aged brain and a dementiaaffected brain

The only objective and quantifiable diagnosticcriteria still remaining valid is cerebral atrophy

Neuropathological examination can sometimesdetect individual with microscopic features typical

of late-onset Alzheimersbut no clinical history ofdementia.

Other times, individuals diagnosed with late stagedementia during their life can show only mild

pathological features ofAlzheimersdisease


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Relation between CVD and

dementia

It is still not clear

if cerebrovascular disease induces dementia or..

if both have the same risk factors and thus are

indirectly linked

Studies on cerebrovascular system in elderly

population have found that..The blood brain

barrier permeabilityincreases with

normal age

can lead to theinitiation/worsenign

of cerebralmicrovasculr

disease/dementia


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An overlap can be found between vasculardementia (VaD) and Alzheimer dementia (AD)

Spontaneous cerebral emboli were detected in43% of AD patients and 45% in VaD cases

Associated with a cognitive and functional decline

within 2 years The patient also had an increase in psychiatric

symptoms


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Neuropathological findings have shown that

the burden and location of cerebral infarcts

are associated with a cognitive decline

However..No evidence was found that stroke prevention

treatment (esp antihypertensive agents) have any

effect on dementia incidence.


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The best available neuropathological evidence

and dementia are scarce, suggesting there are

no boundaries between them.


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Treatment


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In order to remove various behavioral and

psychological symptoms of dementia

Many studies seek other ways of renewing the

natural cargo of brain neurons

Early onset dementia/ late onset dementia

lead to the patient tobe disoriented in time,

place, and identity

M l l d l ti f RNA


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Molecular modulation of mRNA

expression

Recombinant DNA vaccine

Composed of multiple specific inhibitorydomains of neurite growth inhibitors (NOIs)

Mechanisms of action immunological,inducing antibodies against the specificdomains

3 good responses wereobserved

Little formation of solubleAoligomer and amyloid

plaques in the co-

transgenic mice brain

Attenuated neuronaldegeneration

Protection againstbehavioral deficits

M l l d l ti f RNA


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Molecular modulation of mRNA

expression

The modulation of mRNA expression

regarding NOIs was also obtained using

generated channelrhodopsin-mutant

protein expressing microglia

By increasing theintracellular level of the

ioncan control microglial

activation

cause repair/regenerationof neural and

oligodendrocytic damage


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Zhang H, Wang FW, Yao IL, Hao AJ. Microglia-Friend or Foe. Frontiers in Bioscience. 2011; 3: 869-83


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Stem Cells Therapy

Stem cells capable of being integrated into adegenerative environment & releasingneurotrophic cytokines may sustain endogenous neurogenesis and/or

activate neuroprotective pathways (for nestin andconnexin 43)

Quantification of these cytokines revealed aneurogenic/angiogenic predisposition of naive

human chorial villi and amniotic fluid derived cells. These cells also release significant amounts of brain-

derived neurotrophic factors, as well as vascularendothelial growth factor


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Neurotrophic factors

Among others:

the neurotrophin nerve growth factor (NGF),

glial cell-derived neurotrophic factor (GDNF)and

brain-derived neurotrophic factor (BDNF)

Some degree of success has been obtainedregarding survival, existence and regenerationof specific neuronal populations in the adultbrain suffering from Parkinson's or Alzheimer's

disease


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Natural Substances

Cerebrolysin

A peptide preparation mimicking the

action of neurotrophic factors

In vitro and in vivo studies showed that it

enhances neurogenesis in dentate gyrusand subventricular zone

Other effect:

Promotes neuralprogenitor cellmigration

Increases synaptic

density rebuildingneuronal

cytoarchitecture

Inducesrestorativeprocesses

Decreases theinfarct volume andedema formation

And promotesfunctional recovery


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Natural Substances

Quercetin, a natural flavonoid could be protectiveof neuronal precursors of adult brain It neutralizes the oxidative stress by reducing peroxynitrite

formation, protein nitration and M2 isoform of pyruvatekinase depletion

Isoquercitrin (other flavonoid) also promotesneuronal differentiation through multiple Rho GTPasemediated mechanisms Inactivation of RhoA/Rho kinase: isoquercitrin reduces

47% of the RhoA activity and induces neurite growth (atconcentrations 40 M).

Another mechanism is the affection of RhoA localizationthat underwent translocation to the cytoplasm


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Pathways in olygodendrocyte.

Bhat P, Chakrabarty M, Thawani V, Saxena A. Signalled roads to Memory and ItsDegeneration. Annals of Neurosciences. 2012; 19(2)


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Hormonal Substances

Neurosteroid allopregnanolone (AP, 3-

hydroxy-5-pregnan-20-one), a metabolite of

progesterone that is normally generated in the

nervous system

It promoted

neurogenesis,

improved the

cognitive function,

reversed theneurogenic deficits in

the hippocampal

dentate gyrus andthe cerebralsubventricular zone


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Mechanism of allopregnanolone-induced neural stem cell and oligodendrocyte

precursor progenitor mitosis.

Brinton RD. Neurosteroids as regenerative agents in the brain: therapeutic implications.

Nature Reviews Endocrinology. 2013; 9: 241-50


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Hormonal Substances

Melatoninhas good antioxidant properties

In clinical trials using treatments with

melatonin has been effective in slowing the

progression of Alzheimer's disease, but not ofParkinson's disease.

Melatonin has multiple ways of preserving

mitochondrial homeostasis.It reduces free radicalgeneration by

enhancingmitochondrial

glutathione levels and

it safeguards protonpotential and ATP

synthesis by stimulatingcomplex I and IV

activities


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Conclusion

Elucidating the cellular and molecular basis forinvolved in neurodegeneration and neuroregenerationin the aging brain could reveal new therapeuticapproaches to dementia in the elderly.

Development of novel and effective therapies tosustain the brain's self-repair will hopefully lead to animproved management of dementia in olderpopulation.

Multiple strategies should be targeted to prevent thedevelopment and the progression of the disease.Further investigation to update these strategiesare required for an efficient therapeutic response in

dementia.


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Critical Appraisal


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The critical appraisal instrument we used are the

DISCERN instrument which has been designed to

judge the quality of written information about

treatment options.


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Are the aims clear?

Yes, the publication has clear aims.


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Does it achieve its aims ? ?

Yes, it is achieved its first aim which is to summarize

up to date findings describes and evaluates by a

number of different authors

For example:


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Does it achieve its aims ? Contd

But, the publication did not achieved its second

aim. This article does not discussing

contradictory results of different research group

Is it clear what source of information were


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Is it clear what source of information were

used to compile the publication ??

Yes, it is clear. The

article provided

both in the textand in the

bibliography.

Is it clear when the information used/reported in the


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Is it clear when the information used/reported in the

publication was produced ?

No. It is partially

clear when the

information

used/reported inthe publication

was produced

?

?

?


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Is it balanced and unbiased ??

Yes the information is completely balanced and

unbiased.

Does it provide details of additional sources


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Does it provide details of additional sources

of support & information ?

Yes, the publication provides full details of anyadditional source in bibliography

For example...


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Does it refer to areas of uncertainty ?

No uncertainty about treatment choices is

mentioned

The author does not includes a clear reference to

any uncertainty regarding treatment choice


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Does it describe how each treatment works?

No, the details provided are unclear or incomplete

There are no details of how the treatment is

given or administered

Nor the details of how the treatment works

Does it describe the benefits of each


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Does it describe the benefits of each

treatment ?

Yes, the benefit is described for each treatment


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Does it describe the risk for each treatment?

No risks are described for any of these treatment

Does it describe what would happen if no


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Does it describe what would happen if no

treatment is used?

No, the publication does not include any reference to

the risks or benefits of no treatment option

Does it describe how the treatmentchoices affect overall quality of life ?

No, there is no reference to overall quality of

life in relation to treatment choices

Is it clear that there may be more than one


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Is it clear that there may be more than one

possible treatment choice ?

It is partially clear. The publication indicate that there

may be more than one possible choice but the

information is unclear on incomplete

Does it provide support for shared-decision making?

No, the publication does not provide anysupport for shared decision making.


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Conclusion

Based on the question above, the overall quality of

the publication are moderate.

The publication is a useful source of information

about treatment options but has some limitations.

Additional information or support would definitely be

needed.


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