Turmeric Extract Administration Increases the Expression of Brain

Derived Neurotropic Factor Following Repetitive Traumatic

Brain Injuries

Andre Marolop Pangihutan Siahaan

, Iskandar Japardi

, Wismaji Sadewo

Department of Neurosurgery, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia

Department of Neurosurgery, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

Keywords: Repetitive Traumatic Brain Injuries; Turmeric Extract; BDNF.

Abstract: Objective: To demonstrate the role of turmeric extract administration in increasing Brain-Derived

Neurotrophic Factor (BDNF). Method: A model of repetitive traumatic brain injury was used on Sprague

Dawley mouse, using a 40-gr weight dropped onto the vertex from 1-m height with total frequency of

twelve times, divided into four days; three traumas every day. A 500 mg/kg turmeric extract was

administered per oral daily. BDNF expression was assessed using immunohistochemistry examination. As a

comparison, there were also negative sham control group and trauma only group. Result: There was no

significant difference in BDNF expression between the negative sham control group and trauma only group.

Instead, there was a significant increase in BDNF expression in the group with turmeric extract

administration. Conclusion: Turmeric extract administration increased BDNF expression following

repetitive traumatic brain injury.

1 INTRODUCTION

Even though the first long-term effect following

repetitive traumatic brain injury (RTBI) was

reported almost a century ago, it starts to be a

prominent issue in the last decade, especially after

Omalu reported this finding in American Football

(Omalu et al., 2005). This condition, termed Chronic

Traumatic Encephalopathy (CTE), is related to

disturbance of behavior, mood, cognitive, and motor

function (Montenigro et al., 2015). Following RTBI,

the brain will undergo progressive changes

consistent with degeneration process, with tau

protein as the main pathology (McKee et al., 2016).

CTE itself is still a disease of elusive, with varying

diagnostic criteria and no proved effective treatment

(Hay et al., 2016).

This problem becomes significant if we

consider that some people, such as contact sport

athletes (i.e., American football, soccer, and martial

arts) and military personals are prone to encounter

RTBI (McKee et al., 2009). In professional soccer

players, for instance, head impacts during playing

are various, dependent on the season, from four

times up to 125 times in two weeks. A post-mortem

examination in American football players confirmed

this hypothesis. A report showed that NFT was

found in most, if not all retired professional

American football players (Perrine et al., 2017).

RTBI itself will disturb ionic stability in the

neural cell. Following an impact, the released

glutamate will initiate hyperactivation of N-methyl-

D-aspartate (NMDA)-type receptors, burden the cell

with calcium, and induct neuroinflammation

(Guerriero et al., 2015). All of these processes will

lead to neuronal cell death. To overcome it,

neurotrophic factors, especially the brain-derived

neurotrophic factor (BDNF), will be released. BDNF

serves as a crucial mediator of neuronal plasticity

that will lead to neuronal remodeling, the formation

of new synapses, or new neurogenesis (Failla et al.,

2015). However, this response is lessened following

RTBI. Inflammatory cytokines that released

following RTBI seem to play a key role by reducing

the expression of BDNF (Kaplan et al., 2010). This

inhibition is not limited only to BDNF, but also to

other trophic factors, such as nerve growth factor

(NGF) and neurotrophin-3 (NT-3).

Siahaan, A., Japardi, I. and Sadewo, W.

Turmeric Extract Administration Increases the Expression of Brain Derived Neurotropic Factor Following Repetitive Traumatic Brain Injuries.

DOI: 10.5220/0009841200150018

In Proceedings of the 2nd International Conference on Tropical Medicine and Infectious Disease (ICTROMI 2019), pages 15-18

ISBN: 978-989-758-469-5

Turmeric (Curcuma longa) plants commonly

found in South and Southeast Asia. For centuries,

the rhizome of this plant has been used as a spice in

daily food and medicinal properties. Curcumin, its

active component, has been isolated for decades and

proved to have strong anti-inflammation activity

(Aggarwal et al., 2013). The aim of this study was to

demonstrate the effect of turmeric extract

administration on BDNF expression following

RTBI.

2 METHOD

2.1 Animal Model and Experimental

Groups

Thirty Sprague-Dawley young adult rats were

divided randomly into three groups, i.e., the negative

sham control group, trauma-only group, and

turmeric group. Total traumas were twelve times,

divided into four days, i.e. on day 1, 2, 4, and 7, with

a no-trauma period on day 3, 5, and 6. This timing

was carried out to resemble the real condition in

sports. Trauma was applied using a weight model

drop, by dropping a 40-gr mass from 1-meter height

onto the vertex. A metal helmet was put on the

vertex to prevent skull fracture (Xu et al., 2016).

This protocol was approved by the Medical

Research Committee, Medical Faculty Universitas

Sumatera Utara, Medan, Indonesia.

2.2 Turmeric Extract Supplementation

A commercially available turmeric extract (Sido

Muncul, curcumin 18.02%) was given orally with

500 mg/kg dose daily to rats in the turmeric group.

2.3 Brain Extraction

Decapitation was done using sharp scissors. Ether

was used as an anesthetic agent. Craniotomy was

performed started posteriorly from the foramen

magnum to the anterior, without preservation of the

olfactory bulb. A 10% formalin buffer solution was

used as a fixation agent.

2.4 Immunohistochemistry

Examination and Cell Count

A 4-micron paraffin block was stained using BDNF

antibody (Abcam). Brown-stained nuclear was

counted as positive. The observation was carried out

using cell count in twenty visual fields at the cortex

of the vertex with magnification 400 times.

2.5 Statistical Analysis

Values were expressed as means  SEM. The results

were computed statistically using the independent t-

test. A difference was considered significant at the p

<0.05 level.

3 RESULTS

3.1 Mortality and Body Weight Change

There was no mortality found in this protocol, either

in the negative sham control group, trauma only

group, and turmeric group. There was also no

significant difference regarding body weight before

and after protocols in all three groups (table 1).

Table 1: Change of body weight before and after the

protocol

Group

Before protocol

After protocol p

Negative

sham

377.22  29.72

378.44  29.66

0,910

Trauma 351.78  29.89 349.33  38.90 0,482

TE 367.89  36.70 357.89  39.89 0,950

*paired t-test. Significant if p<0.05.

3.2 BDNF Expression

Compared to the negative sham control group, there

was no significant change in BDNF expression

following RTBI (p=0.999). BDNF expression in the

turmeric group was significantly higher compared to

negative sham (p=0.021) and trauma only group

(p=0.007; figure 1)

ICTROMI 2019 - The 2nd International Conference on Tropical Medicine and Infectious Disease

Figure 1: BDNF expression in the negative sham control group (A), trauma only group (B), and turmeric group (C). The

significant difference was found between the turmeric group and trauma only group as well as between the turmeric group

and negative sham control group. BDNF: Brain Derived Neurotropic Factor. *significant.

4 DISCUSSION

To the date, there was no generally accepted

protocol that can reproduce the situation in RTB in

contact sport athletes. The protocol used in this

research itself was considered as "mild" TBI, even

there are no diagnosis criteria of concussion in the

rat (Xu et al., 2016). Even though, we had shown no

change in BDNF expression following RTBI. BDNF

acts in secondary injury caused by a combination of

inflammation, ischemia, cytotoxic process, and

apoptosis. Several experimental studies on rat had

shown an increase in hippocampal BDNF mRNA

days after moderate-severe TBI. Another study

showed

that BDNF level would decrease in 24 hours

following TBI, but not significant again after 36

hours (Yang et al., 2009).

We also found an increase in BDNF

expression following turmeric administration.

Curcumin is shown to be a potent anti-inflammatory

agent in an animal model of TBI. BDNF expression

is affected by inflammation (Failla et al., 2015). The

mRNA levels of BDNF on hippocampal were

reduced following administration of interleukin.

Even so, the inflammatory response itself is very

Turmeric Extract Administration Increases the Expression of Brain Derived Neurotropic Factor Following Repetitive Traumatic Brain

Injuries

crucial in neural remodeling process and recovery. It

makes neuroinflammation is not the only pathway

that should be restricted in treating TBI (Lyman et

al., 2014).

To the best of our knowledge, this is the first

research that demonstrates the effect of turmeric on

BDNF expression following RTBI. The main

limitation of this research was no evaluation of the

status of neuroinflammation itself, even regarding

proinflammatory cytokines or either astrogliosis or

microglia activation. This aspect can be evaluated in

further research.

5 CONCLUSION

Turmeric extract administration increased BDNF

expression following repetitive traumatic brain

injury.

ACKNOWLEDGMENT

This study was funded by Universitas Sumatera

Utara in TALENTA Grant. Authors also thanked

Widi Riawan from Department of Biochemistry,

Faculty of Medicine, Universitas Brawijaya,

Malang, Indonesia, for the help in conducting this

study.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

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ICTROMI 2019 - The 2nd International Conference on Tropical Medicine and Infectious Disease