Brain Derived Neurotrophic Factor Levels In Preeclampsia Biology Essay

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Preeclampsia (PE) is a pregnancy syndrome defined by the new onset of hypertension and proteinuria after 20 weeks gestation and resolves only on the delivery of the placenta (Williams, 2011). It has its origins in the placenta and is characterized by maternal endothelial dysfunction (Maynard et al., 2008). Though it is one of the main global causes of maternal and fetal mortality, preterm birth, perinatal death and intrauterine growth restriction (Mikat et al., 2012; Uzan et al., 2012) its etiology remains elusive (McCarthy et al., 2011). Adverse intrauterine conditions in PE may interfere with fetal brain development (Schlapbach et al., 2010) and may lead to adverse neurodevelopmental disorders such as ADHD (Mann and McDermott, 2011) and schizophrenia (Byrne et al., 2007). (percentage of PE)

The abnormal placentation that results from failure of trophoblast remodeling of uterine spiral arterioles is postulated to be the initiating event leading to PE (Granger et al., 2001). Growth factors, cytokines and hormones produced by trophoblast cells during normal placentation influence the maternal and fetal interface in an autocrine, paracrine and/or juxtacrine manner and these processes may be compromised in complications (Guzeloglu-Kayisli et al., 2009; Dey et al., 2004). Neurotrophic factors such BDNF and NGF are a family of growth factors that support survival, development, and maintenance of neurons (Chowdary et al., 2012). Apart from their role in the nervous system neurotrophins play an important role in angiogenesis, immunomodulation, inflammation, energy metabolism, follicle maturation and development of placenta (Fujita et al., 2011).

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BDNF via signaling through its tyrosine kinase B (TrkB) receptor promotes trophoblast growth in pregnancy (Kawamura et al., 2012). (ADD: Week placental)

BDNF is widely implicated in major depressive disorder, schizophrenia, addiction, Rett syndrome as well as other psychiatric and neurodevelopmental diseases (Autry and Monteggia, 2012).

Our earlier studies have shown that dysregulation of angiogenic factors, reduced antioxidants and increased homocysteine levels and oxidative stress leading to impaired essential polyunsaturated fatty acid levels may be a key factor leading to poor birth outcomes in PE (Mehendale et al., 2008; Kulkarni et al., 2010; Kulkarni et al., 2011). BDNF levels are influenced by omega 3 fatty acids (Wu et al., 2004). DHA is a structural component of the plasma membrane important for membrane fluidity and function of transmembrane receptors, suggests that DHA regulates the function of TrkB receptors (Sharma et al., 2012). Our earlier study by Dhobale et al suggests that placental BDNF/TrkB system in preterm deliveries may exert an important role for the feto-placental development and that it may also be implicated in the etiology of pathologies related to placental and fetal growth disturbances (Dhobale et al., 2012).

Early in pregnancy the fetal brain undergoes complex morphological and functional changes and may be particularly vulnerable to a range of intrauterine influences like stress exposure and inflammation (Catteneo et al., 2010). Stressful experiences during gestation or early in life can lead to enhanced susceptibility for mental illness (Fumagalli et al., 2007). Based on studies conducted by us and others we thus hypothesize that BDNF levels depend on socioeconomic status of the women and are altered during early stages of development in PE increasing the risk of those infants to neurodevelopmental disorders.

There are no studies that have examined the levels of maternal and cord BDNF in the complex pathology of PE. This study for the first time will examine maternal BDNF levels at different time points of gestation and will compare them to cord BDNF levels in women with PE from different socioeconomic backgrounds. It will also analyse the effect of BDNF on birth outcome of babies born to such women.

Materials and Methods

Study Subjects

Pregnant women were enrolled for this longitudinal study from consecutive visits to the Bharati Hospital (BH) and Gupte Hospital (GH), Pune during the year 2010-2012. These women were from the lower and higher socioeconomic background respectively.

Blood samples were obtained at the time of each prenatal visit, scheduled at four-week intervals until delivery. The first sample was obtained between 16 and 20 weeks of gestation (T1), the second between 26 and 30 weeks of gestation (T2), the third sample was taken just before going to the labor room (T3). Umbilical cord blood sample was also collected just after delivery.

Blood was collected from 53 control women and 21 women with PE from BH and 39 control women and 23 women with PE from GH.

Inclusion criteria

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Healthy pregnant women with no medical or obstetrical complications that delivered at term (total gestation ≥ 37 weeks) at BH or GH were recruited for the control group study. PE was diagnosed as per the ACOG standard criteria. PE was defined by systolic and diastolic blood pressures greater than 140/90 mmHg respectively, with the presence of proteinuria (>1+ or 300mg) on a dipstick test and recorded at 2 time points >6 hour apart. This diagnosis of PE has been reported by us in a series of our studies (Mehendale et al., 2008; Kulkarni et al., 2010; Dangat et al., 2010).

Exclusion criteria

Women were excluded from the study if there was evidence of other pregnancy complications, such as preterm birth, multiple gestation, chronic hypertension, type I or type II diabetes mellitus, seizure disorder, renal or liver disease. Pregnant women with alcohol or drug abuse were also excluded from the study.

Clinical assessments

The research protocols and consent forms were approved by the Institutional Ethical Committee. All the women consented to participate in the study and signed written consent forms. Gestational age was calculated by last menstrual period and then confirmed by ultrasound.

Sample collection, processing and storing

10ml of maternal venous blood was drawn into tubes containing ethylenediamine (EDTA) tetra-acetic acid at T1, T2 and T3. 10ml of cord blood was also collected. All blood samples were immediately layered on histopaque (a density gradient obtained from Sigma-Aldrich) and centrifuged at 2000rpm for 30 min to separate the plasma and erythrocyte fractions. The plasma were coded and stored at -800C until further analysis.

Biochemical estimations

Biochemical analyses were performed at laboratories separate from patient recruitment sites. Investigators were blinded to subject identity which was indicated by a code number maintained by the clinical staff until analysis was completed.

Measurement of BDNF levels

BDNF levels were measured in both maternal and cord blood plasma using the brain derived neurotrophic factor Emax Immuno Assay System Promega kit which has been reported by us earlier (Pillai et al., 2010; Dhobale et al., 2012). Briefly, the kit is designed for the sensitive and specific detection of BDNF in an antibody sandwich ELISA format. The amount of BDNF in the test solutions is proportional to the colour generated in the oxidation-reduction reaction and is measured spectrophotometrically at 450nm BDNF concentrations are expressed as pg/mL.

Statistical Analysis

Values are reported as mean ± S.D. The data was analyzed using the SPSS/PC+ package (Version 20.0, Chicago, IL, USA). The data was checked for normal distribution by testing for skewness and kurtosis. Skewed variables (BDNF) were transformed to normality using the following transformations: Natural Logarithm (BDNF). Trends between the means of biochemical parameters across gestation were examined using post-hoc ANOVA. Mean values of the estimates of various parameters for the PE group were compared with those of the control group of both hospitals at conventional levels of significance (p<0.05) using Student't' test. Correlation between variables was studied using Pearson's correlation analysis after adjusting for gestation, age and body mass index (BMI).

Results

Table 1 shows demographic characteristics of the subjects. The ages of control women and women with PE from BH were lower (p<0.01) than respective women from GH. The BMI of women with PE was higher than controls in whole cohort (p<0.01) as well as in individual hospitals (p<0.05). The BMI of control women and women with PE from BH were lower (p<0.01) than respective women from GH.

Maternal and Cord plasma BDNF Levels in

A] Women from whole cohort (GH + BH)

The maternal levels in the control group were 481.49 ± 147.7 pg/mL at T1, 487.52 ± 128.26 pg/mL at T2 and 493.67 ± 140.99 pg/mL at T3 while those in the PE group were 492.28 ± 105.28 pg/mL at T1, 522.95 ± 145.01 pg/mL at T2 and 464.94 ± 146.29 pg/mL at T3. Maternal BDNF levels at T3 were lower (p<0.05) in PE as compared to control (Figure 1A).

The cord levels in the control group were 438 ± 114.15 pg/ml while those in the PE group were 433.52 ± 101.78 pg/mL. No change in cord BDNF levels in PE as compared to control (Figure 1A).

B] Women from GH

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The maternal levels in the control group were 548.28 ± 173.46 pg/mL at T1, 560.83 ± 140.62 pg/mL at T2 and 550.1 ± 155.7 pg/mL at T3 while those in the PE group were were 538.83 ± 94.68 pg/mL at T1, 610.41 ± 132.45 pg/mL at T2 and 537.06 ± 159.64 pg/mL at T3. There was no change in maternal BDNF levels in PE as compared to control (Figure 1B).

The cord levels in the control group were 429.58 ± 134.31 pg/mL while those in the PE group were 470.77 ± 99.99 pg/mL. No change in cord BDNF levels in PE as compared to control (Figure 1B).

C] Women from BH

The maternal levels in the control group were 432.35 ± 101.91 pg/mL at T1, 433.58 ± 85.69 pg/mL at T2 and 456.29 ± 115.2 pg/mL at T3 while those in the PE group were 441.3 ± 93.54 pg/mL at T1, 435.49 ± 97.95 pg/mL at T2 and 404.21 ± 103.21 pg/mL at T3. Maternal BDNF levels at T3 were lower (p<0.05) in PE as compared to control (Figure 1C).

The cord levels in the control group were 444.03 ± 98.11 pg/mL while those in the PE group were 390.68 ± 87.81 pg/mL. Cord BDNF levels were lower (p<0.05) in PE as compared to control (Figure 1C).

Difference in Maternal and Cord BDNF Levels Based on Socioeconomic Groups

Maternal BDNF levels at all time points were reduced (p<0.01) in BH as compared to GH in controls. No change in cord BDNF levels in controls (Figure 2A).

Maternal BDNF levels at all time points were reduced (p<0.01) in BH as compared to GH in PE. Cord BDNF levels were reduced (p<0.01) in BH as compared to GH in PE (Figure 2B).

Association between maternal BDNF levels at different time points and cord BDNF levels

A positive association (p<0.01) was observed between maternal plasma BDNF levels at T1 and T2 in controls. Similarly a positive association (p<0.01) was observed between maternal plasma BDNF levels at T2 and T3 in controls. A positive association (p<0.05) was observed between maternal plasma BDNF levels at T1 and T2 in PE.

A positive association (p<0.01) was observed between maternal plasma BDNF levels at T3 and cord BDNF levels in controls. A positive association (p<0.05) was observed between maternal plasma BDNF levels at T1 and cord BDNF levels in PE. Similarly a positive association (p<0.05) was observed between maternal plasma BDNF levels at T3 and cord BDNF levels in PE. (Table 2)

Association between maternal BDNF levels at different time points and birth outcome parameters (GH+BH)

There was no association of maternal BDNF levels at any time point with birth outcome in control or PE group. (Table 3)

Association between cord BDNF levels and birth outcome parameters (GH+BH)

There was a positive association (p<0.05) of cord BDNF levels with baby head circumference in the control group. There was a positive association of cord BDNF levels with baby weight (p<0.05) and baby chest circumference (p<0.05) in the PE group. (Table 4)

Discussion

This longitudinal study is the first to report maternal and cord BDNF levels from different socioeconomic backgrounds in women with PE and compares them with normal control women. Our results indicate that 1) Maternal BDNF levels are reduced in PE at T3 as compared to control in whole cohort (GH+BH) as well as women from BH 2) Cord BDNF levels are reduced in PE as compared to control in BH 3) Maternal BDNF levels of BH control and PE groups are reduced at all timepoints as compared to those of GH groups respectively. 4) Cord BDNF levels of BH PE group are reduced as compared to those of GH PE group. 5) A positive association was observed between maternal plasma BDNF levels at T1 and T2 in the control group. Similarly a positive association was observed between maternal plasma BDNF levels at T2 and T3. 6) A positive association was observed between maternal plasma BDNF levels at T3 and cord BDNF levels in the control group. 7) A positive association (p<0.05) was observed between maternal plasma BDNF levels at T1 and T2 in the PE group. 8) A positive association (p<0.05) was observed between maternal plasma BDNF levels at T1 and cord BDNF levels in the PE group. Similarly a positive association (p<0.05) was observed between maternal plasma BDNF levels at T3 and cord BDNF levels in the PE group. 9) There was a positive association (p<0.05) of cord BDNF levels with baby head circumference in the control group. There was a positive association of cord BDNF levels with baby weight (p<0.05) and baby chest circumference (p<0.05) in the PE group.

Our data indicates that women with PE have reduced BDNF levels at delivery as compared to control in whole cohort as well as women from BH. Neurotrophins such as BDNF play an important role in feto-placental unit development and may be implicated in the etiology of pathologies related to placental and fetal growth disturbances (Mayeur et al., 2011). Reports suggest there is a cross-talk between the vascular and nervous systems 23. We have recently reported a trend in vascular endothelial growth factor (angiogenic factor) levels in PE which is similar to that observed in this study for brain derived neurotrophic factor and a possibility of a cross talk in PE 11. It has been reported that the maternal brain derived neurotrophic factor levels were similar in mothers delivering intrauterine growth retarded babies as compared to mothers delivering appropriate for gestational age babies 24. However, the above mentioned study included IUGR cases caused by PE, gestational hypertension, chronic diseases such as severe anemia, type I diabetes mellitus, hepatitis B, rheumatoid arthritis, renal insufficiency, asthma and psoriasis. Furthermore, the mothers in their cohort smoked cigarettes and it is well established that smoking affects brain derived neurotrophic factor levels 25. Since none of the women in our cohort smoked, our result mainly indicates the impact of PE on brain derived neurotrophic factor levels. Further, our study subjects were matched for their age and dietary patterns all of which are known to confound the levels of neurotrophins 26.

An altered one carbon cycle (folic acid, vitamin B(12)) and omega 3 fatty acid metabolism during pregnancy can increase the risk for neurodevelopmental disorders in the offspring(Sable et al., 2012). Omega 3 fatty acid supplementation to a micronutrient-imbalanced diet, during pregnancy and lactation protects the levels of BDNF and NGF (Sable et al., 2012).. This may have significant implications in the development of psychiatric disorders/cognitive deficits in later life (Sable et al., 2012). Abnormal brain development in a compromised prenatal and/or early postnatal environment is thought to be a risk factor for several neurobehavioural disorders. increased oxidative stress and reduced DHA levels may lead to changes in the circulating levels of maternal and cord brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) levels (Dhobale et al., 2012). Reduction in cord BDNF levels may have implications for altered neurodevelopment in childhood and later life (Dhobale et al., 2012). Studies need to be undertaken to follow up children born preterm for risk of neurobehavioural disorders like attention deficit hyperactivity disorder (ADHD) to understand the effect of altered BDNF at birth on neurodevelopment. (Dhobale et al., 2012 read full text). BDNF levels were greater for both age groups (26 days old and 4 months old) and sexes (M+F) in the maternally exercised group compared to control group (Aksu et al., 2012). Prenatal stress alters hippocampal synaptic plasticity in young rat offspring through preventing the proteolytic conversion of pro-brain-derived neurotrophic factor (BDNF) to mature BDNF (Ghiglieri et al., 2012).

Table 1: Demographic characteristics of subjects

GH + BH

GH

BH

Control

(n=92)

PE (n=44)

Control

(n=39)

PE

(n=23)

Control

(n=53)

PE (n=21)

Maternal Characteristics

Age (years)

26.5 ± 3.8

26.2 ± 4.3

28.6 ± 3.1

28.6 ± 3.7

25 ± 3.5##

23.7 ± 3.3@@

BMI (kg/m2)

22.2 ± 4.4

25.4 ± 6.1**

23.8 ± 5.2

27.7 ± 7.1*

21.1 ± 3.3##

22.9 ± 3.5*@@

Sys BP (mmHg)

T1

T2

T3

110.9 ± 8.9

112.3 ± 7.7

118.8 ± 8.9

116.1 ± 9.6**

120.6 ± 11**

143.1 ± 16**

106.5 ± 9.4

108.3 ± 7.3

115.5 ± 9.9

117.5 ± 11.9**

120.6 ± 14.8**

142.7 ± 19.7**

114.4 ± 6.9##

115.4 ± 6.5##

121.2 ± 7.3##

114.5 ± 6 120.7 ± 8*

143.3 ± 12.8**

Dias BP (mmHg)

T1

T2

T3

71.9 ± 7.8

70.9 ± 6.8

76.6 ± 6.4

75 ± 7.2*

77.4 ± 8.5**

95.5 ± 13**

66.9 ± 7.6

67 ± 6.9

74.9 ± 8.1

75.9 ± 8.7**

77.5 ± 10.6**

90.4± 11.9**

75.9 ± 5.4##

74 ± 4.9##

77.81 ± 4.4#

74 ± 5

77.3 ± 5.9*

99.4 ± 12.1**@

Neonatal Characteristics

Baby Wt (kg)

2.9 ± 0.27

2.7 ± 0.6**

3 ±0.3

2.6 ±0.7**

2.9 ± 0.3#

2.8± 0.5

Baby Length (cm)

47.9 ± 3

47.58 ± 2.14

47.7 ±4.4

48.3 ± 0.8

48 ± 2.41

47.1 ± 2.5@

Baby HC (cm)

33.8 ± 1.3

33.2 ± 1.6

34.7 ± 1.2

33.7± 1.6

33.6 ± 1.2##

33 ± 1.6

Baby CC (cm)

32.2 ± 1.5

31.9 ± 2.4

32.78 ± 1.3

33 ± 2.5

32.01 ± 1.6

31.45 ± 2.3

Abbreviations: PE, Preeclampsia; BH, Bharati Hospital, GH, Gupte Hospital; BMI, Body Mass Index; Sys BP, Systolic Blood Pressure; Dias BP, Diastolic Blood Pressure; T1, 16-20 weeks of gestation; T2, 26-30 weeks of gestation; T3, at delivery; Wt, Weight; HC, Head Circumference; CC, Chest Circumference; n; number

*p<0.05; **p<0.01 as compared to respective control; #p<0.05; ##p<0.01 as compared to Gupte control, @p<0.05; @@p<0.01 as compared to Gupte PE

Table 2: Association between BDNF levels at T1 and other time points (T2, T3, cord)

GH+BH Control

GH+BH PE

BDNF

BDNF

r

p

n

r

p

n

T1

T2

0.292

0.007**

86

0.657

0.001**

28

T3

0.169

0.132

84

0.382

0.054

29

Cord

0.047

0.676

85

0.361

0.031*

39

T2

T3

0.336

0.002**

84

0.347

0.146

22

Cord

0.185

0.096

85

0.332

0.105

23

T3

Cord

0.329

0.003**

83

0.453

0.023*

28

Abbreviations: PE, Preeclampsia; BDNF, Brain Derived Neurotrophic Factor; BH, Bharati Hospital, GH, Gupte Hospital; T1, 16-20 weeks of gestation; T2, 26-30 weeks of gestation; T3, at delivery; r, correlation; p, significance; n, number.

*p<0.05; **p<0.01

Table 3: Associations between maternal BDNF with birth outcome in whole cohort (GH + BH)

GH+BH Control

Maternal BDNF

T1

T2

T3

r

p

n

r

p

n

r

p

n

Baby weight (kg)

0.98

0.382

85

0.007

0.946

89

0.002

0.987

87

Baby length (cm)

0.004

0.977

63

-0.059

0.645

67

0.037

0.774

64

Head circumference (cm)

0.038

0.774

63

0.085

0.503

67

-0.029

0.824

64

Chest circumference (cm)

0.130

0.322

63

-0.054

0.674

67

-0.171

0.188

64

GH+BH PE

Maternal BDNF

T1

T2

T3

r

p

n

r

p

n

r

p

n

Baby weight (kg)

0.120

0.478

40

-0.091

0.657

29

-0.095

0.653

28

Baby length (cm)

0.240

0.220

31

0.179

0.436

24

0.083

0.726

23

Head circumference (cm)

-0.026

0.901

29

-0.150

0.528

23

-0.044

0.862

21

Chest circumference (cm)

0.172

0.411

28

0.074

0.764

22

-0.109

0.678

20

Abbreviations: PE, Preeclampsia; BDNF, Brain Derived Neurotrophic Factor; BH, Bharati Hospital, GH, Gupte Hospital; T1, 16-20 weeks of gestation; T2, 26-30 weeks of gestation; T3, at delivery; r, correlation; p, significance; n, number.

Table 4: Associations between cord BDNF with birth outcome in whole cohort (GH + BH)

GH+BH Control

Cord BDNF

r

p

n

Baby weight (kg)

0.102

0.375

75

Baby length (cm)

0.191

0.156

60

Head circumference (cm)

0.262

0.049*

60

Chest circumference (cm)

0.026

0.846

60

GH+BH PE

Cord BDNF

r

p

n

Baby weight (kg)

0.424

0.014*

36

Baby length (cm)

0.260

0.209

28

Head circumference (cm)

0.192

0.381

26

Chest circumference (cm)

0.539

0.010*

25

Abbreviations: PE, Preeclampsia; BDNF, Brain derived neurotrophic factor; BH, Bharati hospital, GH, Gupte hospital; r, correlation; p, significance; n, number

*p<0.05

Figure Legends

Figure 1 Maternal and Cord Plasma BDNF Levels in

A: Women from whole cohort (GH+BH)

PE: Preeclampsia; BDNF: Brain derived neurotrophic factor; GH: Gupte hospital; BH: Bharati hospital; T1: 16 to 20 weeks of gestation; T2: 26 to 30 weeks of gestation; T3: at delivery; *p<0.05 as compared to control

B: Women from GH

PE: Preeclampsia; BDNF: Brain derived neurotrophic factor; GH: Gupte hospital;

T1: 16 to 20 weeks of gestation; T2: 26 to 30 weeks of gestation; T3: at delivery

C: Women from BH

PE: Preeclampsia; BDNF: Brain derived neurotrophic factor; BH: Bharati hospital; T1: 16 to 20 weeks of gestation; T2: 26 to 30 weeks of gestation; T3: at delivery; *p<0.05 as compared to control

Figure 2: Difference in BDNF Levels Based on Socioeconomic Groups

PE: Preeclampsia; BDNF: Brain derived neurotrophic factor; GH: Gupte hospital; BH: Bharati hospital; T1: 16 to 20 weeks of gestation; T2: 26 to 30 weeks of gestation; T3: at delivery; ** p<0.01 as compared to GH

Oxidative stress, impaired function of nitric-oxide synthase and cellular and humoral immunological factors in the placenta play an important role in the pathophysiology of the PE (Alasztics et al., 2012). Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of growth factors (Leibrock et al., 1989) and is involved in neuronal proliferation, differentiation, and survival during development (Nakazato et al., 2012). It can also directly penetrate through the utero-placental barrier and regulate fetal development (Kodomari et al., 2009). Angiogenic imbalance characterized by increased soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased free vascular endothelial growth factor (VEGF) are often associated with placental insufficiency and PE (Banek et al., 2012).