1. BIOLOGICAL MARKERS OFBIOLOGICAL MARKERS OF
MENTAL DISORDERSMENTAL DISORDERS
Fatima Shad Kaneez
Center for Health & Technologies
University of Technology Sydney
Australia
2.
3. J Psychiatr Res. 1984;18(4):457-65.
Biological markers in mental
disorders
post-mortem studies.
Rossor M.
Many neurotransmitters, related
enzymes and receptors
are stable at post-mortem and can be
measured
in routine autopsy material.
4.
5. BRAIN AREAS FOR MENTALBRAIN AREAS FOR MENTAL
ACTIVITIESACTIVITIES
8. Exp Brain Res (2006) 173: 353–356
Kaneez Fatima Shad
Effect of D-serine on the serotonin receptors of human platelets
• Patch clamp technique was used to measure the whole cell currents passing through
serotonin receptors in these two types of human platelets.
• The currents were found to be 5-HT3 receptor currents as they were abolished by 10
M D-tubocurarine (nAchR antagonist also block 5-HT3R).
• Similarly, micro molar concentrations of D-serine increased the sensitivity of 5HT3
receptor currents in the normal human platelets but decreased it in the platelets of the
schizophrenic patients.
• This effect was reversed when D-amino acid oxidase (0.3 M) was co applied with 100
M of D-serine, raising the possibility that D-serine by itself may act as a modulator for
platelet 5-HT3 receptor channel currents.
• These observations raised exciting new questions about the role of platelet serotonin
receptors and their regulation by D-serine.
9.
10. a b o u t 4 8 h r s l a t e r
p A
m s
P A T C H C L A M P
R E C O R D I N G :
T R A N S I E N T
E X P R E S S I O N :
T R A N S F E C T I O N :
C D 8 a n t i b o d y + D y n a b e a d s
C D 8 s u r f a c e a n t i g e n
C a - p h o s p h a te
v e c t o r w it h D N A
n u c l e u s
" w h o l e c e l l " o r " o u t s i d e - o u t p a t c h "
n A
s
a b o u t 3 6 h r s l a t e r
v i a b l e f o r a b o u t 4 8 h r s
ts A -2 0 1
5 H T R H o m o m e r s3-
11.
12. ))2010-20132010-2013((ADAD
mild form of AD with disorder of amnestic and semantic memory. Marked
impairment of daily activities. Depressive mood.
Typical bi
temporal
atrophy with
consecutive
dilatation of
temporal
horn,
hippocampal
atrophy and
marked
enlargement
of the sylvian
fissure in T2-
weighted
sequences
)T2 ax 6mm,
FLAIR sag
6mm(
13. Some selected papers 1990-98Some selected papers 1990-98
Fatima-Shad, K. and Barry, P.H. (1998). Morphological and electrical
characteristics of post-natal hippocampal neurons in culture: the presence
of bicuculline- and strychnine-sensitive IPSPs. Tissue & Cell, 30 (2) 236-
250.
Fatima-Shad, K. & Barry, P. H. (1995) Heterogeneous current responses
to GABA and glycine are present in post-natal cultured hippocampal
neurons. Brain Res., 704 (2), 246-255.
Fatima-Shad, K. & Barry, P. H. (1993) Anion permeation in GABA- and
glycine-gated channels of mammalian cultured hippocampal neurons. Proc.
R. Soc. Lond. B., 253, 69-75.
Fatima-Shad, K. & Barry, P. H.(1992) A patch-clamp study of GABA- and
strychnine-sensitive glycine-activated currents in post-natal tissue-cultured
hippocampal neurons. Proc. R. Soc. Lond. B., 250, 99-105.
16. Fatima-Shad, K. and White, M (2004) Patch
clamp study of Serotonin-gated currents via 5-HT
type 3 receptors by using a novel approach SHAM
for receptor channel scanning. J. Biomed. Biotech.
2004 (1), 10-15.
Fatima-Shad, K. & Barry, P. H. 1996. RT-PCR/
Patch-Clamp studies to determine subunit
composition of glycine receptors in cultured
neurons. Proceedings of Australian Physiological
and Pharmacological Society, 27: 17P.
Fatima-Shad, K, .K. Pierce, P. H. Barry & P. R.
Schofield. 1996. Subunit composition of GABA
and Glycine receptors in Hippocampal neurons.
The Australian Society for Medical Research, P-
27.
18. Fatima-Shad, K. 2000. Presence of bicuculline and curare sensitive synaptic currents in
cultured hippocampal neurons. Neuronal plasticity: The key to stroke recovery, 139, 39P
Fatima-Shad, K. 2000. GABA & glycine currents in early post-natal mammalian
neurons. GABA 2000 conference
Fatima-Shad, K. 1999 Evidence for co-existence of 5-HT3 and GABAA receptor
channels in hippocampal neurons. Proceedings of Australian Physiological and
Pharmacological Society. 30)2(, 24p
Fatima-Shad, K. Barry, P. H. & P. R. Schofield, 1998 Anion permeation through glycine
receptor channels in transfected cells and cultured hippocampal neurons. Proceedings
of the Australian Neuroscience Society, 9, 89P
Fatima-Shad, K. & White M. 1998 SHAM: a novel approach for 5HT3R channels
scanning. Curtin Conference Canberra 39,23P
Fatima-Shad, K., Barry, P. H. & White M. 1998.The 5HT3R Channel: An Approach to
compare it with other Members of Ligand-Gated Ion Channel Super Family. Functional
Genomic Conference, 45, 67-68
Fatima-Shad, K. 1998 Ion selectivity in homomeric glycine receptor channels.
Proceedings of Australian Physiological and Pharmacological Society. 29 )2(, 58p
Fatima-Shad, K. & Barry, P. H. 1997. Rate theory modelling of ionic conductance
through GABAA and glycine receptor channels in mammalian cultured hippocampal
neurons. Proceedings of the International Union of Physiological Society Congress, St.
Petersburg Abstracts, 195, p002.03.
Some National and International presentationsSome National and International presentations
19. It is not possible to obtain
neurons from the patients
for receptor function analysis
It is possible to easily collect
platelets from the patience to
study receptor function
These studies may indicate
inborn errors in receptor
function
20. Some examplesSome examples
Fatima Shad K (2005) A comparative study of
serotonin levels from mammalian cortical and
hippocampal cultured neurons with that of human
platelets. Emirates Medical Journal 22 (3(
Fatima-Shad, K. 2001. Serotonin via 5-HT3R
modulates GABAAR currents in mammalian
cultured hippocampal neurons. Proceedings of
the International Union of Physiological Society
Congress, Christchurch, New Zealand (CD-
ROM(.
21.
22.
23. Risk Factors for AtherothrombosisRisk Factors for Atherothrombosis
AtherosclerosisAtherosclerosis
Atherothrombotic ManifestationsAtherothrombotic Manifestations
(MI, Ischaemic Stroke, Vascular Death)(MI, Ischaemic Stroke, Vascular Death)
AgeAgeObesityObesity
DiabetesDiabetes
HyperlipidemiaHyperlipidemiaHypercoagulable statesHypercoagulable states
HypertensionHypertension
GeneticsGenetics
Infection?Infection?
HomocysteinemiaHomocysteinemia
Life-style (e.g.,Life-style (e.g.,
smoking, diet,smoking, diet,
lack of exercise)lack of exercise)
GenderGender
25. Normal
Intimahyperplasia
Inhomogene Plaquebildung
mit Verkalkung
(Schallschatten Pfeile)
Inhomogene Plaquebildung
Hyperechoic plaque
Serum levels mg/dL µmol/L Subjects
Total Serine 1.960±0.32 X 95.2 Control
Total Serine 1.440±0.21 X 95.2 TIA
D- Serine 0.025±0.002 X 95.2 Control
D- Serine 0.040±0.002 X 95.2 TIA
L- Serine 1.935±0.42 X 95.2 Control
L- Serine 1.400±0.12 X 95.2 TIA
Our preliminary biochemical data supported by imaging shows that coronary Intima media thickness
(CIMT) is a better predictor than coronary artery calcium (CAC) scoring and is in line with serine
racemase activity.
Maximum CIMT in adults with normal levels serine racemase was about (0.6 mm) as compared with
high serine racemase levels (TIA) between a range of (0.72 to 0.94 mm)
Serum levels of total serine and L and D-serine were measured by HPLC. Serum level of D-serine in
the patients of Transient Ischemic Attack (TIA) was significantly higher than those of healthy controls.
In contrast serum levels of total (D and L serine) and L- serine in TIA patients were significantly lower
than those of controls. In addition the percentage of D-serine in the total serine in TIA was
significantly higher than that of controls, suggesting that the activity of SR may have increased.
Please see some imaging samples in the left hand panel and serine values in the
table below
Intima hyperplasia 0.72 mm
Power Doppler showing turbulences
Intimahyperplasia 0.94 mm
Ultrasound images for coronary intima thickness (CIT) were obtained in axial and sagittal direction (11
MHz sound, soft tissue filter). We found that coronary artery has an intima thickness of<2mm in control
with lower percentage and concentration of D-serine. While, TIA patients had higher percentage of D-
serine (2.8%) with CIMT of 2.3mm and sometime (with a calcified plaque in combination with
Intimahyperplasia) giving a value of 2.9mm
26.
27.
28. Our review entitled “How Oxidative Stress gated by Fenton and Haber-Weiss reactions
leads to Alzheimer’s disease” is in press with Archives of Neuroscience in which:
•We have discussed the involvement of the reactive oxygen species (ROS) into the underlying
pathophysiological mechanisms of various diseases such as Stroke and Alzheimer’s disease
(AD).
•One of the greatest challenges we found in the field of ROS-gated diseases is to bridge the
knowledge gap between atomic and cellular level, and further understanding of Fenton
reaction may help to bridge this gap.
•In 1890, Fenton used a solution of H2O2 and Iron to oxidized contaminants of waste water.
When transient metals such as iron react with hydrogen peroxide (H2O2), it results in the
production of Ferric (Fe +++
), hydroxy radical (.
OH) and hydroxyl ion (OH-
). The (.
OH) react with
H2O2 again to produce superoxide (O2
-
) and hydroxyl ion (OH-
).
•Reactive oxygen species (ROS) are produced as the by-product of the electron transport chain
(ETC) in mitochondria and are responsible for lipid peroxidation, protein oxidation, DNA damage
and advanced glycation end products (AGEs) formation via effects of ROS on cellular signalling
pathways.
•Since brain is the most aerobically active organ in the body, ROS mostly produced in the brain.
•Iron (Fe), copper (Cu), zinc (Zn) and aluminium (Al), due to their multiple valence states are
enable to react with the molecular oxygen and results in the production of ROS and RNS.
32. Example of our work for some diseasesExample of our work for some diseases
Fatima Shad Kaneez et al(2013) Peripheral markers of
Alzheimer's disease: Surveillance of white blood cells SYNAPSE
Vol 67, Issue 8, start page 541 (P001707260(
Rukhsana Nawaz, Erum Zahir and Kaneez Fatima Shad
et al (2012) Rhodium Interaction with Human NRG1 Gene of
Schizophrenia JPAIR Vol 7 267-281 print ISSN 20123981,
Electronic ISSN 2244-0445
D. Kumar and KF Shad (2010) Genetic profile of
schizophrenic patients in Pakistan. European Psychiatry
Supplement 1 , 1613
Sheikh Arshad Saeed and Kaneez Fatima Shad (2007)
Some new prospects in the understanding of the molecular basis
of the pathogenesis of stroke. Exp Brain Res, 182, 1-10.
Fatima-Shad, K. (2006), Effect of D-serine on the serotonin
receptors of human platelets' Experimental Brain Research 173
33.
34. Serum levels mg/dL µmol/L Subjects
Total Serine 1.960±0.32 186.595 Control
Total Serine 1.440±0.21 137.09 TIA
D- Serine 0.025±0.002 2.380 Control
D- Serine 0.040±0.002 3.808 TIA
L- Serine 1.935±0.42 184.215 Control
L- Serine 1.400±0.12 133.281 TIA
D- Serine %age = 1.275 ------ Control
D- Serine %age = 2.777 ------ TIA
Pilot in a cohort of humans:
Stroke affects the brain, but is really a disease of the heart and/or arteries, so most of the risk for stroke is tied to disease of the heart and/or
arteries.
We observed for the first time that there is a relationship between (SR product) D-serine and coronary intima media thickness (CIMT) was
obtained by measuring common carotid artery intima media thickness. Values of CIMT were in direct correlation with the concentration and
percentage of D-serine. Serum levels of total serine and L and D-serine were measured by HPLC, serum level of D-serine in the patients of
Transient Ischemic Attack (TIA) was significantly higher than those of healthy controls. In contrast serum levels (Table 1) of total (D and L
serine) and L- serine in TIA patients were significantly lower than those of controls. In addition the percentage of D-serine in the total serine
in TIA was significantly higher than that of controls, suggesting that the activity of SR may have increased.
35. More serine racemase inturn activates
more NMDA receptors and vice versa
TAKE HOME MESSAGE IS
MINOR FLUCTUATION IN
THE LEVEL AND ACTIVITY OF
SERINE RACEMASE IS
DANGEROUS
36. ACKNOWLEDGEMENTS
I AM THANKFULL TO THE FOLLOWING FUNDING BODIES
TO SUPPORT MY QUEST FROM
1990 – PRESENT
NH&MRC (NATIONAL HEALTH AND MEDICAL RESEARCH COUNCIL AUSTRALIA(
ARC (AUSTRALIAN RESEARCH COUNCIL(
AHERF (ALLIED HEALTH RESEARCH FOR FACULTIES( USA
HMR (HUNTER MEDICAL RESEARCH( AUSTRALIA
UNIVERSITY OF NEWCASTLE FACULTY GRANT
RAMACIOTII MEDICAL RESEARCH GRANT
SCHIZOPHRENIA RESEARCH FUNDING
ATM (ANSWERS THAT MATTERS( ELI LILLY
INTERDISCIPLINARY GRANT UAEU
INDIVIDUAL GRANT UAEU
HIGHER EDUCATION COMMISSION OF PAKISTAN (3 GRANTS(
UNIVERSITY OF BRUNEI DARUSSALAM
AND
BRUNEI RESEARCH COUNCIL
