Indian Journal of PsychiatryIndian Journal of Psychiatry
Home | About us | Current Issue | Archives | Ahead of Print | Submission | Instructions | Subscribe | Advertise | Contact | Login 
    Users online: 1386 Small font sizeDefault font sizeIncrease font size Print this article Email this article Bookmark this page


    Advanced search

    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  

    Material and Methods
    Article Tables

 Article Access Statistics
    PDF Downloaded285    
    Comments [Add]    
    Cited by others 12    

Recommend this journal


ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 52  |  Issue : 2  |  Page : 140-144
New evidence on iron, copper accumulation and zinc depletion and its correlation with DNA integrity in aging human brain regions

1 Department of Biochemistry and Nutrition, Central Food and Technological Research Institute, Mysore -570 020, India
2 Department of Biochemistry and Nutrition, Central Food and Technological Research Institute, Mysore -570 020, India; and Department of Neurosciences, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
3 Department of Psychiatry, JSS Medical College and Hospital, JSS University, Mysore - 570 004, India
4 Department of Anatomy, JSS Medical College, JSS University, Mysore, India
5 Jawaharlal Nehru Technological University, Hyderabad, India
6 Department of Forensic Science, JSS Medical College, JSS University, Mysore, India

Click here for correspondence address and email

Date of Web Publication22-Jun-2010


Deoxyribonucleic acid (DNA) conformation and stability play an important role in brain function. Earlier studies reported alterations in DNA integrity in the brain regions of neurological disorders like Parkinson's and Alzheimer's diseases. However, there are only limited studies on DNA stability in an aging brain and the factors responsible for genomic instability are still not clear. In this study, we assess the levels of Copper (Cu), Iron (Fe) and Zinc (Zn) in three age groups (Group I: below 40 years), Group II: between 41-60 years) and Group III: above 61 years) in hippocampus and frontal cortex regions of normal brains. The number of samples in each group was eight. Genomic DNA was isolated and DNA integrity was studied by nick translation studies and presented as single and double strand breaks. The number of single strand breaks correspondingly increased with aging compared to double strand breaks. The strand breaks were more in frontal cortex compared to hippocampus. We observed that the levels of Cu and Fe are significantly elevated while Zn is significantly depleted as one progresses from Group I to Group III, indicating changes with aging in frontal cortex and hippocampus. But the elevation of metals was more in frontal cortical region compared to hippocampal region. There was a clear correlation between Cu and Fe levels versus strand breaks in aging brain regions. This indicates that genomic instability is progressive with aging and this will alter the gene expressions. To our knowledge, this is a new comprehensive database to date, looking at the levels of redox metals and corresponding strand breaks in DNA in two brain regions of the aging brain. The biological significance of these findings with relevance to mental health will be discussed.

Keywords: Aging brain, DNA strand breaks, DNA stability, brain regions, trace metals, oxidative stress

How to cite this article:
Vasudevaraju P, Bharathi, Jyothsna T, Shamasundar N M, Rao SK, Balaraj B M, Rao K, Sathyanarayana Rao T S. New evidence on iron, copper accumulation and zinc depletion and its correlation with DNA integrity in aging human brain regions. Indian J Psychiatry 2010;52:140-4

How to cite this URL:
Vasudevaraju P, Bharathi, Jyothsna T, Shamasundar N M, Rao SK, Balaraj B M, Rao K, Sathyanarayana Rao T S. New evidence on iron, copper accumulation and zinc depletion and its correlation with DNA integrity in aging human brain regions. Indian J Psychiatry [serial online] 2010 [cited 2022 Dec 8];52:140-4. Available from:

   Introduction Top

The failure in normal healthy aging leads to mental disorders in aged population. [1] Bipolar disorder (BD) is a major geriatric mental health problem. It affects about 1% of the population and causes severe neuropsychological impairments and has been implicated in functional impairment. [2] What we mean by normal and healthy aging and for that matter what are the triggering risk factors for geriatric mental health problems are still puzzling. To understand this better, we need to explore the biology of aging properly. Both structural, chemical, functional brain imaging using magnetic resonance imaging and postmortem studies have demonstrated volume loss in brain in subjects with BD and also with aging. [3],[4],[5],[6] Recent postmortem studies in BD have demonstrated reductions in number and density of nerve cells, as well as changes in cell body size and shape of neurons and glia, implicating specific cell pathology in the mood disorders and control aged brains. [4]

These studies give an insight into the central role played by neuronal cell death in the pathology of psychiatric disorders and is absent in normal healthy aging. The major risk factors implicated in age related disorders, is the elevation in oxidative stress and failure in antioxidant mechanisms. [7],[8],[9],[10],[11],[12] The oxidative stress phenomenon leads to DNA instability and gene expression failure in normal aging. Does the failure in repair mechanism lead to neuropsychiatric problems? The data base on this aspect is limited. A dysregulation in apoptotic mechanism is believed to play a role in a variety of neuropsychiatric disorders. [13],[14],[15],[16],[17],[18],[19] Further, DNA fragmentations have been well shown to be associated with neurodegenerative disorders like Parkinson disease (PD). [20],[21],[22],[23] The current study aims to assess the genomic integrity in terms of DNA fragmentation and its relation to the levels of redox active metals in frontal cortex and hippocampal brain regions of different age groups and to ascertain whether altered genome integrity plays a role in geriatric psychiatric disorders. To the best of our knowledge, this study is first of its kind in human brain.

   Material and Methods Top

Subjects: The data covering socio-demographic details and cause of death are given in [Table 1].


Radiolabeled 3[ H ] -TTP (Sp.Act.40Ci/nmol) was purchased from Amersham Radiochemicals, UK. Ribonuclease A (RNAse a), Proteinase k, Deoxyribonuclease I (DNAse I), dATP, dTTP, dCTP, dGTP, DNA polymerase I (from  Escherichia More Details coli), terminal deoxynucleotidyl transferase enzymes, 1 kb and 100 bp DNA ladders, and lamda DNA ladder were purchased from Genei, India. All other chemicals were of analytical grade and purchased from Sisco Research Labs, Mumbai, India.

Brain tissues

Brains were categorized into three groups. Group I: below 40 years, Group II: between 41-60 years and Group III: above 60 years. The two regions, namely hippocampus and frontal cortex of normal brains, were separated and stored at -80 o C until further use. Eight brain samples from each group were included in the study. Human brain samples were collected from the Depression Brain Bank of JSS Medical College and Hospital, Mysore, India. Autopsies were performed on donors with written informed consent obtained direct next of kin. The control human brains were collected from accident victims, who had no history of long-term illness, psychiatric diseases, dementia, or neurological disease prior to death. We have excluded subjects who had drug and alcohol abuse. The average postmortem interval between the time of death and collection of brain and freezing was ≤ six hours. Within one hour after death the body was kept in cool chamber maintained at 4˚C. The brain tissue was isolated and stored frozen at -80˚C till the analysis.

Isolation of DNA from brain tissue

Genomic DNA was isolated from hippocampus and frontal cortex of frozen brain tissue by standard 'phenol-chloroform extraction' method after Sambrook et al.[24] with some modifications to prevent DNA fragmentation during isolation. Precautions were taken to prevent in vitro DNA damage during phenol-chloroform genomic DNA extraction. DNA concentration was measured using ultraviolet/visible spectrophotometer noting absorbance at 260 mm and purity checked by recording the ratio of absorbance at 260 nm/280 nm, which should be ideally between 1.6 and 1.8.

a) DNA integrity:

i) Single strand breaks: Single strand breaks (SSBs) are calculated through incorporation of 3 [ H ] -TMP into DNA samples when incubated with E. coli DNA polymerase I (Klenow fragment) in a nick translation assay. [25] DNA polymerase I adds nucleotides at the 3'-OH end of a SSB, generated by various means, using the other strand as template. When one of the deoxynucleotide triphosphates is labeled, the incorporation of radioactivity into substrate DNA would be proportional to the number of SSBs present in the DNA sample. During standardization of the assay conditions with the plasmid DNA (Cos T fragment of l phage) having known number of SSBs, it was found that average of 1500 nucleotides are added at each of the 3'-OH group. From this, it is inferred that each picomole of TMP incorporated is equivalent to 1.6x10 9 3'-OH groups or SSBs. In a total reaction volume of 50 ΅l, the assay mixture consisted of: 40 mM Tris-HC1, pH 8.0, 1 mM b-mercaptoethanol, 7.5 mM MgCl 2 , 4 mM ATP, 100΅M each of dATP, dCTP, and dGTP and 25 ΅M of dTTP, 1 ΅Ci of 3 [ H ] -TTP and 1΅g of genomic DNA and 1 U of E. coli DNA polymerase I.

ii) Double strand breaks: Terminal deoxynucleotidyl transferase catalyzes the addition of deoxynucleotides to the 3' termini of DNA and does not need direction from template strand. Here, 3'- ends of duplex DNA also serve as substrates. Similar conditions to incubate DNA with terminal transferase as in the case of E. coli polymerase I assay were used. The incorporation of the 3[ H ] -dTTP into DNA would be proportional to the number of double strand breaks (DSBs) in the DNA. From the conditions and incubation [26],[27] it is assumed that about 50 TMP residues are added at each of the 3'-ends of the duplex DNA. From this, it is calculated that each femtomole of TMP incorporation would be equivalent to 1.2 x 10 7 3'-ends or half of that number minus one DSBs. The assay mixture for terminal transferase reaction consisted of a total volume of 50 ΅1:100 mM sodium cacodylate buffer, pH 7.0, 1 mM CoCl 2 , 0.2 mM DTT, 1 ΅ Ci of 3[ H ] -dTTP, 1 ΅g DNA, and 1 U of the enzyme.

b) Trace elemental analysis:

Brain tissues were acid digested and preserved in dust free laminar flood hood until further use. All the precautions were taken in accordance with National Committee for Clinical Laboratory Standards (NCCLS) criteria (NCCLS standard approved guidelines to eliminate metal contamination while collecting and storing the samples).

c) Instrumentation and Elemental Analysis

Elemental analysis was carried out using Inductively Coupled Plasma - Atomic Emission Spectrometry (ICP-AES) model JOBIN YVON 38 sequential analyzer. The elements measured were Cu, Fe, and Zn. All dilutions were made with ultra pure milliQ water (18-mega ohms resistance) in a dust free environment. The optimization of ICPAES was carried out by line selection and detection limits for each element. The validation of the analysis was tested by analyzing matrix match multi element synthetic standard and certified standard reference material (Bovine liver 1577a) obtained from National Bureau of Standards, USA. The lines were selected for each element in such a way that interference from the other elements was minimal.

The wavelength used and detection limit of the elements are summarized below:

[Additional file 1]

d) Statistical analysis

All the data obtained in this study were statistically treated and the significance of differences among samples was calculated according to Student's t test. The statistical analysis was carried out using Microsoft Excel 2000 Software.

   Results Top

Trace metals: The levels of Fe and Cu increased, Zn levels decreased from Group I to III. But the significant increase and decrease was more between Group II and III [Table 2]. This data indicates that there was an accumulation of redox active metals like Cu and Fe with aging, while antioxidant metal was decreased with aging. The interesting point was, accumulation of metals was more in Frontal cortex compared to hippocampus. This data is novel and first of its kind in literature.

Single Strand Breaks

The most prevalent type of DNA damage in mammalian cell is the SSBs. Single-stranded breakage is the end point of several types of structural insults inflicted on the genome by both endogenous and exogenous agents. [28] [Table 3] shows numbers of SSBs per microgram of genomic DNA isolated from brain regions. Accumulations of SSBs were more frequent in group III compared to Group II and I. The result shows that frontal cortex (P<0.05) accumulated considerably higher number of SSBs compared to hippocampus.

Double Strand breaks

The DNA isolated from frontal cortex and hippocampus showed significantly higher number of DSBs than respective controls (P<0.01) [Table 4]. Further, frontal cortex accumulated more DSBs than SSBs. The increase in DSBs was more in Group III compared to Group I and II. The present result showed that frontal cortex has more DSBs than SSBs whereas hippocampus had the presence of both DSBs and SSBs accumulated.

   Discussion Top

The present study was done to assess the DNA topology in aging human brain and shows that the structural integrity and topology of genomic DNA is altered and also showed a correlation between redox metal accumulation and DNA strand breaks. The DNA integrity failure may lead to cell atrophy. Magnetic Resonance Imaging (MRI) studies showed that frontal cortex, temporal lobe, hippocampus, thalamus and cerebellum are important brain regions in the pathology of mental illness in adults. [3] The previous studies report that smaller cerebellum, [31] reduction in thalamus volume in adolescent [32] and frontal cortex size reduction [33],[34] in BD compared to controls. Frontal cortex dysfunction plays a major role in the pathophysiology of the bipolar illness and is correlated with reduced frontal lobe size, neuropsychologic deficits [33],[34] and loss of bundle coherence in prefrontal white matter tracts. [35] Other factors like oxidative stress, mitochondrial dysfunction, mitochondrial DNA-deletion, apoptosis are associated with progression of Bipolar mental illness. [9],[10],[11],[12],[36],[37]

The classical apoptotic DNA laddering pattern in aging brain due to strand breaks has great pathophysiological significance. According to Didier et al. [38] the DNA laddering on gel electrophoresis is a hallmark of end-stage apoptotic cell death and by this apoptosis can be distinguished from necrosis. Earlier studies have shown that cell death can also be preceded by DNA fragmentation by Ca 2+ , Mg 2+ dependent DNAase into 180 and 200bp fragments with endonuclease activation occurring early in the process of cell death. [39],[40],[41]

The influences of peri-mortem conditions and of ante-mortem hypoxia on DNA fragmentation in postmortem tissue have been demonstrated in some previous studies. [42] However, we evaluated our results on DNA stability/damage and established that postmortem delay (<7) related DNA damage does not account for the changes in aging brains. It was earlier shown that DNA fragmentation reduces the high activation energy barrier required to induce the conformational and topological changes in DNA. [23] In addition, the recent study showed that there is an empiric link between late-life depression and Alzheimer's Disease (AD) suggesting that the depression may lead to development of AD in some individuals. [43],[44]

Our study is the first report to show that there is a selective increase of single strand and double strand breaks in DNA of normal aging brain. The DNA fragmentation can potentially be triggered through many endogenous and exogenous factors such as trace metals, oxidative stress, mitochondrial dysfunction, apoptosis, decreased antioxidant enzymes, genetic factors etc. [8],[9],[10],[11],[37] The first and most obvious possibility is that neurons may be exposed to oxidative stress. In addition, the postmortem studies have suggested that GABA cells in the anterior cerebral cortex of BD subjects were vulnerable to oxidative stress. [44] Genes play a central role in the clearance of free radicals generated by mitochondrial oxidation reactions such as glutathione synthase, catalase and superoxide dismutase (SOD)- mediated reactions. [42] This suggests that the accumulation of reactive oxygen species (ROS) associated with the oxidative stress would tend to cause potential damage to DNA, proteins and lipids. [45] However, the intact DNA from hippocampus may represent an adaptive compensation to oxidative stress.

In support of this, other finding suggested that GABAergic cells in hippocampus may be resistant to kainic acid - induced excitotoxicity. [44] Our earlier studies have shown that metals like Fe, Al and Cu are accumulated more in BD and these metals can bind and nick DNA. Many of these insults potentially lead to single strand and double strand breaks in DNA leading to genomic instability. [42]

Another possible reason for accumulated DNA fragmentation in aging brain could be due to decreased antioxidant enzymes such as glutathione synthase, catalase and SOD or decreased DNA repair capacity process in BD. Due to increased oxidative stress and genotoxic stress, the genomic DNA's structural integrity is under constant threat. Hence, any insufficiency in the machinery to counteract the damage leads to accumulation of DNA breaks. A decline in DNA stability signifies the shift between DNA damage and repair. In conclusion, this study is the first examination of the genome integrity in terms of DNA damage and its relation to redox metals levels in brain regions of aging groups. Further, this early and first study may provide initial insight to elucidate the correlation between the DNA damage and trace metals and its role in mental health.

   Acknowledgments Top

We thank the director, CFTRI, Mysore, the vice chancellor, JSS University and the Principal, JSS Medical College, Mysore for their encouragement. We thank Muralidhar L Hegde, Suram Anitha for assistance with both tissue collection and statistical approach, K. Subha Rao for providing facilities for nick translation studies and Dr. Ajit V. Bhide, Dr. Swaminath G. and Dr. Dushad Ram for language correction and valuable inputs.

   References Top

1.Kato T. Molecular genetics of Bipolar disorder. Neurosci Res 2001;40:105-13.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]  
2.Oquendo MA, Mann JJ. Identifying and managing suicide risk in bipolar patients. J Clin Psychiatry 2001;62:31-4.  Back to cited text no. 2  [PUBMED]    
3.Brambilla P, Glahn DC, Balestrieri M, Soares JC. Magnetic resonance findings in bipolar disorder. Psychiatr Clin North Am 2005;28:443-67.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]  
4.Rajkowska G. Cell pathology in bipolar disorder. Semin Clin Neuropsychiatry 2002;7:281-92.  Back to cited text no. 4  [PUBMED]    
5.Benes FM, Vincent SL, Todtenkopf M. The density of pyramidal and non pyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects. Biol Psychiatry 2001;50:395-406.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Benes FM, Kwok EW, Vincent SL, Todtenkopf MS. A reduction of non pyramidal cells in sector CA2 of schizophrenics and manic depressive. Biol Psychiatry 1998;44:88-97.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]  
7.Ozcan ME, Gulec M, Ozerol E, Polat R, Akyol O. Antioxidant enzyme activities and oxidative stress in affective disorders. Int Clin Psychopharmacol 2004;19:89-95.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]  
8.Kuloglu M, Ustundag B, Atmaca M, Canatan H, Tezcan AE, Cinkilinc N. Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochem Funct 2002;20:171-5.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Ranjekar PK, Hinge A, Hegde MV, Ghate M, Kale A, Sitasawad S, et al. Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients. Psychiatry Res 2003;121:109-22.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]  
10.Frey BN, Valvassori SS, Gomes KM, Martins MR, Dal-Pizzol F, Kapczinski F, et al. Increased oxidative stress in submitochondrial particles after chronic amphetamine exposure. Brain Res 2006;1097:224-9.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Frey BN, Andreazza AC, Kunz M, Gomes FA, Quevedo J, Salvador M, et al. Increased oxidative stress and DNA damage in bipolar disorder: A twin-case report. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:283-5.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Benes FM, Matzilevich D, Burke RE, Walsh J. The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia. Mol Psychiatry 2006;11:241-51.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]  
13.Margolis RL, Chuang DM, Post RM. Programmed cell death: Implications for neuropsychiatric disorders. Biol Psychiatry 1994;35:946-56.  Back to cited text no. 13  [PUBMED]    
14.Catts VS, Catts SV. Apoptosis and schizophrenia: Is the tumour suppressor gene, p53, a candidate susceptibility gene? Schizophr Res 2000;41:405-15.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]  
15.Evan G, Littlewood T. A matter of life and cell death. Science 1998;281:1317-22.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]  
16.Ansari B, Coates PJ, Greenstein BD, Hall PA. In situ end-labelling detects DNA strand breaks in apoptosis and other physiological and pathological states. J Pathol 1993;170:1-8.  Back to cited text no. 16  [PUBMED]    
17.Benes FM, Walsh J, Bhattacharyya S, Sheth A, Berretta S. DNA fragmentation decreased in schizophrenia but not bipolar disorder. Arch Gen Psychiatry 2003;60:359-64.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]  
18.Buttner N, Bhattacharyya S, Walsh J, Benes FM. DNA fragmentation is increased in non-GABAergic neurons in bipolar disorder but not in schizophrenia. Schizophr Res 2007;93:33-41.   Back to cited text no. 18  [PUBMED]  [FULLTEXT]  
19.Andreazza AC, Frey BN, Erdtmann B, Salvador M, Rombaldi F, et al. DNA damage in bipolar disorder. Psychiatry Res 2007;153:27-32.   Back to cited text no. 19  [PUBMED]  [FULLTEXT]  
20.Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, et al. Oxidative DNA damage in the parkinsonian brain: An apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem 1997;69:1196-203.  Back to cited text no. 20      
21.Tatton WG, Olanow CW. Apoptosis in neurodegenerative diseases: The role of mitochondria. Biochim Biophys Acta 1999;1410:195-213.   Back to cited text no. 21  [PUBMED]  [FULLTEXT]  
22.Hegde ML, Gupta VB, Anitha M, Harikrishna T, Shankar SK, Muthane U, et al. Studies on genomic DNA topology and stability in brain regions of Parkinson's disease. Arch Biochem Biophys 2006;449:143-56.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]  
23.Suram A, Rao KS, Latha KS, Viswamitra MA. First evidence to show the topological change of DNA from B-DNA to Z-DNA conformation from hippocampus of Alzheimer's brain. Neuromolecular Med 2002;2:289-97.  Back to cited text no. 23  [PUBMED]    
24.Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning-A Laboratory Manual. 2 nd ed. Cold Spring Harbor Lab: New York; 1989.  Back to cited text no. 24      
25.Sutherland BM. Titration of pyrimidine dimer contents of nonradioactive deoxyribonucleic acid by electrophoresis in alkaline agarose gels. Biochemistry 1983;22:745-9.  Back to cited text no. 25  [PUBMED]    
26.Bhaskar MS, Rao KS. Altered conformation and increased strand breaks in neuronal and astroglial DNA of aging rat brain. Biochem Mol Biol Int 1994;33:377-84.  Back to cited text no. 26  [PUBMED]    
27.Deng G, Wu R. Terminal transferase: Use of the tailing of DNA and for in vitro mutagenesis. Methods Enzymol 1983;100:96-116.   Back to cited text no. 27  [PUBMED]    
28.Rao KS. Genomic damage and its repair in young and aging brain.Mol Neurobiol 1993;7:23-48.   Back to cited text no. 28  [PUBMED]    
29.DelBello MP, Strakowski SM, Zimmerman ME, Hawkins JM, Sax KW. MRI analysis of the cerebellum in bipolar disorder: A pilot study. Neuropsychopharmacology 1999;21:63-8.  Back to cited text no. 29  [PUBMED]  [FULLTEXT]  
30.Dasari M, Friedman L, Jesberger J, Stuve TA, Findling RL, Swales TP, et al. A magnetic imaging study of thalamic area in adolescent patients with either schizophrenia or bipolar disorder as compared to healthy controls. Psychiatry Res 1999;91:155-62.  Back to cited text no. 30  [PUBMED]    
31.Coffman JA, Bornstein RA, Olson SC, Schwarzkopf SB, Nasrallah HA. Cognitive impairment and cerebral structure by MRI in bipolar disorder. Biol Psychiatry 1990;27:1188-96.   Back to cited text no. 31  [PUBMED]  [FULLTEXT]  
32.Sax KW, Strakowski SM, Zimmerman ME, DelBello MP, Keck PE Jr, Hawkins JM. Frontosubcortical neuroanatomy and the continuous performance test in mania. Am J Psychiatry 1999;156:139-41.  Back to cited text no. 32  [PUBMED]  [FULLTEXT]  
33.Adler CM, Holland SK, Schmithorst V, Wilke M, Weiss KL, Pan H, et al. Abnormal frontal white matter tracts in bipolar disorder: A diffusion tensor imaging study. Bipolar Disord 2004;6:197-203.   Back to cited text no. 33  [PUBMED]  [FULLTEXT]  
34.Kato T, Stine OC, McMahon FJ, Crowe RR. Increased levels of a mitochondrial DNA deletion in the brain of patients with bipolar disorder. Biol Psychiatry 1997;42:871-5.  Back to cited text no. 34  [PUBMED]  [FULLTEXT]  
35.Kato T, Kato N. Mitochondrial dysfunction in bipolar disorder. Bipolar Disord 2000;2:180-90.  Back to cited text no. 35  [PUBMED]  [FULLTEXT]  
36.Didier M, Bursztajn S, Adamec E, Passani L, Nixon RA, Coyle JT, et al. DNA strand breaks induced by sustained glutamate excitotoxicity in primary neuronal cultures. J Neurosci 1996;16:2238-50.  Back to cited text no. 36  [PUBMED]  [FULLTEXT]  
37.Clarke PG. Apoptosis versus necrosis: How valid a dichotomy for neurons? Cell death and Disease of Nervous system. In: Koliatsos VE, Ratan RR, editors. New York: Humana Press; 1999. p. 3-28.  Back to cited text no. 37      
38.Wyllie AH, Kerr JF, Currie AR. Cell death: The significance of apoptosis. Int Rev Cytol 1980;68:251-306.  Back to cited text no. 38  [PUBMED]    
39.Kerr JFR, Gobe GC, Winterford CM, Harmon BV. Anatomical methods in cell death. methods in cell biology: Cell death. In: Schwartz LM, Osborne BA, editors. New York: Academic Press; 1995. p. 1-27.   Back to cited text no. 39      
40.Kingsbury AE, Mardsen CD, Foster OJ. DNA fragmentation in human substantia nigra: apoptosis or perimortem effect? Mov Disord 1998;13:877-84.  Back to cited text no. 40  [PUBMED]    
41.Butters MA, Klunk WE, Mathis CA, Price JC, Ziolko SK, Hoge JA, et al. Imaging alzheimer pathology in late-life depression with PET and Pittsburgh compound-B. Alzheimer Dis Assoc Disord 2008;22:261-8.  Back to cited text no. 41  [PUBMED]  [FULLTEXT]  
42.Mustak MS, Rao TS, Shanmugavelu P, Sundar NM, Menon RB, Rao RV, Assessment of serum macro and trace element homeostasis and the complexity of inter-element relations in bipolar mood disorders. Clin Chim Acta 2008;394:47-53.   Back to cited text no. 42      
43.Polyakova V, Miyagawa S, Szalay Z, Risteli J, Kostin S. Atrial extras cellular matrix remodeling in patients with atrial fibrillation. J Cell Mol Med 2008;12:189-208.   Back to cited text no. 43  [PUBMED]  [FULLTEXT]  
44.Davenport CJ, Brown WJ, Babb TL. GABAergic neurons are spared after intrahippocampal kainate in the rat. Epilepsy Res 1990;5:28-42.  Back to cited text no. 44  [PUBMED]    
45.Davydov V, Hansen LA, Shackelford DA. Is DNA repair compromised in Alzheimer's disease? Neurobiol Aging 2003;24:953-68.  Back to cited text no. 45  [PUBMED]  [FULLTEXT]  

Correspondence Address:
T S Sathyanarayana Rao
Department of Psychiatry, JSS medical College and Hospital, JSS University, Mysore - 570 004, India

Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-5545.64590

Rights and Permissions


  [Table 1], [Table 2], [Table 3], [Table 4]

This article has been cited by
1 Nutrient-sensing amyloid metastasis
Luís Maurício T. R. Lima, Tháyna Sisnande
BioFactors. 2022;
[Pubmed] | [DOI]
2 Age-dependent decline of copper clearance at the blood-cerebrospinal fluid barrier
Luke L. Liu, David Du, Wei Zheng, Yanshu Zhang
NeuroToxicology. 2022; 88: 44
[Pubmed] | [DOI]
3 Is There a Connection between the Metabolism of Copper, Sulfur, and Molybdenum in Alzheimer’s Disease? New Insights on Disease Etiology
Fábio Cunha Coelho, Giselle Cerchiaro, Sheila Espírito Santo Araújo, João Paulo Lima Daher, Silvia Almeida Cardoso, Gustavo Fialho Coelho, Arthur Giraldi Guimarães
International Journal of Molecular Sciences. 2022; 23(14): 7935
[Pubmed] | [DOI]
4 Air Pollution-Related Brain Metal Dyshomeostasis as a Potential Risk Factor for Neurodevelopmental Disorders and Neurodegenerative Diseases
Deborah Cory-Slechta, Marissa Sobolewski, Günter Oberdörster
Atmosphere. 2020; 11(10): 1098
[Pubmed] | [DOI]
5 General Aspects of Metal Ions as Signaling Agents in Health and Disease
Karolina Krzywoszynska, Danuta Witkowska, Jolanta Swiatek-Kozlowska, Agnieszka Szebesczyk, Henryk Kozlowski
Biomolecules. 2020; 10(10): 1417
[Pubmed] | [DOI]
6 An automated tool for cortical feature analysis: Application to differences on 7 Tesla T2*-weighted images between young and older healthy subjects
Nhat Trung Doan,Sanneke van Rooden,Maarten J. Versluis,Mathijs Buijs,Andrew G. Webb,Jeroen van der Grond,Mark A. van Buchem,Johan H.C. Reiber,Julien Milles
Magnetic Resonance in Medicine. 2014; : n/a
[Pubmed] | [DOI]
7 Plasmonics for the study of metal ion–protein interactions
Giuseppe Grasso,Giuseppe Spoto
Analytical and Bioanalytical Chemistry. 2013; 405(6): 1833
[Pubmed] | [DOI]
8 Role of p38MAPK and oxidative stress in copper-induced senescence
Emmanuelle Boilan,Virginie Winant,Elise Dumortier,Jean-Pascal Piret,François Bonfitto,Heinz D. Osiewacz,Florence Debacq-Chainiaux,Olivier Toussaint
AGE. 2013; 35(6): 2255
[Pubmed] | [DOI]
9 Copper interactions with DNA of chromatin and its role in neurodegenerative disorders
M. Govindaraju,H.S. Shekar,S.B. Sateesha,P. Vasudeva Raju,K.R. Sambasiva Rao,K.S.J. Rao,A.J. Rajamma
Journal of Pharmaceutical Analysis. 2013; 3(5): 354
[Pubmed] | [DOI]
10 Metallostasis and amyloid ß-degrading enzymes
Giuseppe Grasso,Maria Laura Giuffrida,Enrico Rizzarelli
Metallomics. 2012; 4(9): 937
[Pubmed] | [DOI]
11 Metallostasis and amyloid β-degrading enzymes
Grasso, G. and Giuffrida, M.L. and Rizzarelli, E.
Metallomics. 2012; 4(9): 937-949
12 Brain iron metabolism and its perturbation in neurological diseases
Robert R. Crichton,David T. Dexter,Roberta J. Ward
Monatshefte für Chemie - Chemical Monthly. 2011; 142(4): 341
[Pubmed] | [DOI]