Trichur R Raju | National Institute of Mental Health & Neuro Sciences (original) (raw)

Papers by Trichur R Raju

Neuroscience Research, 2009

Journal of Neural Transmission, 2010

Accumulating evidence supports neuroprotective role of trophic factors in amyotrophic lateral scl... more Accumulating evidence supports neuroprotective role of trophic factors in amyotrophic lateral sclerosis (ALS). Previous studies from our laboratory report that the CSF of patients with sporadic ALS (ALS-CSF) induces degenerative changes in the rat spinal motor neurons and reactive astrogliosis in the surrounding gray matter. The present study was aimed to investigate if the ALS-CSF affected the expression of trophic factors namely, brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2) and insulin-like growth factor 1 (IGF1) in the newborn rat spinal cords. ALS-CSF was intrathecally injected into the neonatal rats and the mRNA levels of the trophic factors were determined by quantitative real-time polymerase chain reaction. Here, we report significant down regulation in the gene expression of trophic factors for BDNF, FGF2 and IGF1. BDNF mRNA levels were found to be reduced by 6.8-fold in the ALS-CSF injected group compared to control groups. The levels of IGF1 and FGF2 mRNA were also decreased by 3.91- and 2.13-fold, respectively, in the ALS group. We further found that exogenous supplementation of BDNF considerably reduced the aberrant phosphorylation of neurofilaments, complementing our earlier findings of restored expression of voltage gated sodium channel. Reduced expression of trophic factors indicates an altered microenvironment of the motor neurons and could possibly be one of the contributing factors in the degeneration process.

Brain Research, 2009

Cerebro Spinal Fluid (CSF) from patients with ALS has been documented to have a toxic effect on m... more Cerebro Spinal Fluid (CSF) from patients with ALS has been documented to have a toxic effect on motor neurons both in vivo and in vitro. Here we show that the CSF from Amyotrophic Lateral Sclerosis (ALS) patients (ALS-CSF) has the potential to perturb ion channel expression, specifically the Na v 1.6, and K v 1.6 channels in newborn rat spinal motor neurons both in vivo and in vitro. ALS-CSF and CSF from nonALS patients (nonALS-CSF) were intrathecally injected into 3-day-old rat pups at the rate of 1 μl/2.5 min using a microinjector. In addition, embryonic rat spinal cord cultures were also exposed to 10% ALS or nonALS-CSF on the 9th day in vitro (9DIV) in serum free DMEM medium. After 48 h of CSF exposure, the cultures and the spinal cord sections were processed for immunostaining of the above mentioned ion channels. We observed a decrease in the expression of Na v 1.6 and K v 1.6 channels in motor neurons in ALS-CSF treated group, and the presence of trophic factors like Brain Derived Neurotrophic Factor (BDNF) and Ciliary Neurotrophic Factor CNTF partially reversed the effects produced by ALS-CSF. Altered expression of these voltagegated channels may interfere with the electrical activity of motor neurons, and thereby lead to the degeneration of neurons.

Acta Neuropathologica, 1994

Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease, is characterized by degeneratio... more Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease, is characterized by degeneration of lower and upper motor neurons. Serum and cerebrospinal fluid (CSF) of ALS patients have been found to exert toxic effects on neurons in culture. We report here increased phosphorylation of neurofilaments (NF) in the soma of chick spinal cord neurons in culture when exposed to CSF of ALS patients. Spinal cord neurons were cultured from 10-day embryonic chick and exposed to culture medium supplemented with CSF or serum (10 %) from ALS and non-ALS patients for 48 h. There was a significant increase in the number of neuronal soma staining with antibodies against phosphorylated NF, following exposure to CSF from ALS patients. Such an increase, however, was not observed in cultures exposed to serum from ALS patients and also serum and CSF from non-ALS patients. These results suggest that the CSF of ALS patients may contain factor(s) which induces aberrant phosphorylation of NF in the soma, a probable forerunner to the formation of neurofibrillary tangles and eventual degeneration of neurons.

Brain Research, 1980

Aging induced a dramatic increase in the number of glial fibriUary acidic protein (GFA) positive ... more Aging induced a dramatic increase in the number of glial fibriUary acidic protein (GFA) positive cells in monolayer cultures of C-6 cells. Dibutyryl cyclic AMP (DBcAMP) had a similar effect on subconfluent cultures. Both aging and DBcAMP treatment also helped C-6 cells to develop mature astroglia like morphology.

ABSTRACTBoth astroglia and microglia show region-specific distribution in CNS and often maladapt ... more ABSTRACTBoth astroglia and microglia show region-specific distribution in CNS and often maladapt to age-associated alterations within their niche. Studies on autopsied substantia nigra (SN) of Parkinson’s disease (PD) patients and experimental models propose gliosis as a trigger for neuronal loss. Epidemiological studies propose an ethnic bias in PD prevalence, since Caucasians are more susceptible than non-whites. Similarly, different mice strains are variably sensitive to MPTP. We had earlier likened divergent MPTP-sensitivity of C57BL/6J and CD-1 mice with differential susceptibility to PD, based on the numbers of SN neurons.Here, we examined whether the variability was incumbent to inter-strain differences in glial features of male C57BL/6J and CD-1 mice. Stereological counts showed relatively more microglia and fewer astrocytes in the SN of normal C57BL/6J mice, suggesting persistence of an immune-vigilant state. MPTP-induced microgliosis and astrogliosis in both strains, sugge...

Journal of Chemical Neuroanatomy, 2019

 Chronic stress increases the glucocorticoid receptors (GR) expression in the PFC  Enhanced GR ... more  Chronic stress increases the glucocorticoid receptors (GR) expression in the PFC  Enhanced GR density advocates HPA axis dysfunction and GR resistance  Prolonged activation of HPA axis is associated with neurodegeneration and aging  Inactivation of BLA precludes stress-induced increase in GR density in the PFC  We speculate that BLA hyperactivity might be a cause for HPA axis dysfunction

The National medical journal of India

The quantitative sudomotor axon reflex test (QSART) is an autonomic function test to evaluate the... more The quantitative sudomotor axon reflex test (QSART) is an autonomic function test to evaluate the function of postganglionic sympathetic sudomotor axons. The QSART is used for research and in clinical assessment of various neurological diseases, but few studies have assessed the influence of age, gender and reported a normative range. We assessed the influence of age and gender on QSART parameters. We recruited 61 healthy volunteers (41 men and 20 women) after obtaining written informed consent. The QSART was recorded as per standard protocol after iontophoretic stimulation (using acetylcholine) for 5 minutes. We analysed the sweat response to obtain total sweat production, rate of sweat production and latency time from the start of stimulation to sweat response. We assessed these parameters in the right medial forearm, right proximal leg, right distal leg and right proximal foot. Men had significantly higher evoked sweat volume and sweat latency period compared to women. A positive...

The Indian journal of chest diseases & allied sciences

Pulmonary function is one of the important physiological measures that is known to be affected du... more Pulmonary function is one of the important physiological measures that is known to be affected during the changes in the altitude. There is dearth of literature on changes in the pulmonary function variables in the cold climate conditions of Antarctica. We carried out spirometry before, during and after one year stay at Antarctica in members of the Indian expedition. Spirometry was carried out on 23 members of the XXVI Indian Scientific Expedition to Antarctica at baseline, after six months of expedition and at the end of one year, using standard guidelines. The tests were carried out indoor in temperature controlled laboratory. The pulmonary function test parameters did not vary across the period. Although, both forced vital capacity (FVC) and forced expiratory volume in first second (FEV1) showed a decreasing trend but did not attain any statistical significance. However, peak expiratory flow (PEFR) rate was reduced significantly. Our study did not show consistently significant ch...

Molecular Neurobiology, 2016

Disease genetics in admixed populations like Hispanic-Americans, African-Americans, etc. are gain... more Disease genetics in admixed populations like Hispanic-Americans, African-Americans, etc. are gaining importance due to high disease burden in them. Furthermore, epidemiological studies conclusively prove ethnicity-based differential prevalence of Parkinson's disease (PD), since the American-Caucasians are more susceptible than Asian-Indians and Africans. Contradictorily, Anglo-Indians, an admixture of Europeans and Asian-Indians are five-times less susceptible than Indians. We evaluated the neural basis of this phenomenon using the cytomorphological features of susceptibility to nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP). The nigral dopaminergic neuronal numbers, their size and tyrosine hydroxylase (TH), PitX3 and Nurr1 expression were compared in MPTP-susceptible C57BL/6J mice, MPTP-resistant CD-1 mice and their crossbreds using stereology, morphometry and densitometry. Apoptotic index was evaluated by TUNEL-assay and caspase-3 expression. Striatal volume, TH and glial derived neurotrophic factor (GDNF) expression were studied. The normal CD-1 and crossbreds had significantly more, although smaller, nigral dopaminergic neurons than C57BL/6J, and a larger striatum. The crossbreds had higher TH, Nurr1 and PitX3 levels. MPTP administration caused loss of~50-60 % nigral dopaminergic neurons in C57BL/6J and~15 % in CD-1, but none in crossbreds. MPTP-induced cellular shrinkage in C57BL/6J was contrasted by nuclear enlargement without somal alterations in resistant strains. MPTP lowered the striatal TH and GDNF in C57BL/6J. Elevated striatal GDNF in CD-1 and crossbreds could be of compensatory nature and complemented the reduced nigral caspase-3 expression to attenuate and/or block apoptosis. Similar neural correlates of resilience are envisaged in the Anglo-Indian population. Thus, we present the core neuroanatomical features of resilience against PD and evidence for ethnicity-based differential prevalence.

Journal of chemical neuroanatomy, Jan 8, 2016

Parkinson's disease (PD) affects the A9 dopaminergic (DA) neurons of substantia nigra pars co... more Parkinson's disease (PD) affects the A9 dopaminergic (DA) neurons of substantia nigra pars compacta (SNpc) whereas other DA neuronal subtypes are spared. The role of calbindin in this differential vulnerability has been long elicited, and is seen in the MPTP induced mice models of PD. A peculiar feature of mice models is the strain specific differences in the susceptibility to MPTP. Here, calbindin-D28K expression in DA neurons of SNpc of MPTP susceptible C57BL/6 mice and MPTP resistant CD-1 mice was studied as a susceptibility marker of degeneration. Unbiased stereological estimation of immunoperoxidase stained midbrain sections revealed significantly higher number of calbindin immunoreactive cells in SNpc of CD-1 mice compared to that of C57BL/6 strain. Western blotting showed minimal differences in the levels. Calbindin-tyrosine hydroxylase immunofluorescence co-labeling was performed to map the calbindin immunoreactive DA neurons in SNpc and ventral tegmental area (VTA) and ...

Autonomic Neuroscience, 2015

Epileptic disorders : international epilepsy journal with videotape, 2010

Epilepsy is associated with ictal autonomic dysfunction which may extend into the inter-ictal per... more Epilepsy is associated with ictal autonomic dysfunction which may extend into the inter-ictal period. Antiepileptic drugs have often been blamed for cardiac autonomic dysfunction in epilepsy patients. In this study we have investigated cardiac autonomic parameters in order to evaluate autonomic functions of drug-naïve epilepsy patients. Twenty drug-naïve patients (15 males and 5 females) with epilepsy, and an equal number of age and gender matched controls, were evaluated for short-term resting heart rate variability and conventional cardiovascular autonomic measurements. The mean age of patients was 29.30 +/- 9.80 yrs (17-55 yrs), mean age at seizure onset was 19.70 +/- 9.15 yrs (3-40 yrs) and mean length of time since last seizure was 5.60 +/- 7.00 days (1-30 days). While there was no difference in the resting heart rate or conventional autonomic test parameters, time domain heart rate variability measurements showed a decreased percentage of R-R intervals of less than 50 ms and r...

Neurochemical Research, 2000

Inspite of large number of studies on the neurochemical changes in the stress, an equivocal case ... more Inspite of large number of studies on the neurochemical changes in the stress, an equivocal case is yet to be made for the role of a specific neurotransmitter in this important neurobiological disorder. The difficulty arises from the fact that there is no single neurotransmitter system appears to be responsible for the stress induced damage to the hippocampal neurons. The

Clinical Proteomics, 2013

Background Potential biomarkers to aid diagnosis and therapy need to be identified for Amyotrophi... more Background Potential biomarkers to aid diagnosis and therapy need to be identified for Amyotrophic Lateral Sclerosis, a progressive motor neuronal degenerative disorder. The present study was designed to identify the factor(s) which are differentially expressed in the cerebrospinal fluid (CSF) of patients with sporadic amyotrophic lateral sclerosis (SALS; ALS-CSF), and could be associated with the pathogenesis of this disease. Results Quantitative mass spectrometry of ALS-CSF and control-CSF (from orthopaedic surgical patients undergoing spinal anaesthesia) samples showed upregulation of 31 proteins in the ALS-CSF, amongst which a ten-fold increase in the levels of chitotriosidase-1 (CHIT-1) was seen compared to the controls. A seventeen-fold increase in the CHIT-1 levels was detected by ELISA, while a ten-fold elevated enzyme activity was also observed. Both these results confirmed the finding of LC-MS/MS. CHIT-1 was found to be expressed by the Iba-1 immunopositive microglia. Conc...

Current Science, 2001

We have shown previously that chronic restraint stress causes atrophy of apical dendrites and alt... more We have shown previously that chronic restraint stress causes atrophy of apical dendrites and alterations in the spine density of CA3 hippocampal neurons in rats. In the present study, the effect of 45 days of rehabilitation following 21 days of restraint stress on the dendritic morphology of CA3 neurons of the hippocampus was carried out. The results revealed that 45 days of rehabilitation reverses restraint stress-induced (6 h/day for 21 days) apical dendritic atrophy in CA3 neurons of the hippocampus. Whereas prolonged repeated restraint stress during this period also resulted in an atrophy of basal dendrites, suggesting that long-term stress can affect the hippocampal neurons more severely. These results showed that chronic stress-induced structural pathology of hippocampal neurons can be completely reversed by rehabilitation.

Neurochemistry International, 2010

Accumulating evidences suggest that dopaminergic neuronal loss in the substantia nigra pars compa... more Accumulating evidences suggest that dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc) during ageing and in Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD) is linked to neurodegenerative changes like exponential increase in alpha-synuclein expression and protein misfolding. Lewy body formation is also a quintessential observation in neurodegeneration and PD. In experimental models of PD, GRP78 a neuroprotective endoplasmic reticulum (ER) chaperone protein targets misfolded proteins for degradation and prevents release of caspase12 from the ER. Release of active caspase12 and its translocation to the nucleus induces ER mediated apoptosis. The effect of ageing on these proteins in human nigra is not known. We evaluated alpha-synuclein, caspase12, GRP78 and ubiquitin expression in the SNpc of Asian Indians, using immunohistochemistry and stereology. The number of alpha-synuclein and caspase12 immunoreactive neurons increased gradually with age whereas the number of GRP78-labeled neurons remained stable. In contrast, GRP78 protein expression was significantly upregulated with age, while alpha-synuclein and caspase12 increased slightly. An increase in the size and numbers of marinesco bodies was prominent after the sixth decade. The mild increase in alpha-synuclein expression and occurrence of marinesco bodies suggests ageing induced protein misfolding and GRP78 upregulation indicates presence of ER stress. The logarithmic upregulation of GRP78 could even be an indicator of neuroprotective or neuromodulatory response of ER to protein misfolding and initiation of unfolded protein response pathway. Since dopaminergic neurons are preserved in ageing Asian Indians, our study possibly signifies better proteasomal or ER response and partially explains the lower prevalence of PD in them.

Neurobiology of Disease, 2011

We have earlier reported that intrathecal injection of cerebrospinal fluid (CSF) from sporadic Am... more We have earlier reported that intrathecal injection of cerebrospinal fluid (CSF) from sporadic Amyotrophic Lateral Sclerosis patients (ALS-CSF) into neonatal rats and supplementation of rat spinal cord cultures with ALS-CSF induces motor neuron degeneration via aberrant neurofilament phosphorylation and Golgi apparatus fragmentation. Intracellular aggregates immunoreactive to ubiquitin, phosphorylated neurofilaments and choline acetyl transferase (ChAT) were prominently seen in NSC-34 cells exposed to ALS-CSF. Protein aggregation could cause stress on endoplasmic reticulum (ER) and may precede Golgi fragmentation. Here we assessed the effect of ALS-CSF on the expression of GRP-78 and caspase-12 proteins, the markers of ER stress responses, in NSC-34 cells and rat spinal cords by immunochemistry and immunoblotting. Both in vitro and in vivo, increased expression of these proteins accompanied elevated active caspase-12 levels. Apoptotic nuclei and nuclear translocation of caspase-12 were noted in some cells. In vitro, the occurrence of ER stress was supported by electron microscopic observations of numerous free polyribosomes and fragmented ER cisternae. Aggregated mSOD1 protein causes ER stress in familial ALS. ER stress is also reported in the autopsy samples of sporadic ALS. Thus our observation of ER stress may be linked to the protein aggregation, viz. phosphorylated neurofilaments and ChAT, reported earlier.

Journal of Neural Transmission, 2013

Converging evidence from transgenic animal models of amyotrophic lateral sclerosis (ALS) and huma... more Converging evidence from transgenic animal models of amyotrophic lateral sclerosis (ALS) and human studies suggest alterations in excitability of the motor neurons in ALS. Specifically, in studies on human subjects with ALS the motor cortex was reported to be hyperexcitable. The present study was designed to test the hypothesis that infusion of cerebrospinal fluid from patients with sporadic ALS (ALS-CSF) into the rat brain ventricle can induce hyperexcitability and structural changes in the motor cortex leading to motor dysfunction. A robust model of sporadic ALS was developed experimentally by infusing ALS-CSF into the rat ventricle. The effects of ALS-CSF at the single neuron level were examined by recording extracellular single unit activity from the motor cortex while rats were performing a reach to grasp task. We observed an increase in the firing rate of the neurons of the motor cortex in rats infused with ALS-CSF compared to control groups. This was associated with impairment in a specific component of reach with alterations in the morphological characteristics of the motor cortex. It is likely that the increased cortical excitability observed in the present study could be the result of changes in the intrinsic properties of motor cortical neurons, a dysfunctional inhibitory mechanism and/or an underlying structural change culminating in a behavioral deficit.

Journal of Chemical Neuroanatomy, 2010

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigral dopa... more Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigral dopaminergic neurons mostly affecting the elderly (Hassler, 1939). During normal human aging, progressive motor impairment occurs, which is known to be associated with the dysfunction of the nigrostriatal system (Newman et al., 1985). Studies in animal models of PD have demonstrated that glial derived neurotrophic factor (GDNF) and neurturin protect dopaminergic nigral neurons during aging and may retard the progression of the disease (Horger et al., 1998; Lin et al., 1993). GDNF regulates the progression of neurodegeneration in an animal model of PD (Marco et al., 2002). Striatal administration of GDNF increases tyrosine hydroxylase (TH) phosphorylation in the striatum as well as substantia nigra pars compacta (SNpc) of a rat model of PD (Salvatore et al., 2004). GDNF modulates the developmental apoptosis in mice substantia nigra (Oo et al., 2003). Intraventricular administration of GDNF, increases stimulus evoked dopamine release and motor speed in aged rhesus monkeys, which suggests that age-related loss of motor function can be restored by GDNF therapy (Grondin et al., 2003). Thus it is a potential protectant for nigral dopaminergic neurons. GDNF binds to a multi-component receptor complex, which consists of ligand binding cell surface component GDNF receptor alpha1 (GFRa1) and signaling component rearranged during transfection (RET) receptor tyrosine kinase (