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| Abstract: | Parkinson's disease is a chronic progressive neurodegenerative movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Our findings demonstrated that glutamatergic system is impaired during PD. The evaluations of these damages have important implications in understanding the molecular mechanism underlying motor, cognitive and memory deficits in PD. Our results showed a significant increase of glutamate content in the brain regions of 6- OHDA infused rat compared to control. This increased glutamate content caused an increase in glutamatergic and NMDA receptors function. Glutamate receptor subtypes- NMDAR1, NMDA2B and mGluR5 have differential regulatory role in different brain regions during PD. The second messenger studies confirmed that the changes in the receptor levels alter the IP3, cAMP and cGMP content. The alteration in the second messengers level increased the expression of pro-apoptotic factors - Bax and TNF-α, intercellular protein - α-synuclein and reduced the expression of transcription factor - CREB. These neurofunctional variations are the key contributors to motor and cognitive abnormalities associated with PD. Nestin and GFAP expression study confirmed that 5-HT and GABA induced the differentiation and proliferation of the BMC to neurons and glial cells in the SNpc of rats. We also observed that activated astrocytes are playing a crucial role in the proliferation of transplanted BMC which makes them significant for stem cell-based therapy. Our molecular and behavioural results showed that 5-HT and GABA along with BMC potentiates a restorative effect by reversing the alterations in glutamate receptor binding, gene expression and behaviour abnormality that occur during PD. The therapeutic significance in Parkinson’s disease is of prominence. |
| Description: | Department of Biotechnology, Cochin University of Science and Technology |
| URI: | http://dyuthi.cusat.ac.in/purl/2778 |
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| Dyuthi-T0801.pdf | (6.844Mb) |
| Abstract: | Gamma amino outyric acid is a major inhibitory neurotrarsr titter in the central nervous system. In the preset study sv, Have investigate(' the alteration of GABA receptor, In t he hrain stem of rats during pancreatic regeneration. Three groups of rats were used for the study: sham operated, 72 It and 7 days partially pancreatectonnsea. GABA was (juan- (ified by [H]GABA receptor iispiacement method. GABA receptor kin: 10, pat at i et•ers were studied by using the binding of F'.](iAhA as ligand to the Triton X-100 treated me,i1,;-:mes a1,J displacement with unlabelled GABA. GhRA,v receptor activity was studied by using the [` -1 h3cuculline and displacement with unlabellecV euculline. ;.\13A content significantly decreased (1' < (1.(101 ) it, 0-e brain stern during the regeneration of pancreas. 'I hl, high affinity (IAI3A receptor binding sho?:ed it sigii'f cant decrease in 131„.,\ (P < 11.01) and K,I 1).05) n 72 h and 7 days after partial pancreatee 'timv. ";:flhicuculline hin(Iing showed it signih eat, 'le ( r(, :,e in /Jn1,s and K,I (P < 0.001) in 72 h pa^.rcreaw,, mised rats when compared with sham wt--tt' as P,n and K,I reversed to near sham after 7 da,s of pancreatectomv. The results sugge,) that GAB A throur,r; ('GABA receptors in brain Atcem has a regulatory uie during active regeneration of pancreas which will have inunense clinical significance in the treatment of cliahetcs. |
| URI: | http://dyuthi.cusat.ac.in/purl/581 |
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| S Balarama Kaimal and others (2007)4 jan.PDF | (8.945Mb) |
| Abstract: | In the present study, the effects of 5-HT, GABA and Bone Marrow Cells infused intranigrally to substantia nigra individually and in combinations on unilateral rotenone infused Parkinsonism induced rats. Scatchard analysis of DA, DA D1 and D2 receptors in the corpus striatum, cerebral cortex, cerebellum, brain stem and hippocampus showed a significant increase in the Brain regions of rotenone infused rat compared to control. Real Time PCR amplification of DA D1, D2, Bax and ubiquitin carboxy-terminal hydrolase were up regulated in the brain regions of rotenone infused rats compared to control. Gene expression studies of -Synuclien, cGMP and Cyclic AMP response element-binding protein showed a significant down regulation in Rotenone infused rats compared to control. Behavioural studies were carried out to confirm the biochemical and molecular studies.Our study demonstrated that BMC administration alone cannot reverse the above said molecular changes occurring in PD rat. 5-HT and GABA acting through their specific receptors in combination with bone marrow cells play a crucial role in the functional recovery of PD rats. 5-HT, GABA and Bone marrow cells treated PD rats showed significant reversal to control in DA receptor binding and gene expression. 5-HT and GABA have co-mitogenic property. Proliferation and differentiation of cells re-establishing the connections in Parkinson's disease facilitates the functional recovery. Thus, it is evident that 5-HT and GABA along with BMC to rotenone infused rats renders protection against oxidative, related motor and cognitive deficits which makes them clinically significant for cellbased therapy. The BMC transformed to neurons when co-transplanted with 5-HT and GABA which was confirmed with PKH2GL and nestin. These newly formed neurons have functional significance in the therapeutic recovery of Parkinson’s disease. |
| Description: | Department of Biotechnology, Cochin University of Science and Technology |
| URI: | http://dyuthi.cusat.ac.in/purl/2769 |
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| Dyuthi-T0792.pdf | (2.866Mb) |
| Abstract: | The present study demonstrate the functional alterations of the GABAA and GABAB receptors and the gene expression during the regeneration of pancreas following partial pancreatectomy. The role of these receptors in insulin secretion and pancreatic DNA synthesis using the specific agonists and antagonists also are studied in vitro. The alterations of GABAA and GABAR receptor function and gene expression in the brain stem, crebellum and hypothalamus play an important role in the sympathetic regulation of insulin secretion during pancreatic regeneration. Previous studies have given much information linking functional interaction between GABA and the peripheral nervous system. The involvement of specific receptor subtypes functional regulation during pancreatic regeneration has not given emphasis and research in this area seems to be scarce. We have observed a decreased GABA content, down regulation of GABAA receptors and an up regulation of GABAB receptors in the cerebral cortex, brain stem and hypothalamus. Real Time-PCR analysis confirmed the receptor data in the brain regions. These alterations in the GABAA and GABAB receptors of the brain are suggested to govern the regenerative response and growth regulation of the pancreas through sympathetic innervation. In addition, receptor binding studies and Real Time-PCR analysis revealed that during pancreatic regeneration GABAA receptors were down regulated and GABAB receptors were up regulated in pancreatic islets. This suggests an inhibitory role for GABAA receptors in islet cell proliferation i.e., the down regulation of this receptor facilitates proliferation. Insulin secretion study during 1 hour showed GABA has inhibited the insulin secretion in a dose dependent manner in normal and hyperglycaemic conditions. Bicuculline did not antagonize this effect. GABAA agonist, muscimol inhibited glucose stimulated insulin secretion from pancreatic islets except in the lowest concentration of 1O-9M in presence of 4mM glucose.Musclmol enhanced insulin secretion at 10-7 and 10-4M muscimol in presence of 20mM glucose- 4mM glucose represents normal and 20mM represent hyperglycaemic conditions. GABAB agonist, baclofen also inhibited glucose induced insulin secretion and enhanced at the concentration of 1O-5M at 4mM glucose and at 10-9M baclofen in presence of 20mM glucose. This shows a differential control of the GABAA and GABAB receptors over insulin release from the pancreatic islets. During 24 hours in vitro insulin secretion study it showed that low concentration of GABA has inhibited glucose stimulated insulin secretion from pancreatic islets. Muscimol, the GABAA agonist, inhibited the insulin secretion but, gave an enhanced secretion of insulin in presence of 4mM glucose at 10-7 , 10-5 and 1O-4M muscimol. But in presence of 20mM glucose muscimol significantly inhibited the insulin secretion. GABAB agonist, baclofen also inhibited glucose induced insulin secretion in presence of both 4mM and 20mM glucose. This shows the inhibitory role of GABA and its specific receptor subtypes over insulin synthesis from pancreatic bete-islets. In vitro DNA synthesis studies showed that activation of GABAA receptor by adding muscimol, a specific agonist, inhibited islet DNA synthesis. Also, the addition of baclofen, a specific agonist of GABAB receptor resulted in the stimulation of DNA synthesis.Thus the brain and pancreatic GABAA and GABAB receptor gene expression differentially regulates pancreatic insulin secretion and islet cell proliferation during pancreatic regeneration. This will have immense clinical significance in therapeutic applications in the management of Diabetes mellitus. |
| Description: | Department of Biotechnology, Cochin University of Science and Technology |
| URI: | http://dyuthi.cusat.ac.in/purl/2341 |
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| Dyuthi-T0614.pdf | (7.755Mb) |
| Abstract: | The present study was designed to investigate the protective effect of glucose, oxygen and epinephrine resuscitation on impairment in the functional role of GABAergic, serotonergic, muscarinic receptors, PLC, BAX, SOD, CAT and GPx expression in the brain regions of hypoxia induced neonatal rats. Also, the role of hormones - Triiodothyronine (T3) and insulin, second messengers – cAMP, cGMP and IP3 and transcription factors – HIF and CREB in the regulation of neonatal hypoxia and its resuscitation methods were studied. Behavioural studies were conducted to evaluate the motor function and cognitive deficit in one month old control and experimental rats. The efficient and timely supplementation of glucose plays a crucial role in correcting the molecular changes due to hypoxia, oxygen and epinephrine. The sequence of glucose, epinephrine and oxygen administration at the molecular level is an important aspect of the study. The additive neuronal damage effect due to oxygen and epinephrine treatment is another important observation. The corrective measures by initial supply of glucose to hypoxic neonatal rats showed from the molecular study when brought to practice will lead to healthy intellectual capacity during the later developmental stages, which has immense clinical significance in neonatal care. |
| Description: | Department of Biotechnology, Cochin University of Science and Technology |
| URI: | http://dyuthi.cusat.ac.in/purl/2143 |
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| Dyuthi-T0505.pdf | (9.803Mb) |
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