Decreased a2-adrenergic receptor in the brain stem and pancreatic islets during pancreatic regeneration in weanling rats

Sympathetic stimulation inhibits insulin secretion. a2-Adrenergic receptor is known to have a regulatory role in the sympathetic function. We investigated the changes in the a2-adrenergic receptors in the brain stein and pancreatic islets using [3H]Yohimbine during pancreatic regeneration in weanling rats. Brain stem and pancreatic islets of experimental rats showed a significant decrease (p<0.001) in norepinephrine (NE) content at 72 h after partial pancreatectomy. The epinephrine (EPI) content showed a significant decrease (p<0.001) in pancreatic islets while it was not detected in brain stem at 72 h after partial pancreatectomy. Scatchard analysis of [3H]Yohimbine showed a significant decrease (p<0.05) and Kd at 72 h after partial pancreatectomy in the brain stem. In the pancreatic islets, Scatchard analysis of [3H]Yohimbine showed a signiinfiBca'nnatx decrease (p<0.001) in B,nax and Kd (p<0.05) at 72 h after partial pancreatectomy. The binding parameters reversed to near sham by 7 days after pancreatectomy both in brain stein and pancreatic islets. This shows that pancreatic insulin secretion is influenced by central nervous system inputs from the brain stem. In vitro studies with yohimbine showed that the a2-adrenergic receptors are inhibitory to islet DNA synthesis and insulin secretion. Thus our results suggest that decreased a2-adrenergic receptors during pancreatic regeneration functionally regulate insulin secretion and pancreatic 13-cell proliferation in weanling rats.

Decreased GyBAA Receptor Function in the Brain Stem during Pancreatic Regeneration in Rats

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.

Dopamine Receptor Gene Expression In Streptozotocin Induced Diabetic Rats And Its Role In Insulin Secretion

Diabetes Mellitus is a metabolic disorder associated with insulin deficiency, which not.only affects the carbohydrate metabolism but also is associated with various central and peripheral complications. Chronic hyperglycemia during diabetes mellitus is a major initiator of diabetic microvascular complications like retinopathy, neuropathy, The central nervous system (CNS) neurotransmitters play an important role in the regulation of glucose homeostasis. These neurotransmitters mediate rapid intracellular communications not only within the central nervous system but also in the peripheral tissues. They exert their function through receptors present in both neuronal and non neuronal cell surface that trigger second messenger signaling pathways. Dopamine is a neurotransmitter that has been implicated in various central neuronal degenerative disorders like Parkinson's disease and behavioral diseases like Schizophrenia. Dopamine is synthesised from tyrosine, stored in vesicles in axon terminals and released when the neuron is depolarised. Dopamine interacts with specific membrane receptors to produce its effect. Dopamine plays an important role both centrally and peripherally. The recent identification of five dopamine receptor subtypes provides a basis for understanding dopamine's central and peripheral actions . Dopamine receptors are classified into two major groups : DA D1 like and DA D2 like. Dopamine D1 like receptors consists of DA D1 and DA D5 receptors . Dopamine D2 like receptors consists of DA D2, DA D3 and DA D4 receptors. Stimulation of the DA D1 receptor gives rise to increased production of cAMP. Dopamine D2 receptors inhibit cAMP production, but activate the inositol phosphate second messenger system . Impairment of central dopamine neurotransmission causes muscle rigidity, hormonal regulation , thought disorder and cocaine addiction. Peripheral dopamine receptors mediate changes in blood flow, glomerular filtration rate, sodium excretion and catecholamine release. The dopamine D2 receptors increased in the corpus striatum and cerebral cortex but decreased in the hypothalamus and brain stem indicating their involvement in regulating insulin secretion. Dopamine D2 receptor which has a stimulatory effecton insulin secretion decreased in the pancreatic islets during diabetes. Our in vitro studies confirmed the stimulatory role of dopamine D2 receptors in stimulation of glucose induced insulin secretion. A detailed study at the molecular level on the mechanisms involved in the role of dopamine in insulin secretion, its functional modification could lead to therapeutic interventions that will have immense clinical importance.

Dopamine D2 and 5-HT2A receptor gene expression

Neuronal dopamine and serotonin receptors are widely distributed in the central and the peripheral nervous systems at different levels. Dopaminergic and serotonergic systems have crucial role in aldehyde dehydrogenase regulation Stimulation of autonomic nervous system during ethanol treatment is suggested to be an important factor in regulating the ALDH function. The ALDH enzyme activity was increased in plasma, cerebral cortex, and liver but decreased in cerebellum. The ALDH enzyme affinity was decreased in plasma, brainstem and liver and increased in cerebral cortex and cerebellum. Dopamine and serotonin content decreased in liver and brain regions - cerebral cortex, corpus striatum of ethanol treated rats with an increased HVA/DA, 5-HIAA/5-HT tumover rate. Dopamine content decreased in brainstem with an increased HVA/DA turnover rate and serotonin content decreased with an increased 5-HIAA/5-HT turnover rate in the brainstem of ethanol treated rats compared to control. Serotonin content increased in hypothalamus with a decreased 5-HIAA/5—HT turnover rate where as dopamine content decreased in hypothalamus with an increased HVA/DA tumover rate of ethanol treated rats compared to control.alterations of DA D2 and 5-HTQA receptor function and gene expression in the cerebellum, hypothalamus, corpus striatum, cerebral cortex play an important role in the sympathetic regulation of ALDH enzyme in ethanol addiction. There is a serotonergic and dopaminergic functional regulation of ALDH activity in the brain regions and liver of ethanol treated rats. Gene expression studies of DA D2 and 5'HT2A studies confirm these observations. Perfusion studies using DA, 5-HT and glucose showed ALDH regulatory function. Brain activity measeurement using EEG showed a prominentfrontal brain wave difference. This will have immense clinical significance in the management of ethanol addiction.

Neuronal degeneration in streptozotocin induced diabetic rats: Effect of Aegle marmelose and pyridoxine in pancreatic cell proliferation and neuronal Surviva

This thesis Entitled Neuronal degeneration in streptozotocin induced diabetic rats: effect of aegle marmelose and pyridoxine in pancreatic B cell proliferation and neuronal survival. Diabetes mellitus, a chronic metabolic disorder results in neurological dysfunctions and structural changes in the CNS. Antioxidant therapy is a challenging but necessary dimension in the management of diabetes and neurodegenerative changes associated with it. Our results showed regional variation and imbalance in the expression pattern of dopaminergic receptor subtypes in diabetes and its role in imbalanced insulin signaling and glucose regulation. Disrupted dopaminergic signaling and increased hyperglycemic stress in diabetes contributed to the neuronal loss. Neuronal loss in diabetic rats mediated through the expression of pattern of GLUT-3, CREB, IGF-1, Akt-1, NF,B, second messengers- cAMP, cGMP, IP3 and activation of apoptotic factors factors- TNF-a,caspase-8. Disrupted dopaminergic receptor expressions and its signaling in pancreas contributed defective insulin secretion in diabetes. Activation of apoptotic factors- TNF- a,caspase-8 and defective functioning of neuronal survival factors, disrupted second messenger signaling modulated neuronal viability in diabetes. Hyperglycemic stress activated the expression of TNF-a,caspase-8, BAX and differential expression of anti oxidant enzymes- SOD and GPx in liver lead to apoptosis. Treatment of diabetic rats with insulin, Aegle marmelose and pyridoxine significantly reversed the altered dopaminergic neurotransmission, GLUT3, GLUT2, IGF-1 and second messenger signaling. Antihyperglycemic and antioxidant activity of Aegle marmelose and pyridoxine enhanced pancreatic B cell proliferation, increased insulin synthesis and secretion in diabetic rats. Thus our results conclude the neuroprotective and regenerating ability of Aegle marmelose and pyridoxine which in turn has a novel therapeutic role in the management of diabetes.

Studies on the synthesis and cns activity of strychnine derivatives

Strychnine, the major alkaloid present in Strychnos nuxvomica seeds has been reported to stimulate the entire central nervous system with preference for the spinal cord. It is a powerful convulsant and because of this property, it is an important pharmacological tool as it plays a unique role as an inhibitor of post synaptic inhibitory impulses. It is useful to study inhibitory transmitter and receptor types. However, because of its extreme toxicity, strychnine does not have any therapeutic application in the Western system of medicine. The present work was undertaken with a view to obtaining strychnine derivatives having CNS stimulating properties but with sufficiently low toxicity so that they may eventually find some application in medicine. As strychnine is isolated from the locally available strychnos Nugvomica seeds, it’s possible utilization in therapeutics will have considerable commercial significance. This work tries to provide several new compounds which are significantly less toxic than strychnine and its N—oxide as shown from the pharmacological Studio As they also possessed CNS stimulating properties, they are well suited for further screening to assess their potential as valuable therapeutic agents.

Studies in the microbial tranformation of alkaloids strychnine and 2-nitrostrychnine

Strychnine is the major alkaloid present in the seeds of _Strychnos, nuxvomica tree which grow naturally in this area. Strychnine has a very complex chemical structure and is known to stimulate all portions of the central nervous system with preference to the spinal cord. However, it is a powerful convulsant and death results from asphyxia. Consequently strychnine has no therapeutic application in the western system of medicine at present. The objective of this work, therefore, was to convert strychnine by microbial transformation into a product having more desirable pharmacological properties so that this locally available natural product may find some use in the preparation of a therapeutic agent.

Glutamatergic Nmda And Ampa Receptors Functional Regulation In Streptozotocin Induced Diabetic Rats: Effect Of Vitamin D3 And Curcumin Supplementation

The present study was designed to investigate the protective effect of curcumin and vitamin D3 in the functional regulation of glutamatergic NMDA and AMPA receptors in streptozotocin (STZ) induced diabetic rats. Alterations in glutamatergic neurotransmission in the brain were evaluated by analyzing the glutamate content, glutamate receptors - NMDA and AMPA receptors binding parameters and gene expression, GAD and GLAST gene expression. Immunohistochemistry studies using confocal microscope were carried out to confirm receptor density and gene expression results of NMDA and AMPA receptors. The role of glutamatergic receptors in pancreas was studied using the following parameters; glutamate content, GLAST expression, glutamate receptors - NMDA and AMPA receptor binding and gene expression. Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of diabetes. In the present study SOD assay and GPx gene expression were done to evaluate the activity of antioxidant enzymes in the brain regions and pancreas. NeuroD1 and Pdx1 gene expression were performed in pancreas of experimental rats to evaluate pancreatic islet survival. Gene expression profiles of caspase 8, Bax, and Akt in brain regions and pancreas were studied to understand the possible mechanism behind curcumin and vitamin D3 mediated neuroprotection and islet survival. Gene expression studies of vitamin D3 receptor localisation in the pancreas was done to understand the mechanism of vitamin D3 in insulin secretion. Curcumin and vitamin D3 mediated insulin secretion via Ca2+ release were studied using confocal microscope.