Muscarinic M1, M3, Nicotinic,GABAA and GABAB Receptor ...

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of the key contributors to motor deficits and cellular stress associated with hypoglycemia in diabetes which is suggested to cause more damage at molecular level than hyperglycemia. Dysfunction of cerebellar cholinergic receptors are reported in hypoglycemia and hyperglycemia (Antony et al., 2010). Brain stem Brain stem reticular formation has been considered to play an important role in generating behavioural states as well as in the modulation of pain sensation (Pare & Steriade 1993). These reticular functions originate from interacting neuronal groups in the brain stem, including cholinergic, adrenergic and serotoninergic neurons (Steriade, 1996). Hypoglycemia result primarily from a lowered glucose level in the brain and it adversely affects the central and autonomic nervous systems (Charles et al., 2005). When glucose level was lowered to 2.8 mmoles/L, the brain function was impaired in nondiabetic rats. Symptoms of hypoglycemia result from the actions of hormones and neurotransmitters in the process of restoring blood glucose levels. Severe hypoglycemia triggers a cascade of events in vulnerable neurons that culminate in cell death even after glucose normalization (Suh et al. 2003; 2005). Brainstem is an important part of the brain in monitoring the glucose status and the regulation of feeding (Guillod et al., 2003). Also, it serves as one of the key centres of the central nervous system for regulating body homeostasis. Present study on brainstem muscarinic receptors showed that the total muscarinic receptors increased during hypoglycemic condition compared to diabetic and control. Muscarinic M1 receptors are decreased and muscarinic M3 receptors are increased during hypoglycemia. RT-PCR analysis also revealed a down regulation of the muscarinic M1 receptor mRNA level during glucose deprivation in hypoglycemia. This is in accordance with our receptor binding studies. Also, confocal studies using specific antibodies of muscarinic M1 and M3 in brain stem confirmed the Real time PCR analysis and binding assays. The adverse effects of mild 111
112 Discussion hypoglycemia on brain function are not limited to higher centres but also involve the brainstem. Previous studies suggest that moderate hypoglycemia impairs brainstem function in normal humans and rats (McNay et al., 2001). Recent studies suggest that moderate hypoglycemia impairs brainstem function in normal humans and rats. It is reported that mild hypoglycemia causes a functional impairment in the inferior colliculus (IC) region of the brainstem in both nondiabetic and diabetic rats (Jacob et al., 1995). The brain stem provides the main motor and sensory innervation via the cranial nerves. Though some earlier studies reported that brainstem is less vulnerable to hypoglycemic brain damage (Auer, 2004), our results indicated that the cholinergic function mediated through muscarinic receptors in the brain stem is altered in hypoglycemic and hyperglycemic rats impairing ACh related functions of brain stem. Corpus striatum Corpus striatum regulates endocrine functions indirectly through the secretion of other hormones like thyroxine. In the rat striatum, Ach content, AchE and ChAT activity are among the highest in the brain (Calabresi et al., 1998). Muscarinic modulation of ACh released by muscarinic autoreceptors are observed even in the presence of AChE, showing that this modulation plays a key role in the physiological function of cholinergic transmission (Dodt & Misgeld, 1986). Scatchard analysis of total muscarinic receptors revealed a decreased Bmax in corpus striatum during hypoglycemia compared to diabetic and control rats. Within the striatum, the postsynaptic effects of Ach are mediated primarily by muscarinic receptors and the postsynaptic `excitatory' effects produced by muscarine seem to be generated by the activation of M1 receptors (Calabresi et al., 2000). Muscarinic M1 receptors were increased and muscarinic M3 receptors decreased during hypoglycemia. mRNA expression analysis also showed an up regulation of the muscarinic M1 receptor and down regulation of M3 receptor
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MUSCARINIC M1, M3, NICOTINIC, GABAA
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ACKNOWLEDGEMENT To the Almighty God
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Seema Chandran, Ms. Neema Ani Manga
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ABBREVIATIONS 5-HIAA 5 Hydroxy indo
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PFC Prefrontal cortex PLC Phospholi
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GABAC Receptors 34 Glutamic Acid De
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Behavioural response of control and
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the cerebral cortex of control and
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Muscarinic M1 receptor analysis Sca
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REAL TIME-PCR ANALYSIS 81 Real Time
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Real Time PCR analysis of GABAAα1
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pancreas of control and experimenta
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utilization is decreased in the bra
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impairment, coma or seizure (Cryer,
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achieving optimal blood sugar contr
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OBJECTIVES OF THE PRESENT STUDY 1.
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Literature Review Diabetes mellitus
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12 Literature Review from the adren
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14 Literature Review Hypoglycemic c
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16 Literature Review respectively)
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18 Literature Review in extracellul
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20 Literature Review substrates in
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22 Literature Review nucleus, altho
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24 Literature Review al., 1990; Lev
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26 Literature Review muscarinic M2
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Signal transduction by muscarinic a
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30 Literature Review nicotinic acet
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GABAA Receptors 32 Literature Revie
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34 Literature Review GABAB-mediated
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36 Literature Review (Erlander et a
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38 Literature Review which could be
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40 Literature Review administration
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42 Literature Review the hippocampu
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44 Literature Review understanding
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Confocal Dyes Rat primary antibody
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antipyryl)-p-benzo quinoneimine. Th
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was analyzed. Data was expressed as
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ANALYSIS OF THE RECEPTOR BINDING DA
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Taqman probes of muscarinic M1, M3,
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Taylor, 1968). The islets were isol
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Results BODY WEIGHT AND BLOOD GLUCO
Page 85 and 86: 60 Results IIH and C + IIH rats sho
Page 87 and 88: Real Time-PCR analysis of muscarini
Page 89 and 90: Real Time PCR analysis of SOD 64 Re
Page 91 and 92: 66 Results GABAAα1 receptor antibo
Page 93 and 94: 68 Results compared to diabetic gro
Page 95 and 96: 70 Results compared to diabetic rat
Page 97 and 98: 72 Results Muscarinic M3 receptor a
Page 99 and 100: Muscarinic M3 receptor analysis 74
Page 101 and 102: 76 Results group, α7 nAChR mRNA si
Page 103 and 104: 78 Results diabetic rats. In C + II
Page 105 and 106: Muscarinic M1 receptor analysis 80
Page 107 and 108: Real Time-PCR analysis of α7 nAChR
Page 109 and 110: Real Time PCR analysis of phospholi
Page 111 and 112: HIPPOCAMPUS Total muscarinic recept
Page 113 and 114: 88 Results IIH and C + IIH group sh
Page 115 and 116: 90 Results group, GLUT3 mRNA signif
Page 117 and 118: 92 Results α7 nACh receptor antibo
Page 119 and 120: GABA receptor analysis 94 Results S
Page 121 and 122: 96 Results control. D + IIH and C +
Page 123 and 124: Discussion Glucose is the principal
Page 125 and 126: 100 Discussion The ability to sense
Page 127 and 128: 102 Discussion The Y-maze test is a
Page 129 and 130: 104 Discussion CHOLINERGIC ENZYME A
Page 131 and 132: 106 Discussion Pancreas Insulin sec
Page 133 and 134: 108 Discussion 2003). Cholinergic m
Page 135: 110 Discussion brain for learning,
Page 139 and 140: 114 Discussion shows impaired expre
Page 141 and 142: 116 Discussion glycemic control is
Page 143 and 144: 118 Discussion release (Ilcol et al
Page 145 and 146: 120 Discussion al., 1992), it has t
Page 147 and 148: 122 Discussion metabolic cycles are
Page 149 and 150: 124 Discussion al., 1988). Low bloo
Page 151 and 152: 126 Discussion modulate the second
Page 153 and 154: 128 Discussion between excitation a
Page 155 and 156: 130 Discussion hypoglycemic seizure
Page 157 and 158: 132 Discussion Insulin secretion fr
Page 159 and 160: 134 Discussion hyper and hypoglycem
Page 161 and 162: 136 Discussion receptors in glucose
Page 163 and 164: 138 Discussion exacerbated by recur
Page 165 and 166: 140 Discussion Haces et al., 2010).
Page 167 and 168: 142 Discussion hypoglycemic and dia
Page 169 and 170: 144 Discussion transcription factor
Page 171 and 172: Summary 1. Insulin induced hypoglyc
Page 173 and 174: 148 Summary specific antibodies con
Page 175 and 176: 150 Summary 16. Transcription facto
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Body weight (gm) 300 250 200 150 10
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Figure-3 Blood glucose levels at di
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Figure-5 Behavioural response of co
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Figure-7 Scatchard analysis of [ 3
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Figure-11 Real Time PCR amplificati
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C D + IIH Figure--25 Muscarinic M1
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Figure--27 α 7 nACh receptor expre
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Figure--47 Muscarinic M1 receptor e
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Figure--49 α7 nicotinic acetylchol
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Figure--71 α7 nicotinic acetylchol
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C Figure--93 GABAAα1 receptor expr
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Figure-101 Real Time PCR amplificat
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Figure—113 Muscarinic M3 receptor
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Figure--115 GABAAα1 receptor expre
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Figure-117 Scatchard analysis of [
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Figure-119 Scatchard analysis of [
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Figure-131 Muscarinic M1 receptor e
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C D + IIH Figure-133 GABAAα1 recep
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