Advertisement

Effects of Intracerebroventricular Glycogen Phosphorylase Inhibitor CP-316,819 Infusion on Hypothalamic Glycogen Content and Metabolic Neuron AMPK Activity and Neurotransmitter Expression in Male Rat

  • Mostafa M. H. Ibrahim
  • Khaggeswar Bheemanapally
  • Hussain N. Alhamami
  • Karen P. BriskiEmail author
Article
  • 24 Downloads

Abstract

Brain glycogen is a vital energy source during metabolic imbalance. Metabolic sensory neurons in the ventromedial hypothalamic nucleus (VMN) shape glucose counter-regulation. Insulin-induced hypoglycemic (IIH) male rats were infused icv with the glycogen breakdown inhibitor CP-316,819 (CP) to investigate whether glycogen-derived fuel controls basal and/or hypoglycemic patterns of VMN gluco-regulatory neuron energy stability and transmitter signaling. CP caused dose-dependent amplification of basal VMN glycogen content and either mobilization (low dose) or augmentation (high dose) of this depot during IIH. Drug treatment also prevented hypoglycemic diminution of tissue glucose in multiple structures. Low CP dose caused IIH-reversible augmentation of AMPK activity and glutamate decarboxylase (GAD) protein levels in laser-microdissected VMN GABA neurons, while the higher dose abolished hypoglycemic adjustments in these profiles. VMN steroidogenic factor-1 (SF-1) neurons exhibited suppressed (low CP dose) or unchanged (high CP dose) basal SF-1 expression and AMPK refractoriness of hypoglycemia at each dose. CP caused dose-proportionate augmentation of neuronal nitric oxide synthase protein and enhancement (low dose) or diminution (high dose) of this profile during IIH; AMPK activity in these cells was decreased in high dose-pretreated IIH rats. CP exerted dose-dependent effects on basal and hypoglycemic patterns of glucagon, but not corticosterone secretion. Results verify that VMN GABA, SF-1, and nitrergic neurons are metabolic sensory in function and infer that these populations may screen unique aspects of neurometabolic instability. Correlation of VMN glycogen augmentation with attenuated hypoglycemic VMN gluco-regulatory neuron AMPK activity implies that expansion of this fuel reservoir preserves cellular energy stability during this metabolic threat.

Keywords

Glycogen CP-316,819 Ventromedial hypothalamic nucleus Laser-catapult microdissection Glutamate decarboxylase65/67 AMPK 

Abbreviations

CP-316,819

[R-R*,S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide

ARH

Arcuate hypothalamic nucleus

DMN

Dorsomedial hypothalamic nucleus

GABA

γ-Aminobutyric acid

GAD65/67

Glutamate decarboxylase65/67

GP

Glycogen phosphorylase

icv

Intracerebroventricular

IIH

Insulin-induced hypoglycemia

LCM

Laser-catapult microdissection

LHA

Lateral hypothalamic area

NO

Nitric oxide

nNOS

Neuronal nitric oxide synthase

SF-1

Steroidogenic factor-1

VMN

Ventromedial hypothalamic nucleus

Notes

Compliance with Ethical Standards

Experimental procedures were carried out in accordance with the Guide for the Care and Use of Laboratory Animals, 8th Edition, and approved by the University of Louisiana at Monroe Institutional Animal Care and Use Committee.

References

  1. Ali MH, Napit PR, Mahmood ASMH, Bheemanapally K, Alhamami HN, Uddin MM, Mandal KS, Ibrahim MMH, Briski KP (2019) Hindbrain estrogen receptor regulation of ventromedial hypothalamic glycogen metabolism and glucoregulatory transmitter expression in the hypoglycemic male rat. Neuroscience 409:253–260CrossRefGoogle Scholar
  2. Alhamami HN, Uddin MM, Mahmood ASMH, Briski (2018) Lateral but not medial hypothalamic AMPK activation occurs at the hypoglycemic nadir in insulin-injected rats: Impact of caudal dorsomedial hindbrain catecholaminergic signaling. Neuroscience 379:103–114CrossRefGoogle Scholar
  3. Bai W, Fang X, Zhao W, Huang S, Zhang H, Qian M (2015) Determination of oligosaccharides and monosaccharides in Hakka rice wine by precolumn high-performance liquid chromatography. J Food Drug Anal 23:645–651CrossRefGoogle Scholar
  4. Brown AM (2004) Brain glycogen re-awakened. J Neurochem 89:537–552CrossRefGoogle Scholar
  5. Chan O, Zhu W, Ding Y, McCrimmon RJ, Sherwin RS (2006) Blockade of GABA(A) receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia. Diabetes 55:1080–1087CrossRefGoogle Scholar
  6. Chan O, Paranjape SA, Horblitt A, Zhu W, Sherwin RS (2013) Lactate-induced release of GABA in the ventromedial hypothalamus contributes to counterregulatory failure in recurrent hypoglycemia and diabetes. Diabetes 62:4239–4246CrossRefGoogle Scholar
  7. Cryer PE (2013) Hypoglycemia-associated autonomic failure in diabetes. Handb Clin Neurol 117:295–307CrossRefGoogle Scholar
  8. Cryer PE (2014) Glycemic goals in diabetes: trade-off between glycemic control and iatrogenic hypoglycemia. Diabetes 63:2188–2195CrossRefGoogle Scholar
  9. Donovan CM, Watts AG (2014) Peripheral and central glucose sensing in hypoglycemic detection. Physiology 29:314–324CrossRefGoogle Scholar
  10. Fuller M, Duplock S, Turner C, Davey P, Brooks DA, Hopwood JJ, Meikle PJ (2012) Mass spectrometric quantification of glycogen to assess primary substrate accumulation in the Pompe mouse. Anal Biochem 421:759–763CrossRefGoogle Scholar
  11. Garfield AS, Shah BP, Madara JC, Burke LK, Patterson CM, Flak J, Neve RL, Evans ML, Lowell BB, Myers MG, Heisler LK (2014) A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia. Cell Metab 20:1030–1037CrossRefGoogle Scholar
  12. Gruetter R (2003) Glycogen: the forgotten cerebral energy store. J Neurosci Res 74:179–183CrossRefGoogle Scholar
  13. Herzog RI, Chan O, Yu S, Dziura J, McNay EW, Sherwin RS (2008) Effect of acute and recurring hypoglycemia on changes in brain glycogen concentrations. Endocrinology 149:1499–1504CrossRefGoogle Scholar
  14. Honda S, Akao E, Suzuki S, Okuda M, Kakehi K, Nakamura J (1989) High-performance liquid chromatography of reducing carbohydrates as strongly ultraviolet-absorbing and electrochemically sensitive 1-phenyl-3-methyl5-pyrazolone derivatives. Anal Biochem 180:351–357CrossRefGoogle Scholar
  15. Martin WH, Hoover DJ, Armento SJ, Stock IA, McPherson PK, Danley DE, Stevenson RW, Barrett EJ, Treadway JL (1998) Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo. Proc Natl Acad Sci 95:1776–1781CrossRefGoogle Scholar
  16. Napit PR, Ali MH, Shakya M, Mandal SK, Bheemanapally K, Mahmood ASMH, Ibrahim MMH, Briski KP (2019) Hindbrain estrogen receptor regulation of counter-regulatory hormone secretion and ventromedial hypothalamic nucleus glycogen content and glucoregulatory transmitter signaling in hypoglycemic female rats. Neuroscience 411:211–221CrossRefGoogle Scholar
  17. Nehlig A, Wittendorp-Rechenmann E, Lam CD (2004) Selectve uptake of [14C]-2deoxyglucose by neurons and astrocytes: high-resolution microautoradiographic imaging by cellular 14C-trajectography combined with immunohistochemistry. J Cereb Blood Flow Metab 24:1004–1014CrossRefGoogle Scholar
  18. Shakya M, Shrestha PK, Briski (2018) Hindbrain 5'-monophosphate-activated protein kinase mediates short-term food deprivation inhibition of the gonadotropin-releasing hormone-luteinizing hormone axis: role of nitric oxide. Neuroscience 383:46–59CrossRefGoogle Scholar
  19. Stobart JL, Anderson CM (2013) Role of astrocytes as gatekeepers of neuronal energy supply. Front Cell Neurosci 7:1–21CrossRefGoogle Scholar
  20. Suh SW, Bergher JP, Anderson CM, Treadway JL, Fosgerau K, Swanson RA (2007) Astrocyte glycogen sustains neuronal activity during hypoglycemia: studies with the glycogen phosphorylase inhibitor CP-316,819 ([R-R*,S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)-propyl]-1H-indole-2-carboxamide). J Pharmacol Exp Ther 321:45–50CrossRefGoogle Scholar
  21. Watts AG, Donovan CM (2010) Sweet talk in the brain: glucosensing, neural networks, and hypoglycemic counterregulation. Front Neuroendocrinol 31:32–43CrossRefGoogle Scholar
  22. Zhu W, Czyzyk D, Paranjape SA, Zhou L, Horblitt A, Szabó G, Seashore MR, Sherwin RS, Chan O (2010) Glucose prevents the fall in ventromedial hypothalamic GABA that is required for full activation of glucose counterregulatory responses during hypoglycemia. Amer J Physiol Endocrinol Metab 298:E971–E977CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.School of Basic Pharmaceutical and Toxicological Sciences, College of PharmacyUniversity of Louisiana at MonroeMonroeUSA
  2. 2.Department of Pharmacology and Toxicology, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia

Personalised recommendations