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10. Repeated Activation of Noradrenergic Receptors in the Ventromedial Hypothalamus Suppresses the Response to Hypoglycemia.

Author

Sejling, Anne-Sophie, Wang, Peili, Zhu, Wanling, Farhat, Rawad, Knight, Nicholas, Appadurai, Daniel, and Chan, Owen

Subjects
HYPOTHALAMUS, HYPOGLYCEMIA, EXTRACELLULAR fluid, ALBUTEROL, LACTATES
Abstract

Activation of the adrenergic system in response to hypoglycemia is important for proper recovery from low glucose levels. However, it has been suggested that repeated adrenergic stimulation may also contribute to counterregulatory failure, but the underlying mechanisms are not known. The aim of this study was to establish whether repeated activation of noradrenergic receptors in the ventromedial hypothalamus (VMH) contributes to blunting of the counterregulatory response by enhancing local lactate production. The VMH of nondiabetic rats were infused with either artificial extracellular fluid, norepinephrine (NE), or salbutamol for 3 hours/day for 3 consecutive days before they underwent a hypoglycemic clamp with microdialysis to monitor changes in VMH lactate levels. Repeated exposure to NE or salbutamol suppressed both the glucagon and epinephrine responses to hypoglycemia compared to controls. Furthermore, antecedent NE and salbutamol treatments raised extracellular lactate levels in the VMH. To determine whether the elevated lactate levels were responsible for impairing the hormone response, we pharmacologically inhibited neuronal lactate transport in a subgroup of NE-treated rats during the clamp. Blocking neuronal lactate utilization improved the counterregulatory hormone responses in NE-treated animals, suggesting that repeated activation of VMH β2-adrenergic receptors increases local lactate levels which in turn, suppresses the counterregulatory hormone response to hypoglycemia. [ABSTRACT FROM AUTHOR]

Published
2021
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15. Therapeutic hypothermia modulates complement factor C3a and C5a levels in a rat model of hypoxic ischemic encephalopathy

Author

Shah, Tushar A., Nejad, Jasmine E., Pallera, Haree K., Lattanzio, Frank A., Farhat, Rawad, Kumar, Parvathi S., Hair, Pamela S., Bass, W. Thomas, and Krishna, Neel K.

Abstract

Background:Therapeutic hypothermia (HT) is the only intervention that improves outcomes in neonatal hypoxic-ischemic encephalopathy (HIE). However, the multifactorial mechanisms by which HT impacts HIE are incompletely understood. The complement system plays a major role in the pathogenesis of ischemia-reperfusion injuries such as HIE. We have previously demonstrated that HT modulates complement activity in vitro.Methods:Term equivalent rat pups were subjected to unilateral carotid ligation followed by hypoxia (8% O2) for 45 min to simulate HIE. A subset of animals was subjected to HT (31–32°C for 6 h). Plasma and brain levels of C3a and C5a were measured. Receptors for C3a (C3aR) and C5a (C5aR) along with C1q, C3, and C9 were characterized in neurons, astrocytes, and microglia.Results:We found that HT increased systemic expression of C3a and decreased expression of C5a after HIE. In the brain, C3aR and C5aR are predominantly expressed on microglia after HIE. HT increased local expression of C3aR and decreased expression on C5aR after HIE. Furthermore, HT decreased local expression of C1q, C3-products, and C9 in the brain.Conclusion:HT is associated with significant alteration of complement effectors and their cognate receptors. Complement modulation may improve outcomes in neonatal HIE.

Published
2017
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