Initiation of protein synthesis and heat-shock protein-72 expression in the rat brain following severe insulin-induced hypoglycemia

Abstract

Following stress such as heat shock or transient cerebral ischemia, global brain protein synthesis initiation is depressed through modulation of eucaryotic initiation factor (eIF) activities, and modification of ribosomal subunits. Concomitantly, expression of a certain class of mRNA, heat-shock protein (HSP) mRNA, is induced. Here we report that the activity of eucaryotic initiation factor-2 (eIF-2), a protein that participates in the regulation of a rate-limiting initiation step of protein synthesis, transiently decreases following insulin-induced severe hypoglycemia in the rat brain neocortex. Expression of HSP 72, a 72-kDa HSP, in surviving neurons was seen at 1-7 days of recovery following 30 min of hypoglycemic coma, but not at 1 h and 6 h of recovery. In the neocortex, HSP 72 was first seen in layer IV, and later also in surviving neurons in layer II. In the CA1 region and in the crest of dentate gyrus, HSP 72 expression was evident in cells adjacent to irreversibly damaged neurons. In the CA3 region and the hilus of dentate gyrus, HSP 72 was expressed in a few scattered neurons. In septal nucleus, HSP 72 was expressed in a lateral to medial fashion over a period of 1-3 days of recovery. We conclude that severe insulin-induced hypoglycemia induces a stress response in neurons in the recovery phase, including inhibition of protein synthesis initiation, depression of eIF-2 activity, and a delayed and prolonged expression of HSP 72 in surviving neurons. The HSP 72 expression may be a protective response to injurious stress.

Presumed apoptosis and reduced arcuate nucleus neuropeptide Y and pro-opiomelanocortin mRNA in non-coma hypoglycemia.

“…Interestingly, prior bouts of hypoglycemia may actually confer some degree of protection on certain aspects of cognitive function during subsequent hypoglycemic episodes (29). The lack of HSP-72 expression in the hypoglycemic brains here is in keeping with previous studies showing that such expression occurs only after severe bouts of hypoglycemia, which produce burst suppression and an isoelectric electroencephalogram (35).…”

“…The transition to necrosis requires sustained levels of reduced glucose (and oxygen) to decrease intracellular ATP levels well below those required to produce apoptosis (34). Finally, there was no evidence that the cells in this or any other brain area induced HSP-72 expression, which is often found in damaged cells that are destined to survive their injury (35). The induction of HSP-72 is thought to confer a degree of protection and it is rarely seen in cells undergoing apoptosis or necrosis (36,37).…”

“…In situ hybridization for prepro-NPY and POMC mRNA. Brains were processed for in situ hybridization by minor modifications of previously described methods (21-23) using 35 S-labeled riboprobes for NPY (24) and POMC (25) on 5-µm frozen brain sections post-fixed in 4% paraformaldehyde. Of all the brains run, 24 (14 hypoglycemic and 10 controls) had been run previously for the TUNEL procedure.…”

“…The induction of HSP-72 is thought to confer a degree of protection and it is rarely seen in cells undergoing apoptosis or necrosis (36,37). However, severe hypoglycemia does induce HSP-72 in both neurons (35) and astrocytes (36). Interestingly, prior bouts of hypoglycemia may actually confer some degree of protection on certain aspects of cognitive function during subsequent hypoglycemic episodes (29).…”

Muscle as an Endocrine Organ: Focus on Muscle-Derived Interleukin-6

“…The observation that indomethacin, a member of the nonsteroid anti-inflammatory drugs (NSAID), which are known to inhibit NFB activity, reduces the exercise-induced increase of IL-6 further supports the notion that NFB is likely to serve as a link between contractile activity and IL-6 synthesis (176, 299). On the other hand, increased oxidative stress, as well as low glucose availability, low glycogen content, catecholamines, increased intracellular calcium levels, hyperthermia, and ischemia-reperfusion are all features of exercise capable of inducing heat shock proteins (HSPs) (25,56,95,256,378,391), which may in turn activate IL-6 synthesis via HSF1 and HSF2 (289).…”