Insulin protects cognitive function in experimental stroke.

Strong, Ashley; Fairfield, Jane; Monteiro, Edson G.; Kirby, Melanie; Hogg, Annette; Snape, Michael; Ross-Field, L

doi:10.1136/jnnp.53.10.847

Cited by 49 publications

(17 citation statements)

References 41 publications

(5 reference statements)

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“…Certainly, a number of studies have pre sented evidence of a reduced severity of neurologic abnormalities, increased survival, and diminished brain damage following such exposures (Robertson and Grossman 1987;LeMay et al, 1988a,b;Voll and Auer, 1988;Voll et al, 1989;Strong et al, 1990). If hypoglycemia protects the brain against anoxia or global ischemia, then it can be speculated that it may protect against focal ischemia (ischemic stroke in humans, MCA occlusion in animals) where the blood flow to brain regions may be re duced rather than abolished.…”

Section: Discussionmentioning

confidence: 99%

Normoglycemia (Not Hypoglycemia) Optimizes Outcome from Middle Cerebral Artery Occlusion

Courten-Myers

Kleinholz

Wagner

et al. 1994

J Cereb Blood Flow Metab

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Summary:We examined the effects of serum glucose concentration during middle cerebral artery (MCA) oc clusion in the cat on death rates in animals that died from hemispheric edema and on infarct size in animals that survived. We occluded the MCA permanently in some groups and released the clip after 8 h in others. By inject ing or infusing glucose solutions, saline, or insulin, we maintained six animal groups steadily either hyper-, normo-, or slightly hypoglycemic before and for 6 or 8 h after permanent or 8-h temporary MCA occlusion. Stud ies with these groups revealed a distinct optimal outcome with normoglycemic animals. In three additional groups, we altered the glycemia after permanent occlusion from hyper-to normo-or hypoglycemia and from normo-to hyperglycemia. Two of the three hypoglycemic groups (8-h reversible and permanent hyper-to hypoglycemic occlusions) yielded the worst outcomes in this study, with > 10 x larger median infarcts than the best outcome group Hyperglycemia as an influence that greatly aggra vates the brain pathologic consequences of expo sure to cardiac arrest (anoxia) was first described over 15 years ago (Myers and Yamaguchi, 1976). The view that hyperglycemia accentuates the brain damage in anoxia has become widely accepted based on a large body of evidence (Myers and de Courten-Myers, 1985; Siesj6, 1988). Similarly, with respect to focal ischemia, elevating the serum glu cose concentrations at the time of either permanent or temporary middle cerebral artery (MCA) occlu sion in cats also increases both the frequency with which the animals die of hemispheric edema sec-

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Section: Discussionmentioning

confidence: 99%

Normoglycemia (Not Hypoglycemia) Optimizes Outcome from Middle Cerebral Artery Occlusion

Courten-Myers

Kleinholz

Wagner

et al. 1994

J Cereb Blood Flow Metab

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“…Several studies have suggested that brain insulin, in particular, can have effects on neuronal excitability and memory. In vitro, insulin has been reported to depress the activity of hippocampal neurones (Palovcik et al 1984) and was neuroprotective in a model of stroke (Strong et al 1990), arguing that insulin regulates hippocampal function. In support of these findings, diabetic rats are impaired in both the establishment of hippocampal LTP and in hippocampus-dependent spatial learning (Biessels et al 1998), but this does not distinguish between specific signalling by insulin/glucose and loss of glucose control (in this instance) leading to neuronal dysfunction; note that increases in blood glucose can improve memory performance (Gold et al 1986, Hall & Gold 1986, and that memory problems can be encountered in diabetic patients (Prescott et al 1990, Hershey et al 1997.…”

Section: Insulinmentioning

confidence: 99%

Hormones and the hippocampus

Lathe

2001

Journal of Endocrinology

222

163

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Hippocampal lesions produce memory deficits, but the exact function of the hippocampus remains obscure. Evidence is presented that its role in memory may be ancillary to physiological regulation. Molecular studies demonstrate that the hippocampus is a primary target for ligands that reflect body physiology, including ion balance and blood pressure, immunity, pain, reproductive status, satiety and stress. Hippocampal receptors are functional, probably accessible to their ligands, and mediate physiological and cognitive changes. This argues that an early role of the hippocampus may have been in sensing soluble molecules (termed here 'enteroception') in blood and cerebrospinal fluid, perhaps reflecting a common evolutionary origin with the olfactory system ('exteroception').Functionally, hippocampal enteroception may reflect feedback control; evidence is reviewed that the hippocampus modulates body physiology, including the activity of the hypothalamus-pituitary-adrenal axis, blood pressure, immunity, and reproductive function. It is suggested that the hippocampus operates, in parallel with the amygdala, to modulate body physiology in response to cognitive stimuli. Hippocampal outputs are predominantly inhibitory on downstream neuroendocrine activity; increased synaptic efficacy in the hippocampus (e.g. long-term potentiation) could facilitate throughput inhibition. This may have implications for the role of the hippocampus and long-term potentiation in memory. Journal of Endocrinology (2001) 169, 205-231The hippocampus and memory Attention has focused on the hippocampus in view of its likely role in memory encoding and its dysfunction in Alzheimer's disease. The hippocampal formation undoubtedly contributes to the encoding of long-term memories, but an exclusive focus on memory would be a mistake. The present review emphasises an important aspect of hippocampal function: that of responding to and governing body physiology. What follows briefly revisits the role of the hippocampus in learning and memory, and the electrophysiological correlates of memory processes, before considering how the spectrum of genes expressed in the hippocampal formation may cast light on the involvement of the hippocampus in other processes. (In this paper, 'hippocampus' and 'hippocampal formation' are used interchangably to denote the juxtaposition of the fields of the cornu ammonis with the dentate gyrus.) Memory and the hippocampusThe hippocampus, located beneath the cerebral hemispheres, resembles a large 'wishbone' (the curved Y-shaped bone in the chicken neck), but takes its name from the appearance of its arms in cross-section -the interlocking double-U formed by the tightly aligned cell bodies of ammon's horn (cornu ammonis) and the dentate gyrus -reminiscent of the shape of Hippocampus spp. ( Fig. 1; for detailed reviews of hippocampal structure see Amaral 1987, Amaral & Witter 1989. Memory problems in a patient with limbic damage (i.e. at the edge of the forebrain) were first recorded in 1898; another 60 years elapsed be...

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“…In addition, one study suggests that in calf chondrocytes, insulin reduced eIF2ex(P) (Towle et a!., 1984). Furthermore, several studies show that adminis tration of insulin during reperfusion substantiaIIy reduces both neuronal death and the final extent of neurologic disability (LeMay et a!., 1988;Voll et a!., 1989;Strong et a!., 1990;Shigeno et a!., 1991;Voll and Auer, 1991b) independent of hypoglycemia (Voll and Auer, 1991a). Thus, we hypothesize that reduction of the levels of eIF2ex(P) would enhance protein synthesis in vulnerable hippocampal neurons during reperfusion, and that this might be accomplished by insulin administration.…”

mentioning

confidence: 99%

Insulin Induces Dephosphorylation of Eukaryotic Initiation Factor 2α and Restores Protein Synthesis in Vulnerable Hippocampal Neurons after Transient Brain Ischemia

Sullivan

Alousi

Hikade

et al. 1999

J Cereb Blood Flow Metab

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Brain reperfusion causes prompt, severe, and prolonged protein synthesis suppression and increased phosphorylation of eukaryotic initiation factor 2alpha [eIF2alpha(P)] in hippocampal CA1 and hilar neurons. The authors hypothesized that eIF2alpha(P) dephosphorylation would lead to recovery of protein synthesis. Here the effects of insulin, which activates phosphatases, were examined by immunostaining for eIF2alpha(P) and autoradiography of in vivo 35S amino acid incorporation. Rats resuscitated from a 10-minute cardiac arrest were given 0, 2, 10 or 20 U/kg of intravenous insulin, underwent reperfusion for 90 minutes, and were perfusion fixed. Thirty minutes before perfusion fixation, control and resuscitated animals received 500 microCi/kg of 35S methionine/cysteine. Alternate 30-microm brain sections were autoradiographed or immunostained for eIF2alpha(P). Controls had abundant protein synthesis and no eIF2alpha(P) in hippocampal neurons. Untreated reperfused neurons in the CA1, hilus, and dentate gyrus had intense staining for eIF2alpha(P) and reduced protein synthesis; there was little improvement with treatment with 2 or 10 U/kg of insulin. However, with 20 U/kg of insulin, these neurons recovered protein synthesis and were free of eIF2alpha(P). These results show that the suppression of protein synthesis in the reperfused brain is reversible; they support a causal association between eIF2alpha(P) and inhibition of protein synthesis, and suggest a mechanism for the neuroprotective effects of insulin.

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Insulin protects cognitive function in experimental stroke.

Cited by 49 publications

References 41 publications

Normoglycemia (Not Hypoglycemia) Optimizes Outcome from Middle Cerebral Artery Occlusion

Normoglycemia (Not Hypoglycemia) Optimizes Outcome from Middle Cerebral Artery Occlusion

Hormones and the hippocampus

Insulin Induces Dephosphorylation of Eukaryotic Initiation Factor 2α and Restores Protein Synthesis in Vulnerable Hippocampal Neurons after Transient Brain Ischemia

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