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Effects of estradiol, progesterone, and norethisterone on regional concentrations of galanin in the rat brain
Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
1999 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 20, no 6, 743-748 p.Article in journal (Refereed) Published
Abstract [en]

Concentrations of immunoreactive galanin were compared in eight gross brain regions of ovariectomized female rats treated with either estradiol, estradiol + progesterone, estradiol + norethisterone, or placebo. Higher concentrations with estradiol treatment compared with placebo were found in the pituitary (357%), frontal cortex (162%), occipital cortex (174%), hippocampus (170%), and median eminence (202%). A more profound difference with addition of progesterone or norethisterone was seen in the pituitary (529% and 467%, respectively). Sex steroids, particularly estradiol, modulate galanin concentrations not only in reproductive, but also in nonreproductive, brain regions.

Place, publisher, year, edition, pages
1999. Vol. 20, no 6, 743-748 p.
Keyword [en]
Galanin, Estradiol, Progesterone, Norethisterone, Hippocampus, Pituitary, Frontal cortex
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-13442DOI: 10.1016/S0196-9781(99)00057-1OAI: diva2:20734
Available from: 2005-11-11 Created: 2005-11-11 Last updated: 2012-09-06Bibliographically approved
In thesis
1. Estrogen-inducible neuropeptides in the rat brain: role in focal ischemic lesions
Open this publication in new window or tab >>Estrogen-inducible neuropeptides in the rat brain: role in focal ischemic lesions
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Sex steroids in general and estrogens in particular – in addition to their effects on the reproductive organs – affect a large number of crucial bodily functions, including “higher” brain functions.

Neuropeptides constitute the phylogenetically oldest neurotransmitter system and are currently thought to act mainly during stress, disease or injury. The concentration of galanin is i.a. up-regulated by injury to the nervous system and by estrogen.

The main focus of the present thesis was to investigate whether the reported neuroprotective effect of 17β-estradiol in experimental animal stroke models is partially mediated through its effects on galanin and if galanin per se exerts neuroprotective effects in stroke.

An exploratory study of the effects of sex steroid concentrations due to gender and pubertal development showed differences in concentrations of i.a. the neuropeptides galanin and neuropeptide Y also in brain regions of female rats important for higher brain functions, including hippocampus and cortex, brain regions not directly involved in reproduction. Puberty brings about changes in several hormonal mechanisms, and our studies showed that the major effect on the concentrations of galanin in various brain regions of ovariectomized (ovx) rats, was brought about by 17β-estradiol.

The pathophysiological mechanisms involved in thrombolysis – the current treatment of choice in human stroke – attempts the re-establishment of perfusion (reperfusion) to the lesioned area of the brain. This prompted us to develop a reperfusion stroke model in rats designed to be mild, focal and transient, allowing long-term observation periods of animals thriving well postoperatively. Mortality and morbidity during and after the middle cerebral artery (MCA) occlusion are important confounding factors crucial for the results. Changing anaesthesia from intraperitoneally administered chloral hydrate to isofl urane inhalation anaesthesia using endotracheal intubation and controlled ventilation markedly reduced the mortality rate from 25% to 10.6%, which was even further reduced down to 2.7 % by successively improved surgical skills.

Contrary to our initial hypothesis, long-term 17β-estradiol treatment resulted in larger ischemic lesions in our stroke model compared to control treatment. After 3 days the cerebral ischemic lesion area was doubled after 17β-estradiol treatment in rats subjected to 60 min microclip occlusion of the MCA followed by reperfusion. A similar, but not statistically signifi cant difference was found after 7 and 14 days. Three groups studying different types of experimental animal stroke and different doses of 17β-estradiol treatment have recently also demonstrated lack of neuroprotection by 17β-estradiol treatment. Furthermore, large epidemiological clinical studies have recently also reported an increased risk and poorer outcome in postmenopausal women subjected to hormone replacement therapy.

The concentrations of galanin-like immunoreactivity in extracts of punch biopsies from the penumbra area after transient MCA occlusion were found unchanged, but were decreased (p=0.015) in the apparently undamaged ipsilateral hippocampus. Galanin administered by continuous intracerebroventricular infusion (2.4 nmol/day) resulted in a 30% larger ischemic lesion compared to controls, measured 7 days after the MCA occlusion. Taken together, these results indicate that galanin in the brain is primarily a factor reacting to ischemic injury rather than a neuroprotective factor in its own right.

Very limited information is available about the steady state serum concentrations of 17β-estradiol in response to different modes of administration to rats for days and weeks. The need for this information has become especially apparent during recent years due to the observable dichotomy of estrogens effects – neuroprotective or not – in the various animal models of brain ischemia reported in the current scientific literature. The cause of this dichotomy is likely to be found in the experimental setup, including the mode of administration of 17β-estradiol. Delayed steady state of serum 17β-estradiol concentrations were found when comparing two common modes of exogenous administration of 17β-estradiol – slow-release osmotic pumps vs. daily subcutaneously injections of 17β-estradiol solved in sesame oil – to ovx rats during 2 times 6 weeks crossover treatment. Steady state was reached at week 4 in the daily injections group compared to at week 6 in the slow release osmotic pumps group. Once steady state was reached, the concentration was the same in both groups for the reminder of the experiment (in total 12 weeks).

Place, publisher, year, edition, pages
Institutionen för biomedicin och kirurgi, 2005
Linköping University Medical Dissertations, ISSN 0345-0082 ; 923
Estrogen, neuropeptides, galanin, cerebral ischemia, middle cerebral artery occlusion
National Category
urn:nbn:se:liu:diva-4716 (URN)91-85497-58-4 (ISBN)
Public defence
2005-12-09, Berzeliussalen, Ingång 65, Campus US, Linköpings universitet, Linköping, 09:00 (English)
On the day of the public defence of the doctoral thesis, the status of article V was: Available on line since 24th of May 2005.Available from: 2005-11-11 Created: 2005-11-11 Last updated: 2009-08-23
2. Effects of gonadal steroids on galanin and other neuropeptides in the rat brain
Open this publication in new window or tab >>Effects of gonadal steroids on galanin and other neuropeptides in the rat brain
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Many women experience mental or emotional changes when variations occur in the plasma concentrations of their ovarian hormones. These observations are supported by a large number of scientific reports concerning interactions between ovarian steroids and cerebral functions, e.g. mood, cognition and motor function. Activation of genes is a fundamental principle by which steroids exert effects in neurons, thereby regulating the expression of enzymes, receptor proteins, trophic factors and regulatory peptides. This thesis examines the hypothesis that sex steroid hormones can modify concentrations of peptides important for neuronal transmission in brain areas relevant for the above-mentioned modalities. A necessary starting point in this quest is to develop good quantitative data on neuropeptide concentrations in relation to sex steroid status. Accordingly, the general aim of the thesis is to investigate the influence of gender and sex steroid exposure on neuropeptide concentrations and identify one or several steroid-sensitive neuropeptides in extrahypothalamic brain regions of the rat.

Neuropeptide concentrations were measured with radioimmunoassay in extracts of extrahypothalarnic brain regions. A new radioimmunoassay, specific for rat galanin, was developed. Concentrations of neuropeptides were compared between sexes, across puberty and in ovariectomized animals treated with different doses and durations of estradiol, progesterone and norethisterone.

We found that differences in sex steroid exposure between gender, across puberty, and duting exogenous treatment correlate with differences in concentrations of neuropeptide immunoreactivities in several extrahypothalarnic regions of the rat brain. In particular galanin in rat hippocampus is sensitive to estrogen and can be increased in a dose-dependent manner with chronic estradiol treatment. It is likely that the increase mainly sterns from the ascending noradrenergic neuron system originating in locus cemleus. Chromatographic characterization shows that galanin, measured by the antisera Ga1Rat4 and Ga1Rat5, has a high degree of homogeneity in rat brain tissue. Norethisterone and progesterone have different effects on substance P and neuroldnin A in rat frontal cortex and striatum.

These findings could contribute to the understanding of how mood and cognition are affected by sex steroids in females and how estradiol interacts with neurons affected by Alzheimer's disease.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2001. 64 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 673
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-25705 (URN)10081 (Local ID)91-7219-973-3 (ISBN)10081 (Archive number)10081 (OAI)
Public defence
2001-05-17, Elsa Brändströms sal, Hälsouniversitetet, Linköping, 09:00
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-06Bibliographically approved

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Rugarn, OlofTheodorsson, AnnetteHammar, MatsTheodorsson, Elvar
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