Biomedical subjects

Inga-Maj Johansson

Publications and source records attributed to Inga-Maj Johansson.

11 recordsLinked to original sources

PubMed2006

Neurosteroid modulation of recombinant rat alpha5beta2gamma2L and alpha1beta2gamma2L GABA(A) receptors in Xenopus oocyte.

GABA(A) receptors containing alpha(5)-subunit have an important role in cognitive function. As the agonistic effect of 3alpha-hydroxy ring-A reduced steroids depends on subunit combinations of the GABA(A) receptor, the antagonistic effect of pregnenolone sulfate and 3beta-hydroxypregnane steroids may vary between alpha(5)-subunit and alpha(1)-subunit containing receptors. We investigated the effect of agonist and antagonist steroids in the recombinant rat alpha(1)beta(2)gamma(2L) and alpha(5)beta(2)gamma(2L) receptors expressed in Xenopus oocytes using a two electrodes voltage-clamp technique. We did not find any significant difference in potency and efficacy of GABA response between alpha(1)beta(2)gamma(2L) and alpha(5)beta(2)gamma(2L) receptors. Compared to the alpha(1)beta(2)gamma(2L) receptor, a significantly lower degree of desensitization was observed in the alpha(5)beta(2)gamma(2L) receptor. In addition, the potencies of 3alpha-OH-5alpha-pregnan-20-one (3alpha5alphaP), 5alpha-pregnan-3alpha,21-diol-20-one (3alpha5alphaTHDOC) and 5alpha-androstane-3alpha,17beta-diol (3alpha5alphaADL) to enhance GABA response were significantly higher in the alpha(5)beta(2)gamma(2L) receptor, whereas their efficacies remained unchanged between two receptors. In either receptor, the efficacy of 3alpha5alphaTHDOC was significantly higher than 3alpha5alphaP and 3alpha5alphaADL. The efficacies of 5beta-pregnan-3beta,21-diol-20-one(UC1015) and 5alpha-pregnan-3beta,20alpha-diol(UC1019) to inhibit 30 microM GABA response, and the efficacies of 3beta-OH-5beta-pregnan-20-one (UC1014) and 5beta-pregnan-3beta, 20beta-diol (UC1020) to inhibit 3 microM 3alpha5alphaTHDOC+3 microM GABA response were higher in the alpha(5)beta(2)gamma(2L) receptor compared to the alpha(1)beta(2)gamma(2L) receptor. The potencies of pregnenolone sulfate and 3beta-hydroxypregnane steroids to inhibit the GABA response and the 3alpha5alphaTHDOC+GABA response did not vary between two receptors. Interestingly, the potencies and efficacies of pregnenolone sulfate and 3beta-hydroxypregnane steroids to inhibit the GABA response were positively correlated to their potencies and efficacies to inhibit the 3alpha5alphaTHDOC+GABA response. Results from the current study revealed a different modulation pattern by neurosteroids between the alpha(1)beta(2)gamma(2L) and alpha(5)beta(2)gamma(2L) receptor.

Androstane-3,17-diol↗

PubMed2006

Progesterone withdrawal effects in the open field test can be predicted by elevated plus maze performance.

Allopregnanolone (3alpha-hydroxy-5alpha-pregnane-20-one) is a ring-A-reduced metabolite of progesterone, which is naturally produced during the luteal phase of the menstrual cycle, during pregnancy and by stressful events. The steroid hormone inhibits neural functions through increased chloride ion flux through the GABA(A) receptor. The effects and subsequent withdrawal symptoms are similar to those caused by alcohol, benzodiazepines and barbiturates. This study examined the withdrawal effects of progesterone with regards to the influence of individual baseline exploration and risk taking. Rats were tested on the elevated plus maze (EPM) before hormonal treatment, in order to evaluate differences in risk taking and exploration of open and elevated areas. Treatment consisted of ten consecutive once a day progesterone or vehicle s.c. injections. On the last day of treatment, estradiol was injected in addition to progesterone, followed by a 24-h withdrawal before testing in the open field test (OF). Progesterone-treated rats showed a withdrawal effect of open area avoidance in the OF. The vehicle-treated control rats showed strong correlations between the EPM and OF parameters. This relationship was not found for the progesterone group at withdrawal. Rats with greater numbers of open arm entrance in the EPM pretest showed an increased sensitivity to progesterone withdrawal (PWD) compared to rats with low exploration and risk taking. The results indicate that the effects of PWD relate to individual exploration and risk taking. Furthermore, the possible analogy of PWD and PMS/PMDD in relation to individual traits is discussed.

Animals↗

PubMed2006

GABA(A) receptor changes in acute allopregnanolone tolerance.

To study acute tolerance, rats were anesthetized with interrupted i.v. allopregnanolone infusions where the "silent second" in the electroencephalogram (EEG) was the target. Animals were killed either directly at the first silent second or at the silent second level after 30 or 90 min of anaesthesia. Acute tolerance was demonstrated at 90 min of anaesthesia as earlier shown. In situ hybridization showed a decreased expression of the gamma-aminobutyric acid(A) (GABA(A)) receptor subunit alpha4mRNA amount in the thalamus ventral-posteriomedial nucleus of the tolerant rats. A parallel change in the abundance of the alpha4 subunit was detected with immunohistochemistry. The increase in maintenance dose rate (MDR) was significantly negatively correlated with the alpha4mRNA in the thalamus ventral-posteriomedial nucleus, and positively correlated with alpha2mRNA in different hippocampal subregions. There was also a positive relationship between the alpha1mRNA amounts in the different hippocampal subregions, with significant differences between groups. These changes in GABA(A) receptor subunits mRNA expression and protein (alpha4) might be of importance for the development of acute tolerance to allopregnanolone.

Anesthetics↗

PubMed2005

Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems.

This article will review neuroactive steroid effects on serotonin and GABA systems, along with the subsequent effects on cognitive functions. Neurosteroids (such as estrogen, progesterone, and allopregnanolone) are synthesized in the central and peripheral nervous system, in addition to other tissues. They are involved in the regulation of mood and memory, in premenstrual syndrome, and mood changes related to hormone replacement therapy, as well as postnatal and major depression, anxiety disorders, and Alzheimer's disease. Estrogen and progesterone have their respective hormone receptors, whereas allopregnanolone acts via the GABA(A) receptor. The action of estrogen and progesterone can be direct genomic, indirect genomic, or non-genomic, also influencing several neurotransmitter systems, such as the serotonin and GABA systems. Estrogen alone, or in combination with antidepressant drugs affecting the serotonin system, has been related to improved mood and well being. In contrast, progesterone can have negative effects on mood and memory. Estrogen alone, or in combination with progesterone, affects the brain serotonin system differently in different parts of the brain, which can at least partly explain the opposite effects on mood of those hormones. Many of the progesterone effects in the brain are mediated by its metabolite allopregnanolone. Allopregnanolone, by changing GABA(A) receptor expression or sensitivity, is involved in premenstrual mood changes; and it also induces cognitive deficits, such as spatial-learning impairment. We have shown that the 3beta-hydroxypregnane steroid UC1011 can inhibit allopregnanolone-induced learning impairment and chloride uptake potentiation in vitro and in vivo. It would be important to find a substance that antagonizes allopregnanolone-induced adverse effects.

Animals↗

PubMed2004

Dynamic changes of the anti- and pro-apoptotic proteins Bcl-w, Bcl-2, and Bax with Smac/Diablo mitochondrial release after photothrombotic ring stroke in rats.

The anti-apoptotic proteins Bcl-w and Bcl-2 and the pro-apoptotic protein Bax may mediate cell death or survival via regulation of the mitochondria including second mitochondria-derived activator of caspase (Smac)/direct inhibitor of apoptosis protein (IAP)-binding protein with low pI (DIABLO) release. This study aimed to explore alterations in Bcl-w, Bcl-2, and Bax and the relationship between these proteins and Smac/DIABLO by means of in situ hybridization, immunohistochemical (IHC) staining, and Western blots after low- and high-intensity photothrombotic ring stroke. At 4 h after low-intensity irradiation, we found widespread bcl-w overexpression on both the mRNA and protein levels in the bilateral cortex except the ring lesion region and in subcortical regions. A prolonged elevation of Bcl-2 with relatively unchanged Bax in the mitochondrial fraction was demonstrated from 4 to 72 h. These upregulated anti-apoptotic proteins combined with little Smac/DIABLO release might be associated with increased cell survival and thereby remarkable morphological recovery after low-intensity irradiation. After high-intensity irradiation, we observed decreased bcl-w and bcl-2 mRNA with increased Bcl-2 protein in the cytosolic fraction, whereas the Bax protein remained in scattered ischaemic cells in the ring lesion and the region at risk that corresponded with release of Smac/DIABLO from mitochondria to the cytosol at 1-24 h. These changes might be related to the massive cell death observed after high-intensity irradiation. Taken together, the balance and the location of anti-apoptotic proteins vs. pro-apoptotic proteins could be associated with the translocation of Smac/DIABLO from the mitochondria to the cytosol and therefore closely related to cell death or survival after focal cerebral ischaemia.

Animals↗

PubMed2004

3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) antagonism of the GABA potentiation and the learning impairment induced in rats by allopregnanolone.

Allopregnanolone is a progesterone metabolite and GABA-A receptor modulator with benzodiazepine like effects, including decreased learning and memory. In vitro 3beta-hydroxypregnane steroids antagonize allopregnanolone-induced effects, but no antagonism has been shown in vivo. Our purpose was to evaluate 3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) as a blocker of allopregnanolone-induced effects in vivo and in vitro in rats. We tested adult male Wistar rats in the Morris water maze 8 min after daily injections (i.v.) of allopregnanolone 2 mg/kg (n = 21); allopregnanolone : UC1011 2 : 6 (n = 7), 2 : 8 (n = 7), 2 : 20 (n = 14) mg/kg; UC1011 20 mg/kg (n = 14); or vehicle (10% 2-hydroxypropyl-beta-cyclodextrin, n = 4). Studies of chloride ion uptake into cortical and hippocampal membrane preparations were performed. The latency to find the hidden platform was still high in the allopregnanolone-injected group on day 6. Day 3-6 rats injected with allopregnanolone and UC1011 (2 : 20 mg/kg) had lower latency (P < 0.05), compared to the allopregnanolone-injected group. The group that only received UC1011 learned the location of the platform as fast as the controls. There was no significant difference in swim speed between groups. The time spent swimming close to the pool wall was in the allopregnanolone : UC1011 group (2 : 20 mg/kg) significantly decreased (P < 0.05, day 3-6), compared to the allopregnanolone-injected group. The increased chloride ion uptake induced by increasing dosage of allopregnanolone in the presence of 10 micro m GABA was significantly decreased with UC1011 (P < 0.01), in both cortical and hippocampal homogenates. In conclusion, UC1011 can via antagonism at the GABA-A receptor reduce the negative allopregnanolone effect on learning in the water maze.

Analysis of Variance↗

PubMed2003

Mineralocorticoid receptor expression and increased survival following neuronal injury.

Glucocorticoids, acting via the mineralocorticoid receptor, are required for granule neuronal survival in the rat dentate gyrus. Whether this mineralocorticoid receptor-mediated neuroprotective effect has more general applicability is unknown. Here we report increased mineralocorticoid receptor expression in rat hippocampal and cortical neurons exposed in vitro to low levels of staurosporine and in rat hippocampal pyramidal neurons exposed in vivo to hypothermic transient global ischaemia. In both the cell culture system and the in vivo system increased mineralocorticoid receptor expression is associated with increased neuronal survival, and this increase is reversed by mineralocorticoid receptor antagonism. Modulation of mineralocorticoid receptor gene expression may therefore be an important target for reduction of brain injury in conditions caused by cerebral ischaemia including brain damage following cardiac arrest and stroke.

Animals↗

PubMed2003

Pathogenesis in menstrual cycle-linked CNS disorders.

That 3alpha-hydroxy-5alpha/beta-pregnane steroids (GABA steroids) have modulatory effects on the GABA-A receptor is well known. In behavioral studies in animals high exogenous dosages give concentrations not usually reached in the brain under physiological conditions. Animal and human studies show that GABA-A receptor-positive modulators like barbiturates, benzodiazepines, alcohol, and allopregnanolone have a bimodal effect. In pharmacological concentrations they are CNS depressants, anesthetic, antiepileptic, and anxiolytic. In low dosages and concentrations, reached endogenously, they can induce adverse emotional reactions in up to 20% of individuals. GABA steroids can also induce tolerance to themselves and similar substances, and rebound occurs at withdrawal. Menstrual cycle-linked disorders can be understood by the concept that they are caused by the action of endogenously produced GABA-steroids through three mechanisms: (a) direct action, (b) tolerance induction, and (c) withdrawal effect. Examples of symptoms and disorders caused by the direct action of GABA steroids are sedation, memory and learning disturbance, clumsiness, increased appetite, worsening of petit mal epilepsy, negative mood as tension, irritability and depression during hormone treatments, and the premenstrual dysphoric disorder (PMDD). A continuous exposure to GABA steroids causes tolerance, and women with PMDD are less sensitive to GABA-A modulators. A malfunctioning GABA-A receptor system is related to stress sensitivity, concentration difficulties, loss of impulse control, irritability, anxiety, and depression. An example of withdrawal effect is "catamenial epilepsy," when seizures increase during menstruation after the withdrawal of GABA steroids. Similar phenomena occur at stress since the adrenals produce GABA steroids during stress.

Affect↗

PubMed2003

The role of hormones and hormonal treatments in premenstrual syndrome.

Premenstrual syndrome (PMS) is a menstrual cycle-linked condition with both mental and physical symptoms. Most women of fertile age experience cyclical changes but consider them normal and not requiring treatment. Up to 30% of women feel a need for treatment. The aetiology is still unclear, but sex steroids produced by the corpus luteum of the ovary are thought to be symptom provoking, as the cyclicity disappears in anovulatory cycles when a corpus luteum is not formed. Progestogens and progesterone together with estrogen are able to induce similar symptoms as seen in PMS. Symptom severity is sensitive to the dosage of estrogen. The response systems within the brain known to be involved in PMS symptoms are the serotonin and GABA systems. Progesterone metabolites, especially allopregnanolone, are neuroactive, acting via the GABA system in the brain. Allopregnanolone has similar effects as benzodiazepines, barbiturates and alcohol; all these substances are known to induce adverse mood effects at low dosages in humans and animals. SSRIs and substances inhibiting ovulation, such as gonadotrophin-releasing hormone (GnRH) agonists, have proven to be effective treatments. To avoid adverse effects when high dosages of GnRH agonists are used, add-back hormone replacement therapy is recommended. Spironolactone also has a beneficial effect, although not as much as SSRIs and GnRH agonists.

Clinical Trials as Topic↗

PubMed2002

Long-lasting neuronal apoptotic cell death in regions with severe ischemia after photothrombotic ring stroke in rats.

Apoptotic and necrotic cell death may act in concert in focal cerebral ischemia. This study explored the temporal and spatial pattern of apoptosis and necrosis in a novel photothrombotic ring stroke model with or without spontaneous reperfusion. Adult male Wistar rats were subjected to a ring-shaped laser irradiation beam simultaneously with intravenous erythrosin B infusion. The presence and attributes of apoptosis and necrosis in the anatomically well-defined cortical region at risk and ring-lesion region were verified under light microscopy with TUNEL, Hoechst 33342, and hematoxylin and eosin staining. Cells exhibiting apoptotic morphology with chromatin condensation and apoptotic bodies and necrotic ghost appearance were observed. The occurrence of apoptosis and necrosis in the ischemic regions was confirmed by electron microscopy and gel electrophoresis, in which DNA isolated from the lesion area revealed both a ladder and a smear. Double staining with TUNEL and the cell markers NeuN, glial fibrillary acidic protein, and ED-1 revealed that the majority of apoptotic cells were of neuronal origin. Cells exhibiting pyknosis/eosinophilia, apoptosis, or ghost appearance were quantified by stereological means. In subregions with severe ischemia, the peak appearance of apoptotic cells started earlier, i.e., at 24 h, than the peak of necrotic cells, and the high concentration of the apoptotic cells remained as long as that of necrotic cells, i.e., until 72 h post-ischemia. The ratio of apoptotic to necrotic cells was approximately 1:2. Therefore, apoptosis may be an important contributor to neuronal cell death in brain regions with severely reduced blood flow after thrombo-embolic stroke.

Animals↗

PubMed2002

Ovarian hormone effects on 5-hydroxytryptamine(2A) and 5-hydroxytryptamine(2C) receptor mRNA expression in the ventral hippocampus and frontal cortex of female rats.

Alterations in female gonadal hormones are associated with anxiety and mood changes. The aim of the present study was to determine influences of chronic gonadal hormone supplementation on 5-HT(2A) and 5-HT(2C) receptor mRNA levels in the ventral hippocampus and the frontal cerebral cortex. Ovariectomized adult female Sprague-Dawley rats (n=37) received implantation of subcutaneous pellets containing different dosages of 17beta-estradiol alone or in combination with progesterone, or placebo pellets, for 2 weeks. Serotonin receptor mRNA levels were analyzed by in situ hybridization in the ventral hippocampus and 5-HT(2A) receptor mRNA also in the frontal cortex. Estradiol treatment in combination with low-dose progesterone increased 5-HT(2A) receptor mRNA by 43% in the CA2 region of the ventral hippocampus, while estradiol combined with high-dose progesterone increased the expression of this gene by 84% in ventral CA1. 5-HT(2A) mRNA expression in the frontal cortex was not influenced by hormone manipulation. 5-HT(2C) receptor gene expression was in the ventral hippocampus decreased in the CA2, ventral CA1 and the subiculum subregions by high-dose estradiol treatment (8-20% decreases). Effects on mood by gonadal hormones can be mediated, at least partly, through influences on 5-HT(2A) and 5-HT(2C) receptor expression.

Animals↗