Biomedical subjects

Lydia L Doncarlos

Publications and source records attributed to Lydia L Doncarlos.

5 recordsLinked to original sources

PubMed2005

Glia-neuron crosstalk in the neuroprotective mechanisms of sex steroid hormones.

Proteins involved in the intramitochondrial trafficking of cholesterol, the first step in steroidogenesis, such as the steroidogenic acute regulatory protein (StAR) and the peripheral-type benzodiazepine receptor (PBR), are upregulated in the nervous system after injury. Accordingly, a local increase in the levels of steroids, such as pregnenolone and progesterone, is observed following traumatic injury in the brain and spinal cord. The expression and activity of aromatase, the enzyme that synthesizes estradiol, is also increased in injured brain areas and its inhibition results in an increased neurodegeneration. These findings suggest that an increase in steroidogenesis is part of an overall mechanism used by the nervous tissue to cope with neurodegenerative conditions. Neural steroidogenesis is the result of a coordinated interaction of neurons and glia. For example, after neural injury, there is an upregulation of StAR in neurons and of PBR in microglia and astroglia. Aromatase is expressed in neurons under basal conditions and is upregulated in reactive astrocytes after injury. Some of the steroids produced by glia are neuroprotective. Progesterone and progesterone derivatives produced by Schwann cells, promote myelin formation and the remyelination and regeneration of injured nerves. In the central nervous system, the steroids produced by glia regulate synaptic function, affect anxiety, cognition, sleep and behavior, and exert neuroprotective and reparative roles. In addition, glial cells are targets for steroids and mediate some of the effects of these molecules on neurons, including the regulation of survival and regeneration.

Animals↗

PubMed2004

Estrogen reduces serotonin-1A receptor-mediated oxytocin release and Galpha(i/o/z) proteins in the hypothalamus of ovariectomized rats.

The present study examined the effect of estradiol on hypothalamic serotonin-1A (5-HT(1A)) receptor signaling in female rats. We first examined the time-course effects of a single injection of the 5-HT(1A) receptor agonist (+/-)8-OH-DPAT (5, 15 or 30 min prior to decapitation), and dose response of (+)8-OH-DPAT (50, 100, 200 or 500 microg/kg, s.c.) on plasma hormones in ovariectomized rats that received a daily injection of beta-estradiol 3-benzoate (10 microg/day, s.c.) or vehicle (sesame oil) for 2 days. In vehicle- and estrogen-treated rats, the peak response of hormones occurred at 15 min after injection and the time-course of oxytocin and adrenocorticotropic hormone (ACTH) responses to an injection of 8-OH-DPAT were comparable. However, only the oxytocin response was reduced by estrogen treatment. A second experiment compared the ACTH and oxytocin responses with doses of 50 or 200 microg/kg, s.c. of (+)8-OH-DPAT vs. (+/-)8-OH-DPAT in ovariectomized rats that were treated with oil or beta-estradiol 3-benzoate (10 microg/day, s.c.) for 2 days. (+)8-OH-DPAT and (+/-)8-OH-DPAT produced a similar magnitude of increase in plasma levels of ACTH and oxytocin. Treatment with beta-estradiol 3-benzoate produced a significant and comparable reduction in the oxytocin response to the highest dose (200 microg/kg, s.c.) of both (+)8-OH-DPAT and (+/-)8-OH-DPAT but did not alter the ACTH response to either (+)8-OH-DPAT or (+/-)8-OH-DPAT. In the dose-response experiment, a dose of 50 microg/kg of (+)8-OH-DPAT produced a maximal increase in plasma levels of ACTH, while the maximal oxytocin response was achieved with a dose of 200 microg/kg, s.c. Treatment with beta-estradiol 3-benzoate reduced the maximal oxytocin response to (+)8-OH-DPAT (by 29%) but did not alter the ACTH response to any doses of (+)8-OH-DPAT. To examine potential mechanisms mediating the effects of estrogen on 5-HT(1A) receptor signaling, we measured the levels of Galpha(i), Galpha(o) and Galpha(z) proteins, which couple 5-HT(1A) receptors to their effector enzymes, in two subregions of the hypothalamus. The levels of Galpha(z) protein were reduced in the mediobasal hypothalamus (containing the ventromedial and arcuate nuclei), which mainly expresses estrogen receptor-alpha, but not in the paraventricular hypothalamus, which mainly expresses estrogen receptor-beta. Estradiol reduced the levels of Galpha(i2) and Galpha(i3 )proteins in both hypothalamic regions but did not affect Galpha(i1) levels in either area. Combined, the data suggest that racemic and stereoselective 8-OH-DPAT have similar neuroendocrine effects and that both estrogen receptor-alpha and estrogen receptor-beta mediate the reduction in levels of Galpha(i2,3) proteins.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2002

Glial expression of estrogen and androgen receptors after rat brain injury.

Estrogens and androgens can protect neurons from death caused by injury to the central nervous system. Astrocytes and microglia are major players in events triggered by neural lesions. To determine whether glia are direct targets of estrogens or androgens after neural insults, steroid receptor expression in glial cells was assessed in two different lesion models. An excitotoxic injury to the hippocampus or a stab wound to the parietal cortex and hippocampus was performed in male rats, and the resultant expression of steroid receptors in glial cells was assessed using double-label immunohistochemistry. Both lesions induced the expression of estrogen receptors (ERs) and androgen receptors (ARs) in glial cells. ERalpha was expressed in astrocytes immunoreactive (ERalpha-ir) for glial fibrillary acidic protein or vimentin. AR immunoreactivity colocalized with microglial markers, such as Griffonia simplicifolia lectin-1 or OX-6. The time course of ER and AR expression in glia was studied in the stab wound model. ERalpha-ir astrocytes and AR-ir microglia were observed 3 days after lesion. The number of ERalpha-ir and AR-ir glial cells reached a maximum 7 days after lesion and returned to low levels by 28 days postinjury. The studies of ERbeta expression in glia were inconclusive; different results were obtained with different antibodies. In sum, these results suggest that reactive astrocytes and reactive microglia are a direct target for estrogens and androgens, respectively.

Animals↗

PubMed2002

Estrogen and brain vulnerability.

Accumulated clinical and basic evidence suggests that gonadal steroids affect the onset and progression of several neurodegenerative diseases and schizophrenia, and the recovery from traumatic neurological injury such as stroke. Thus, our view on gonadal hormones in neural function must be broadened to include not only their function in neuroendocrine regulation and reproductive behaviors, but also to include a direct participation in response to degenerative disease or injury. Recent findings indicate that the brain up-regulates both estrogen synthesis and estrogen receptor expression at sites of injury. Genetic or pharmacological inactivation of aromatase, the enzyme involved in estrogen synthesis, indicates that the induction of this enzyme in the brain after injury has a neuroprotective role. Some of the mechanisms underlying the neuroprotective effects of estrogen may be independent of the classically defined nuclear estrogen receptors (ERs). Other neuroprotective effects of estrogen do depend on the classical nuclear ERs, through which estrogen alters expression of estrogen responsive genes that play a role in apoptosis, axonal regeneration, or general trophic support. Yet another possibility is that non-classical ERs in the membrane or cytoplasm alter phosphorylation cascades, such as those involved in the signaling of insulin-like growth factor-1 (IGF-1). Indeed, ERs and IGF-1 receptor interact in the activation of PI3K and MAPK signaling cascades and in the promotion of neuroprotection. The decrease in estrogen and IGF-1 levels with aging may thus result in an increased risk for neuronal pathological alterations after different forms of brain injury.

Journal Article↗

PubMedDate not supplied

Sex hormones and brain aging.

Sex steroids exert pleiotropic effects in the nervous system, preserving neural function and promoting neuronal survival. Therefore, the age-related decrease in sex steroids may have a negative impact on neural function. Progesterone, testosterone and estradiol prevent neuronal loss in the central nervous system in different experimental animal models of neurodegeneration. Furthermore, progesterone and its reduced derivatives dihydroprogesterone and tetrahydroprogesterone reduce aging-associated morphological abnormalities of myelin and aging-associated myelin fiber loss in rat peripheral nerves. However, the results from hormone replacement studies in humans are thus far inconclusive. A possible alternative to hormonal replacement therapy is to increase local steroidogenesis by neural tissues, which express enzymes for steroid synthesis and metabolism. Proteins involved in the intramitochondrial trafficking of cholesterol, the first step in steroidogenesis, such as the peripheral-type benzodiazepine receptor and the steroidogenic acute regulatory protein, are up-regulated in the nervous system after injury. Furthermore, steroidogenic acute regulatory protein expression is increased in the brain of 24-month-old rats compared with young adult rats. This suggests that brain steroidogenesis may be modified in adaptation to neurodegenerative conditions and to the brain aging process. Furthermore, recent studies have shown that local formation of estradiol in the brain, by the enzyme aromatase, is neuroprotective. Therefore, steroidogenic acute regulatory protein, peripheral-type benzodiazepine receptor and aromatase are attractive pharmacological targets to promote neuroprotection in the aged brain.

Aged↗