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Biomedical subjects

L M Garcia-Segura

Publications and source records attributed to L M Garcia-Segura.

At least 19 recordsLinked to original sources
PubMed2006

Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis.

One important complication of diabetes is damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Neuroactive steroids might be interesting since they have been recently identified as promising neuroprotective agents in several models of neurodegeneration. We have assessed whether chronic treatment with progesterone (P), dihydroprogesterone (DHP) or tetrahydroprogesterone (THP) had neuroprotective effects against streptozotocin (STZ)-induced diabetic neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Using gas chromatography coupled to mass-spectrometry, we found that three months of diabetes markedly lowered P plasma levels in male rats, and chronic treatment with P restored them, with protective effects on peripheral nerves. In the model of STZ-induced of diabetic neuropathy, chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na(+),K(+)-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22, suggesting that these neuroactive steroids, might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while the expression of myelin proteins and Na(+),K(+)-ATPase activity are only stimulated by P and DHP (i.e. two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber (IENF) density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoted to evaluating the role of PR and GABA-A receptor in these protective effects.

20-alpha-Dihydroprogesterone↗
PubMed2006

Fluctuation of synapse density in the arcuate nucleus during the estrous cycle.

The hypothalamic arcuate nucleus integrates different hormonal and neural signals to control neuroendocrine events, feeding, energy balance and reproduction. Previous studies have shown that in adult female rats the arcuate nucleus undergoes a cyclic fluctuation in the number of axo-somatic synapses during the estrous cycle, in parallel to the variation of ovarian hormone levels in plasma. In the present study we have used an unbiased stereological analysis in conjunction with postembedding immunocytochemistry to assess whether the synaptic remodeling during the estrous cycle in rats is specific for certain types of synapses. Our findings indicate that there is a significant decrease in the number of GABAergic axo-somatic synapses on proestrus afternoon and estrus day compared with other days of the estrous cycle. This decrease in GABAergic synapses is accompanied by an increase in the number of dendritic spine synapses. The synaptic density appears to cycle back to proestrus morning values on metestrus day. In contrast, the number of synapses on dendritic shafts does not change during the cycle. These results indicate that a rapid and selective synaptic turnover of arcuate synapses occurs in physiological circumstances.

Animals↗
PubMed2006

Aromatase expression in the human temporal cortex.

The expression of the human cyp19 gene, encoding P450 aromatase, the key enzyme for estrogen biosynthesis, involves alternative splicing of multiple forms of exon I regulated by different promoters. Aromatase expression has been detected in the human cerebral cortex, although the precise cellular distribution and promoter regulation are not fully characterized. We examined the variants of exon I of cyp19 by PCR analysis and the cellular distribution of the enzyme using immunohistochemistry in the human temporal cortex. We detected four different variants of exon I, suggesting a complex regulation of cyp19 in the cerebral cortex. In addition, the enzyme was localized mainly in a large subpopulation of pyramidal neurons and in a subpopulation of astrocytes. However, the majority of GABAergic interneurons identified by their expression of the calcium-binding proteins calbindin, calretinin and parvalbumin, did not display aromatase immunoreactivity. The broad range of potential modulators of the cyp19 gene in the cortex and the widespread expression of the protein in specific neuronal and glial subpopulations suggest that local estrogen formation may play an important role in human cortical function.

Adult↗
PubMed2005

Steroidogenic acute regulatory protein in the brain.

The nervous system synthesizes steroids that regulate the development and function of neurons and glia, and have neuroprotective properties. The first step in steroidogenesis involves the delivery of free cholesterol to the inner mitochondrial membrane where it can be converted into pregnenolone by the enzyme cytochrome P450side chain cleavage. The peripheral-type benzodiazepine receptor and the steroidogenic acute regulatory protein are involved in this process and appear to function in a coordinated manner. Steroidogenic acute regulatory protein mRNA and protein are widely expressed throughout the adult brain. Steroidogenic acute regulatory protein expression has been detected in many neuronal populations, in ependymocytes, in some astroglial cells, in Schwann cells from peripheral nerves and in proliferating cells of the developing and adult brain. Steroidogenic acute regulatory protein is colocalized in the same neural cells with P450side chain cleavage and with other steroidogenic enzymes. Steroidogenic acute regulatory protein expression in the brain shows marked changes with development, aging and injury. The steroidogenic acute regulatory protein gene may be under the control of diverse mechanisms in different neural cell types, since its expression is upregulated by cyclic AMP (cAMP) in gliomas and astrocytes in culture and downregulated by cyclic AMP (cAMP) in Schwann cells. In addition, activation of N-methyl-D-aspartate receptors, and the consequent rise in intracellular calcium levels, activates steroidogenic acute regulatory protein and steroidogenesis in hippocampal neurons. In conclusion, steroidogenic acute regulatory protein is regulated in the nervous system by different physiological and pathological conditions and may play an important role during brain development, aging and after injury.

Animals↗
PubMed2005

Brain aromatase expression after experimental stroke: topography and time course.

Brain aromatase has been shown to be increased in expression after neurotoxic damage and to exert neuroprotection via generation of local oestrogens. The present study investigates the topography and time course of brain aromatase expression after experimental stroke (middle cerebral artery occlusion (MCAO)). Ovariectomised stroke prone spontaneously hypertensive rats underwent distal MCAO by electrocoagulation. Immunohistochemistry revealed increased brain aromatase expression at 24h and 8 days in the cortical penumbra/peri-infarct zones with no increase evident at 2h or 30 days post-MCAO. Double label studies indicate that some of the increased aromatase expression is associated with astrocytic processes. Thus, this is the first evidence that aromatase protein is increased after MCAO and the location (peri-infarct), time course (within 24h) and cellular localisation (astrocytic) indicate the potential for aromatase to promote the survival of cells in the penumbra after experimental stroke by local synthesis of oestrogens.

Animals↗
PubMed2004

Brain steroidogenesis: emerging therapeutic strategies to prevent neurodegeneration.

Decreasing levels of gonadal steroids with aging are associated to an increase in cognitive, neurological and psychiatric disturbances. Estradiol is neuroprotective in animal models of neurodegeneration. However, the effects of hormonal replacement therapy on brain function in postmenopausal women are controversial. A possible alternative to hormonal replacement therapy is to increase local brain steroidogenesis, since experimental studies indicate that local estrogen formation in the brain is neuroprotective.

Animals↗
PubMed2004

Estradiol inhibits GSK3 and regulates interaction of estrogen receptors, GSK3, and beta-catenin in the hippocampus.

Estrogens regulate a wide set of neuronal functions such as gene expression, survival and differentiation in a manner not very different from that exerted by neurotrophins or by growth factors. The best-studied hormonal action is the transcriptional activation mediated by estrogen receptors. However, the direct effects of estrogen on growth factor signaling have not been well clarified. The present data show that estradiol, in vivo, induces a transient activation of GSK3 in the adult female rat hippocampus, followed by a more sustained inhibition, as inferred from phosphorylation levels of Tau. Similar data was obtained from cultured hippocampal neurons when treated with the hormone. The transient activation was confirmed by direct measure of GSK3 kinase activity. In addition, our results show a novel complex of estrogen receptor alpha, GSK3, and beta-catenin. The presence of the hormone removes beta-catenin from this complex. There is a second complex, also affected by estradiol, in which Tau is associated with GSK3, beta-catenin, and elements of the PI3 kinase complex. Considering the role of GSK3 in neurodegeneration, our data suggest that part of the neuroprotective effects of estrogen may be due to the control of GSK3.

Animals↗
PubMed2004

Reduced progesterone metabolites protect rat hippocampal neurones from kainic acid excitotoxicity in vivo.

The ovarian hormone progesterone is neuroprotective in some animal models of neurodegeneration. Progesterone actions in the brain may partly be mediated by the locally produced metabolites 5alpha-dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone. The neuroprotective effects of these two metabolites of progesterone were assessed in this study. Ovariectomized Wistar rats were injected with kainic acid, to induce excitotoxic neuronal death in the hippocampus, and with different doses of 5alpha-dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone. The number of surviving neurones in the hilus of the dentate gyrus of the hippocampus was assessed with the optical disector method. The administration of kainic acid resulted in a significant decrease in the number of hilar neurones and in the induction of vimentin expression in reactive astrocytes, a sign of neural damage. Low doses of 5alpha-dihydroprogesterone (0.25 and 0.5 mg/kg body weight, b.w.) prevented the loss of hilar neurones and the appearance of vimentin immunoreactivity in astrocytes. Higher doses (1-2 mg/kg b.w.) were not neuroprotective. By contrast, low doses of 3alpha,5alpha-tetrahydroprogesterone (0.25-1 mg/kg b.w.) were unable to protect the hilus from kainic acid while higher doses (2-4 mg/kg b.w.) were protective. The different optimal neuroprotective doses of 5alpha-dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone suggest that these two steroids may protect neurones using different mechanisms. The neuroprotective effects of 3alpha,5alpha-tetrahydroprogesterone may be exerted by the inhibition of neuronal activity via the GABAA receptor. This latter possibility is supported by the observation that 3beta,5alpha-tetrahydroprogesterone, an isomer of 3alpha,5alpha-tetrahydroprogesterone that does not bind to GABAA receptor, was not neuroprotective. In summary, our findings suggest that progesterone neuroprotective effects may be, at least in part, mediated by its reduced metabolites 5alpha-dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone.

Animals↗
PubMed2003

Neuroactive steroids influence peripheral myelination: a promising opportunity for preventing or treating age-dependent dysfunctions of peripheral nerves.

The process of aging deeply influences morphological and functional parameters of peripheral nerves. The observations summarized here indicate that the deterioration of myelin occurring in the peripheral nerves during aging may be explained by the fall of the levels of the major peripheral myelin proteins [e.g., glycoprotein Po (Po) and peripheral myelin protein 22 (PMP22)]. Neuroactive steroids, such as progesterone (PROG), dihydroprogesterone (5alpha-DH PROG), and tetrahydroprogesterone (3alpha,5alpha-TH PROG), are able to stimulate the low expression of these two myelin proteins present in the sciatic nerve of aged male rats. Since Po and PMP22 play an important physiological role in the maintenance of the multilamellar structure of PNS myelin, we have evaluated the effect of PROG and its neuroactive derivatives, 5alpha-DH PROG and 3alpha,5alpha-TH PROG, on the morphological alterations of myelinated fibers in the sciatic nerve of 22-24-month-old male rats. Data obtained clearly indicate that neuroactive steroids are able to reduce aging-associated morphological abnormalities of myelin and aging-associated myelin fiber loss in the sciatic nerve.

Aging↗
PubMed2003

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system.

Without medical progress, dementing diseases such as Alzheimer's disease will become one of the main causes of disability. Preventing or delaying them has thus become a real challenge for biomedical research. Steroids offer interesting therapeutical opportunities for promoting successful aging because of their pleiotropic effects in the nervous system: they regulate main neurotransmitter systems, promote the viability of neurons, play an important role in myelination and influence cognitive processes, in particular learning and memory. Preclinical research has provided evidence that the normally aging nervous system maintains some capacity for regeneration and that age-dependent changes in the nervous system and cognitive dysfunctions can be reversed to some extent by the administration of steroids. The aging nervous system also remains sensitive to the neuroprotective effects of steroids. In contrast to the large number of studies documenting beneficial effects of steroids on the nervous system in young and aged animals, the results from hormone replacement studies in the elderly are so far not conclusive. There is also little information concerning changes of steroid levels in the aging human brain. As steroids present in nervous tissues originate from the endocrine glands (steroid hormones) and from local synthesis (neurosteroids), changes in blood levels of steroids with age do not necessarily reflect changes in their brain levels. There is indeed strong evidence that neurosteroids are also synthesized in human brain and peripheral nerves. The development of a very sensitive and precise method for the analysis of steroids by gas chromatography/mass spectrometry (GC/MS) offers new possibilities for the study of neurosteroids. The concentrations of a range of neurosteroids have recently been measured in various brain regions of aged Alzheimer's disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimer's patients, there was a general trend toward lower levels of neurosteroids in different brain regions, and neurosteroid levels were negatively correlated with two biochemical markers of Alzheimer's disease, the phosphorylated tau protein and the beta-amyloid peptides. The metabolism of dehydroepiandrosterone has also been analyzed for the first time in the aging brain from Alzheimer patients and non-demented controls. The conversion of dehydroepiandrosterone to Delta5-androstene-3beta,17beta-diol and to 7alpha-OH-dehydroepiandrosterone occurred in frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimer's patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of beta-amyloid deposits.

Aging↗
PubMed2003

Neuroanatomical relationship between type 1 cannabinoid receptors and dopaminergic systems in the rat basal ganglia.

Dopamine and endocannabinoids are neurotransmitters known to play a role in the activity of the basal ganglia motor circuit. While a number of studies have demonstrated functional interactions between type 1 cannabinoid (CB1) receptors and dopaminergic systems, we still lack detailed neuroanatomical evidence to explain their relationship. Single- and double-labeling methods (in situ hybridization and immunohistochemistry) were employed to determine both the expression and localization of CB1 receptors and tyrosine hydroxylase (TH) in the basal ganglia. In the striatum, we found an intense signal for CB1 receptor transcripts but low signal for CB1 receptor protein, whereas in the globus pallidus and substantia nigra we found the opposite; no hybridization signal but intense immunoreactivity. Consequently, CB1 receptors are synthesized in the striatum and mostly transported to its target areas. No co-expression or co-localization of CB1 receptors and TH was found. In the caudate-putamen, globus pallidus and substantia nigra, TH-immunoreactive fibers were interwoven with the CB1 receptor-immunoreactive neuropil and fibers. Our data suggest that the majority of the striatal CB1 receptors are located presynaptically on inhibitory GABAergic terminals, in a position to modulate neurotransmitter release and influence the activity of substantia nigra dopaminergic neurons. In turn, afferent dopaminergic fibers from the substantia nigra innervate CB1 receptor-expressing striatal neurons that are known to also express dopamine receptors. In conclusion, these data provide a neuroanatomical basis to explain functional interactions between endocannabinoid and dopaminergic systems in the basal ganglia.

Animals↗
PubMed2002

Rapid stimulation of the PI3-kinase/Akt signalling pathway in developing midbrain neurones by oestrogen.

Oestrogen promotes the differentiation of neurones in the central nervous system. In the rodent midbrain, the maturation of dopaminergic neurones appears to be under oestrogen control. This is supported by the fact that dopaminergic cells contain nuclear oestrogen receptors-alpha/beta (ER). Second, aromatase is transiently expressed in the developing midbrain. In previous studies, we have shown that oestrogen increases dopamine synthesis and plasticity of dopamine cells. These effects are transmitted through classical nuclear ER but require also the stimulation of nonclassical signalling pathways involving the activation of membrane receptors. This study attempted to identify nonclassical oestrogen-dependent signalling cascades which might be stimulated downstream of membrane ERs. Using cultured mouse midbrain cells, we could demonstrate by Western blotting, that oestrogen rapidly phosphorylates Akt, a kinase which is implicated in the phosphatidylinositol 3 (PI3)-kinase pathway. This effect was only seen in midbrain neurones but not astrocytes. Oestrogen-induced Akt phosphorylation was time- and dose-dependent, showing highest responses after 30 min and at a steroid concentration of 10(-8) and 10(-6) M. Immunocytochemistry for phosphorylated Akt (pAkt) demonstrated that pAkt is predominantly found in a nuclear/perinuclear position and that oestrogen exposure increased the number of pAkt-positive cells. To investigate the mechanisms which are involved in transmitting oestrogen effects on the cellular level, cells were treated with antagonists for distinct signalling pathways. The application of the nuclear ER antagonist ICI 182 780 did not abolish the oestrogen-induced Akt phosphorylation. In contrast, interrupting intracellular calcium signalling with BAPTA completely prevented this effect. The PI3-kinase inhibitor LY294002 also inhibited the activation of Akt by oestrogen. Our study clearly indicates that oestrogen can rapidly stimulate the PI3-kinase/Akt signalling cascade in differentiating midbrain neurones. This effect requires the intermediate activation of calcium-dependent signalling pathways. In conclusion, oestrogen effects in the developing midbrain appear to be connected with the PI3-kinase/Akt signalling mechanism.

Animals↗
PubMed2002

Leptin uptake by serotonergic neurones of the dorsal raphe.

The effects of leptin on food intake, metabolism, sleep patterns and reproduction may be mediated, in part, by the midbrain serotonergic systems. Here, we report on the distribution of neurones that accumulate leptin in the raphe nuclei of male and female rats after intracerebroventricular administration of mouse recombinant leptin labelled with digoxigenin. Direct leptin-targeted cells were present in the periventricular grey, pontine and raphe nuclei. Confocal microscopy revealed that raphe neurones which accumulated leptin were predominantly serotonergic. The temporal pattern of leptin accumulation by raphe neurones showed a marked gender difference: 6 h after leptin administration, all male and female rats showed massive leptin binding in the dorsal raphe, while 30 min after leptin treatment, only 10% of male rats exhibited leptin-labelled cells in contrast to 50% of females. The present observations reveal that leptin can be selectively accumulated by serotonergic neurones in the raphe nuclei and that this mechanism is gender specific. These findings support the idea that the midbrain serotonergic system is an important mediator of the effects of leptin on brain function and may provide an explanation for gender differences in metabolism regulation and its coordination with higher functions of the brain.

Animals↗
PubMed2002

Hormonal enhancement of neuronal firing is linked to structural remodelling of excitatory and inhibitory synapses.

The ovarian hormone estradiol induces morphological changes in the number of synaptic inputs in specific neuronal populations. However, the functional significance of these changes is still unclear. In this study, the effect of estradiol on the number of anatomically identified synaptic inputs has been assessed in the hypothalamic arcuate nucleus. The number of axo-somatic, axodendritic and spine synapses was evaluated using unbiased stereological methods and a parallel electrophysiological study was performed to assess whether synaptic anatomical remodelling has a functional consequence on the activity of the affected neurons. Estradiol administration to ovariectomized rats induced a decrease in the number of inhibitory synaptic inputs, an increase in the number of excitatory synapses and an enhancement of the frequency of neuronal firing. These results indicate that oestrogen modifications in firing frequency in arcuate neurons are temporally linked to anatomical modifications in the numerical balance of inhibitory and excitatory synaptic inputs.

Animals↗
PubMed2001

Brain aromatase is neuroprotective.

The expression of aromatase, the enzyme that catalyzes the biosynthesis of estrogens from precursor androgens, is increased in the brain after injury, suggesting that aromatase may be involved in neuroprotection. In the present study, the effect of inactivating aromatase has been assessed in a model of neurodegeneration induced by the systemic administration of neurotoxins. Domoic acid, at a dose that is not neurotoxic in intact male mice, induced significant neuronal loss in the hilus of the hippocampal formation of mice with reduced levels of aromatase substrates as a result of gonadectomy. Furthermore, the aromatase substrate testosterone, as well as its metabolite estradiol, the product of aromatase, were able to protect hilar neurons from domoic acid. In contrast, dihydrotestosterone, the 5 alpha-reduced metabolite of testosterone and a nonaromatizable androgen, was not. These findings suggest that aromatization of testosterone to estradiol may be involved in the neuroprotective action of testosterone in this experimental model. In addition, aromatase knock-out mice showed significant neuronal loss after injection of a low dose of domoic acid, while control littermates did not, indicating that aromatase deficiency increases the vulnerability of hilar neurons to neurotoxic degeneration. The effect of aromatase on neuroprotection was also tested in male rats treated systemically with the specific aromatase inhibitor fadrozole and injected with kainic acid, a well characterized neurotoxin for hilar neurons in the rat. Fadrozole enhanced the neurodegenerative effect of kainic acid in intact male rats and this effect was counterbalanced by the administration of estradiol. Furthermore, the neuroprotective effect of testosterone against kainic acid in castrated male rats was blocked by fadrozole. These findings suggest that neuroprotection by aromatase is due to the formation of estradiol from its precursor testosterone. Finally, a role for local cerebral aromatase in neuroprotection is indicated by the fact that intracerebral administration of fadrozole enhanced kainic acid induced neurodegeneration in the hippocampus of intact male rats. These findings indicate that aromatase deficiency decreases the threshold for neurodegeneration and that local cerebral aromatase is neuroprotective. Brain aromatase may therefore represent a new target for therapeutic approaches to neurodegenerative diseases.

Animals↗
PubMed2001

Seasonal activation and inactivation of song motor memories in wild canaries is not reflected in neuroanatomical changes of forebrain song areas.

Seasonal, testosterone-dependent changes in sexual behaviors are common in male vertebrates. In songbirds such seasonal changes occur in a learned behavior--singing. Domesticated male canaries (Serinus canaria) appear to lose song units (syllables) after the breeding season and learn new ones until the next breeding season. Here we demonstrate in a longitudinal field study of individual, free-living nondomesticated (wild) canaries (S. canaria) a different mode of seasonal behavioral plasticity, seasonal activation, and inactivation of auditory-motor memories. The song repertoire composition of wild canaries changes seasonally: about 25% of the syllables are sung seasonally; the remainder occur year-round, despite seasonal changes in the temporal patterns of song. In the breeding season, males sing an increased number of fast frequency-modulated syllables, which are sexually attractive for females, in correlation with seasonally increased testosterone levels. About 50% of the syllables that were lost after one breeding season reappear in the following breeding season. Furthermore, some identical syllable sequences are reactivated on an annual basis. The seasonal plasticity in vocal behavior occurred despite the gross anatomical and ultrastructural stability of the forebrain song control areas HVc and RA that are involved in syllable motor control.

Animals↗
PubMed2001

Interactions of estrogens and insulin-like growth factor-I in the brain: implications for neuroprotection.

Data from epidemiological studies suggest that the decline in estrogen following menopause could increase the risk of neurodegenerative diseases. Furthermore, experimental studies on different animal models have shown that estrogen is neuroprotective. The mechanisms involved in the neuroprotective effects of estrogen are still unclear. Anti-oxidant effects, activation of different membrane-associated intracellular signaling pathways, and activation of classical nuclear estrogen receptors (ERs) could contribute to neuroprotection. Interactions with neurotrophins and other growth factors may also be important for the neuroprotective effects of estradiol. In this review we focus on the interaction between insulin-like growth factor-I (IGF-I) and estrogen signaling in the brain and on the implications of this interaction for neuroprotection. During the development of the nervous system, IGF-I promotes the differentiation and survival of specific neuronal populations. In the adult brain, IGF-I is a neuromodulator, regulates synaptic plasticity, is involved in the response of neural tissue to injury and protects neurons against different neurodegenerative stimuli. As an endocrine signal, IGF-I represents a link between the growth and reproductive axes and the interaction between estradiol and IGF-I is of particular physiological relevance for the regulation of growth, sexual maturation and adult neuroendocrine function. There are several potential points of convergence between estradiol and IGF-I receptor (IGF-IR) signaling in the brain. Estrogen activates the mitogen-activated protein kinase (MAPK) pathway and has a synergistic effect with IGF-I on the activation of Akt, a kinase downstream of phosphoinositol-3 kinase. In addition, IGF-IR is necessary for the estradiol induced expression of the anti-apoptotic molecule Bcl-2 in hypothalamic neurons. The interaction of ERs and IGF-IR in the brain may depend on interactions between neural cells expressing ERs with neural cells expressing IGF-IR, or on direct interactions of the signaling pathways of alpha and beta ERs and IGF-IR in the same cell, since most neurons expressing IGF-IR also express at least one of the ER subtypes. In addition, studies on adult ovariectomized rats given intracerebroventricular (i.c.v.) infusions with antagonists for ERs or IGF-IR or with IGF-I have shown that there is a cross-regulation of the expression of ERs and IGF-IR in the brain. The interaction of estradiol and IGF-I and their receptors may be involved in different neural events. In the developing brain, ERs and IGF-IR are interdependent in the promotion of neuronal differentiation. In the adult, ERs and IGF-IR interact in the induction of synaptic plasticity. Furthermore, both in vitro and in vivo studies have shown that there is an interaction between ERs and IGF-IR in the promotion of neuronal survival and in the response of neural tissue to injury, suggesting that a parallel activation or co-activation of ERs and IGF-IR mediates neuroprotection.

Animals↗