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Biomedical subjects

Luis M Garcia-Segura

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

At least 19 recordsLinked to original sources
PubMed2006

Cross-talk between IGF-I and estradiol in the brain: focus on neuroprotection.

The actions of estradiol in the brain involve the interaction with growth factors, such as insulin-like growth factor-I (IGF-I). Many cells in the brain coexpress receptors for estradiol (ERs) and IGF-I (IGF-IR) and both factors interact to regulate neural function. Several studies have shown that there is an interaction of IGF-IR and ERs in neuroprotection. Neuroprotective effects of estradiol are blocked by the inhibition of IGF-IR signaling, while the neuroprotective effects of IGF-I are blocked by the inhibition of ER signaling. These findings suggest that the neuroprotective actions of estradiol and IGF-I after brain injury depend on the coactivation of both ERs and IGF-IR in neural cells. The relationship of ERalpha with IGF-IR through the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta (PI3K/Akt/GSK3) signaling pathway may represent the point of convergence used by estradiol and IGF-I to cooperatively promote neuroprotection. Administration of estradiol to ovariectomized rats results in the association of ERalpha with IGF-IR and with components of the PI3K/Akt/GSK3 signaling pathway and in the regulation of the activity of Akt and GSK3 in the brain. Conversely, IGF-I regulates ERalpha transcriptional activity in neuroblastoma cells and the PI3K/Akt/GSK3 signaling pathway is involved in this effect.

Animals↗
PubMed2006

Steroids and glial cell function.

Hormonal and locally produced steroids act in the nervous system as neuroendocrine regulators, as trophic factors and as neuromodulators and have a major impact on neural development and function. Glial cells play a prominent role in the local production of steroids and in the mediation of steroid effects on neurons and other glial cells. In this review, we examine the role of glia in the synthesis and metabolism of steroids and the functional implications of glial steroidogenesis. We analyze the mechanisms of steroid signaling on glia, including the role of nuclear receptors and the mechanisms of membrane and cytoplasmic signaling mediated by changes in intracellular calcium levels and activation of signaling kinases. Effects of steroids on functional parameters of glia, such as proliferation, myelin formation, metabolism, cytoskeletal reorganization, and gliosis are also reviewed, as well as the implications of steroid actions on glia for the regulation of synaptic function and connectivity, the regulation of neuroendocrine events, and the response of neural tissue to injury.

Animals↗
PubMed2006

Cross-talk between estrogen receptors and insulin-like growth factor-I receptor in the brain: cellular and molecular mechanisms.

Accumulating evidence suggests that insulin-like growth factor-I (IGF-I) and estradiol interact to regulate neural function. In this review, we focus on the cellular and molecular mechanisms involved in this interaction. The expression of estrogen receptors (ERs) and IGF-I receptor is cross-regulated in the central nervous system and many neurons and astrocytes coexpress both receptors. Furthermore, estradiol activates IGF-I receptor and its intracellular signaling. This effect may involve classical ERs since recent findings suggest that ERalpha may affect IGF-I actions in the brain by a direct interaction with some of the components of IGF-I signaling. In turn, IGF-I may regulate ER transcriptional activity in neuronal cells. In conclusion, ERs appear to be part of the signaling mechanism of IGF-I, and IGF-I receptor part of the mechanism of estradiol signaling in the nervous system.

Animals↗
PubMed2006

Neuroactive steroids prevent peripheral myelin alterations induced by diabetes.

The effect of the neuroactive steroids progesterone, dihydroprogesterone and tetrahydroprogesterone on myelin abnormalities induced by diabetes was studied in the sciatic nerve of adult male rats treated with streptozotocin. Streptozotocin increased blood glucose levels and decreased body weight gain, parameters not affected by steroids. Streptozotocin increased the number of fibers with myelin infoldings in the axoplasm, 8 months after the treatment. Chronic treatment for 1 month with progesterone and dihydroprogesterone resulted in a significant reduction in the number of fibers with myelin infoldings to control levels. Treatment with tetrahydroprogesterone did not significantly affect this myelin alteration. These results suggest that neuroactive steroids such as progesterone and dihydroprogesterone may represent therapeutic alternatives to counteract peripheral myelin alterations induced by diabetes.

20-alpha-Dihydroprogesterone↗
PubMed2006

Sex differences, developmental changes, response to injury and cAMP regulation of the mRNA levels of steroidogenic acute regulatory protein, cytochrome p450scc, and aromatase in the olivocerebellar system.

Compelling evidence has now demonstrated direct biological actions of sex steroids at the cerebellum. Likewise, the expression of key steroidogenic factors, such as the steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage (P450scc), and aromatase, at this neural site has been reported. Little is known, however, about the regulation of their genes in the cerebellum. Assessment of StAR, P450scc, and aromatase mRNAs in the cerebellum of male and female rats revealed that the expression of these genes is developmentally regulated, with the highest levels at early postnatal ages in both sexes and with significantly higher mRNA levels in postnatal males. Expression of these genes in the female remained unaltered after perinatal androgenization and along the estrous cycle. In contrast, damage of cerebellar afferent neurons of the inferior olivary nucleus evoked a significant increase in StAR, P450scc, and aromatase mRNA levels at this site, as well as a transient elevation in StAR mRNA at the cerebellum. Finally, enhancement of cAMP levels in cultured cerebellar neurons induced a significant increase in StAR and aromatase mRNA levels. In summary, we present herein novel evidence for the developmentally regulated and partially sexually dimorphic pattern of expression of StAR, P450scc, and aromatase genes in the rat cerebellum. These observations, together with the finding that the mRNA levels of these steroidogenic molecules are sensitive to injury and are regulated by intracellular cAMP, strongly suggest that local steroidogenesis is likely to play an important role during development and adaptation to neurodegenerative processes in the olivocerebellar system.

Animals↗
PubMed2006

Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus. The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective.

The ovarian hormone progesterone is neuroprotective in different experimental models of neurodegeneration. In the nervous system, progesterone is metabolized to 5alpha-dihydroprogesterone (DHP) by the enzyme 5alpha-reductase. DHP is subsequently reduced to 3alpha,5alpha-tetrahydroprogesterone (THP) by a reversible reaction catalyzed by the enzyme 3alpha-hydroxysteroid dehydrogenase. In this study we have analyzed whether progesterone metabolism is involved in the neuroprotective effect of the hormone in the hilus of the hippocampus of ovariectomized rats injected with kainic acid, an experimental model of excitotoxic cell death. Progesterone increased the levels of DHP and THP in plasma and hippocampus and prevented kainic-acid-induced neuronal loss. In contrast to progesterone, the synthetic progestin medroxyprogesterone acetate (MPA, Provera) did not increase DHP and THP levels and did not prevent kainic-acid-induced neuronal loss. The administration of the 5alpha-reductase inhibitor finasteride prevented the increase in the levels of DHP and THP in plasma and hippocampus as a result of progesterone administration and abolished the neuroprotective effect of progesterone. Both DHP and THP were neuroprotective against kainic acid. However, the administration of indomethacin, a 3alpha-hydroxysteroid dehydrogenase inhibitor, blocked the neuroprotective effect of both DHP and THP, suggesting that both metabolites are necessary for the neuroprotective effect of progesterone. In conclusion, our findings indicate that progesterone is neuroprotective against kainic acid excitotoxicity in vivo while the synthetic progestin MPA is not and suggest that progesterone metabolism to its reduced derivatives DHP and THP is necessary for the neuroprotective effect of the hormone.

3-Hydroxysteroid Dehydrogenases↗
PubMed2006

Neuroprotective effects of soy phytoestrogens in the rat brain.

Soy extracts are widely used as an alternative to hormone replacement therapy for the treatment of menopausal symptoms. Soy phytoestrogens, such as genistein, may act on the nervous system, affecting mood, cognitive function and behavior. In addition, several studies suggest that soy phytoestrogens are neuroprotective. The hypothesis of the present study was that soy extracts may exert neuroprotection and that this effect is mediated by phytoestrogens such as genistein. To test this hypothesis we assessed whether an acute administration of soy extract or genistein in vivo affects hippocampal neuronal loss induced by the systemic administration of kainic acid to adult Wistar female rats. One week after ovariectomy, animals received one intraperitoneal injection of soy extract (0.2, 1, 2 or 20 mg/kg), one injection of genistein (0.1, 1 or 10 mg/kg) or one injection of vehicle. Thirty minutes later, all animals received one intraperitoneal injection of kainic acid (7 mg/kg) or vehicle. One week after the injections, all animals were fixed by perfusion and the number of Nissl-stained neurons in the hilus of the dentate gyrus was estimated by the optical disector method. Administration of soy extract, even at high doses, did not induce neuronal loss and did not increase neuronal degeneration after kainic acid injury. On the contrary, soy extract at doses ranging from 1 to 20 mg/kg prevented neuronal loss induced by kainic acid. Genistein showed neuroprotective effects only at high dose (10 mg/kg), suggesting that other components in the soy extract are involved in the neuroprotective effect.

Animals↗
PubMed2006

Sex-dimorphic effects of progesterone and its reduced metabolites on gene expression of myelin proteins by rat Schwann cells.

Data obtained in our and other laboratories have indicated that progesterone (P) and its derivatives, dihydroprogesterone (DHP) and tetrahydroprogesterone (THP), stimulate the expression of two myelin proteins of the peripheral nervous system (PNS) [i.e., glycoprotein zero (P0) and peripheral myelin protein 22 (PMP22)]. We have now considered the effects of P and its derivatives on these and other myelin proteins [i.e., myelin-associated glycoprotein (MAG) and myelin and lymphocyte protein (MAL)] in sex-specific cultures of rat Schwann cells. Gene expression of myelin proteins was assessed by RNase protection assay. Treatment with P or DHP induced a stimulatory effect on P0 mRNA levels in male but not in female Schwann cells. In contrast, treatment with THP increased gene expression of P0 exclusively in female Schwann cells. A similar sex-difference was also evident for other myelin proteins. Indeed, PMP22 expression was stimulated by treatment with P in male cultures, whereas THP induced an increase of mRNA levels in female cultures. Moreover, MAG was stimulated by THP treatment in male cultures only, whereas MAL expression was unaffected by neuroactive steroid treatment in both male and female cultures. In conclusion, the present observations indicate that the effects of neuroactive steroids on myelin proteins are sexually dimorphic. This finding might represent an important background for sex-specific therapies of acquired and inherited peripheral neuropathies.

20-alpha-Dihydroprogesterone↗
PubMed2005

Extragonadal synthesis of estradiol is protective against kainic acid excitotoxic damage to the hippocampus.

Gonadal or exogenous estradiol is neuroprotective in multiple experimental paradigms. The role exerted by endogenous extragonadal estradiol synthesis in neuroprotection, however, is poorly understood. Here we show that a dose of kainic acid (3 mg/kg body weight) that does not produce detectable neuronal damage in control male and female gonadectomized rats induces a significant loss of hippocampal hilar neurons after the systemic inhibition of aromatase, the enzyme involved in estradiol biosynthesis from androgens. Extragonadal aromatase inhibition exerts a similar neuronal loss in both male and female rats (26% and 30% reduction in the number of hilar neurons, respectively). These findings indicate that extragonadal estradiol exerts a neuroprotective effect in both sexes, which prevents neuronal loss as a consequence of mild neurodegenerative signals.

Animals↗
PubMed2005

Estradiol and soy extract increase the production of new cells in the dentate gyrus of old rats.

In young rodents, estradiol increases cell proliferation in the dentate gyrus of the hippocampus. However, it is unknown if the old brain retains this response to estradiol. Here we assessed the generation of new cells in the dentate gyrus of old rats after administration of estradiol or a soy extract, since soy is used as an alternative to hormonal replacement therapy in postmenopausal women. In a first experiment, 12-month-old animals were ovariectomized and studied at 14, 18 or 22 months of age. The production of new cells, assessed by the incorporation of bromodeoxyuridine (BrdU), was similar in 14- and 18-month-old rats. However, there was a significant reduction in the number of BrdU-immunoreactive cells at 22 months of age. In a second experiment, 22-month-old ovariectomized animals were treated for 10 weeks with a weekly s.c. injection of 150 microg estradiol valerianate or with 60 mg/kg per day soy extract added to the drinking water. Both treatments increased significantly the production of new cells in the dentate gyrus. These findings indicate that the brains of old rats retain the ability to increase the production of new cells in response to estradiol and soy extracts.

Aging↗
PubMed2005

Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity.

The peripheral-type benzodiazepine receptor (PBR) is a critical component of the mitochondrial permeability transition pore, which is involved in the regulation of cell survival. Different forms of brain injury result in induction of the expression of the PBR in the areas of neurodegeneration, mainly in reactive glial cells. The consequences of induction of PBR expression after brain injury are unknown. To test whether PBR may be involved in the regulation of neuronal survival after injury, we have assessed the effect of two PBR ligands, Ro5-4864 and PK11195, on neuronal loss induced by kainic acid in the hippocampus. Systemic administration of kainic acid to male rats resulted in the induction of a reactive phenotype in astrocytes and microglia and in a significant loss of hilar neurons in the dentate gyrus. Administration of Ro5-4864, before the injection of kainic acid, decreased reactive gliosis in the hilus and prevented hilar neuronal loss. In contrast, PK11195 was unable to reduce reactive gliosis and did not protect hilar neurons from kainic acid. These findings suggest that the PBR is involved in control of neuronal survival and gliosis after brain injury and identify this molecule as a potential target for neuroprotective interventions.

Animals↗
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↗
PubMed2005

Growth hormone prevents neuronal loss in the aged rat hippocampus.

Decline of growth hormone (GH) with aging is associated to memory and cognitive alterations. In this study, the number of neurons in the hilus of the dentate gyrus has been assessed in male and female Wistar rats at 3, 6, 12, 14, 18, 22 and 24 months of age, using the optical fractionator method. Male rats had more neurons than females at all the ages studied. Significant neuronal loss was observed in both sexes between 22 and 24 months of age. In a second experiment, 22 month-old male and female rats were treated for 10 weeks with 2 mg/kg/day of GH or saline. At 24 months of age, animals treated with GH had more neurons in the hilus than animals treated with saline. These findings indicate that GH is neuroprotective in old animals and that its administration may ameliorate neuronal alterations associated to aging.

Age Factors↗
PubMed2004

Aromatase, the enzyme responsible for estrogen biosynthesis, is expressed by human and rat glioblastomas.

The biosynthesis of estradiol and related estrogens is catalyzed by the enzyme aromatase. Among other tissues, aromatase is expressed in the brain, where it is involved in the regulation of neuroendocrine events and reproduction. Under physiological conditions, the expression of aromatase in the mammalian brain is restricted to neurons. However, recent studies have shown that reactive astrocytes express aromatase after brain injury. This opens the possibility for the expression of the enzyme in other altered forms of glial cell, such as gliomas. In the present study, the expression of aromatase has been assessed, by RT-PCR and immunocytochemistry, in the rat glioblastoma C6 and in two human glioblastoma cell lines T98G and U373MG. The three cell lines expressed aromatase mRNA and showed a cytoplasmic pattern of aromatase immunoreactivity. In addition, the three cell lines express estrogen receptor alpha, suggesting that estradiol formed by aromatase may act as an autocrine or paracrine factor for glioblastoma cells. By analogy to the implication of aromatase into the growth of other forms of estrogen-sensitive tumors, such as some breast cancers, it is conceivable that the expression of aromatase may play a role in the growth of glioblastomas.

Animals↗
PubMed2004

Down-regulation of Bcl-2 in rat substantia nigra after focal cerebral ischemia.

After occlusion of the middle cerebral artery in rats, a robust neuronal loss occurs in the ipsilateral substantia nigra reticulata. In this study we have assessed whether degeneration of the substantia nigra is accompanied by changes in the expression of the anti-apoptotic protein Bcl-2. Neuronal loss was assessed by neuronal nuclei (NeuN) immunoreactivity. A significant decrease of Bcl-2 expression was observed in the substantia nigra 12, 24 and 72 h after middle cerebral artery occlusion. These results suggest that the secondary neuronal loss in the substantia nigra could be related with the modification of proteins regulating programmed cell death. Exo-focal cell death may explain the appearance of neuropsychiatric symptoms that are not correlated with the primary site of lesion.

Animals↗
PubMed2004

Selective estrogen receptor modulators protect hippocampal neurons from kainic acid excitotoxicity: differences with the effect of estradiol.

Neuroprotective effects of estradiol are well characterized in animal experimental models. However, in humans, the outcome of estrogen treatment for cognitive function and neurological diseases is very controversial. Selective estrogen receptor modulators (SERMs) may represent an alternative to estrogen for the treatment or the prevention of neurodegenerative disorders. SERMs interact with the estrogen receptors and have tissue-specific effects distinct from those of estradiol, acting as estrogen agonists in some tissues and as antagonists in others. In this study we have assessed the effect of tamoxifen, raloxifene, lasofoxifene (CP-336,156), bazedoxifene (TSE-424), and 17beta-estradiol on the hippocampus of adult ovariectomized rats, after the administration of the excitotoxin kainic acid. Administration of kainic acid induced the expression of vimentin in reactive astroglia and a significant neuronal loss in the hilus. SERMs did not affect vimentin immunoreactivity in the hilus, while 17beta-estradiol significantly reduced the surface density of vimentin immunoreactive profiles. Estradiol, tamoxifen (0.4-2 mg/kg), raloxifene (0.4-2 mg/kg), and bazedoxifene (2 mg/kg) prevented neuronal loss in the hilus after the administration of kainic acid. Lasofoxifene (0.4-2 mg/kg) was not neuroprotective. These findings indicate that SERMs present different dose-dependent neuroprotective effects. Furthermore, the mechanisms of neuroprotection by SERMs and estradiol are not identical, because SERMs do not significantly affect reactive gliosis while neuroprotection by estradiol is associated with a strong down-regulation of reactive astroglia.

Animals↗
PubMed2003

Minireview: Role of glia in neuroendocrine function.

Long relegated to the backwaters of neuroendocrinology, it is becoming increasingly apparent that glial cells of the central and peripheral nervous system are key participants because they are capable of both sending and receiving hormonal signals. Hormones are also a critical component of neuronal/glial cross talk, leading to neuromodulatory and neurotrophic actions under physiological and pathological conditions. In the peripheral nervous system, hormonal actions on Schwann cells and hormonal metabolites produced by these glial cells promote myelin formation and the remyelination and regeneration of injured nerves. In the central nervous system, glial cells participate in the hormonal regulation of synaptic function, synaptic plasticity, myelin formation, cognition, sleep, and the response of nervous tissue to injury. In addition, central glial cells participate in the regulation of hormonal secretion by hypothalamic neurons. Therefore, glial cells are a key element to understanding hormonal actions in the nervous system and the regulation of neuroendocrine events.

Animals↗