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

Brain Research Reviews 37 (2001) 320–334 www.elsevier.com / locate / bres

Review

Interactions of estrogens and insulin-like growth factor-I in the brain: implications for neuroprotection a a b c ˜ ´ Gloria Patricia Cardona-Gomez , Pablo Mendez , Lydia L. DonCarlos , Inigo Azcoitia , a, Luis M. Garcia-Segura * b

a Instituto Cajal, C.S.I.C., Avenida Doctor Arce 37, E-28002 Madrid, Spain Department of Cell Biology, Neurobiology and Anatomy, Loyola University Chicago School of Medicine, Maywood, IL 60153, USA c ´ Celular, Facultad de Biologıa ´ , Universidad Complutense, E-28040 Madrid, Spain Departamento de Biologıa

Accepted 12 June 2001

Abstract 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 a and b 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.  2001 Elsevier Science B.V. All rights reserved. Theme: Development and regeneration Topic: Neurotrophic factors: receptors and cellular mechanisms

Keywords: Insulin-like growth factor-I; Estradiol; Estrogen receptor; Neuroprotection; Apoptosis

*Corresponding author. Tel.: 134-9-1585-4729; fax: 134-9-1585-4754. E-mail address: [email protected] (L.M. Garcia-Segura). 0165-0173 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0165-0173( 01 )00137-0

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Contents 1. Introduction: neuroprotection by estrogen.................................................................................................................................................. 2. Mechanisms of neuroprotection by estrogen .............................................................................................................................................. 2.1. Antioxidant effects .......................................................................................................................................................................... 2.2. Neuroprotection mediated by classical nuclear estrogen receptors (ERs).............................................................................................. 2.3. Interaction with growth factor signaling ............................................................................................................................................ 3. Insulin like growth factor-I (IGF-I) in the brain: development, plasticity and neuroprotection ....................................................................... 4. Interactions of estrogen and IGF-I in the brain ........................................................................................................................................... 4.1. A neuroendocrine link between estrogen and IGF-I............................................................................................................................ 4.2. Interaction of estrogen with IGF-I receptor (IGF-IR) signaling in the brain.......................................................................................... 4.3. Coexpression of ERs and IGF-IR in the rat brain ............................................................................................................................... 4.4. Cross-regulation of the expression of ERs and IGF-IR in the rat brain................................................................................................. 4.5. Estrogen and IGF-I interact in the promotion of neuronal differentiation ............................................................................................. 4.6. Estrogen and IGF-I interact to regulate synaptic plasticity .................................................................................................................. 4.7. Interaction of ERs and IGF-IR in the control of neuronal survival and neuroprotection......................................................................... 5. Concluding remarks................................................................................................................................................................................. Acknowledgements ...................................................................................................................................................................................... References...................................................................................................................................................................................................

1. Introduction: neuroprotection by estrogen Estrogen is thought to protect neurons against numerous traumatic or chronic neurological and mental diseases in humans. Observations from epidemiological studies suggest that moderate exposure to exogenous estrogen in postmenopausal women may decrease the risk of stroke [108] and reduce the motor disability associated with Parkinson’s disease [131,156]. Although it is unclear whether estrogen may be effective in preventing further cognitive decline in women who already have Alzheimer’s disease [54,78,80,101], several studies indicate that estrogen replacement therapy ameliorates cognitive performance of postmenopausal women [34,159,172] and may delay the onset of Alzheimer’s disease [34,109,142,149,164,174]. While the neuroprotective properties of estrogen in humans are still controversial, there is now a rich literature on experimental animal models showing that estrogen is neuroprotective. Estrogen increases the viability, survival and differentiation of primary neuronal cultures deprived of growth factors and protects neuronal cell lines and primary neuronal cultures from anoxia and from different neurotoxic insults such as exposure to excitatory amino acids, oxidative agents or amyloid b-peptide [11,32,63,72,133]. These findings in vitro are in agreement with numerous studies in vivo, showing that estradiol protects cortical neurons from experimental forebrain ischemia [63,82,126,162,170,171,178] and nigrostriatal dopaminergic neurons [42,71,70] and hippocampal neurons [6–8,123,157] against neurotoxins. 2. Mechanisms of neuroprotection by estrogen

2.1. Antioxidant effects The mechanisms involved in the neuroprotective effects

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of estrogen are still unclear. It has been clearly demonstrated that estradiol has antioxidant properties that depend on the presence of the hydroxyl group in the C3 position on the A ring of the steroid molecule and are independent of the activation of estrogen receptors [11]. The antioxidant effects of estradiol have been detected in vitro, but depend on high supraphysiological concentrations of the hormone. It should be noted, however, that the local concentrations of estradiol in an injured brain region are unknown. It has been recently discovered that aromatase expression is increased in the central nervous system after different forms of neurodegenerative insults and that the enzyme is induced de novo in reactive astrocytes near the lesion sites [61,115]. Thus, in injured brain areas, local estrogen levels may reach concentrations compatible with antioxidant effects.

2.2. Neuroprotection mediated by classical nuclear estrogen receptors ( ERs) In some circumstances, the neuroprotective effects of estradiol appear to be mediated by the activation of classical estrogen receptors (ERs), which belong to the steroid / thyroid hormone superfamily of transcription factors. For instance, estrogen enhances the survival of PC12 cells transfected with the full-length rat ER a, but does not affect the survival of control cells transfected with vector DNA alone [68,69]. Furthermore, several studies have shown that neuroprotective effects of estradiol in primary and explant cultures are blocked by ER antagonists [30,47,112,138,169] as well as by an antisense oligonucleotide directed against the estrogen receptor a [47]. The finding that the expression of ERs is increased in cortical areas affected by focal cerebral ischemia [45], suggests that these receptors are involved in the response of neural tissue to injury and may, therefore, mediate

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neuroprotective effects of estradiol in vivo. It has been reported that female ER a knockout mice do not shown an enhanced tissue damage compared with wild-type mice after middle cerebral artery occlusion [129]. However, the ER antagonist ICI 182,780, which acts on both a and b ERs, exacerbates ischemic injury in the striatum of female mice [134] and inhibits the neuroprotective effect of estradiol against kainic acid in hippocampal hilar neurons of ovariectomized rats [7]. Furthermore, selective ER modulators have neuroprotective effects in vivo [71,127]. Further studies should determine the precise role of each ER form in neuroprotection in vivo. It is possible that neuroprotective effects of estradiol in vivo may involve different receptor subtypes, as well as mechanisms independent of ERs, depending on the type of neurodegenerative insult, the brain area involved [134], the time after injury or even the sex or age of the individual [134]. Involvement of ERs in neuroprotective effects of estradiol does not necessarily means that the effect is exclusively mediated through binding of ERs to the estrogen response element in target genes, since ERs may affect transcription acting through the activator protein-1 (AP-1) site as well [107]. In a recent study, Sawada et al. [135] found that the ER antagonist ICI 182,780 blocked protection of nigral dopaminergic neurons from neurotoxin induced apoptosis, but a peptide that inhibits binding of the ERs to the estrogen response element did not block protection. These data suggest that the neuroprotective effects of ERs are independent of binding to an estrogen response element, and may instead be exerted by regulating transcription through the AP-1 site.

2.3. Interaction with growth factor signaling It has been proposed that some of the trophic and plastic effects of estradiol in neural tissue may be mediated by the activation of growth factor signaling. In accordance with this, several studies have shown that, in specific neuronal populations, estrogens regulate the expression of neurotrophins such as BDNF [65,137,140,144,145] and NGF [66,137], and the expression of neurotrophin receptors such as p75, trkA [66,97,144] and trkB [20]. Furthermore, estradiol may interact with estrogen binding sites, or still uncharacterized ERs, in the plasma membrane and promote neuronal survival by regulating activation of the intracellular signaling pathways of neurotrophin receptors and other membrane receptors [152]. For instance, estradiol may have rapid effects on neurons via G proteins [100,121], activation of the mitogen-activated protein kinase (MAPK) cascade [14,138,141,152], activation of the phosphoinositol-3 kinase (PI3K) pathway [81], the phosphorylation of the cAMP response element binding protein [73,102,110,179] and the modification of intracellular calcium levels [13,98,119]. All of these hormonal effects provide multiple potential sites for interactions

between the signaling pathways of estradiol and growth factors. One of the growth factors that interacts with estradiol in many cell types is insulin-like growth factor-I (IGF-I). Evidence has accumulated to support the idea that the actions of estrogen and IGF-I in the brain are interdependent. This interdependence between estrogen and IGF-I, or between ERs and IGF-I receptors (IGF-IR), has been documented for different events, such as neuronal differentiation, synaptic plasticity and neuroprotection. In this review we will focus on the interactions between IGF-I signaling and estrogen signaling in the brain and on the potential implications of these interactions for neuroprotection.

3. Insulin like growth factor-I (IGF-I) in the brain: development, plasticity and neuroprotection The main source of IGF-I is the liver, where its production is induced by growth hormone [37]. Other organs, including the brain and spinal cord, also synthesize this peptide. Furthermore, systemic IGF-I enters the brain [5,27,124]. Therefore, both locally produced and systemic IGF-I may affect brain function. Effects of IGF-I are mediated by the IGF-I receptor (IGF-IR), a member of the growth factor tyrosine kinase receptor family that signals through the PI3K pathway and the MAPK cascade [90]. IGF-I actions are regulated by at least six IGF-binding proteins [83]. During development of the nervous system, IGF-I has prominent neurotrophic effects, stimulating differentiation and survival of specific neuronal populations [10,38,154,155]. In the adult central nervous system, IGF-I is a neuromodulator and regulates synaptic plasticity [153]. Furthermore, IGF-I is involved in the response of neural tissue to injury [12,17,56,86,91,130,161,175] and protects neurons against various neurodegenerative stimuli. For instance, IGF-I is a trophic factor for motoneurons [41,93,105,158] and protects motoneurons as well as retinal ganglion neurons [87] from axotomy induced cell death. IGF-I is also protective against hypoxia–ischemia [67,76,74,147,163] and protects a variety of neurons from neurotoxic insults, such as cerebellar granule cells [92] and hilar hippocampal neurons [7] from kainic acid toxicity, hippocampal neurons from b-amyloid [43] and iron [177] toxicity, inferior olivary nucleus neurons against 3-acetyl pyridine [50], striatal neurons against quinolinic acid [4] and dopaminergic nigral neurons against 6-hydroxydopamine [75]. In some cases, the effect of IGF-I is mediated by the N-terminal tripeptide (glycine-prolineglutamate) of the molecule [4,75,132]. In addition to protect neurons from death, IGF-I is able to induce recovery of function after different forms of brain injury [50,128].

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4. Interactions of estrogen and IGF-I in the brain

4.1. A neuroendocrine link between estrogen and IGF-I As an endocrine signal, IGF-I regulates growth hormone and gonadotrophins acting in the hypothalamus and the pituitary [16,79,113,166] and regulates gonadotropin responsiveness in the ovary [180]. IGF-I and estrogen interact in neuroendocrine regulation in the pituitary [31,99]. Decreased plasma levels of IGF-I in growth hormone deficient mice as well as in growth hormone receptor deficient mice are associated with reproductive deficits, a delay of female puberty and alterations in the function of the hypothalamic–pituitary–gonadal axis [9,35]. In addition, IGF-I regulates estradiol production [49,122,146,176] and deletion of insulin receptor substrate2 (IRS-2), a component of the insulin / IGF-IR signaling cascade, causes female infertility [19]. In turn, estradiol regulates expression and activation of IGF-I receptors in the uterus [64,125], IGF-I synthesis by the liver and IGF-I plasma levels [15,143,167]. Furthermore, adult female mice with inactivated ER a have decreased serum levels of IGF-I [160]. Therefore, 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.

4.2. Interaction of estrogen with IGF-I receptor ( IGFIR) signaling in the brain Several potential points of convergence of estradiol and IGF-IR signaling may be involved in neuroprotection. It has been shown that IGF-I and other growth factors may activate ERs in the absence of estradiol in different cell types, including SK-ER3 neuroblastoma cells transfected with the ER a [1,94]. In turn, estrogen may activate the PI3K and the MAPK (or extracellular-signal regulated kinase, ERK) signaling pathways, the two signal transduction cascades coupled to the IGF-IR and other tyrosine kinase receptors: for instance, in explants of the cerebral cortex, estradiol induces a rapid and sustained activation of ERK1 and ERK2 [141,152]. This signaling pathway interferes with c-Jun N-terminal protein kinase activation, protecting cells from apoptosis [28]. It is possible that the interaction of estradiol with the IGF-IR signaling may be mediated by the activation of ERs and may be selective for each ER form. In COS7 and HEK293 cells transfected with ER a, but not in cells transfected with ER b, estradiol rapidly induces phosphorylation of the IGF-IR and of ERK1 and ERK2 [84]. Furthermore, upon stimulation with estradiol, ER a, but not ER b, binds rapidly to the IGF-IR [84]. Whether such a selectivity in the interaction of ERs with IGF-IR is also valid for the nervous system remains to be determined. Estrogen may regulate the activation of Akt, also known

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as protein kinase B (PKB) or RAC-PK (related to A and C protein kinase), a serine / threonine protein kinase that is downstream of PI3K [46,116]. Recent studies have shown that estrogen treatment results in the phosphorylation of Akt in dissociated cerebral cortical neurons [81], in cerebral cortical explants [139,168] in the hippocampal cell line H19-7 [3] and in the hypothalamus of ovariectomized rats in vivo [25], suggesting that the neuroprotective effects of estrogen may be exerted in part by the activation of this component of the IGF-IR signaling pathway. It has been proposed that Akt activation may result in the phosphorylation of the Bcl-2 family member Bad, blocking Bad-induced cell death [36,39]. Akt can also regulate intracellular glucose levels [29,165], as well as several transcription factors that may be involved in the control of neuronal survival, such as CREB [44,120], NF-kB [85] and several members of the Forkhead family [18,40,77,89,150]. Furthermore, Akt activation enhances Bcl-2 promoter activity [120] and may elicit the phosphorylation of procaspase-9, preventing the activation of procaspase-3 [26,87,148]. The effects of IGF-I in protecting hippocampal neurons from nitric oxide-induced apoptosis [96], and retinal ganglion cells from axotomy-induced secondary death [87] have been shown to involve Akt activation. Estradiol and IGF-I act synergistically to increase Akt activity in the human breast cancer cell line MCF-7 [2] and Akt mediates the effects of IGF-I on ER a expression and activity in these cells [21,95]. We have recently analyzed the activation of Akt by IGF-I and estradiol in the rat brain in vivo. Adult ovariectomized rats received i.c.v. infusions of IGF-I (10 24 M, 0.5 ml / h, 7 days) and then were treated i.p. with 17 b-estradiol (300 mg / rat), 24 h before killing. Under these conditions, a synergistic action of estradiol and IGF-I on the phosphorylation of Akt was observed in all areas examined, including the hippocampus, the cerebral cortex, the hypothalamus and the cerebellum (Cardona-Gomez, unpublished results). This finding suggests that estrogen signaling may interact with the IGF-IR signaling pathway in the activation of Akt and the promotion of cellular survival in the CNS. As mentioned before, the activation of Akt may regulate the expression of the anti-apoptotic molecule Bcl-2. Since both IGF-I and estrogen induce Bcl-2 expression in the CNS [58,50], we assessed whether estrogen and IGF-I interact in the regulation of Bcl-2 in the brain. We tested whether IGF-IR is necessary for the expression of Bcl-2 in the hypothalamus of adult ovariectomized rats in response to estradiol. Animals receiving estradiol alone (i.p., 300 mg / rat) had an increased number of Bcl-2 immunoreactive neurons in the hypothalamus compared with animals receiving vehicles. However, i.c.v. infusion of a IGF-IR antagonist, the peptide JB1 [117] (20 mg / ml; 0.5 ml / h, 7 days) blocked the effect of estradiol on the number of Bcl-2 immunoreactive neurons (Fig. 1). This suggests that IGF-IR activation is necessary for the induction of Bcl-2

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Fig. 1. Number of Bcl-2 immunoreactive neurons in the hypothalamic arcuate nucleus of adult ovariectomized rats given i.c.v. infusions of the IGF-IR antagonist JB1 or vehicle for 7 days and killed 24 h after i.p. injection of 300 mg of 17b-estradiol or oil vehicle. For additional experimental details, see Ref. [58]. C, control rats treated with vehicles. E, Rats treated with estradiol. JB1, Rats infused with the IGF-IR antagonist. JB11E, Rats infused in the lateral cerebral ventricle with the IGF-IR antagonist and injected with estradiol. Data are the mean6S.E.M. of six rats. *Significant difference (P,0.01) versus control values.

by estradiol in the adult CNS. Therefore, Akt and Bcl-2 may represent molecular targets for the interaction of estrogen and IGF-I in the promotion of neuronal survival.

4.3. Coexpression of ERs and IGF-IR in the rat brain The interaction of estrogen and IGF-I signaling in the central nervous system may depend on interactions between neural cells expressing ERs with neural cells expressing IGF-IR. Direct interactions between the signaling pathways of a and b ERs and IGF-IR in the same cell are also possible. Analysis of the distribution of ERs, a and b, and IGF-IR in selected regions of the female rat brain by confocal microscopy revealed that most neurons expressing IGF-IR also express at least one form of ER; in contrast, many ER expressing cells do not express IGF-IR. In addition, some astrocytes co-express ER b and IGF-IR [23]. This finding indicates that interactions between the signaling pathways of ERs and IGF-IR are possible at the cellular level in the central nervous system, in neurons as well as in glial cells.

4.4. Cross-regulation of the expression of ERs and IGFIR in the rat brain In addition to an interaction between estrogen and IGF-I signaling and the coexpression of ERs and IGF-IR in the same cells, there is also evidence that the expression of ERs and IGF-IR is cross-regulated in the brain. Estradiol increases the expression of IGF-IR [20,118] and IGF binding proteins [118] in monolayer hypothalamic cul-

tures. Estradiol also increases IGF-I levels [48] and the expression of IGF binding protein-2 in the hypothalamus in vivo [22]. To determine whether ERs regulate the expression of IGF-IR in the central nervous system, an antagonist for the a and b forms of ERs (ICI 182,780, 10 27 M, 0.5 ml / h) was infused for 7 days into the lateral cerebral ventricle of adult ovariectomized Wistar rats. This treatment resulted in the down-regulation of IGF-IR mRNA and IGF-IR protein levels in the hippocampus (Fig. 2) and the cerebral cortex (Fig. 2) compared with the levels observed in control animals given vehicle. A similar decrease was observed in IGF-IR mRNA levels in the hypothalamus of the rats treated with the ER antagonist. However, the ER antagonist did not affect IGF-IR protein levels in this brain region. Furthermore, acute systemic administration of estradiol did not affect IGF-IR mRNA or protein levels in the hypothalamus of ovariectomized rats [25]. These data suggest that ERs are necessary to maintain the expression of IGF-IR in the hippocampus and the cerebral cortex, but the role of ERs in the regulation of IGF-IR in the hypothalamus is less clear. Interestingly, the effect of ERs in the cerebellum may be different from other brain areas. In the cerebellum, the ER antagonist resulted in an increase in IGF-IR mRNA and protein levels (Fig. 2). ERs in the cerebellum appear to down-regulate IGF-IR expression. ER b is the predominant, if not the exclusive, form of ER in the cerebellum [136], while in the other brain areas studied both receptor subtypes are expressed. Therefore, the regional differences observed in the regulation of IGF-IR by the ER antagonist may be explained if ER b down-regulates IGF-IR expression, while homodimers of ER a or heterodimers of ER a and ER b up-regulate IGF-IR expression. Further studies should determine whether ER a and ER b have different effects on IGF-IR expression. To assess whether IGF-IR regulates the expression of ERs, adult ovariectomized Wistar rats received i.c.v. infusions of IGF-I (10 24 M, 0.5 ml / h), or the IGF-IR antagonist peptide JB1 (20 mg / ml, 0.5 ml / h) or vehicle for 7 days. Infusion of IGF-I resulted in the down-regulation of ER a protein levels in the hypothalamus (Fig. 3) and the up-regulation of ER a levels in the hippocampus (Fig. 3), compared with control rats infused with vehicle. No significant effect was observed in the cerebral cortex (Fig. 3). The infusion of the IGF-IR antagonist JB1 had effects opposite to those of IGF-I: ER a levels were increased in the hypothalamus (Fig. 3) and decreased in the hippocampus (Fig. 3), compared with control rats infused with vehicle. The IGF-IR antagonist was also able to induce a small, although significant, decrease in ER a levels in the cerebral cortex (Fig. 3). Infusion of IGF-I, or of the IGF-IR antagonist JB1, into the lateral cerebral ventricle did not significantly affect ER b expression in the hypothalamus, the hippocampus or the cerebral cortex (Cardona-Gomez, unpublished results). However, IGF-I increased, and JB1 decreased, the expression of ER b in the cerebellum (Fig. 4). These findings suggest that IGF-IR

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Fig. 2. Effect of the estrogen receptor antagonist ICI 182,780 (ICI) on the expression of the IGF-I receptor (IGF-IR) in the hypothalamus (a,b), the hippocampus (c,d), the cerebral cortex (e,f) and the cerebellum (g,h) of adult ovariectomized rats. ICI was infused for 7 days, at a concentration of 10 27 M, into the lateral cerebral ventricle. Control rats (C) were infused with vehicle. a, c, e and f, protein levels; b, d, f and h, mRNA levels. Data are mean6S.E.M. of six rats. *Significant difference (P,0.01) versus control values.

regulates the expression of ERs in the female rat central nervous system, that this effect is regionally specific and that it is selective for the two ER subtypes. Based on the results summarized above, we conclude that there is a cross-regulation of the expression of ERs and IGF-IR in the rat brain.

4.5. Estrogen and IGF-I interact in the promotion of neuronal differentiation The interactions between estradiol and IGF-I signaling and the coexpression and the cross-regulation of their receptors in the central nervous system may be involved in

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Fig. 3. Effect of IGF-I and the IGF-IR antagonist JB1 on the expression of the estrogen receptor a in the hypothalamus (a,b), the hippocampus (c,d) and the cerebral cortex (e,f) of adult ovariectomized rats. IGF-I (10 24 M) and JB1 (20 mg / ml) were infused for 7 days in the lateral cerebral ventricle. Control rats (C) were infused with vehicle. Data are mean6S.E.M. of six rats. *Significant difference (P,0.01) versus control values.

many different maturational milestones during development, adult life and aging. The first report of an interaction of estrogen and IGF-I on neuronal differentiation in the central nervous system was made by Toran-Allerand et al. [151] in explant cultures from fetal rat hypothalamus. These authors observed that insulin, at a concentration that acts on IGF-IR, had a synergistic action with estrogen on the induction of neuritic growth. Consecutive studies showed that IGF-I and estradiol cooperate in the promotion of dendritic growth in rat hypothalamic primary cultures [47]. Both IGF-I and estrogen induce dendritic growth in these cultures. The effect of IGF-I was blocked by the ER antagonist ICI 182,780 and by an antisense oligonucleotide directed against ER a, indicating that ERs are involved in IGF-I-dependent dendritic growth [47]. Furthermore, the

inhibition of IGF-I synthesis in the cultures, using an antisense oligonucleotide, resulted in the prevention of estrogen-induced dendritic growth, indicating that IGF-I mediates the effect of estradiol [47]. These findings suggest that IGF-I and estrogen cooperate in the induction of hypothalamic neuronal differentiation in vitro, and that both substances are needed for the morphological differentiation of these neurons.

4.6. Estrogen and IGF-I interact to regulate synaptic plasticity Both estradiol [33,55,57,59,102,173] and IGF-I [153] are modulators of synaptic plasticity in the adult central nervous system. In the mediobasal hypothalamus of female

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Fig. 4. Effect of IGF-I (a) and the IGF-IR antagonist JB1 (b) on the expression of estrogen receptor b in the cerebellum of adult ovariectomized rats. IGF-I (10 24 M) and JB1 (20 mg / ml) were infused for 7 days in the lateral cerebral ventricle. Control rats (C) were infused with vehicle. Data are mean6S.E.M. of six rats. Asterisk, significant difference (P,0.01) versus control values.

rodents [59,111,114] and primates [103,181], estradiol induces a transient disconnection of inhibitory axo-somatic synapses, that is associated with an increased frequency of neuronal firing [88]. This transient disconnection of axosomatic synapses is observed in the arcuate nucleus of the rat hypothalamus during the estrous cycle, after the increase of estrogen levels on the afternoon of proestrus [59,104,106]. The i.c.v. infusion of the ER antagonist ICI 182,780 blocks the transient disconnection of axo-somatic synapses induced in ovariectomized rats by the administration of estradiol, indicating that ERs are involved in the effect of estradiol on synapses [24]. Synaptic changes in the arcuate nucleus during the estrous cycle, or after estradiol administration to ovariectomized rats, are accompanied by a fluctuation in local IGF-I levels in the mediobasal hypothalamus [48,60]. These changes are due to an effect of estradiol and progesterone on the accumulation of exogenous IGF-I by hypothalamic glia [22,48,53,51,60]. IGF-I levels fluctuate during the estrous cycle in the hypothalamus in parallel with the synaptic changes: IGF-I levels increase when synapses are disconnected and return to basal conditions when synapses are reconnected [53,59,60]. The parallel between synaptic changes and IGF-I levels suggested that IGF-I may be involved in the induction of synaptic plasticity. To test this possibility, the IGF-IR antagonist peptide JB1 was infused i.c.v. into cycling female rats. Under these conditions, synaptic plasticity was abolished [52]. Furthermore, the i.c.v. infusion of the IGF-IR antagonist ovariectomized rats blocked the synaptic disconnection induced by estrogen administration [24]. These findings indicate that IGF-I receptors are necessary for the induction of synaptic plasticity in the arcuate nucleus of the hypothalamus of adult female rats. Since synaptic changes also depend on ERs [24], it appears that the induction of synaptic plasticity in the mediobasal hypothalamus depends on the parallel activation of estrogen and IGF-I

signaling and potentially interdependent mechanisms, as those described in previous sections.

4.7. Interaction of ERs and IGF-IR in the control of neuronal survival and neuroprotection The results discussed in the previous sections suggest that an interaction between estrogen and IGF-I may also be involved in the prevention of neuronal death. This is further supported by studies in vitro and in vivo that have shown that there is an interaction between ERs and IGF-IR in the promotion of neuronal survival and in the response of the neural tissue to injury. The first evidence came from a series of studies with hypothalamic primary neuronal cultures grown in a defined medium deprived of serum and hormones. Using antisense oligonucleotides for IGF-I and ER a, the ER antagonist ICI 182,780 and pharmacological inhibitors of the signaling pathways of the IGF-IR, it was shown that there is an interdependence of ERs and IGF-IR in the promotion of neuronal survival [48,62]. In these experiments, the induction of neuronal survival by IGF-I was prevented by inhibiting the synthesis of ER a, using a specific ER a antisense oligonucleotide [48]. The effect of IGF-I was also prevented by the ER antagonist ICI 182,780 [48]. In turn, the promotion of hypothalamic neuronal survival by estradiol was prevented by blocking the synthesis of IGF-I in the cultures using a specific IGF-I antisense oligonucleotide [48], as well as by the pharmacological blockade of the MAPK and the PI3K signaling pathways of the IGF-IR [62]. These findings suggest that ERs, at least ER a, are involved in the mechanisms used by IGF-I to promote neuronal survival. Activation of ERs by IGF-IR signaling pathways [1,94] may be part of this mechanism. In addition, these experiments suggest that IGF-I, and IGF-IR signaling pathways, are involved in the mechanism used by estradiol to promote neuronal survival. Therefore, it is possible that neuronal survival in these

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cultures may be dependent on a synchronized activation, or coactivation, of both ERs and IGF-IR. The interaction of IGF-IR and ERs in neuroprotection has also been assessed in vivo, using systemic administra-

tion of kainic acid to induce degeneration of hippocampal hilar neurons in ovariectomized rats [7]. Both the systemic administration of 17b-estradiol, as well as the i.c.v. infusion of IGF-I, prevented hilar neuronal loss induced by

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kainic acid in adult ovariectomized rats (Fig. 5). To determine the role of IGF-IR in the neuroprotective effect of estrogen, the specific IGF-IR antagonist JB1 was infused i.c.v. for 14 days (20 mg / ml, 0.5 ml / h) to neutralize the local action of endogenous IGF-I in the hippocampus. The neuroprotective action of 17b-estradiol was abolished under these conditions (Fig. 5). This finding indicates that IGF-IR activation is necessary for the neuroprotective effect of estradiol in this experimental model. Furthermore, the neuroprotective effect of IGF-I was blocked by the i.c.v. infusion of the ER antagonist ICI 182,780 (Fig. 5), indicating that activation of ERs is also necessary for the effect of IGF-I on hippocampal neurons [7]. In summary, the in vitro and in vivo experiments demonstrate that the actions of estradiol and IGF-I in neuroprotection depend on coactivation of both ERs and IGF-IR.

5. Concluding remarks Clearly, estradiol and IGF-I have the potential to act as powerful, synergistic neuroprotective agents. It is of enormous clinical significance to determine whether these agents can be exploited as part of the therapeutic arsenal directed against neurodegenerative diseases, stroke or trauma. Long-term treatment with estradiol and IGF-I for neurological disorders may not be effective, practical or safe, given the multiple effects of both molecules on many target organs other than the brain, and given the known actions of both in cancer progression. However, understanding the mechanisms involved in the synergistic effects of estradiol and IGF-I in neuroprotection will provide essential information as to how neurons can survive and retain plasticity in the face of various insults. Ligandindependent activation of the receptors or activation of downstream signaling pathways may prove to be effective avenues for therapeutic intervention. Alternatively, it may be useful to exploit the endogenous capacity of the brain to synthesize estrogens and IGF-I. If vulnerable brain regions can be coaxed into producing more estrogen and IGF-I, at sufficiently high levels to offer neuroprotection, the brain may be able to promote its own protection and survival.

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Acknowledgements This study has been carried out with financial support from the Commission of the European Communities, specific RTD programme ‘Quality of Life and Management of Living Resources’, QLK6-CT-2000-00179, from DGESIC (PM98-0110) and USPHS MH 48794. G.P.C.-G. is a fellow from Colciencias, Colombia.

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Fig. 5. Effect of estradiol (E2), IGF-I, the antagonist of ERs (ICI) and the antagonist of IGF-IR (JB1) on the number of hilar neurons of ovariectomized rats after systemic kainic acid (KA) administration. Sections were stained with toluidine blue. For experimental details, see Ref. [7]. (a) Low magnification of the dentate gyrus of a control rat treated with vehicles. (b) Low magnification of the dentate gyrus of a rat injected with kainic acid. (c) Low magnification of the dentate gyrus of a rat treated with estradiol and kainic acid. (d) High magnification of the hilus of a control rat. (e) High magnification of the hilus of a rat treated with kainic acid. (f) High magnification of the hilus of a rat treated with estradiol and kainic acid. (g) Low magnification of the dentate gyrus of a rat infused i.c.v. with the IGF-IR antagonist JB1 and injected with estradiol and kainic acid. (h) Low magnification of the dentate gyrus of a rat infused i.c.v.with IGF-I and injected with kainic acid. (i) Low magnification of the dentate gyrus of a rat infused i.c.v. with IGF-I and the antagonist of ERs and injected with kanic acid. (j) High magnification of the hilus of a rat infused i.c.v. with the IGF-IR antagonist JB1 and injected with estradiol and kainic acid. (k) High magnification of the hilus of a rat infused i.c.v. with IGF-I and injected with kainic acid. (l) High magnification of the hilus of a rat infused i.c.v. with IGF-I and the antagonist of ERs and injected with kanic acid.

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