Biomedical subjects

Darrell W Brann

Publications and source records attributed to Darrell W Brann.

At least 19 recordsLinked to original sources

PubMed2006

Cloning, distribution, and colocalization of MNAR/PELP1 with glucocorticoid receptors in primate and nonprimate brain.

MNAR/PELP1 (see text) is a newly identified scaffold protein/coactivator initially thought to modulate nongenomic and genomic actions of the estrogen receptor; however, it has been recently shown to interact with multiple steroid receptors, including androgen and glucocorticoid receptors. In the present study, we cloned the monkey MNAR/PELP1 gene, deduced its domain structure, examined its localization pattern and colocalization with glucocorticoid receptor in monkey brain, and determined its subcellular localization. PCR-based cloning of MNAR/PELP1 from monkey brain produced a transcript of approximately 3.4 kb which showed high homology to the human and rat MNAR/PELP1 gene. Domain analysis showed that all the key steroid-receptor-interacting (LXXLL) domains, SH3-interacting (PXXP) domains and several C-terminal glutamic-acid-rich clusters, as well as various kinase domains are conserved in the monkey MNAR/PELP1 gene. Anatomical mapping of MNAR/PELP1 immunoreactivity in several regions of the monkey brain showed a similar pattern of MNAR/PELP1 distribution as previously observed in rat and mouse brains. MNAR/PELP1 also showed an absolute colocalization with glucocorticoid receptors in both primate and nonprimate brain, including those regions of the brain, where other steroid receptors are not significantly expressed, such as hippocampus, striatum, and thalamus - suggesting that MNAR/PELP1 may modulate glucocorticoid actions in the brain. Finally, ultrastructural electron microscopic studies showed that MNAR/PELP1-reactive gold particles are located within nucleus, cytoplasm, dendritic/synaptic terminals, and astrocytic processes. As a whole, the studies demonstrate that MNAR/PELP1 is expressed and colocalizes with glucocorticoid receptors in monkey and rat brains and may have multiple cellular functions based on its subcellular localizations.

Amino Acid Sequence↗

PubMed2006

Role of astrocytes in estrogen-mediated neuroprotection.

Recent work has suggested that the ovarian steroid hormone, 17beta-estradiol (E2), at physiological concentrations, may exert protective effects in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and acute ischemic stroke. While physiological concentrations of E2 have consistently been shown to be protective in vivo, direct protection of neurons remains controversial, suggesting that while direct protection of neurons may occur in some instances, an alternative or parallel pathway for protection may exist which could involve another cell type in the brain. In the present review, we summarize the data in support of a possible role for astrocytes in the mediation of neuroprotection by E2. We also summarize the data suggesting a non-classical estrogen receptor may underlie some of the protective effects of E2 by activating cellular signaling pathways, such as extracellular-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt. A possible indirect pathway involving astrocytes may act in concert with the proposed direct pathway to achieve a widespread, global protection of both ER positive and negative neurons.

Apoptosis↗

PubMed2006

Role of astrocytes in reproduction and neuroprotection.

Hypothalamic astrocytes secrete TGF-beta and 3 alpha,5 alpha-tetrahydro progesterone (3 alpha,5 alpha-THP) in culture. When the astrocyte-conditioned medium (ACM) was incubated with the hypothalamic cell line GT1-7, it resulted in the secretion of GnRH. Immunoneutralization with TGF-beta antibody or ultra-filteration with a 10 kDa cut off filter resulted in attenuation of the GnRH releasing ability of ACM, indicating that TGF-beta was a major factor involved with GnRH release. Treatment with estrogens increases TGF-beta secretion. These observations indicate a significant role of astrocytes in GnRH secretion. Serum-deprivation results in the death of GT1-7 neurons in culture and addition of ACM or TGF-beta to the culture, attenuates cell death. The mechanism of protection from cell death appears to involve phosphorylation of MKK4, JNK, c-Jun(Ser63), and enhancement of AP-1 binding. Co-administration of JNK inhibitors, but not MEK inhibitors attenuated ACM or TGF-beta-induced c-Jun(Ser63) phosphorylation and their neuroprotective effects. These studies suggest that astrocytes can protect neurons, at least in part, by the release of TGF-beta and activation of a c-Jun/AP-1 protective pathway.

Animals↗

PubMed2006

Curriculum development and technology incorporation in teaching neuroscience to graduate students in a medical school environment.

Today's neuroscience faculty member wears multiple hats and requires diverse skills to succeed in the competitive environment in which they find themselves. A common refrain from graduates is that there is a need for better training in the diverse, multiple skills that they will need to succeed in obtaining a faculty position and excelling in that position once it is obtained. Our university recently developed a new neuroscience graduate program that allowed us to create a curriculum and core courses de novo and that could be tailored to provide training in diverse skills used by everyday neuroscience faculty members. The current article details our rationale, design, and implementation of this new curriculum and its two major core courses. The genesis of the new curriculum also provided an opportune time to introduce and test new teaching technology in the two neuroscience core courses. The technology incorporated included on-line WebCT course sites, computer performance system, and the Tegrity system. Herein, we elaborate on our experiences with the use of this technology in the small class graduate course setting and provide insight on student feedback on the perceived effectiveness of the technology. The mechanisms and considerations that are needed for incorporation of such technology are also discussed. While no single curriculum or technology incorporation scheme will be applicable to all programs, it is hoped that our experiences in curriculum design and technology incorporation will be beneficial to other universities as they consider refining existing programs or beginning new ones.

Curriculum↗

PubMed2005

Cloning, expression, and localization of MNAR/PELP1 in rodent brain: colocalization in estrogen receptor-alpha- but not in gonadotropin-releasing hormone-positive neurons.

MNAR/PELP1 is a recently identified scaffold protein in the human that modulates the nongenomic activity of estrogen receptors by facilitating linkage/cross talk with the Src/Erk activation cascade. We report herein the cloning of rat MNAR/PELP1 and provide new information concerning its distribution in the female rat brain and its degree of colocalization with estrogen receptor-alpha (ER-alpha) and GnRH. PCR-based cloning of MNAR/PELP1 from rat hypothalamus yielded a transcript of approximately 3.4 kb, which shows 86% homology to the published human MNAR/PELP1 sequence and retained all the key binding motifs (PXXP, LXXLL, and glutamic acid clusters) in its primary structure that are known to be critical for its interaction with Src and steroid receptors. RT-PCR revealed that the MNAR/PELP1 transcript is expressed in many regions of the brain, and immunohistochemistry studies showed intense MNAR/PELP1 immunoreactivity (MNAR/PELP1-ir) in areas such as the hypothalamus, cerebral cortex, hippocampus, amygdala, and cerebellum. MNAR/PELP1-ir principally localized in the nucleus, but some cytoplasmic and plasma membrane-associated staining was also observed. MNAR/PELP1-ir was also primarily neuronal, although some localization in glia cells was observed in select brain regions. Colocalization studies revealed that a majority of ER-alpha-positive cells in the brain colocalized MNAR/PELP1-ir. In contrast, MNAR/PELP1-ir rarely colocalized in GnRH neurons. In conclusion, the current study provides evidence that MNAR/PELP1 is expressed in key neural tissues of the rat brain that are known targets of steroid action, that its expression is primarily neuronal, and that MNAR/PELP1-ir is strongly colocalized in ER-alpha, but not GnRH neurons in the rodent brain.

Animals↗

PubMed2005

Expression of glutamate receptor subunits in the hypothalamus of the female rat during the afternoon of the proestrous luteinizing hormone surge and effects of antiprogestin treatment and aging.

The excitatory transmitter, glutamate has been implicated in the control of reproduction, hormone secretion and neuroendocrine regulation. The present study examined whether the hypothalamic expression of three key ionotropic glutamate receptor subunits (NMDAR1, GluR1 and GluR6) fluctuates significantly on proestrus in the rat, and whether treatment with the antiprogestin, RU486 affected glutamate receptor subunit expression. The studies revealed that NMDAR1, GluR1 and GluR6 mRNA levels in the mediobasal hypothalamus (MBH) and preoptic area (POA) fluctuate little throughout the day of proestrus. However, treatment with the antiprogestin, RU486 induced a significant elevation of GluR6 mRNA levels at 14.00 and 16.00 h on proestrus in the MBH, suggesting that endogenous progesterone (P4) may act to inhibit hypothalamic GluR6 levels. In support of this suggestion, exogenous P4 treatment to estrogen (E2)-primed ovariectomized (ovx) rats significantly suppressed GluR6 mRNA levels in the afternoon (12.00-16.00 h) in the MBH, and at 12.00 h in the POA, which preceded LH surge induction. Likewise, temporal examination of hypothalamic GluR6 protein levels in E2 + P4-treated young and middle-aged ovx rats revealed an early elevation from 12.00 to 14.00 h, which was followed by a fall from 16.00 to 20.00 h. The early elevation of GluR6 protein levels was most pronounced in the POA of the young rat, and this elevation was markedly attenuated in the middle-aged rat. As a whole, the studies suggest that glutamate receptor expression fluctuates little on proestrus in the hypothalamus, but that expression of the kainate GluR6 receptor subunit may be modulated by progesterone and aging.

Aging↗

PubMed2005

Astrocyte-derived transforming growth factor-{beta} mediates the neuroprotective effects of 17{beta}-estradiol: involvement of nonclassical genomic signaling pathways.

17beta-Estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen, mediate numerous effects in the brain, including neurosecretion, neuroprotection, and the induction of synaptic plasticity. Astrocytes, the most abundant cell type in the brain, influence many of these same functions and thus may represent a mediator of estrogen action. The present study examined the regulatory effect and underlying cell signaling mechanisms of E2-induced release of neurotropic growth factors from primary rat cortical astrocyte cultures. The results revealed that E2 (0.5, 1, and 10 nm) and tamoxifen (1 mum) increased both the expression and release of the neuroprotective cytokines, TGF-beta1 and TGF-beta2 (TGF-beta), from cortical astrocytes. The stimulatory effect of E2 was attenuated by the estrogen receptor (ER) antagonist, ICI182,780, suggesting ER dependency. The effect of E2 also appeared to involve mediation by the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway, because E2 rapidly induced Akt phosphorylation, and pharmacological or molecular inhibition of the PI3K/Akt pathway prevented E2-induced release of TGF-beta. Additionally, the membrane-impermeant conjugate, E2-BSA, stimulated the release of TGF-beta, suggesting the potential involvement of a membrane-bound ER. Finally, E2, tamoxifen, and E2-BSA were shown to protect neuronal-astrocyte cocultures from camptothecin-induced neuronal cell death, effects that were attenuated by ICI182,780, Akt inhibition, or TGF-beta immunoneutralization. As a whole, these studies suggest that E2 induction of TGF-beta release from cortical astrocytes could provide a mechanism of neuroprotection, and that E2 stimulation of TGF-beta expression and release from astrocytes occurs via an ER-dependent mechanism involving mediation by the PI3K/Akt signaling pathway.

Animals↗

PubMed2005

The aging reproductive neuroendocrine axis.

It is well known that the reproductive system is one of the first biological systems to show age-related decline. While depletion of ovarian follicles clearly relates to the end of reproductive function in females, evidence is accumulating that a hypothalamic defect is critical in the transition from cyclicity to acyclicity. This minireview attempts to present a concise review on aging of the female reproductive neuroendocrine axis and provide thought-provoking analysis and insights into potential future directions for this field. Evidence will be reviewed, which shows that a defect in pulsatile and surge gonadotropin hormone-releasing hormone (GnRH) secretion exists in normal cycling middle-aged female rats, which is thought to explain the significantly attenuated pulsatile and surge luteinizing hormone (LH) secretion at middle-age. Evidence is also presented, which supports the age-related defect in GnRH secretion as being due to a reduced activation of GnRH neurons. Along these lines, stimulation of GnRH secretion by the major excitatory transmitter glutamate is shown to be significantly attenuated in middle-aged proestrous rats. Corresponding age-related defects in other major excitatory regulatory factors, such as catecholamines, neuropeptide Y, and astrocytes, have also been demonstrated. Age-related changes in hypothalamic concentrations of neurotransmitter receptors, steroid receptors, and circulating steroid hormone levels are also reviewed, and discussion is presented on the complex interrelationships of the hypothalamus-pituitary-ovarian (HPO) axis during aging, with attention to how a defect in one level of the axis can induce defects in other levels, and thereby potentiate the dysfunction of the entire HPO axis.

Aging↗

PubMed2005

Differential expression of the peripheral benzodiazepine receptor and gremlin during adipogenesis.

This study used the mRNA differential display technique to identify differentially expressed genes during the process of adipogenesis in the preadipocyte cell line, 3T3-L1. 3T3-L1 cells were treated with dexamethasone, isobutyl-1-methylxanthine, and insulin to induce differentiation into mature adipocytes. Cells were collected at three time-points during differentiation: Day 0 (d0), or nondifferentiated; Day 3 (d3), during differentiation; and Day 10 (d10), >90% of the cells had differentiated into mature adipocytes. Initial studies yielded 18 potentially differentially regulated cDNA candidates (8 down-regulated and 10 up-regulated). Reverse Northern and Northern blots confirmed differential expression of six of the candidates. Four of the candidates up-regulated on d3 and d10 were identified by sequence analysis to be lipoprotein lipase, a well-known marker of adipocyte differentiation. A fifth candidate that was expressed in d0, but not d3 or d10, was identified as DRM/gremlin, a bone morphogenetic protein antagonist. Finally, a sixth candidate that was increased at d3 and d10 was identified as the peripheral benzodiazepine receptor, which has been implicated in proliferation, differentiation, and cholesterol transport in cells. This study is the first to show that peripheral benzodiazepine receptor and DRM/gremlin are expressed in preadipocyte cell lines and that they are differentially regulated during adipogenesis.

3T3-L1 Cells↗

PubMed2005

Neuroprotection by stem cell factor in rat cortical neurons involves AKT and NFkappaB.

Stem cell factor (SCF) is a highly expressed cytokine in the central nervous system. In the present study, we demonstrate a neuroprotective role for SCF and its tyrosine kinase receptor, c-kit, against camptothecin-induced apoptosis and glutamate excitotoxicity in rat cortical neurons. This protection was blocked by pharmacological or molecular inhibition of either the MEK/ERK or PI3K/Akt signaling pathways. The importance of these pathways was further confirmed by the activation of both ERK, in a MEK-dependent manner, and Akt, via PI3K. Activation of Akt increased the binding of the p50 and p65 subunits of NFkappaB, which was also important for neuroprotection. Akt inhibition prevented NFkappaB binding, suggesting a role for Akt in SCF-induced NFkappaB. Pharmacological inhibition of NFkappaB or dominant negative IkappaB also prevented neuroprotection by SCF. SCF up-regulated the anti-apoptotic genes, bcl-2 and bcl-xL in an NFkappaB-dependent manner. Together, these findings demonstrate a neuroprotective role for SCF in cortical neurons, an effect that was mediated by Akt and ERK, as well as NFkappaB-mediated gene transcription. SCF represents a novel therapeutic target in the treatment of neurodegenerative disease.

Animals↗

PubMed2005

Regulatory role of excitatory amino acids in reproduction.

Glutamate, the major excitatory amino acid (EAA) transmitter in the central nervous system, has been implicated as a critical mediator in brain function. Glutamate and its receptors are found in all key hypothalamic areas critically involved in reproduction. Administration of glutamate and its agonists can bring about LH release in animals with a steroid background. Antagonists of the ionotropic glutamate receptors inhibited LH release and abolished the steroid-induced and the preovulatory LH surge. Both NMDA and non-NMDA receptor antagonists can also inhibit pulsatile LH release in castrated animals. The preoptic area has been implicated as a primary site of action of NMDA, while non-NMDA agonists have been suggested to act primarily at the arcuate/median eminence level. While EAAs may act directly on GnRH neurons to enhance GnRH release, the majority of evidence suggests that an indirect mechanism, involving EAA activation of nitric oxide and/or catecholamines, plays a major role in the GnRH-releasing effects of EAAs. Furthermore, there is also some evidence that the tonic inhibitory effect of opioids on GnRH may also involve, at least in part, a suppression of glutamate. Finally, EAA stimulation of GnRH/LH release is markedly attenuated in middle-aged rats, suggesting that a defect in glutamate neurotransmission may underlie the attenuated LH surge observed in aging.

Animals↗

PubMed2003

Astrocyte protection of neurons: role of transforming growth factor-beta signaling via a c-Jun-AP-1 protective pathway.

Astrocytes have become a focal point for research in neurobiology, especially regarding their purported ability to regulate neuronal communication and survival. The present study addressed a poorly understood but important focus in this area, the mechanism(s) underlying astrocyte-induced survival of neurons. The results of the study show that soluble factors in astrocyte-conditioned media (ACM) protect murine GT1-7 neurons from serum deprivation-induced cell death and that this neuroprotection is correlated with enhanced activation/phosphorylation of the AP-1 transcription factor, c-JunSer-63. A parallel and correlated activation of the upstream kinases, c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase-4 (MKK4) was also demonstrated. Furthermore, co-administration of JNK inhibitors, but not a MEK inhibitor, significantly attenuated ACM-induced phosphorylation of c-JunSer-63 and blocked its neuroprotective action. Gel shift analysis demonstrated that ACM enhanced AP-1 binding, an effect that appears functionally important, since an AP-1 binding inhibitor significantly attenuated the neuroprotective action of ACM. Further studies implicated transforming growth factor (TGF)-beta1 and TGF-beta2 as critical active soluble factors released by astrocytes, since both were demonstrated in ACM, and immunoneutralization of the conditioned media with a panspecific TGF-beta antibody significantly attenuated the enhanced AP-1 binding and neuroprotective action of the ACM. Furthermore, exogenous application of TGF-beta1 and TGF-beta2 was found to enhance c-JunSer-63 phosphorylation and to be neuroprotective, and co-administration of JNK inhibitors or an AP-1 binding inhibitor blocked TGF-beta-induced neuroprotection. Taken together, these studies suggest that astrocytes can protect neurons from serum deprivation-induced cell death, at least in part, by release of TGF-beta and activation of a c-Jun/AP-1 protective pathway.

Animals↗

PubMed2003

Tamoxifen, a selective estrogen receptor modulator, reduces ischemic damage caused by middle cerebral artery occlusion in the ovariectomized female rat.

Previous work has demonstrated that physiological concentrations of 17beta-estradiol can protect the female rat brain against middle cerebral artery occlusion (MCAO)-induced ischemic damage. The present study examined whether therapeutic doses of the clinically relevant selective estrogen receptor modulator (SERM), tamoxifen, can similarly protect the female rat brain against ischemic stroke damage. Adult female rats were bilaterally ovariectomized and implanted subcutaneously with either a placebo or tamoxifen time-release pellet (0.1, 0.8 or 2.4 mg/kg/day). One week later, the animals underwent permanent MCAO to assess the protective ability of the different tamoxifen doses on brain infarct size. As expected, MCAO produced a large infarct ( approximately 53%) of the affected cerebral hemisphere in placebo (control) animals. The 0.1 mg/kg/day dose of tamoxifen did not exhibit any significant protective effects, however; the 0.8 and 2.4 mg/kg/day doses of tamoxifen, which are in the therapeutic range, dramatically reduced infarct of the affected cerebral hemisphere ( approximately 70% reduction) as compared to the controls. The reduction of infarct size was primarily due to protection of two major structures, the cerebral cortex and striatum. Laser Doppler analysis further revealed that tamoxifen had no significant effect on cerebral blood flow either before or after MCAO, suggesting that tamoxifen protection is independent of cerebral blood flow changes. Further studies showed that tamoxifen pellets implanted at the time of MCAO did not reduce infarct size, suggesting that pretreatment with tamoxifen is necessary to observe a protective effect. These studies suggest that clinically important SERMs may have an additional unrecognized beneficial effect of protection of the female brain.

Animals↗

PubMed2003

Brain and retinal vascular endothelial cells with extended life span established by ectopic expression of telomerase.

PURPOSE: To study blood-retina barrier (BRB) regulation, we sought to establish neuronal microvascular endothelial cells (ECs) with expanded life span by ectopic expression of the human telomerase gene (hTERT). METHODS: Primary cultures of human brain and bovine retinal microvascular endothelial cells (HBECs and BRECs, respectively) were transfected with the catalytic component of human telomerase human telomerase reverse transcriptase (hTERT), and colonies were selected with puromycin. The endothelial origin of these cells was confirmed by immunocytochemistry. Reconstituted basement membrane matrix and three-dimensional collagen gel were used to induce the formation of tubulelike structures. To assess endothelial permeability, ECs were cultured on the upper chamber of migration assay membrane filters, with or without astrocyte coculture. Transepithelial electrical resistance (TER) was measured using a voltohmmeter. RESULTS: Both bovine retinal and human brain microvascular ECs expressing hTERT resembled young primary ECs in their morphology and growth response after more than 100 population doublings. Both bovine and human hTERT cells expressed von Willebrand factor, a key marker distinguishing ECs from other cell types; formed angiogenic webs in reconstituted basement membrane matrix; and, in a VEGF-dependent manner, formed tubule-like structures in three-dimensional collagen gel. Coculture of both types of cells with astrocytes resulted in a decrease in EC permeability, as assessed by TER. VEGF induced the breakdown of the HBEC monolayer barrier, and astrocytes in coculture appeared to attenuate the effects of VEGF. CONCLUSIONS: Ectopic expression of hTERT enables adult HBECs to bypass the first mortality checkpoint but not the second mortality checkpoint, allowing generation of neuronal ECs with extended, but not indefinite life span.

Adenoviridae↗

PubMed2003

Astrocytes and brain function: implications for reproduction.

Recent evidence suggests that astrocytes have important neuroregulatory functions in addition to their classic functions of support and segregation of neurons. These newly revealed functions include regulation of neuron communication, neurosecretion, and synaptic plasticity. Although these actions occur throughout the brain, this review will focus on astrocyte-neuron interactions in the hypothalamus, particularly with respect to their potential contribution to the regulation of gonadotropin-releasing hormone (GnRH) secretion and reproduction. Hypothalamic astrocytes have been documented to release a variety of neuroactive factors, including transforming growth factors-alpha and -beta, insulin-like growth factor-1, prostaglandin E2, and the neurosteroid, 3 alpha-hydroxy-5 alpha-pregnane-20-one. Each of these factors has been shown to stimulate GnRH release, and receptors for each factor have been documented on GnRH neurons. Astrocytes have also been implicated in the regulation of synaptic plasticity in key areas of the hypothalamus that control GnRH release, an effect achieved by extension and retraction of glial processes (i.e., glial ensheathment). Through this mechanism, the number of synapses on GnRH neurons and GnRH regulatory neurons can potentially be modulated, thereby influencing the activation state of GnRH neurons. The steroid hormone 17beta-estradiol, which triggers the GnRH and luteinizing hormone surge, has been shown to induce the astrocyte-regulated changes in hypothalamic synaptic plasticity, as well as enhance formation and release of the astrocyte neuroactive factors, thereby providing another potential mechanistic layer for astrocyte regulation of GnRH release. As a whole, these studies provide new insights into the diversity of astrocytes and their potential role in reproductive neuroendocrine function.

Animals↗

PubMed2003

Transforming growth factor-beta: a neuroprotective factor in cerebral ischemia.

Transforming growth factor-beta (TGF-beta) has diverse and multiple roles throughout the body. This review focuses on the evidence supporting its functions in the central nervous system, with a particular emphasis on its purported role in cerebral ischemia. Numerous studies have documented that TGF-beta1 levels are enhanced in the brain following cerebral ischemia. As evidence that such an upregulation is beneficial, agonist studies have demonstrated that TGF-beta1 reduces neuronal cell death and infarct size following middle cerebral artery occlusion (MCAO), while conversely, antagonist studies have shown increased neuronal cell death and infarct size after MCAO. These studies suggest that TGF-beta1 has a neuroprotective role in cerebral ischemia. Recent work with adenoviral- mediated overexpression of TGF-beta1 in vivo in mice has further implicated a neuroprotective role for TGF-beta1 in cerebral ischemia, as evidenced by a reduction in neuronal cell death, infarct size, and neurological outcome. Additionally, numerous in vitro studies have documented the neuroprotective ability of TGF-beta1 in neurons from a variety of species, including rats, mice, chicks, and humans. Of significant interest, TGF-beta1 was shown to be protective against a wide variety of death-inducing agents/insults, including hypoxia/ischemia, glutamate excitotoxicity, beta-amyloid, oxidative damage, and human immunodeficiency virus. The mechanism of TGF-beta1-mediated neuroprotection remains to be resolved, but early evidence suggests that TGF-beta1 regulates the expression and ratio of apoptotic (Bad) and antiapoptotic proteins (Bcl-2, Bcl-x1), creating an environment favorable for cell survival of death-inducing insults. Taken as a whole, these results suggest that TGF-beta1 is an important neuroprotective factor that can reduce damage from a widearray of death-inducing agents/insults in vitro, as well as exert protection of the brain during cerebral ischemia.

Animals↗

PubMed2002

Orphanin FQ inhibits GnRH secretion from rat hypothalamic fragments but not GT1-7 neurons.

Orphanin FQ is a novel opioid family member, which is densely localized in the hypothalamus, a region of the brain important for the control of reproduction. This study tested the hypothesis that orphanin FQ might regulate the secretion of gonadotropin-releasing hormone, the key central regulator of the ovulatory cycle. To test this hypothesis, we used rat hypothalamic fragments and immortalized gonadotropin-releasing hormone neurons (GT1-7) in vitro and examined whether orphanin FQ would inhibit forskolin-induced gonadotropin-releasing hormone release. The studies revealed that orphanin FQ potently and dose-dependently inhibits forskolin-induced gonadotropin-releasing hormone release from rat hypothalamic fragments. In contrast, orphanin FQ had no effect on gonadotropin-releasing hormone release from GT1-7 neurons. Reverse transcriptase-polymerase chain reaction analysis further revealed that the orphanin FQ receptor, ORL-1 is expressed in hypothalamic fragments, but not in GT1-7 neurons. Together, these findings are the first to suggest a role for orphanin FQ in the regulation of gonadotropin releasing hormone secretion.

Animals↗

PubMed2002

Estrogen-astrocyte interactions: implications for neuroprotection.

BACKGROUND: Recent work has suggested that the ovarian steroid 17beta-estradiol, at physiological concentrations, may exert protective effects in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and acute ischemic stroke. While physiological concentrations of estrogen have consistently been shown to be protective in vivo, direct protection upon purified neurons is controversial, with many investigators unable to show a direct protection in highly purified primary neuronal cultures. These findings suggest that while direct protection may occur in some instances, an alternative or parallel pathway for protection may exist which could involve another cell type in the brain. PRESENTATION OF THE HYPOTHESIS: A hypothetical indirect protective mechanism is proposed whereby physiological levels of estrogen stimulate the release of astrocyte-derived neuroprotective factors, which aid in the protection of neurons from cell death. This hypothesis is attractive as it provides a potential mechanism for protection of estrogen receptor (ER)-negative neurons through an astrocyte intermediate. It is envisioned that the indirect pathway could act in concert with the direct pathway to achieve a more widespread global protection of both ER+ and ER- neurons. TESTING THE HYPOTHESIS: We hypothesize that targeted deletion of estrogen receptors in astrocytes will significantly attenuate the neuroprotective effects of estrogen. IMPLICATIONS OF THE HYPOTHESIS: If true, the hypothesis would significantly advance our understanding of endocrine-glia-neuron interactions. It may also help explain, at least in part, the reported beneficial effects of estrogen in neurodegenerative disorders. Finally, it also sets the stage for potential extension of the hypothetical mechanism to other important estrogen actions in the brain such as neurotropism, neurosecretion, and synaptic plasticity.

Animals↗