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D K Sarkar

Publications and source records attributed to D K Sarkar.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effect of voltage-dependent calcium channel blockers on ethanol-induced beta-endorphin release from hypothalamic neurons in primary cultures.

The voltage-dependent calcium channel (VDCC) has been shown to mediate calcium entry into neurons that regulates neurotransmission in many neuronal cells. Four major types of VDCCs (three high-voltage-activated L-, N-, and P-types and one low-voltage-activated T-type) have been identified in neurons. Involvement of the VDCC in ethanol-stimulated beta-endorphin (beta-EP) release from hypothalamic neurons has not been studied. In the present study, the role of VDCC on basal and ethanol-induced beta-EP release was determined by using rat fetal hypothalamic cells in primary cultures. Treatments with a 50 mM dose of ethanol for 3 hr increased immunoreactive beta-EP (IR-beta-EP) release from hypothalamic cells maintained in cultures for 9 days. Ethanol-induced IR-beta-EP release was inhibited by a P/Q-type channel blocker omega-agatoxin TK (0.1-1 microM), an N-type channel blocker omega-conotoxin (0.1-1 microM), an L-type blocker nifedipine (1-10 microM), and a T-type blocker flunarizine (1-10 microM). The minimal effective doses of these blockers that blocked the ethanol response produced no significant effects on basal release of IR-beta-EP; neither did these doses of the blockers produce any significant effects on cell viability. These results suggest that ethanol-stimulated IR-beta-EP release is regulated by extracellular calcium involving P-, N-, L- and T-type channels.

Animals↗
PubMed1998

Hormonal control of pituitary prolactin-secreting tumors.

Prolactin secreting adenomas (prolactinomas) are the most prevalent form of pituitary tumors in humans. Prolactinomas have been linked to estrogen exposure in humans and animals. However, the mechanism by which estrogen increases mitogenesis in lactotropes, as well as other estrogen responsive cells, is not well understood. Given the complex nature of steroid hormones and their wide array of actions, it seems plausible that there are multiple ways in which estrogen can exert its cell-transforming actions. Estrogen has a wide range of actions on cells depending on the cell type, receptor levels, and other factors present in the cell. A defect at any point could play a potential role in cell transformation. The source of such defects could be the result of any of a wide range of possibilities, including genetic predisposition, prolonged exposure to sufficient levels of the steroid hormone, or other insults to the cell which lead to altered responsiveness to estrogen in some way. This review discusses the recent advances that have been made in the area of understanding estrogen action in transformation of pituitary lactotropes.

Animals↗
PubMed1998

Differential regulation by estrogens of growth and prolactin synthesis in pituitary cells suggests that only a small pool of estrogen receptors is required for growth.

PR1 cells are a prolactin (PRL)-secreting cell line derived from a pituitary lactotroph tumor found in 17beta-estradiol-treated Fischer 344 rats. We examined the effect of estrogen on cell proliferation and PRL synthesis under various culture conditions. Estrogen, at extremely low concentrations, induces cell proliferation in this cell line, whereas antiestrogen inhibits proliferation. Interestingly, the proliferation response is much more sensitive than the PRL response because 0.01 pM estradiol or diethylstilbestrol induces half-maximal growth induction [ approximately 0.1% estrogen receptor (ER) occupancy is required], whereas 0.01 nM concentration is required for half-maximal PRL induction ( approximately 50% ER occupancy is required). The proliferation response is not as sensitive to antiestrogen as the PRL response, because 10 nM concentration of the pure antiestrogen ICI 182,780 could not inhibit 1 nM estradiol- or diethylstilbestrol-induced proliferation. The same concentration of ICI 182,780 decreased PRL secretion to 1% of estradiol- or diethylstilbestrol-induced prolactin secretion suggesting a possible dichotomy of ER control of proliferation and PRL synthesis. The Kd of ER binding in these cells is about 3 x 10(-11) M. These results with the PR1 cells extend previous studies in other estrogen- regulated systems and suggest that only a small pool of ER is required for cell proliferation in contrast with the regulation of expression of specific genes. They also raise questions as to how a dimeric receptor functions when only one ligand site is occupied or when both an estrogen and an antiestrogen occupy one dimer.

Animals↗
PubMed1998

Role of transforming growth factor (TGF)-beta Type I and TGF-beta type II receptors in the TGF-beta1-regulated gene expression in pituitary prolactin-secreting lactotropes.

Transforming growth factor beta1 (TGF-beta1) inhibits pituitary lactotrope proliferation and secretion of PRL in an autocrine/paracrine manner. In this study, the role of TGF-beta1 type I (TbetaR-I) and TGF-beta type II (TbetaR-II) receptors in TGF-beta1-regulated gene expression in lactotropes was determined using anterior pituitary cells known to be responsive to TGF-beta1 growth inhibition and using a transformed PR1 cell line known to be nonresponsive to TGF-beta1 growth inhibition. Treatment with TGF-beta1 inhibited cell proliferation and decreased PRL mRNA levels in anterior pituitary cells, but in PR-1 cells, the treatment caused only decreased PRL mRNA levels. Affinity labeling of TGF-beta binding proteins indicated that anterior pituitary cells contain several TGF-beta-binding protein complexes, including the 65 kDa size TbetaR-I and 95 kDa size TbetaR-II. In the PR1 cells, the major complex found was similar to the 65 kDa size of TbetaR-I. Immunocytochemistry identified TbetaR-I and TbetaR-II receptor proteins in lactotropes but detected primarily TbetaR-I receptor protein in PR1 cells. RT-PCR detection of TbetaR-I and TbetaR-II mRNA identified both receptor mRNA transcripts in anterior pituitary cells and in PR1 cells but the levels of TbetaR-II and TbetaR-I mRNA transcripts in PR1 cells was much lower than that in anterior pituitary cells. Determination of the TGF-beta1 gene responses in PR1 cells following TbetaR-I and TbetaR-II gene transfection indicated that PR1 cells transactivate transcription of the TGF-beta-responsive p3TP-Lux reporter in the absence of cotransfected TbetaR-II receptor. The introduction of the TbetaR-II receptor alone or in combination with TbetaR-I confer ligand-independent reporter transactivation in these cells. When only TbetaR-I was introduced along with reporter, a ligand-dependent transactivation was observed. These data suggest for the first time that the TGF-beta1-mediated transcriptional activation response can be distinguished from the growth response in lactotropes. Furthermore, the TGF-beta1 gene-transcription response is less dependent on TbetaR-II receptor expression than is the TGF-beta1 growth-inhibitory response.

Activin Receptors, Type I↗
PubMed1997

Downregulation of TGF-beta 1 gene expression in anterior pituitary cells treated with forskolin.

Transforming growth factor beta 1 (TGF-beta 1) has recently been shown to inhibit the growth of lactotropes by an autocrine/paracrine mechanism. Because the growth and function of lactotropic cells in the anterior pituitary are under control by hormones that modulate intracellular cAMP levels, the effect of a cAMP elevating agent forskolin on TGF-beta 1 and TGF-beta 1 gene expression in primary cultures of anterior pituitary cells was tested. Treatment with a dose of forskolin (5 microM), known to induce PRL gene transcription, significantly inhibited TGF-beta 1 levels in culture medium and TGF-beta 1 mRNA levels in cellular extracts. Nuclear run-off transcription analysis revealed that the forskolin effect on TGF-beta 1 mRNA expression is due to reduced transcription initiation rates. These data suggest that the transcription of TGF-beta 1 may be regulated by cAMP dependent mechanisms in anterior pituitary cells.

Animals↗
PubMed1997

The secretory response of hypothalamic beta-endorphin neurons to acute and chronic nicotine treatments and following nicotine withdrawal.

In the present study, we determined the effect of acute and chronic nicotine treatments on the secretion of immunoreactive beta-endorphin (IR-beta-EP) and cell viability of cultured hypothalamic neurons. Also, we determined the secretory response of IR-beta-EP following withdrawal from a long-term nicotine treatment. Fetal hypothalamic cells were dissociated and maintained in cultures for 9 days and were treated with various doses of nicotine (1, 6, 12 and 18 microM) for 6 h (acute treatment) or treated with nicotine at 12 h intervals for 96 h (chronic treatment). Determination of IR-beta-EP concentrations in the media revealed that 6-18 microM doses of nicotine increased IR-beta-EP secretion from these cultures for a period of 24 h; after this period, the cultured cells did not respond to these doses of nicotine. The desensitization of beta-EP neurons 24 h after treatment with nicotine did not appear to be related to the loss of viable cells. Determination of withdrawal response after 72 h of constant nicotine (6 microM) treatments revealed that the hypothalamic neurons secrete elevated amounts of IR-beta-EP for a period of 72 h after nicotine withdrawal. These results suggest that: 1) acute treatment with nicotine stimulates hypothalamic IR-beta-EP release; 2) chronic nicotine treatment desensitizes beta-EP-secreting neurons and, 3) beta-EP neurons in primary culture show withdrawal response to nicotine.

Animals↗
PubMed1997

Over expression of vascular endothelial growth factor and its receptor during the development of estrogen-induced rat pituitary tumors may mediate estrogen-initiated tumor angiogenesis.

Estrogens, which have been associated with several types of human and animal cancers, can induce tumor angiogenesis in the pituitary of Fischer 344 rats. The mechanistic details of tumor angiogenesis induction, during estrogen carcinogenesis, are still unknown. To elucidate the role of estrogen in the regulation of tumor angiogenesis in the pituitary of female rats, the density of blood vessels was analysed using factor VIII related antigen (FVIIIRAg) immunohistochemistry and the expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) was examined by Western blot and immunohistochemical analysis. The expression of VEGF receptor (VEGFR-2/Flk-1/KDR) was also examined by immunohistochemistry. The results demonstrated that 17beta-estradiol (E2) induces neovascularization, as well as the growth and enlargement of blood vessels after 7 days of exposure. The high tumor angiogenic potential was associated with an elevated VEGF/VPF protein expression in the E2 exposed pituitary of ovariectomized (OVEX) rats. VEGF/VPF and FVIIIRAg immunohistochemistry and endothelial specific lectin (UEA1) binding studies, indicate that the elevation of VEGF protein expression initially occurred in both blood vessels and non-endothelial cells. After 15 days of E2 exposure, VEGF/VPF protein expression, in the non-endothelial cell population, sharply declined and was restricted to the blood vessels. The function of non-endothelial-derived VEGF is not clear. Furthermore, immunohistochemical studies demonstrated that VEGFR-2 (flk-1/KDR), expression was elevated significantly in the endothelial cells of microblood vessels after 7 days of E2 exposure. These findings suggest that over expression of VEGF and its receptor (VEGFR-2) may play an important role in the initial step of the regulation of estrogen induced tumor angiogenesis in the rat pituitary.

Animals↗
PubMed1997

Forskolin delays the ethanol-induced desensitization of hypothalamic beta-endorphin neurons in primary cultures.

Ethanol and its metabolite acetaldehyde have been shown to stimulate immunoreactive beta-endorphin (IR-beta-EP) secretion from hypothalamic neurons in primary cultures. Also, chronic ethanol and acetal-dehyde have been shown to cause the development of tolerance and desensitization of these neurons. In this study, we determined some of the cellular events leading to desensitization of the function of beta-endorphin (beta-EP) secretory neurons. The fetal hypothalamic cells were treated with various doses of ethanol (25 and 50 mM) or acetaldehyde (6.25, 12.5, and 25 mM) for 6 hr or treated with these drugs at 12 hr intervals for 72 hr. Determination of IR-beta-EP concentrations in the media revealed that ethanol increased IR-beta-EP secretion from these cultures for 12 hr, after this period, the cultured cells did not respond to ethanol. Acetaldehyde stimulated IR-beta-EP secretion from this culture for a period of 48 hr, but the IR-beta-EP secretory response to acetaldehyde reduced gradually with time during the first 48-hr period and reached the basal level at 72 hr. The desensitization of beta-EP neurons 12 hr after treatment with alcohol did not seem to be related to the loss of viable cells, because chronic ethanol exposures did not produce any effect on cell viability. However, reduced IR- beta-EP secretory response to acetaldehyde with time was associated with the time-dependent increase in cell death. Pretreatment of cultures with a cAMP analog, forskolin, increased the activity of functional beta-EP neurons and delayed the ethanol desensitization effects on these neurons. Pretreatment of forskolin did not delay the acetaldehyde desensitization of beta-EP neurons, but protected these cells from acetaldehyde toxicity. These results suggest that (i) chronic treatment with ethanol desensitizes beta-EP-secreting neurons due to reduced cellular functions and (ii) chronic acetaldehyde reduces beta-EP neurotransmission due to cell death. Furthermore, data suggest for the first time that cAMP pretreatments delay the ethanol-induced desensitization of opioid neurons and partly protect against the neurotoxic action of acetaldehyde on opioid neurons.

Animals↗
PubMed1997

The role of cAMP in ethanol-regulated beta-endorphin release from hypothalamic neurons.

We have previously shown that ethanol acutely stimulates immunoreactive beta-endorphin (IR-beta-EP) release from hypothalamic neurons, whereas chronic administration of ethanol desensitizes these neurons. In the study reported herein, the role of the intracellular cAMP system in the ethanol-regulated IR-beta-EP release from hypothalamic cells in primary cultures was investigated. Acute treatment with ethanol or with the cAMP analog, dibutyryl cAMP, revealed that both agents stimulate the release of IR-beta-EP from the hypothalamic cells. Combined treatment of ethanol and the cAMP analog produced a synergistic effect on IR-beta-EP release. Treatment with ethanol and a cAMP-elevating agent, forskolin, increased cAMP levels in cultured hypothalamic cells. However, prior exposure to ethanol reduced the cAMP-elevating responses of these neurons to ethanol and forskolin. These results indicate that the stimulatory and adaptive responses of IR-beta-EP neurons to ethanol may involve the cAMP system.

Animals↗
PubMed1997

Effects of ethanol on basal and prostaglandin E1-induced increases in beta-endorphin release and intracellular cAMP levels in hypothalamic cells.

Our recent studies determining the effect of cAMP-elevating agents forskolin and dibutyryl cAMP on ethanol-induced immunoreactive beta-endorphin (IR-beta-EP) release from hypothalamic cells in primary cultures suggested the possibility that both stimulatory and adaptive secretory responses of beta-EP neurons after ethanol exposure may involve the cAMP system. To determine further the role of cAMP, the effects of prostaglandin E1 (PGE1) on basal and ethanol-regulated IR-beta-EP secretion and cAMP productions were determined in primary cultures of hypothalamic cells. The results presented in this study show that a 50 mM dose of ethanol, which is within the EC50 dose of ethanol required to elevate IR-beta-EP release from hypothalamic cells, increased cellular levels of cAMP and elevated IR-beta-EP release simultaneously from the cultured neurons for a period of 6 hr. The cAMP and IR-beta-EP secretory responses developed desensitization to ethanol challenge after 24 hr of constant ethanol incubation. The cAMP-elevating agent PGE1 increased the cellular content of cAMP and IR-beta-EP release in a dose-dependent manner. The EC50 dose of PGE1 for elevation of IR-beta-EP and cAMP was approximately 0.5 microM. As with ethanol, chronic treatment with PGE1 desensitized the cAMP and IR-beta-EP responses of hypothalamic neurons to PGE1. Acute exposure to ethanol increased the PGE1-stimulated levels of cAMP and IR-beta-EP, whereas chronic exposure to ethanol resulted in diminished cAMP responses to PGE1. These data provide evidence that the cAMP system may be involved in controlling hypothalamic beta-EP secretion, as well in regulating the stimulatory and adaptive responses of beta-EP neurons to ethanol.

Alprostadil↗
PubMed1996

Pituitary lactotrope expresses transforming growth factor beta (TGF beta) type II receptor mRNA and protein and contains 125I-TGF beta 1 binding sites.

Transforming growth factor beta 1 (TGF beta 1) has recently been shown to be produced in the prolactin (PRL)-secreting lactotropes of the pituitary gland. TGF beta 1 inhibits lactotropic secretion and proliferation, and the production of TGF beta 1 in lactotropes is reduced during lactotropic growth following estrogen treatment in ovariectomized rats. In many estrogen-responsive tissues, TGF beta 1 has been shown to exert its effect by binding to TGF beta 1 type II receptors (T beta R II) at the cell surface. In this study, we sought to ascertain whether T beta R II is involved in TGF beta 1 action on lactotropes by determining the changes of T beta R II mRNA and protein levels and specific 125I-TGF beta 1 binding sites on the lactotropes during estrogen-induced proliferation of lactotropes in Fischer 344 rats. Double immunohistochemical procedures were employed to identify immunoreactive T beta R II in PRL-reactive cells. The majority of T beta R II-reactive cells in the anterior pituitary were observed to be lactotropes. Dual immunohistochemistry and in situ hybridization procedures also indicated that lactotropes were the major cell types containing T beta R II mRNA hybrids. Both the levels of immunoreactive T beta R II protein and in situ T beta R II mRNA hybrids in the pituitary were significantly decreased in ovariectomized rats after 15 days of estrogen treatment. Determination of 125I-TGF beta 1 binding sites in lactotropes by double immunohistochemistry and receptor autoradiography also revealed specific binding sites of 125I-TGF beta 1 in lactotropes in the anterior pituitary. 125I-TGF beta 1 binding in the anterior pituitary was also reduced following estrogen treatment in ovariectomized rats. These data suggest that down-regulation of T beta R II may be an important mechanism of estrogen action on lactotropic cell growth and PRL secretion, and further support the notion that TGF beta 1 controls lactotropic function by autocrine/paracrine mechanisms.

Animals↗
PubMed1995

Reduction in the expression and action of transforming growth factor beta 1 on lactotropes during estrogen-induced tumorigenesis in the anterior pituitary.

We have previously shown that transforming growth factor beta 1 (TGF-beta 1) receptor and TGF-beta type II receptor (T beta R-II) are produced in lactotropes, and that TGF-beta 1 inhibits the growth of these anterior pituitary cells by an autocrine mechanism. To study the changes of the expression and function of this growth factor during tumorigenesis, we have measured the levels of TGF-beta 1 and T beta R-II mRNAs and proteins in the normal and tumor anterior pituitary cells in vivo and in vitro and have compared the cell growth responses to TGF-beta 1 in normal and tumor pituitary cells in vitro. Treatment with estradiol-17 beta for 1, 2, 4, and 8 weeks caused a time-dependent increase in pituitary protein, prolactin, and prolactin mRNA levels and in plasma prolactin levels, suggesting that estrogen enhanced lactotropic proliferation in anterior pituitary glands. The levels of TGF-beta 1 protein and mRNA in anterior pituitary tissues were reduced over time after estrogen treatment during the development of pituitary tumors. The mRNA and protein levels of T beta R-II decreased markedly during the development of pituitary tumors. In addition, two transformed lactotropes, GH3 and PR1 cell lines, showed markedly reduced levels of TGF-beta 1 as well as T beta R-II mRNA. Comparison of the antiproliferative effects of TGF-beta in transformed and normal lactotropes in cultures revealed that the sensitivity of GH3 cells is reduced, and that PR1 cells are virtually resistant to TGF-beta 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Diurnal variation in luteinizing hormone-releasing hormone and beta-endorphin release in pituitary portal plasma during the rat estrous cycle.

In this study, we investigated the pattern of both LHRH and beta-endorphin (beta-EP) secretion from the median eminence of cyclic female rats during the estrous cycle by collecting pituitary portal blood for hormone measurements by RIA. On diestrus, proestrus, or estrus (0900 h or 1300 h), rats were hypophysectomized (in order to prevent contamination of portal beta-EP with pituitary beta-EP) and were given a 50-60-min resting period of postsurgical recovery prior to blood sampling. Between 1000 h and 1800 h of the same day, pituitary portal blood samples were collected at 10-min intervals from these animals under Saffan anesthesia. Hormone RIA data revealed that LHRH and beta-EP levels in the portal plasma ranged from 25 to 600 pg/ml and from 0.6 to 4.6 ng/ml, respectively, whereas no discernible amounts of these hormones were detected in the peripheral plasma. Analysis further revealed that secretion of both LHRH and beta-EP showed a diurnal rhythmicity and that both neuropeptides were secreted in a pulsatile manner on each day of the cycle, with most dramatic changes seen in female rats on proestrus. In proestrus rats, portal plasma levels of beta-EP were highest during 1000-1500 h and lower around 1600-1800 h. In contrast, morning and early afternoon values of LHRH were obviously higher in rats on proestrus than in animals on other days of the cycle, and an even greater rise in portal plasma levels of LHRH occurred in late afternoon on proestrus, when beta-EP values were lowest.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effects of dopamine D1 and D2 receptor agonists and antagonists on basal and ethanol-modulated beta-endorphin secretion from hypothalamic neurons in primary cultures.

In the present study, we determined the effects of dopamine receptor agonists and antagonists on basal and ethanol-modulated beta-endorphin (beta-EP) secretion from hypothalamic neurons in primary cultures. Treatment with various concentrations of dopamine D1 agonist SKF 38393 and D1 antagonist SCH 23390 did not affect basal IR-beta-EP release. However, dopamine D2 receptor agonist LY 141865 reduced basal immunoreactive (IR)-beta-EP release in a concentration dependent manner. D2 receptor antagonist, sulpiride, on the other hand, stimulated basal IR-beta-EP release and blocked LY 141865-induced inhibition of IR-beta-EP release in a concentration dependent manner. When the actions of these DA receptor agents on ethanol-modulated IR-beta-EP release were studied, both D1 and D2 receptor agents failed to affect ethanol-modulated IR-beta-EP release. These data suggest that the endogenous secretion of beta-EP from hypothalamic neurons is under the influence of an inhibitory dopaminergic system involving the D2 receptor. Furthermore, ethanol's effects on beta-EP secretion are not mediated by dopamine.

Animals↗
PubMed1995

Effect of ethanol, propanol, butanol, and catalase enzyme blockers on beta-endorphin secretion from primary cultures of hypothalamic neurons: evidence for a mediatory role of acetaldehyde in ethanol stimulation of beta-endorphin release.

Previously, we have shown that low doses of ethanol (12.5-100 mM) and acetaldehyde (12.5-50 microM), but not salsolinol, enhanced immunoreactive beta-endorphin (IR-beta-EP) secretion from fetal hypothalamic neurons in primary culture. In this study, the effects of ethanol, propanol, and butanol, as well as the effect of catalase inhibitors on IR-beta-EP secretion were studied in vitro to determine the role of membrane fluidization and ethanol metabolism on ethanol-induced IR-beta-EP secretion. The primary cultures of fetal hypothalamic neurons were maintained for 8-9 days in chemically defined medium and treated for 5 hr with ethanol (50 mM), propanol (25 and 50 mM), and butanol (25 and 50 mM). Determination of hourly secretion of IR-beta-EP from the cultures revealed that only 50 mM ethanol caused stimulation of IR-beta-EP secretion, whereas propanol and butanol did not alter IR-beta-EP response at any given concentration. Pretreatment of these cultures with the catalase inhibitors, 3-amino-1,2,4-triazole (3-AT; 1, 5, and 10 mM), caused a dose-dependent inhibition of ethanol-stimulated IR-beta-EP secretion, but did not inhibit dibutyryl cAMP (dcAMP)-stimulated IR-beta-EP secretion. Another catalase inhibitor, sodium azide (5 mM), also inhibited ethanol-stimulated IR-beta-EP secretion. Measurement of acetaldehyde production in cultured cells and media after ethanol or dcAMP treatments revealed that cultured cells produce acetaldehyde only after ethanol treatment and at levels of acetaldehyde (8-24 microM) that are known to evoke IR-beta-EP release. The catalase inhibitor 3-AT (10 mM) treatment reduced ethanol-evoked acetaldehyde production.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Butanol↗
PubMed1994

Colocalization of prolactin and proliferating cell nuclear antigen in the anterior pituitary during estrogen-induced pituitary tumors.

Chronic estrogen treatment induces prolactin (PRL)-secreting pituitary tumors in laboratory animals. To determine earlier events of tumorigenesis, we studied cell proliferation in the pituitary following 7-30 days of estrogen administration in Fischer 344 rats. Immunohistochemical localization of proliferative cells by proliferating cell nuclear antigen (PCNA) staining and lactotropes by PRL staining revealed that estrogen treatment caused a time-dependent increase in the number of proliferative cells and lactotropes. Although the increase in lactotropic cell number paralleled the increase in PCNA-reactive cell number, only approximately 30% of lactotropes reacted simultaneously with the PCNA antibody. These results indicate that a subset population of lactotropes proliferates under the influence of estrogen during tumorigenesis.

Animals↗
PubMed1994

Cyclic AMP and ethanol interact to control apoptosis and differentiation in hypothalamic beta-endorphin neurons.

In this study we have determined the role of cyclic AMP on the function and differentiation of beta-endorphin (beta-EP) neurons in rat fetal hypothalamic cell cultures. Addition of Bt2cAMP or the cAMP elevating agent, forskolin, in cultures, dose and time dependently increased beta-endorphin secretion. The increased beta-EP secretion after Bt2cAMP or forskolin treatment was associated with proopiomelanocortin gene expression, enhanced neurite growth, and increased neuronal viability. Determination of internucleosomal cleavage of DNA by agarose gel electrophoresis revealed that apoptosis occurred in hypothalamic neurons during the first 6-8 days in culture. Addition of Bt2cAMP during this developmental period inhibited DNA degradation in hypothalamic neurons. Furthermore, incubation with various doses of ethanol, which is known to reduce intracellular levels of Bt2cAMP, increased DNA degradation in these cells. Ethanol-induced DNA degradation was blocked by concomitant incubation with Bt2cAMP. Histochemical identification of apoptotic cells following ethanol and Bt2cAMP treatments further revealed that apoptosis occurred in beta-EP neurons during the developmental period, and that ethanol increased and Bt2cAMP reduced apoptotic beta-EP cell numbers. These results suggest that ethanol neurotoxicity on beta-EP neurons during early neuronal differentiation involves an apoptotic process and that the cAMP signaling system plays an important role in controlling apoptosis and differentiation of the beta-EP neuronal system.

Animals↗