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Biomedical subjects

A R Kennedy

Publications and source records attributed to A R Kennedy.

At least 19 recordsLinked to original sources
PubMed2003

Effect of direct injection of melanin-concentrating hormone into the paraventricular nucleus: further evidence for a stimulatory role in the adrenal axis via SLC-1.

Melanin-concentrating hormone (MCH) is implicated in the control of a number of hormonal axes including the hypothalamic-pituitary adrenal (HPA) axis. Previous studies have shown that there is evidence for both a stimulatory and an inhibitory action on the HPA axis; therefore, we attempted to further characterize the effects of MCH on this axis. Intracerebroventricular injection of MCH increased circulating adrenocorticotropic hormone (ACTH) at 10 min post injection. Injection of MCH directly into the paraventricular nucleus (PVN) was found to increase both circulating ACTH and corticosterone 10 min after injection. Additionally, MCH was found to increase corticotropin-releasing factor (CRF) release from hypothalamic explants, and this effect was abolished by the specific SLC-1 antagonist SB-568849. Neuropeptide EI, a peptide from the same precursor as MCH was also found to increase CRF release from explants. These results suggest that MCH has a stimulatory role in the HPA axis via SLC-1, and that MCH exerts its effects predominantly through the PVN CRF neuronal populations

Adrenocorticotropic Hormone↗
PubMed2003

Central orexin A has site-specific effects on luteinizing hormone release in female rats.

Orexin A stimulates GnRH release from hypothalamic explants in vitro. The sites of action of orexin A in the regulation of LH release have been investigated in vivo in ovariectomized rats that were given vehicle or estradiol benzoate (EB), with or without an injection of progesterone 48 h later. Orexin A was administered intrahypothalamically under Saffan anesthesia, 50 h after the EB or vehicle; its effects on plasma LH levels were monitored in sequential blood samples. Orexin A (1.0 microg/side) injected into the rostral preoptic area (rPOA) at the level of the organum vasculosum of the lamina terminalis had a stimulatory effect on LH release in EB-treated ovariectomized rats. When orexin A was injected into the medial POA (mPOA) or the arcuate/median eminence, it had an inhibitory effect on the LH surge that occurs in ovariectomized rats primed with EB plus progesterone. Orexin A injected into the mPOA also reduced LH levels in ovariectomized rats untreated with ovarian steroids. Both the stimulatory and inhibitory effects of orexin A were antagonized by SB334867A, a selective orexin 1 receptor antagonist. Furthermore, when given alone into the rPOA, this antagonist attenuated the LH surge induced by EB plus progesterone. Thus, orexin appears to have a dual effect on LH release, being stimulatory in the rPOA and inhibitory in the mPOA or arcuate/median eminence. Both effects may be mediated, at least in part, by the orexin 1 receptor. Double label immunohistochemistry revealed close appositions between orexin A immunoreactive varicosities and a small proportion of GnRH cell bodies in the rPOA. It is suggested that the stimulatory effect of orexin A on LH release may involve direct actions on GnRH neurons.

Animals↗
PubMed2002

Hypothalamic actions of neuromedin U.

The central nervous system and gut peptide neuromedin U (NMU) inhibits feeding after intracerebroventricular injection. This study explored the hypothalamic actions of NMU on feeding and the hypothalamo-pituitary-adrenal axis. Intraparaventricular nucleus (intra-PVN) NMU dose-dependently inhibited food intake, with a minimum effective dose of 0.1 nmol and a robust effect at 0.3 nmol. Feeding inhibition was mapped by NMU injection into eight hypothalamic areas. NMU (0.3 nmol) inhibited food intake in the PVN (0-1 h, 59 +/- 6.9% of the control value; P < 0.001) and arcuate nucleus (0-1 h, 76 +/- 10.4% of the control value; P < 0.05). Intra-PVN NMU markedly increased grooming and locomotor behavior and dose-dependently increased plasma ACTH (0.3 nmol NMU, 24.8 +/- 1.9 pg/ml; saline, 11.4 +/- 1.0; P < 0.001) and corticosterone (0.3 nmol NMU, 275.4 +/- 40.5 ng/ml; saline, 129.4 +/- 25.0; P < 0.01). Using hypothalamic explants in vitro, NMU stimulated CRH (100 nM NMU, 5.9 +/- 0.95 pmol/explant; basal, 3.8 +/- 0.39; P < 0.01) and arginine vasopressin release (100 nM NMU, 124.5 +/- 21.8 fmol/explant; basal, 74.5 +/- 7.6; P < 0.01). Leptin stimulated NMU release (141.9 +/- 20.4 fmol/explant; basal, 92.9 +/- 9.4; P < 0.01). Thus, we describe a novel role for NMU in the PVN to stimulate the hypothalamo-pituitary-adrenal axis and locomotor and grooming behavior and to inhibit feeding.

Adrenal Glands↗
PubMed2001

Key tricyclic synthetic intermediates for the preparation of the sesquiterpenes alpha- and beta-cedrene.

A completely novel and direct route towards the synthesis of the natural sesquiterpenes alpha-cedrene and beta-cedrene delivered the compounds (3 beta,3a beta,7 beta)-(+/-)-6,6-ethylenedioxy-3,8,8-trimethyl-2,3,3a,4,5,6,7,8-octahydro-3a,7-methanoazulen-2-one, C(16)H(22)O(3), and (3 beta,3a beta,7 beta,8a alpha)-(+/-)-6,6-ethylenedioxy-3,8,8-trimethyl-1,2,3,3a,4,5,6,7,8,8a-decahydro-3a,7-methanoazulen-2-one, C(16)H(24)O(3), at key stages of the preparative programme. Structural elucidation showed the latter compound to have added an H atom to the same face of the cyclopentenone ring as that occupied by the methyl substituent, and also allowed correct isomer identification for further reaction.

Journal Article↗
PubMed2001

A monomeric three-coordinate magnesium bis(amide).

The metallation reaction between dibutylmagnesium and 2,6-diisopropyl-N-(trimethylsilyl)aniline gives the unusual monomeric three-coordinate complex (diethyl ether-kappa O)bis[2,6-diisopropyl-N-(trimethylsilyl)anilido-kappa N]magnesium(II), [Mg(C(15)H(26)NSi)(2)(C(4)H(10)O)] or [Mg[(Me(3)Si)(2,6-(i)Pr(2)C(6)H(3))N](2)(Et(2)O)]. This low-coordinate species has a distorted trigonal-planar coordination environment, with an additional short Mg-C(ipso) contact of 2.799 (2) A.

Journal Article↗
PubMed2001

Structural transformations in zopiclone.

A monoclinic centrosymmetric form of zopiclone dihydrate undergoes a sequential, two-step transformation in the solid-state upon heating which results in separation of the enantiomers into a racemic conglomerate or racemic twins.

Journal Article↗
PubMed2001

1,4-pentadienyl-3-sulfonamides: frameworks for "disfavored" radical cascade cyclizations.

[reaction: see text]. 1,4-pentadienyl-3-sulfonamides afford products including those resulting from disfavored 5-endo-trig reactions when subjected to radical cyclization conditions. Products resulting from pathways featuring 4-exo-trig cyclizations are also detected, even when the 4-exo-trig reaction leads to a highly strained bicyclo[3.2.0] ring system.

Alkadienes↗
PubMed2001

The use of sulfur ylides in the synthesis of substituted indoles.

[reaction: see text] This letter describes the insertion of rhodium carbenoids into thioindoles. C-10 thioindoles undergo fragmentation-coupling reactions when exposed to rhodium carbenoids. In an analogous fashion, ketoester- and malonate-substituted carbenoids have been found to insert into C-2 thioindoles. In contrast, vinylogous carbenoids were found to alkylate C-2 thioindoles at C-3.

Indoles↗
PubMed2001

Effects of Bowman-Birk inhibitor concentrate (BBIC) in patients with benign prostatic hyperplasia.

BACKGROUND: The Bowman-Birk inhibitor is a soybean-derived protease inhibitor that has anti-inflammatory and anticarcinogenic activities. METHODS: A Phase I trial of Bowman-Birk inhibitor concentrate (BBIC) in 19 male subjects with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) has been performed. RESULTS: The results of the trial indicated that there was no dose-limiting toxicity of BBIC. There was a statistically significant decrease in serum PSA levels in all BBIC-treated patients. Some BBIC-treated patients exhibited a relatively large reduction in serum PSA levels, ranging up to a 43% reduction. There was also a statistically significant decrease in serum triglyceride levels and a decrease in prostate volume in the treated patients. The scores recorded in response to a urinary symptom questionnaire indicated improved urinary activities in the BBIC-treated patients; however, the control subjects exhibited similar improvements in urinary activities during the course of the trial. CONCLUSIONS: The data obtained in this trial, particularly the data suggesting that BBIC treatment may lead to reduced serum PSA levels and reduced prostate volumes, suggest that a Phase II clinical trial of BBIC for the therapy of BPH is warranted.

Aged↗
PubMed2001

Dichlorobis(dibenzylamino)bis(tetrahydrofuran)zirconium(IV) toluene hemisolvate.

The title complex, [ZrCl2(C4H8O)2(C14H14N)2].0.5C7H8, was prepared in an unusual manner by utilizing [Mg[N(CH2Ph)2]2] as a ligand transfer reagent. The Zr atom lies in a distorted octahedral environment where steric repulsion from the large dibenzylamino ligands leads to a widening of the N-Zr-N angle [99.95 (9) degrees ] and corresponding compression of other angles [Cl-Zr-Cl 160.95 (3) degrees and O-Zr-O 78.22 (7) degrees ]. This distortion is compared with those found in the previously determined structures of the dimethylamino and diethylamino analogues.

Journal Article↗
PubMed2001

A nido-6-manganadecaborane salt.

A new manganadecaborane has been isolated as a previously unsuspected product from the reaction of [Mn(CO)(5)Br] with K[B(9)H(14)]. The anion of tetrabutylammonium 5-bromo-6,6,6-tricarbonyl-6-manganadodecahydrodecaborate(1-), (C(16)H(36)N)[Mn(B(9)H(12)Br)(CO)(3)], has a nido cage structure. The Mn atom is bonded through three B--Mn bonds of similar length [2.221 (4), 2.224 (3) and 2.236 (3) A] and two bridging H atoms. The position of the bromo substituent breaks the twofold symmetry of the cage found in simple analogues, and this is reflected in the B--B bond parameters.

Journal Article↗
PubMed2001

Orexin A interactions in the hypothalamo-pituitary gonadal axis.

The distribution of orexin A-immunoreactive neurons and orexin type I receptors in the CNS suggests important roles in regulating the hypothalamo-pituitary gonadal (HPG) axis and sexual behaviors. We examined orexin A interactions in the HPG axis in vivo and in vitro. Orexin A stimulated LH-releasing hormone (LHRH) release in hypothalamic explants harvested from male rats (+133%) and from females at proestrus (+233%), with no effect at estrus or metestrus. Orexin A dose dependently inhibited LHRH-stimulated LH release in dispersed pituitaries from proestrous females only. A selective NPY1-receptor antagonist abolished in vitro release of LHRH by orexin A. Hyperestrogenization in female rats reduced orexin A content in hypothalamus (-28%), midbrain (-26%), medulla (-40%), thalamus (-36%), olfactory tubercles (-25%), and cortex (-35%), brain regions that are important in HPG control and sex-cycle specific behaviors. Orexin A content was lower in hypothalamus (-20%) and higher in midbrain (+40%), medulla (+31%), and thalamus (+33%) at late proestrus vs. other cycle stages. Orexin A release after administration of 56 mM KCl was significantly greater in hypothalamic explants harvested on the morning of proestrus than at estrus or metestrus, and orexin A release was stimulated by estradiol (E2) in explants from males. These results reveal important interactions for orexin A in the HPG axis.

Animals↗
PubMed2001

Melanin-concentrating hormone (MCH) suppresses thyroid stimulating hormone (TSH) release, in vivo and in vitro, via the hypothalamus and the pituitary.

Melanin-concentrating hormone (MCH) is an orexigenic peptide encoded in the pre-pro MCH gene. Targeted deletion of MCH causes a phenotype of hypophagia and leanness with an inappropriately high metabolic rate, suggesting a role for MCH in the control of energy balance. In order to further elucidate the mechanism by which MCH controls, energy expenditure, we have investigated the effects of MCH on the hypothalamic pituitary thyroid (HPT) axis. The thyroid axis is important in energy homeostasis and starvation leads to profound suppression of the HPT axis. MCH significantly reduces plasma TSH in vivo at 10 min (0.5 +/- 0.07 ng/ml, p < 0.05, n = 8) and 60 min (0.33 +/- 0.04 ng/ml, p < 0.01, n = 10) compared to saline (0.7 +/- 0.07 ng/ml and 0.69 +/- 0.07 ng/ml respectively) when administered intracerebroventricularly. Release of TRH form hypothalamic explants was significantly reduced in the presence of MCH production (7.1 +/- 0.99 fmol/explant to 2.3 +/- 0.4 fmol/explant p < 0.01, n = 18) and Neuropeptide EI (NEI) (8.47 +/- 1.28 fmol/explant to 4.6 +/- 1.13 p < 0.05, n = 16), a peptide, also encoded in the pre-pro-MCH gene. MCH was also shown to significantly reduce TRH stimulated TSH release from dispersed pituitary cell cultures (basal = 0.5 +/- 0.06 ng/ml, 100 nM TRH = 0.9 +/- 0.2 ng/ml, p < 0.05 0.1 nM MCH = 0.5 +/- 0.1 ng/ml, p < 0.05, 1 nM MCH = 0.3 +/- 0.03 ng/ml, p < 0.01, 10 nM MCH = 0.4 +/- 0.02 ng/ml, p < 0.01, 1000 nM MCH = 0.4 +/- 0.05 ng/ml, P < 0.01, n = 4), although basal release of TSH from these cultures was unaffected. These data suggest a possible role for MCH in the control of energy homeostasis via inhibition of the thyroid axis.

Animals↗
PubMed2001

Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei.

Cocaine- and amphetamine-regulated transcript is expressed in hypothalamic regions involved in the central control of food intake. Previous data have implicated cocaine- and amphetamine-regulated transcript as an anorectic peptide. We studied the effect of the active fragment of cocaine- and amphetamine-regulated transcript, cocaine- and amphetamine-regulated transcript-(55-102), on feeding when injected into discrete nuclei of the hypothalamus. Cocaine- and amphetamine-regulated transcript-(55-102) (0.04 nmol) elicited a delayed, but significant, increase in feeding in 24-h fasted rats after injection into the ventromedial nucleus (1-2 h, 261 +/- 60% of control; P < 0.05) and arcuate nucleus (1-2 h, 225 +/- 38% of control; P < 0.05) of the hypothalamus. Administration of a higher dose of cocaine- and amphetamine-regulated transcript-(55-102) (0.2 nmol) elicited a significant increase in feeding after injection into the ventromedial nucleus (1-2 h, 1253 +/- 179% of control; P < 0.001), arcuate nucleus (1-2 h, 265 +/- 43% of control; P < 0.05), paraventricular nucleus (2-4 h food intake, 186 +/- 29% of control; P < 0.05), lateral hypothalamic area (2-4 h, 280 +/- 34% of control; P < 0.001), anterior hypothalamic area (2-4 h, 252 +/- 42% of control; P < 0.01), dorsomedial nucleus (2-4 h, 368 +/- 29% of control;P < 0.001) and supraoptic nucleus (2-4 h, 212 +/- 34% of control; P < 0.05) of the hypothalamus. Administration of cocaine- and amphetamine-regulated transcript-(55-102) into the third ventricle of the hypothalamus resulted in an inhibition in feeding [0-4 h (0.4 nmol), 33 +/- 13% control; P < 0.001], but was associated with marked abnormalities in behavior, which may have interfered with feeding. These behavioral abnormalities were not observed after the administration of cocaine- and amphetamine-regulated transcript-(55-102) directly into the arcuate nucleus. These data suggest that cocaine- and amphetamine-regulated transcript may play an orexigenic role in the hypothalamic feeding circuitry.

Animals↗
PubMed2001

The actions of tuberoinfundibular peptide on the hypothalamo-pituitary axes.

Tuberoinfundibular peptide is a recently discovered agonist for the PTH receptor-2; the latter has a wide distribution including the external zone of the median eminence of the hypothalamus, suggesting a role in neuroendocrine function. We have investigated the effects of tuberoinfundibular peptide on the hypothalamo-pituitary axes in vitro and in vivo. Tuberoinfundibular peptide had effects on the hypothalamo-pituitary-adrenal axis with increased release of ACTH-releasing factor (tuberoinfundibular peptide 100 nM 4.4 +/- 0.6 pmol/explant vs. control 2.9 +/- 0.4 pmol/explant, P < 0.001) and increased release of arginine vasopressin (tuberoinfundibular peptide 100 nM 563.5 +/- 55.5 fmol/explant vs. control 73.4 +/- 9.6 fmol/explant, P < 0.01) from in vitro hypothalamic explants. Intracerebroventricular administration of tuberoinfundibular peptide and PTH((1-34)) resulted in elevated plasma ACTH at 10 min post injection (saline 13.5 +/- 2.1 pg/ml, tuberoinfundibular peptide 3 nmol 32.3 +/- 4.0 pg/ml; P < 0.01 to saline: PTH((1-34)) 10 nmol 28.9 +/- 3.2 pg/ml: P < 0.05 to saline). Tuberoinfundibular peptide also had both in vitro and in vivo effects on the hypothalamo-pituitary-gonadal axis with increased release of LH-releasing hormone (tuberoinfundibular peptide 100 nM 28.5 +/- 5.1 fmol/explant vs. control 19.3 +/- 2.5 fmol/explant, P < 0.05) from in vitro hypothalamic explants. Both intracerebroventricular and peripheral administration of tuberoinfundibular peptide had effects on the hypothalamo-pituitary-gonadal axis. Intracerebroventricular injection of tuberoinfundibular peptide increased plasma LH (tuberoinfundibular peptide 10 nmol 0.70 +/- 0.09 ng/ml vs. saline 0.42 +/- 0.04 ng/ml at 10 min, P < 0.05). Intraperitoneal administration of tuberoinfundibular peptide also increased plasma LH (tuberoinfundibular peptide 30 nmol 0.53 +/- 0.09 ng/ml vs. saline 0.21 +/- 0.04 ng/ml at 10 min, P < 0.05). In addition to these actions on the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes, an increased release of GH-releasing factor (GRF) from hypothalamic explants (tuberoinfundibular peptide 100 nM 770.9 +/- 90.7 pg/explant vs. control 657.8 +/- 77.7 pg/explant, P < 0.01) was observed. Overall, these data show the actions of tuberoinfundibular peptide on the hypothalamo-pituitary axes and suggest that it may play a role in the control of the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes.

Animals↗
PubMed2000

Cascades to substituted indoles.

This paper describes the synthesis of dithioindoles from the free-radical cyclizations of arylisonitriles having pendant alkynes. Also described is the synthesis of substituted indoles and spiro-fused indoles from the coupling of dithioindoles with active hydrogen-containing compounds.

Cyclization↗