The Gonadotropin Connection in Alzheimer's Disease

Meethal, Sivan Vadakkadath; Smith, Mark A.; Bowen, Richard L.; Atwood, Craig S.

doi:10.1385/endo:26:3:317

Cited by 73 publications

(49 citation statements)

References 151 publications

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“…This hypothesis is yet to be tested, and a role for LH is potentially problematical because this large glycoprotein molecule seems unlikely to cross the blood-brain barrier. However, there is evidence of LH receptors in the hippocampus of rodents [12,30], and LH is thought to have a role in Alzheimer disease in humans [31] and thus may have a role in the brain of ungulates.…”

Section: Discussionmentioning

confidence: 99%

Rapid Induction of Cell Proliferation in the Adult Female Ungulate Brain (Ovis aries) Associated with Activation of the Reproductive Axis by Exposure to Unfamiliar Males1

Hawken

Jorre

Rodger

et al. 2009

Biology of Reproduction

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In many species, the reproductive centers of the brain are profoundly affected by sociosexual stimuli. This is particularly evident in female ungulates such as sheep, in which exposure to males switches them from reproductively quiescent to fertile. In two experiments with female sheep, we tested whether the brain centers that control gonadotropin-releasing hormone (GnRH) neuronal activity respond differentially to ''novel'' vs. familiar males and whether the neuroendocrine response is associated with increased cell proliferation in the hippocampus, a site associated with memory formation. In experiment 1, groups of 10 female sheep that had previously been habituated to males for 3 mo were re-exposed to familiar males or were exposed to novel males. Only the novel males increased luteinizing hormone (LH) pulse frequency, indicating stimulation of GnRH neuronal activity. In experiment 2, groups of six female sheep were injected with bromodeoxyuridine (BrdU) and then maintained in isolation from males or exposed to novel males. Two days later, the hippocampus and hypothalamus were removed and processed for fluorescence immunohistochemistry. Again, exposure to males increased LH pulse frequency. Most important, male exposure also doubled the number of BrdUpositive cells in the dentate gyrus of the hippocampus. No BrdUpositive cells were detected in the hypothalamus. We conclude that the stimulus from novel males switches on the reproductive centers of the brain of female sheep and rapidly doubles the rate of cell proliferation in the hippocampus. The rapidity of this response contrasts with rodents, in which several days of exposure to male pheromones seem necessary for an effect on neurogenesis.

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Section: Discussionmentioning

confidence: 99%

Rapid Induction of Cell Proliferation in the Adult Female Ungulate Brain (Ovis aries) Associated with Activation of the Reproductive Axis by Exposure to Unfamiliar Males1

Hawken

Jorre

Rodger

et al. 2009

Biology of Reproduction

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“…18−21 Currently, LA is also being evaluated in Phase II clinical trials for the treatment of Alzheimer's glycofurol. 22,23 Also release, erosion and morphology study of ISFI both in the presence and absence of ethyl benzoate as a rate-modifying agent is reported. …”

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confidence: 99%

Effects of ethyl benzoate on performance, morphology, and erosion of PLGA implants formed in situ

et al. 2008

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An in situ forming implant (ISFI) is a novel drug delivery system used for protein and peptide delivery, especially for cancer treatment. An ISFI based on 33% (w/w) poly(D,L-lactide-co-glycolide)(PLGA; 50:50)/3% (w/w) leuprolide acetate (LA)/64% (w/w) N-methyl-2-pyrrolidone (NMP) was prepared for this study. After injection of the final formulation, which is a viscous liquid to an aqueous medium, it deforms to become a semisolid or solid matrix. The performance of this matrix was investigated on the basis of peptide release from it. Erosion and morphology of ISFI were also studied. The effects of adding 12.8% (w/w) ethyl benzoate (EB) as a rate-modifying agent on performance, erosion, and morphology of ISFI were assessed. The implant containing EB showed very low burst release (5.53% ± 0.82%) and the morphology turns to closed pore-like structures. After adding EB, the morphology turns to closed pore-like structures. This type of morphology has very close relation to the performance of the implant as well. Finally, the effect of EB on performance, erosion, and morphology is explained by means of solvent-nonsolvent affinity, water permeation, and the rate of phase inversion.

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“…Actually, activation of GnRHR alters the electrical properties of hippocampal neurons through a protein kinase C-dependent action 10 and exerts a significant control of synaptic plasticity. In fact, the activation of GnRH receptors with the analog leuprolide was found to increase the intrinsic neuronal excitability of pyramidal neurons (of region CA1 and CA3) 26 and an enhancement of synaptic transmission mediated by ionotropic glutamate receptors. 27 GnRH was found to regulate the expression of pre-and post-synaptic markers spinophilin, synaptophisin and Egr1 in neurons obtained from hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Physiology of Gonadotropin-Releasing Hormone (Gnrh): Beyond the Control of Reproductive Functions

Maggi¹

2016

MOJAP

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Abbreviations: cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol 1,4,5-triphosphate; HPG, hypothalamic-pituitary-gonadal; APP, amyloid precursor protein; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinase; PI3K, phosphatidylinositol-3-kinase; EGR1, early growth response 1; PP, phosphotyrosine phosphatase; NF-Kb, nuclear factor kappa-light-chain-enhancer of activated b cells; DHCR24, 3-betahydroxysterol delta-24-reductase; St AR, steroidogenic acute regulatory protein; IKK-β, inhibitor of nuclear factor kappa-b kinase subunit beta; Aβ, amyloid beta peptide IntroductionGonadotropin releasing hormone (GnRH) is 35year-old neuropeptide recognized as the central regulator of reproductive functions.1 It was actually one of the earliest hypothalamic-releasing hormones sequenced and characterized and led its discoverer Andrew Schally to be awarded by the Nobel prize in 1977. 2 The peptide is a sequence of ten aminoacids ( Figure 1A) with a cyclized proline at the N-terminal and a glycine-amide residue at C-terminal, which confer some resistance to terminal peptidases.In mammals, GnRH is mainly produced by a limited number of hypothalamic neurons, which do not form a defined nucleus but show a dispersed organization in the mediobasal hypothalamus. Making axonal contacts with the hypothalamo-hypophyseal portal vessels, GnRH neurons release the decapeptide in the bloodstream directed to the adenohypophysis in a pulsatile manner. 3 At the pituitary level, the decapeptide interact with specific G protein-coupled receptors (GnRHR) present on gonadotrope cells inducing the release of the two gonadotropins (LH, luteinizing hormone and FSH, follicle stimulating hormones) which in turn coordinate male and female gonadal functions promoting the folliculogenesis and the ovulation in female, the spermatogenesis in male, and the production of sex steroid hormones (estrogen, progesterone and testosterone) ( Figure 1B). 4,5 GnRHR may be coupled either to Gaq/11 or Gas subunits which activate different intracellular responses including cAMP and DAG/IP3 pathways, as well as the mitogen-activated protein kinase (MAPK) cascades. 6 The separate activation of Gaq/11 or Gas subunits, by changes in the frequency of decapeptide pulsatile release, is the basis for the differential control of gonadotropin release. 7The actions of GnRH on reproductive functions cover the whole lifespan and characterize the maturation, the pubertal activation and the adult functions of the hormonal hypothalamo-pituitary-gonadal axis. Because of its importance on reproductive functions, a series of synthetic analogues, with agonist or antagonist activities have been developed soon after GnRH identification (Table 1). 8,9The pharmacological approach with GnRH analogues has been so far limited to the induction of puberty or, more in general, for recovery of fertility through a pulsatile administration; on the contrary, a continuous administration of GnRH agonists or antagonist is used to block the gonadotropin r...

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The Gonadotropin Connection in Alzheimer's Disease

Cited by 73 publications

References 151 publications

Rapid Induction of Cell Proliferation in the Adult Female Ungulate Brain (Ovis aries) Associated with Activation of the Reproductive Axis by Exposure to Unfamiliar Males1

Rapid Induction of Cell Proliferation in the Adult Female Ungulate Brain (Ovis aries) Associated with Activation of the Reproductive Axis by Exposure to Unfamiliar Males1

Effects of ethyl benzoate on performance, morphology, and erosion of PLGA implants formed in situ

Physiology of Gonadotropin-Releasing Hormone (Gnrh): Beyond the Control of Reproductive Functions

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