Aromatase: A neuroprotective enzyme

Estradiol, in addition to its participation in neuroendocrine regulation and sexual behavior, has neuroprotective properties. Different types of brain injury induce the expression of the enzyme aromatase in reactive astroglia. This enzyme catalyzes the conversion of testosterone and other C19 steroids to estradiol. Genetic or pharmacological inhibition of brain aromatase results in marked neurodegeneration after different forms of mild neurodegenerative stimuli that do not compromise neuronal survival under control conditions. Furthermore, aromatase mediates neuroprotective effects of precursors of estradiol such as pregnenolone, dehydroepiandrosterone (DHEA) and testosterone. These findings strongly suggest that local formation of estradiol in the brain is neuroprotective and that the induction of aromatase and the consecutive increase in the local production of estradiol are part of the program triggered by the neural tissue to cope with neurodegenerative insults. Aromatase may thus represent an important pharmacological target for therapies conducted to prevent aging-associated neurodegenerative disorders. © 2003 Elsevier Ltd. All rights reserved.Peer Reviewe

Androgen receptor immunoreactivity in forebrain axons and dendrites in the rat

As members of the steroid receptor superfamily, androgen receptors (ARs) have been traditionally identified as transcription factors. In the presence of ligand, ARs reside in the nucleus, where, upon ligand binding, the receptors dimerize and bind to specific response elements in the promoter region of hormone-responsive genes. However, in this report, we describe the discovery that ARs are also present in axons and dendrites within the mammalian central nervous system. AR expression in axons was identified in the rat brain at the light microscopic level using two different antibodies directed against the N terminus of the AR protein and nickel intensified 3′-3′-diaminobenzidine, and also using fluorescence methods and confocal microscopy. This distribution was confirmed at the ultrastructural level. In addition, AR immunoreactivity was identified in small dendrites at the ultrastructural level. AR-immunoreactive axons were observed primarily in the cerebral cortex and were rare in regions where nuclear AR expression is abundant. The observation that ARs are present in axons and dendrites highlights the possibility that androgens play an important and novel extranuclear role in neuronal function.Peer Reviewe

Neuroactive steroids influence peripheral myelination: A promising opportunity for preventing or treating age-dependent dysfunctions of peripheral nerves

The process of aging deeply influences morphological and functional parameters of peripheral nerves. The observations summarized here indicate that the deterioration of myelin occurring in the peripheral nerves during aging may be explained by the fall of the levels of the major peripheral myelin proteins [e.g., glycoprotein Po (Po) and peripheral myelin protein 22 (PMP22)]. Neuroactive steroids, such as progesterone (PROG), dihydroprogesterone (5α-DH PROG), and tetrahydroprogesterone (3α,5α-TH PROG), are able to stimulate the low expression of these two myelin proteins present in the sciatic nerve of aged male rats. Since Po and PMP22 play an important physiological role in the maintenance of the multilamellar structure of PNS myelin, we have evaluated the effect of PROG and its neuroactive derivatives, 5α-DH PROG and 3α,5α-TH PROG, on the morphological alterations of myelinated fibers in the sciatic nerve of 22-24-month-old male rats. Data obtained clearly indicate that neuroactive steroids are able to reduce aging-associated morphological abnormalities of myelin and aging-associated myelin fiber loss in the sciatic nerve. © 2003 Elsevier Ltd. All rights reserved.Peer Reviewe

Growth hormone and aging

Les alteracions vasculars i degeneratives del sistema nerviós central (SNC) són dues de les causes més comunes de malaltia i de mort entre la gent gran; ambdues es correlacionen amb l'edat, amb la deficiència en GH, i poden afectar les funcions fisiològiques de la població d'edat avançada. Amb la finalitat de clarificar els efectes de la GH en el metabolisme, en els vasos i en el SNC, hem dut a terme un estudi in vivo utilitzant rates vellesWistar tractades crònicament amb GH. Les rates velles varen presentar un augment en el pes de greix i una disminució de l'índex específic de gravetat (SGI) (p < 0,05) en comparar-les amb les rates adultes no tractades. La GH va reduir el pes en greix (p < 0,05), i va mostrar també una tendència a augmentar l'SGI. Es va analitzar també la resposta de diverses substàncies vasoactives en els anells aòrtics, i es va demostrar una disminució de la vasodilatació per acetilcolina i isoprenalina (p < 0,05) en els animals vells. La contracció induïda per acetilcolina+L-NAME era més alta en els animals vells que en els adults. L'administració de GH millorava les respostes vasodilatadores (p < 0,05) mentre que tendia a reduïr les respostes vasoconstrictores. L'àrea aòrtica mitja augmentava també en les rates velles, mentre que la GH reduïa aquest paràmetre (p < 0,05). Les poblacions neuronals es reduïen en els hipocamps de les rates velles en comparar-les amb les joves. Aquesta reducció estava asociada a un augment dels nucleosomes i a una reducció de Bcl2 en el cervell. Les caspases 3 i 9 també varen augmentar. El tractament amb GH va augmentar significativament el nombre de neurones i va reduir els nucleosomes i les caspases i augmentar el Bcl2. En conclusió, el tractament perGHindueix l'aparició d'efectes beneficiosos en la composició del cos i ha restablert també les funcions cerebrals i vasculars en les rates velles.Vascular and degenerative alterations of the central nervous system (CNS) are two of the most common reasons for illness and death in elderly people; they exhibit an age-related GH deficiency that can affect their physiological functions. A study was conducted under chronic in vivo conditions using old Wistar rats, in order to clarify the effects of GH on the metabolism, vessels, and the CNS. The old rats showed an increased fat weight and a decreased Specific Gravity Index (SGI) (p < 0.05), as compared to the adult animals. GH reduced the fat weight (p < 0.05) and tended to increase the SGI (N.S.). The response to several vasoactive substances in aortic rings showed impaired vasodilatation to Acetylcholine and Isoprenaline (p < 0.05) in the old animals. Contraction, induced by Acetylcholine+ L-NAME, was higher in the old rats than in the adults. GH administration improved the vasodilatory responses (p < 0.05) and tended to reduce the constrictory responses. The aortic media area was increased in the old rats, and GH reduced this parameter (p < 0.05). The neuronal populations were reduced in the hippocampi of the old rats as compared to the young ones. This reduction was associated with an increase in nucleosomes and a reduction in Bcl2 in the brain. An increase was also detected in caspases 3 and 9. GH treatment was able to significantly enhance the number of neurons by reducing the nucleosomes and the caspases and by increasing Bcl2. In conclusion,GHtreatment was able to show beneficial effects on body composition and was able to restore both vascular and brain functions in the old rats

Minerales supergénicos de Hg de Almadén: Una forma natural de fijar mercurio

Como es conocido, la zona de Almadén constituye uno de los reservorios de mercurio más importantes del mundo (Higueras et al., 2006)

Estradiol synthesis within the human brain

Estradiol biosynthesis is catalyzed by the enzyme aromatase, the product of the CYP19A1 gene. Aromatase is expressed in the brain, where it is involved not only in the control of neuroendocrine events and reproduction, but also in the regulation of neural development, synaptic plasticity and cell survival. In this review we summarize the existing data related with the detection of aromatase in human brain, with particular emphasis in the so-called “non-primary reproductive” areas. Besides hypothalamus, amygdala and preoptic/septal areas, aromatase is expressed in certain regions of basal forebrain, cerebral cortex, hippocampus, thalamus, cerebellum and brainstem of the human brain. Aromatase in human brain is produced by neurons, but there is also an astrocyte subpopulation that constitutively expresses the enzyme. The use of different methodological approaches, including the in vivo analysis by positron emission tomography of human subjects, has permitted to draw a general map of human brain aromatase, but the detailed distribution map is still far to be completed. On the other hand, despite the fact that there is only one aromatase protein, there are multiple mRNA transcripts that differ in the 5'-untranslated region, where regulatory elements reside. To date, some of the aromatase transcripts characteristic of cerebral cortex, as well as of human cell lines of neural origin, have been identified. This characteristic may confer tissue or even region-specific regulation of the expression and therefore it is conceivable to develop selective aromatase modulators to regulate the expression of the enzyme in the human brai

Growth hormone responsive neural precursor cells reside within the adult mammalian brain

The detection of growth hormone (GH) and its receptor in germinal regions of the mammalian brain prompted our investigation of GH and its role in the regulation of endogenous neural precursor cell activity. Here we report that the addition of exogenous GH significantly increased the expansion rate in long-term neurosphere cultures derived from wild-type mice, while neurospheres derived from GH null mice exhibited a reduced expansion rate. We also detected a doubling in the frequency of large (i.e. stem cell-derived) colonies for up to 120 days following a 7-day intracerebroventricular infusion of GH suggesting the activation of endogenous stem cells. Moreover, gamma irradiation induced the ablation of normally quiescent stem cells in GH-infused mice, resulting in a decline in olfactory bulb neurogenesis. These results suggest that GH activates populations of resident stem and progenitor cells, and therefore may represent a novel therapeutic target for age-related neurodegeneration and associated cognitive decline

Establishment of canine hemangiosarcoma xenograft models expressing endothelial growth factors, their receptors, and angiogenesis-associated homeobox genes

<p>Abstract</p> <p>Background</p> <p>Human hemangiosarcoma (HSA) tends to have a poor prognosis; its tumorigenesis has not been elucidated, as there is a dearth of HSA clinical specimens and no experimental model for HSA. However, the incidence of spontaneous HSA is relatively high in canines; therefore, canine HSA has been useful in the study of human HSA. Recently, the production of angiogenic growth factors and their receptors in human and canine HSA has been reported. Moreover, the growth-factor environment of HSA is very similar to that of pathophysiological angiogenesis, which some homeobox genes regulate in the transcription of angiogenic molecules. In the present study, we established 6 xenograft canine HSA tumors and detected the expression of growth factors, their receptors, and angiogenic homeobox genes.</p> <p>Methods</p> <p>Six primary canine HSAs were xenografted to nude mice subcutaneously and serially transplanted. Subsequently, the expressions of vascular endothelial growth factor (VEGF)-A, basic fibroblast growth factors (bFGF), flt-1 and flk-1 (receptors of VEGF-A), FGFR-1, and angiogenic homeobox genes HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 were investigated in original and xenograft tumors by histopathology, immunostaining, and reverse transcription polymerase chain reaction (RT-PCR), using canine-specific primer sets.</p> <p>Results</p> <p>Histopathologically, xenograft tumors comprised a proliferation of neoplastic cells that were varied in shape, from spindle-shaped and polygonal to ovoid; some vascular-like structures and vascular clefts of channels were observed, similar to those in the original tumors. The expression of endothelial markers (CD31 and vWF) was detected in xenograft tumors by immunohistochemistry and RT-PCR. Moreover, the expression of VEGF-A, bFGF, flt-1, flk-1, FGFR-1, HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 was detected in xenograft tumors. Interestingly, expressions of bFGF tended to be higher in 3 of the xenograft HSA tumors than in the other tumors.</p> <p>Conclusion</p> <p>We established 6 xenograft canine HSA tumors in nude mice and found that the expressions of angiogenic growth factors and their receptors in xenograft HSAs were similar to those in spontaneous HSA. Furthermore, we detected the expression of angiogenic homeobox genes; therefore, xenograft models may be useful in analyzing malignant growth in HSA.</p