Valenzuela, R. (Rita)
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- Estrogen and angiotensin interaction in the substantia nigra. Relevance to postmenopausal Parkinson's disease(Elsevier, 2010) Villar, B. (Begoña); Valenzuela, R. (Rita); Rodriguez-Perez, A.I. (Ana I.); Guerra, M.J. (M. J.); Lanciego, J.L. (José Luis); Labandeira-Garcia, J.L. (José L.)Epidemiological studies have reported that the incidence of Parkinson's disease (PD) is higher in postmenopausal than in premenopausal women of similar age. Several laboratory observations have revealed that estrogen has protective effects against dopaminergic toxins. The mechanism by which estrogen protects dopaminergic neurons has not been clarified, although estrogen-induced attenuation of the neuroinflammatory response plays a major role. We have recently shown that activation of the nigral renin-angiotensin system (RAS), via type 1 (AT1) receptors, leads to NADPH complex and microglial activation and induces dopaminergic neuron death. In the present study we investigated the effect of ovariectomy and estrogen replacement on the nigral RAS and on dopaminergic degeneration induced by intrastriatal injection of 6-OHDA. We observed a marked loss of dopaminergic neurons in ovariectomized rats treated with 6-OHDA, which was significantly reduced by estrogen replacement or treatment with the AT1 receptor antagonist candesartan. We also observed that estrogen replacement induces significant downregulation of the activity of the angiotensin converting enzyme as well as downregulation of AT1 receptors, upregulation of AT2 receptors and downregulation of the NADPH complex activity in the substantia nigra in comparison with ovariectomized rats. The present results suggest that estrogen-induced down-regulation of RAS and NADPH activity may be associated with the reduced risk of PD in premenopausal women, and increased risk in conditions causing early reduction in endogenous estrogen, and that manipulation of brain RAS system may be an efficient approach for the prevention or coadjutant treatment of PD in estrogen-deficient women.
- Location of prorenin receptors in primate substantia nigra: effects on dopaminergic cell death(Lippincott Williams and Wilkins, 2010) Villar, B. (Begoña); Valenzuela, R. (Rita); Lanciego, J.L. (José Luis); Joglar, B. (B.); Barroso-Chinea, P. (P.); Labandeira-Garcia, J.L. (José L.); Muñoz-Patiño, A.M. (A.M.)Angiotensin II acts via angiotensin type 1 receptors and is a major inducer of inflammation and oxidative stress. Local renin-angiotensin systems play a major role in the development of age-related disorders in several tissues. These processes are delayed, but not totally abolished, by blockade of angiotensin signaling. A specific receptor for renin and its precursor prorenin has recently been identified. We previously showed that neurotoxin-induced dopaminergic (DA) cell loss is decreased by inhibition of angiotensin receptors, but the location and functional effects of prorenin receptor (PRR) in the brain, including the DA system, are unknown. In the substantia nigra of Macaca fascicularis and in rat primary mesencephalic cultures, double immunofluorescence analysis revealed PRR immunoreactivity in neurons (including DA neurons) and microglia, but not in astrocytes. Administration of the PRR blocker, handle region peptide, led to a significant decrease in 6-hydroxydopamine-induced DA cell death in the cultures,whereas administration of renin with simultaneous blockade of angiotensin receptors led to an increase in 6-hydroxydopamine-induced cell death. These results suggest that active agent angiotensin II-independent PRR intracellular signaling may contribute to exacerbation of DA cell death in vivo. Therefore, potential neuroprotective strategies for DA neurons in Parkinson disease should address both angiotensin and PRR signaling.