Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF

被引：73

作者：

Puerta, Elena ^{[1
]}

Hervias, Isabel ^{[1
]}

Barros-Minones, Lucia ^{[1
]}

Jordan, Joaquin ^{[2
]}

Ricobaraza, Ana ^{[3
]}

Cuadrado-Tejedor, Mar ^{[3
]}

Garcia-Osta, Ana ^{[3
]}

Aguirre, Norberto ^{[1
]}

机构：

[1] Univ Navarra, Sch Med, Dept Pharmacol, Pamplona 31008, Spain

[2] Univ Castilla La Mancha, Dept Med Sci, Sch Med, Grp Neuropharmacol,Reg Ctr Biomed Res, Albacete, Spain

[3] Univ Navarra, CIBERNED, CIMA, Div Neurosci, Pamplona 31008, Spain

来源：

NEUROBIOLOGY OF DISEASE | 2010年 / 38卷 / 02期

关键词：

3-Nitropropionic acid; BDNF; Calpain; CREB; Excitotoxicity; Huntington's disease; Phosphodiesterase; 5; Sildenafil; Vardenafil; STRIATAL PROJECTION NEURONS; DISEASE MOUSE MODEL; NEURAL STEM-CELLS; HUNTINGTONS-DISEASE; NEUROTROPHIC FACTOR; BINDING-PROTEIN; IN-VIVO; RAT MODEL; MITOCHONDRIAL TOXIN; MUTANT HUNTINGTIN;

D O I：

10.1016/j.nbd.2010.01.013

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD. (C) 2010 Elsevier inc. All rights reserved.

引用

页码：237 / 245

页数：9

共 69 条

[1] BDNF regulates BIM expression levels in 3-nitropropionic acid-treated cortical neurons [J].

Almeida, Sandra ;

Laco, Mario ;

Cunha-Oliveira, Teresa ;

Oliveira, Catarina R. ;

Rego, A. Cristina .

NEUROBIOLOGY OF DISEASE, 2009, 35 (03) :448-456

[2] Anterograde transport of brain-derived neurotrophic factor and its role in the brain [J].

Altar, CA ;

Cai, N ;

Bliven, T ;

Juhasz, M ;

Conner, JM ;

Acheson, AL ;

Lindsay, RM ;

Wiegand, SJ .

NATURE, 1997, 389 (6653) :856-860

[3] Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor [J].

Baquet, ZC ;

Gorski, JA ;

Jones, KR .

JOURNAL OF NEUROSCIENCE, 2004, 24 (17) :4250-4258

[4] Effects of sildenafil on long-term retention of an inhibitory avoidance response in mice [J].

Baratti, CM ;

Boccia, MM .

BEHAVIOURAL PHARMACOLOGY, 1999, 10 (08) :731-737

[5] Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington's disease, as demonstrated by adenoviral gene transfer [J].

Bemelmans, AP ;

Horellou, P ;

Pradier, L ;

Brunet, I ;

Colin, P ;

Mallet, J .

HUMAN GENE THERAPY, 1999, 10 (18) :2987-2997

[6] Cyclic nucleotide phosphodiesterases: Molecular regulation to clinical use [J].

Bender, Andrew T. ;

Beavo, Joseph A. .

PHARMACOLOGICAL REVIEWS, 2006, 58 (03) :488-520

[7] Neuroprotective effect of zVAD against the neurotoxin 3-nitropropionic acid involves inhibition of calpain [J].

Bizat, N ;

Galas, MC ;

Jacquard, C ;

Boyer, F ;

Hermel, JM ;

Schiffmann, SN ;

Hantraye, P ;

Blum, D ;

Brouillet, E .

NEUROPHARMACOLOGY, 2005, 49 (05) :695-702

[8]

Bizat N, 2003, J NEUROSCI, V23, P5020

[9] In vivo calpain/caspase cross-talk during 3-nitropropionic acid-induced striatal degeneration -: Implication of a calpain-mediated cleavage of active caspase-3 [J].

Bizat, N ;

Hermel, JM ;

Humbert, S ;

Jacquard, C ;

Créminon, C ;

Escartin, C ;

Saudou, F ;

Krajewski, S ;

Hantraye, P ;

Brouillet, E .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (44) :43245-43253

[10]

Blum D, 2003, J NEUROSCI, V23, P5361

← 1 2 3 4 5 6 7 →