Ciliary neurotrophic factor infused intracerebroventricularly shows reduced catabolic effects when linked to the TAT protein transduction domain

Autor(es)

Vieira, Andre S. ^[1] ; Rezende, Alexandre C. S. ^[1] ; Grigoletto, Jessica ^[2] ; Rogerio, Fabio ^[1] ; Velloso, Licio A. ^[3] ; Skaper, Stephen D. ^[4] ; Negro, Alessandro ^[2] ; Langone, Francesco ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Dept Genet Evolut & Bioagents, Campinas, SP - Brazil

^[2] Univ Padua, CRIBI, Dept Vet Sci, Padua - Italy

^[3] Univ Estadual Campinas, Dept Internal Med, Campinas, SP - Brazil

^[4] Univ Padua, CRIBI, Dept Pharmacol & Anesthesiol, Padua - Italy

• Tipo de documento: Artigo Científico
• Fonte: Journal of Neurochemistry; v. 110, n. 5, p. 1557-1566, SEP 2009.
• Citações Web of Science: 16

Resumo

Ciliary neurotrophic factor (CNTF) regulates the differentiation and survival of a wide spectrum of developing and adult neurons, including motor neuron loss after injury. We recently described a cell-penetrant recombinant human CNTF (rhCNTF) molecule, formed by fusion with the human immunodeficiency virus-1 transactivator of transcription (TAT) protein transduction domain (TAT-CNTF) that, upon subcutaneous administration, retains full neurotrophic activity without cytokine-like side-effects. Although the CNTF receptor is present in hypothalamic nuclei, which are involved in the control of energy, rhCNTF but not TAT-CNTF stimulates signal transducers and activators of transcription 3 phosphorylation in the rat hypothalamus after subcutaneous administration. This could be due limited TAT-CNTF distribution in the hypothalamus and/or altered intracellular signaling by the fusion protein. To explore these possibilities, we examined the effect of intracerebroventricular administration of TAT-CNTF in male adult rats. TAT-CNTF-induced weight loss, although the effect was smaller than that seen with either rhCNTF or leptin (which exerts CNTF-like effects via its receptor). In contrast to rhCNTF and leptin, TAT-CNTF neither induced morphological changes in adipose tissues nor increased uncoupling protein 1 expression in brown adipose tissue, a characteristic feature of rhCNTF and leptin. Acute intracerebroventricular administration of TAT-CNTF induced a less robust phosphorylation of signal transducers and activators of transcription 3 in the hypothalamus, compared with rhCNTF. The data show that fusion of a protein transduction domain may change rhCNTF CNS distribution, while further strengthening the utility of cell-penetrating peptide technology to neurotrophic factor biology beyond the neuroscience field. (AU)

• Processo FAPESP: 05/52991-4 - Investigação dos efeitos da aplicação intracerebroventricular do fator neurotrófico ciliar (CNTF) conjugado com peptídeo contendo domínio de translocação de proteína (PTD) sobre a via de sinalização JAK/STAT3 no hipotálamo e suas implicações no tecido adiposo
• Beneficiário: Francesco Langone
• Modalidade de apoio: Auxílio à Pesquisa - Regular