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1.
J Clin Invest ; 111(4): 507-14, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12588889

RESUMO

Hedgehog proteins modulate development and patterning of the embryonic nervous system. As expression of desert hedgehog and the hedgehog receptor, patched-1, persist in the postnatal and adult peripheral nerves, the hedgehog pathway may have a role in maturation and maintenance of the peripheral nervous system in normal and disease states. We measured desert hedgehog expression in the peripheral nerve of maturing diabetic rats and found that diabetes caused a significant reduction in desert hedgehog mRNA. Treating diabetic rats with a sonic hedgehog-IgG fusion protein fully restored motor- and sensory-nerve conduction velocities and maintained the axonal caliber of large myelinated fibers. Diabetes-induced deficits in retrograde transport of nerve growth factor and sciatic-nerve levels of calcitonin gene-related product and neuropeptide Y were also ameliorated by treatment with the sonic hedgehog-IgG fusion protein, as was thermal hypoalgesia in the paw. These studies implicate disruption of normal hedgehog function in the etiology of diabetes-induced peripheral-nerve dysfunction and indicate that delivery of exogenous hedgehog proteins may have therapeutic potential for the treatment of diabetic neuropathy.


Assuntos
Neuropatias Diabéticas/tratamento farmacológico , Transativadores/uso terapêutico , Animais , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/fisiopatologia , Proteínas Hedgehog , Humanos , Imunoglobulina G/genética , Imunoglobulina G/uso terapêutico , Masculino , Condução Nervosa/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/uso terapêutico , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiopatologia , Transativadores/genética
2.
Arterioscler Thromb Vasc Biol ; 24(11): 2102-7, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15358602

RESUMO

OBJECTIVE: The embryonic morphogen sonic hedgehog (SHh) has been shown to induce neovascularization of ischemic tissue but has not been shown to play a role in regulating vascular nerve supply. Accordingly, we investigated the hypothesis that systemic injection of SHh protein could improve nerve blood flow and function in diabetic neuropathy (DN). METHODS AND RESULTS: Twelve weeks after induction of diabetes with streptozotocin, motor and sensory nerve conduction velocities (MCV and SCV) of the sciatic nerves were significantly reduced in diabetic rats. SHh-treated diabetic rats demonstrated marked improvement of both MCV and SCV (P<0.05). Laser Doppler perfusion imaging showed that nerve blood flow was significantly reduced in the diabetic rats but was restored in SHh-treated diabetic rats (P<0.05 versus diabetic saline-treated rats) to levels similar to those achieved with vascular endothelial growth factor-2 (VEGF-2) gene therapy. In vivo perfusion of Bandeuraea simplicifolia (BS)-1 lectin showed marked reduction in the vasa nervora in diabetic sciatic nerves but restoration of nerve vasculature to nondiabetic levels in the SHh-treated and plasmid DNA encoding human VEGF-2 (phVEGF-2)-treated diabetic nerves. Interestingly, the SHh-induced vasculature was characterized by larger diameter and more smooth muscle cell-containing vessels, compared with VEGF-2 gene-treated diabetic rats. CONCLUSIONS: These data indicate that Shh induces arteriogenesis and restores nerve function in DN.


Assuntos
Diabetes Mellitus Experimental/sangue , Neuropatias Diabéticas/sangue , Neovascularização Fisiológica/efeitos dos fármacos , Transativadores/farmacologia , Vasa Nervorum/efeitos dos fármacos , Vasa Nervorum/crescimento & desenvolvimento , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Fibroblastos/citologia , Proteínas Hedgehog , Humanos , Fluxometria por Laser-Doppler/métodos , Masculino , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Perfusão/métodos , Lectinas de Plantas/análise , Lectinas de Plantas/metabolismo , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Nervo Isquiático/irrigação sanguínea , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiologia , Estreptozocina , Vasa Nervorum/química , Vasa Nervorum/patologia , Fator A de Crescimento do Endotélio Vascular/farmacologia
4.
Mol Cell Neurosci ; 19(1): 88-96, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11817900

RESUMO

In ventromedial cells of the developing CNS, Sonic hedgehog (Shh) has been shown to affect precursor proliferation, phenotype determination, and survival. Here we show that Shh and its receptor, Ptc-1, are expressed in the adult rat basal forebrain, and that Ptc-1 is expressed specifically by cholinergic neurons. In basal forebrain cultures, Shh was added alone and in combination with nerve growth factor (NGF), and the number of cholinergic neurons was determined by choline acetyltransferase (ChAT) immunocytochemistry. By 8 days in vitro, Shh and NGF show a synergistic effect: the number of ChAT-positive cells after treatment with both factors is increased over untreated cultures or cultures treated with either factor alone. While Shh increases the overall basal level of proliferation, double-labeling of dividing neuronal precursors with [(3)H]thymidine followed by ChAT immunocytochemistry after they mature, demonstrates that the specific increase in cholinergic neurons is not due to this proliferation enhancement. These experiments imply a role for Shh in the development of postmitotic cholinergic neurons and suggest a therapeutic value for Shh in neurodegenerative disease.


Assuntos
Fator de Crescimento Neural/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Transativadores/farmacologia , Acetilcolina/fisiologia , Fatores Etários , Doença de Alzheimer/tratamento farmacológico , Animais , Contagem de Células , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Colina O-Acetiltransferase/análise , Sinergismo Farmacológico , Expressão Gênica/fisiologia , Proteínas Hedgehog , Proteínas de Membrana/análise , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Neurônios/enzimologia , Receptores Patched , Receptor Patched-1 , Prosencéfalo/citologia , RNA Mensageiro/análise , Receptores de Superfície Celular , Transativadores/genética
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