Recombinant human TNF-binding protein-1 (rhTBP-1) treatment delays both symptoms progression and motor neuron loss in the wobbler mouse.
TNF-alpha overexpression may contribute to motor neuron death in amyotrophic lateral sclerosis (ALS). We investigated the intracellular pathway associated with TNF-alpha in the wobbler mouse, a murine model of ALS, at the onset of symptoms. TNF-alpha and TNFR1 overexpression and JNK/p38MAPK phosphorylation occurred in neurons and microglia in early symptomatic mice, suggesting that this activation may contribute to motor neuron damage. The involvement of TNF-alpha was further confirmed by the protective effect of treatment with rhTNF-alpha binding protein (rhTBP-1) from 4 to 9 weeks of age. rhTBP-1 reduced the progression of symptoms, motor neuron loss, gliosis and JNK/p38MAPK phosphorylation in wobbler mice, but did not reduce TNF-alpha and TNFR1 levels. rhTBP-1 might possibly bind TNF-alpha and reduce the downstream phosphorylation of two main effectors of the neuroinflammatory response, p38MAPK and JNK.
Bigini
Paolo
P
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa, 19, 20156 Milano, Italy.
Repici
Mariaelena
M
Cantarella
Giuseppina
G
Fumagalli
Elena
E
Barbera
Sara
S
Cagnotto
Alfredo
A
De Luigi
Ada
A
Tonelli
Rossella
R
Bernardini
Renato
R
Borsello
Tiziana
T
Mennini
Tiziana
T
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D000818:Animals; D002452:Cell Count / Q000379:methods; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000008:administration & dosage / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000008:administration & dosage / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1